September

SEPTEMBER 1993
$4.95
SPECIAL
ISSUE
L I F E , D E A T H A N D
THE IMMUNE SYSTEM

TOLERATING GRAFTS
FIGHTING CANCER
AIDS
ALLERGY
INFECTION
MULTIPLE SCLEROSIS
RHEUMATOID ARTHRITIS
THE PROMISE OF THERAPY
WILL HUMANS OR MICROBES WIN?
Copyright 1993 Scientific American, Inc.

September 1993 Volume 269 Number 3
SPECIAL
ISSUE
52 Life, Death and the Immune System

Sir Gustav J. V. Nossal
From before birth until death, the immune system is in a state of constant alert.
A diverse array of molecules and cells, such as the neutrophils that ingest
bacteria [see cover illustration], protects us against parasites and pathogens.
Without those defenses, humans could not survive. Investigators have deduced
how these specialized cells protect the body, how their failure can produce
catastrophic illness and how they may be used as powerful therapeutic tools.
64 How the Immune System Develops

Irving L . Weissman and Max D. Cooper
Just nine weeks after conception, a handful of precursor cells begins to

differentiate into the marvelous panoply of deftly interacting cells that
defend the body. Within the past few decades, researchers have determined
the way this process is mediated by genetic and environmental signals.
72 How the Immune System Recognizes Invaders

Charles A . Janeway, Jr.
Unlike that of some lower animals, our immune system has a memory that
enhances its ability to fend oÝ the myriad pathogens we encounter. Millions
of molecular receptors identify interlopers and guide the bodyÕs defenses.
This process is crucial to the function of the immune systemÑand its failure.
80 How the Immune System Recognizes the Body

Philippa Marrack and John W. Kappler
The cells of the immune system must be capable of launching an assault in

response to countless substances. But they must also learn to tolerate every
tissue, cell and protein in the body. Only recently have researchers learned
how key groups of defenders are prevented from attacking their hosts.
90 Infectious Diseases and the Immune System

William E . Paul
Bacteria, parasites and viruses have evolved elaborate ways of concealing

themselves from the immune system. Similarly, the immune system has evolved
clever ways of foiling their challenges. The result is that a fatal infection is
often the only serious loss in a lifelong campaign against disease.

4
Scientific American (ISSN 0036-8733), published monthly by Scientific American, Inc., 415 Madison Avenue, New York, N.Y. 10017-1111. Copyright © 1993 by Scientific American, Inc. All
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98 AIDS and the Immune System

Warner C. Greene
AIDS is the deÞning immunologic problem of our time. The HIV pathogen
stands out as the preeminent threat to human health and therefore is the
most intensely studied virus in history. Although eÝective treatments and
vaccines are still beyond reach, current Þndings oÝer some encouragement.
106 Autoimmune Disease

Lawrence Steinman
Misguided assaults by the immune system cause a surprising number of

chronic diseases that aÝect an estimated 5 percent of the adults in the U.S. and
EuropeÑand the number may be higher. Promising experimental treatments
for multiple sclerosis may also yield dividends for treating the other illnesses.
116 Allergy and the Immune System

Lawrence M . Lichtenstein
Asthma, hay fever and other allergies may be the products of a response
designed to defeat parasites. In their absence the immune system overreacts
to other substances, such as pollen. Common interactions underlie the various
allergies. Recent discoveries are generating new ideas for prevention and control.
126 The Immune System as a Therapeutic Agent

Hans Wigzell
Knowledge of the immune system has given clinicians a potent instrument:

the system itself. Researchers are seeking to guide immune responses not
only to augment attacks on cancer and on pathogens but to encourage the
tolerance of transplanted tissue and to short-circuit autoimmune disease.
136 Will We Survive?

Avrion Mitchison
In the ongoing relationship between the immune system and the exterior world,
all parties have found ways to adapt to one another, be it by warfare or accom-
modation. But changing conditions, from air travel to emerging megacities,
facilitate the spread of diseases that challenge our defenses as never before.
DEPARTMENTS
20 Science and the Citizen 146 Science and Business 12 Letters to the Editors
SSC woes. . . . A proof for Fermat . . . . Crystalline data . . . . Charged cat-
16 50 and 100 Years Ago
Pollutants that mimic estrogen. . . . tle . . . . Rethinking HDTV. . . . Acid 154 Mathematical Recreations
Strange bedfellows . . . . Jove bash- test . . . . Why baseball teams re-
er . . . . Sorting nuts . . . . PROFILE: Mr. locate . . . . THE ANALYTICAL ECON- 158 Book Reviews
Buckyball Richard E. Smalley. OMIST: Hidden costs in garbage. 164 Essay : Barry R . Bloom

5
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8 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

LETTERS TO THE EDITORS
Critic or Clown? mediately after feeding on its blood. The I discuss these issues more thoroughly
longer an infected rabbit lived, the long- in my forthcoming book.
John HorganÕs conciliatory, pat-on-the- er the virus was available to be picked
back proÞle of Paul Karl Feyerabend [SCI- up by additional mosquitoes and passed
ENTIFIC AMERICAN, May] makes as much to new hosts. Viral strains that killed the Science Goes Hollywood
sense as letting a young child play with rabbits were at a distinct disadvantage.
a loaded gun. You unwittingly give cred- In contrast, the virus was transmitted by Hollywood simply gives the public
ibility to a man who has made a career rabbit ßeas in Europe. Because ßeas leave what it wants [ÒScientists in the Movies,Ó
of advocating the anticonceptual and only when the host dies, viral strains that by Anne Eisenberg, ÒEssay,Ó SCIENTIFIC
the irrational by featuring him where killed rabbits were more eÛcient for AMERICAN, April]. And what the public
you customarily celebrate our Þnest ob- transmitting the virus. Hence, the habits wants, it seems, is someone to blame
jective thinkers. Proper philosophy teach- of the vectors drove the evolution of the for what are perceived as ever more
es us how to integrate the facts of real- virus in diÝerent directions. complex problems. Scientists and engi-
ity into concepts from which we derive Ewald states that pathogens do not neers are convenient targets, because
the principles needed to live in peace harm their insect vectors, but that is they make up one of the few profes-
and prosperity. FeyerabendÕs postmod- not true for some disease cycles. The sional groups that contribute to society
ernism encourages us to abandon our Rickettsia organism that causes classi- rather than merely manipulating it.
only tool of survival, our minds. cal typhus multiplies in the gut of its Unfortunately, while most scientists
insect host, the human body louse. and engineers are quite good at ad-
RICHARD FISHER That infection kills the louse in less vancing othersÕ quality of life, they are
Scottsdale, Ariz. than 12 days, but not before the infec- quite bad at advancing their own im-
tious rickettsiae are passed on in its fe- age. Perhaps more articles like Eisen-
I thoroughly enjoyed HorganÕs pro- ces. Pathogens are under no more obli- bergÕs will ameliorate that condition.
Þle of Feyerabend. Including this hu- gation to spare the vector than they are
morous character piece provided a wel- to spare the vertebrate host. JEROLD S. WEINER
come diversion from your many seri- Blairstown, N.J.
ous objective articles on science. Any- CHAD P. MCHUGH
one who maintains that Òthere are no San Antonio, Tex. Witold Rybczynski is incorrect in dat-
objective standards by which to estab- ing, as Eisenberg says, Òthe change in the
lish truthÓ and then expects readers to Ewald replies: image of scientists to the second half
accept this claim as true has got to be The diÝerence in lethality between of the 20th century.Ó As early as 1813,
the clown prince of science critics. I got European and Australian myxomatosis when France was witnessing an explo-
a great guÝaw from his warning that may result from diÝerences in the vec- sion of scientiÞc discoveries, Claude-
the search for truth leads to Òtyranny tors, but the literature is so rich that Henri de Rouvroy, the count of Saint-
of the mind.Ó What a hoot this guy is! one can select examples to support vir- Simon, had already expressed concern
The only way that Feyerabend could tually any hypothesis. My approach has about the activities of scientists. Al-
be scienceÕs worst enemy is for anyone been to determine whether overall trends though he dreamed of a Council of New-
to take him seriously. are consistent with predictions from ton, a gathering of scientists who would
evolutionary theory. Both the Australian solve all the problems of the world,
KURT SCHMIDT and European myxoma viruses contin- Saint-Simon understood that the scien-
Traverse City, Mich. ue to be severe, which accords with the tists would never organize themselves
general trend for vector-borne patho- into what he hoped to be a politically
gens to be particularly harmful to their responsible body: ÒAll Europe is in a
WhoÕs Eating Whom vertebrate hosts. death-struggle: what are you doing to
Although I noted a tendency for patho- stop this butchery? Nothing. It is you
Paul W. EwaldÕs article ÒThe Evolution gens to treat their vectors kindly, I nev- who perfect the means of destruction.Ó
of VirulenceÓ [SCIENTIFIC AMERICAN, er suggested that pathogens would al- When the heroine of the Terminator
April] helps to debunk the myth that ways do so. In fact, variation in harm movies claims that scientists know only
all host-pathogen relationships evolve to vectors has been a focus of my re- Òhow to create death and destruction,Ó
to benign coexistence. Yet in using a search. Benign associations with mos- she repeats almost verbatim what Saint-
mosquito as the exemplar for all arthro- quitoes can be ascribed to vector-borne Simon said nearly 200 years ago.
pods, he missed the best example of transmission, but the data for lice, ticks
how transmission patterns inßuence vir- and ßeas are too scanty. Lice appear to NICOLAS MERTENS
ulence: that of myxoma virus in rabbits. be particularly vulnerable to their gut Albuquerque, N.M.
Myxoma is a pox virus transmitted parasites. Because they usually Òaban-
among rabbits by blood-feeding arthro- don shipÓ when a person has a fever, Because of the volume of mail, letters
pods. When it was introduced into Aus- they can transmit typhus eÝectively so to the editor cannot be acknowledged.
tralia, it was transmitted by mosqui- long as people are within a louseÕs walk- Letters selected for publication may be
toes and was initially very virulent. Se- ing distance. The vulnerability of lice edited for length and clarity. Unsolicited
lection favored attenuation of the virus, may explain why typhus generally be- manuscripts must be accompanied by a
however. Mosquitoes leave their host im- comes epidemic in crowded conditions. stamped, self-addressed envelope.

50 AND 100 YEARS AGO
SEPTEMBER 1943 ments so far down as to give a draft of did these early men appear? A perplex-
160 to 180 feet. To fly the Seadrome ing question. We used to be told that it
ÒHigh-frequency heating really start- route from Washington to Cherbourg was 6,000 years ago; but we now know
ed when engineers working on short- means only 3,200 miles in four hops of that there were at that time thousands
wave transmitters contracted artificial 800 miles each.Ó of men living in Europe, Asia, Africa,
fevers. The great virtues of this kind of and America.Ó
heat are as follows: The heat is generat-
ed directly in the object itself; no trans- ÒThere is no reason why a micros-
fer of heat is involved. Associated ap- copist, especially if he is a naturalist,
paratus need not be heated. The sur- should not make use of the telescope
faces of the material need not be af- SEPTEMBER 1893 in some of his investigations. Watching
fected. The people who work with the insects and the smaller animals at work
equipment have cooler working condi- ÒScientific men are agreed that the hu- is an interesting occupation which may
tions. No gases are involved and thus man race did in some way arise from be carried on by the aid of a small tele-
the likelihood of corroded surfaces is some inferior animal formÑnot neces- scope, provided the objective be suÛ-
eliminated. The material can be heated sarily monkeys. The transition may not ciently perfect to permit the use of pow-
from the inside-out. Finally, objects of have been gradual, but abruptÑevolu- erful eye pieces. Such an instrument
unusual size or shape can be heated.Ó tion per saltum. We do not find the might properly be called a long-range
Ômissing linkÕ; it is still missing; it may microscope. The illustration (below)
ÒA new antibacterial substance, peni- be forever missing. There are diÝerent shows an instrument of this kind in
cillin, has joined the ranks of the Ômira- opinions on how many early men there use. In the stage of the microscope stand
cle drugs.Õ Clinical tests of the material were. There may have been several dis- is secured a fine objectiveÑof about
give good reason for belief that it is su- tinct centers, but science as well as or- eight-inch focusÑborrowed from an
perior to any of the sulfonamides in thodoxy points toward the conclusion engineerÕs transit. Focusing is accom-
the treatment of Staphylococcus aureous that all men originated from one primal plished by means of the milled head of
infections. Preliminary tests on wounds pair living in one definite place. When the microscope.Ó
and infections of soldiers returned from
the battlefronts have been so encour-
aging that the tests are going forward
on a broad scale. In this work many
diÛculties are encountered. They arise
chiefly from the facts that the mold,
Penicillium notatum, from which peni-
cillin is obtained, produces only tiny
amounts of antibacterial substances af-
ter a long period of growth in a culture
medium that must be very carefully
protected and controlled. According to
a recent report, a yield of as much as
one gram of purified penicillin from 20
liters of culture fluid would be an ex-
cellent result.Ó
ÒFor very fast de luxe air passenger

service of the future it will not be sur-
prising to see non-stop operation be-
tween New York and London or Paris.
For less expensive passenger service,
however, and for carrying cargo or ex-
press, such long hops involve diÛcul-
ties. A tremendous amount of fuel has
to be carried. It is to meet this funda-
mental drawback of the airplane that
there has once more come to light the
idea of man-made islands to be moored
in the North Atlantic for use as refuel-
ing stations. Invented by Edward R.
Armstrong as far back as 1915, the Arm-
strong Seadrome is an island of steel
consisting of a floating platform 70
feet above the ocean, with buoyant ele- Long-distance microscope

SCIENCE AND THE CITIZEN
JOHN BIRD SSC Laboratory
WAXAHACHIE TUNNELS: construction

Super Trouble Frederick S. Upton of Michigan ex-
pressed a view shared by many repre- of the $10-billion Super Collider proceeds
The threatened SSC casts sentatives: ÒI donÕt doubt that there while Congress debates its fate.
a pall over particle physics would be some scientiÞc beneÞt to hav-
ing [the SSC], but we cannot aÝord it.Ó
The Congressional Budget OfÞce esti-
T
he fact that Bill would talk about mates that if the accelerator were ter- distribute the fund to particle physics
the Superconducting Super Col- minated, the government would save programs around the world.
lider (SSC) only if he were not iden- about $600 million in 1994Ñor about The builders of the SSC realize they
tiÞed speaks sad volumes about the 0.2 percent of the 1992 federal deÞcitÑ are unlikely to survive the political tur-
spirit that prevails in the community of and would gain about the same amount moil if they do not make some conces-
high-energy physicists. Two years ago in each of several subsequent years. sions to Congress. ÒThere is a strong ex-
he gave up an associate professorship Though the SSC may be down, it is pectation that we can gain Senate sup-
in one of the worldÕs top three physics not out. Last year, after 232 members port, but it may involve re-looking at
departments to work at the SSC. Like of the House voted to halt the SSC, the the whole project,Ó says Roy F. Schwit-
other colleagues at the laboratory, Bill Senate rescued the laboratory. The fate ters, director of the Super Collider.
entered the Þeld to unravel the great of the collider now rests on the ability The position of the main SSC contrac-
mysteries of physics, among them the of the Senate to pull oÝ the same feat tor, the Universities Research Associa-
question of why all the fundamental this year. The SenateÕs chief SSC advo- tion (URA), is particularly precarious.
particles have the masses they do. Now cate, J. Bennett Johnston of Louisiana, In June, Secretary of Energy Hazel R.
he wonders if his profession has a future. believes he and others can muster OÕLeary took the URA to task. ÒSpeciÞc
After 15,000 physicists, engineers and enough support. management deÞciencies have been
other workers have spent years creat- Even so, the House must be con- identiÞed in the Super Collider project.
ing the SSC, after they have construct- vinced to change its mind, something They are not acceptable, and I will ad-
ed about a sixth of the facility and after that George E. Brown, Jr., chairman of dress them directly and forcefully,Ó she
they have spent some $2 billion, the U.S. the House Science, Space and Technol- told the oversight and investigations
government is no longer sure it wants ogy Committee, hopes to do by increas- subcommittee of the House Energy and
to fund the project. In June the House ing international support for high-ener- Commerce Committee. She undertook
of Representatives voted 280 to 150 to gy physics. Japan has long been seen to decide within 30 days whether to
kill the $10-billion laboratory. The Clin- by SSC proponents as a likely source of keep the URA on as the primary con-
ton administration, which has so far about $1 billion. But despite polite tractor or relegate it to an advisory role.
supported the collider, had requested words, the money is not in sight. Brown OÕLeary had little choice. The inspec-
$640 million, but the House allocated envisages a fund to which countries in tor general of the Energy Department
$200 million for the speciÞc purpose AsiaÑprincipally JapanÑwould con- and oÛcials at the General Accounting
of shutting down the laboratory. tribute about $100 million per year. An OÛce have both produced reports high-
Before the House vote, Congressman international organization would then ly critical of the management of the

SSC. The oÛce noted that the URA has he says. Happer takes a cynical view of For instance, he would be ready to
still not perfected a cost and schedul- URA bashing. ÒHe whom the gods eliminate one of the two detectors for
ing system to track all past and project- would destroy, they Þrst make to ap- the accelerator. Present plans call for
ed expenditures. It also says the collid- pear foolish,Ó he notes, paraphrasing two detectors, with foreign countries
er is over budget and behind schedule, an ancient Greek proverb. SSC director sharing the cost. A decision to proceed
an accusation denied by John Toll, pres- Schwitters acknowledges that remov- with only one detector could be adver-
ident of the URA. ing the URA from its position as prima- tised as saving the taxpayer in the re-
William Happer, Jr., a Princeton Uni- ry contractor might be one way to sal- gion of $300 million. ÒOne detector
versity physicist who was director of vage the projectÕs political prospects. could do much of the physics planned
energy research during the Bush ad- Schwitters is also prepared to take for the SSC,Ó Schwitters comments.
ministration, defends the URA. ÒI think other measures to make it easier to win Cancellation, on the other hand, would
they have been doing a creditable job,Ó the support of a conference committee. be Òa staggering blow for particle phys-
ics,Ó Schwitters claims. The SSC, if com-
pleted, would be the premiere instru-
ment of particle physics. The only com-
parable machine is the Large Hadron
Shaking Conventional Wisdom Collider (LHC), which CERN plans to
build at its particle physics facility near
T hose who adore Brazil nuts have no doubt wondered why shaking a can
of assorted kernels always brings the large ones to the top. This some-
what counterintuitive ability of vigorous agitation to separate grains accord-
Geneva at the turn of the century. But
the LHC cannot Þll the shoes of the SSC,
and the European governments that
ing to size, no matter how dense they are or what they are made of, has puz- support CERN have not committed any
zled engineers and academics as well. Now a team of physicists from the funds for the construction of the LHC.
University of Chicago reports it has discovered a mechanism entirely differ- Carlo Rubbia, general director of CERN,
ent from previous explanations. says if the SSC were canceled, CERN
Conventional wisdom holds that local avalanching causes the segregation would not be in a position to utilize the
by size: vibrations open gaps underneath the larger particles; smaller parti- talents of the unemployed scientists
cles cascade into the voids, gradually pushing the biggest ones toward the and engineers.
surface. To test computer models of this idea, James B. Knight, H. M. Jaeger Meanwhile the more than 2,000 work-
and Sidney R. Nagel decided to build their own “can of nuts”: a cylinder 35 ers at the site in Waxahachie, Tex., are
millimeters in diameter, filled with spherical glass beads two millimeters in still digging tunnels, testing magnets
diameter. The researchers added various numbers of larger beads, up to 25 and trying to debug the troublesome ac-
millimeters in diameter, which were dyed so their movement could be traced. counting system. But morale is low, ac-
The container received a vertical shake, or “tap,” once each second. “There cording to SSC oÛcials. Many have giv-
was a wager as to whether the small beads rose with the larger beads as well,” en up homes and jobs to move to Tex-
Knight says. as. ÒI have never seen the young people
Although no one collected on the bet, the hypothesis was correct. The re- in the Þeld so frightened,Ó observes Mel-
searchers found an unexpected mechanism at work: convection. They wrote vyn J. Shochet, a scientiÞc spokesper-
in a recent issue of Physical Review Letters that the vibrating cylinder estab- son for the Collider Detector at Fermi
lishes a symmetric, fountainlike flow pattern that carries the beads up National Accelerator Laboratory.
through the cylinder’s center and then back down in a thin layer along the Bill, the 35-year-old SSC physicist,
container wall. strongly agrees. Termination of the col-
The girth of the upward flow easily accommodates the larger beads, en- lider, he believes, not only would mean
abling them to rise with all the others. Once at the top, however, the larger the loss of his job and that of his col-
beads cannot be swept into the narrow downward stream. They are trapped leagues at the laboratory but also would
at the surface while the smaller beads continue to circulate. Unlike earlier cause many American universities to
models that linked the segregation to different-sized, neighboring beads abandon research in particle physics.
bumping each other along, the convective separation does not depend on size Even if the collider survives for another
differences. In fact, convection occurs even with beads all the same size. “We year, the political upheaval has taken a
didn’t expect this at all,” Nagel admits. personal toll. ÒFor two years now, we
Nagel and his colleagues suspect that the convection is caused by friction have postponed notions such as buying
between the beads and the container wall—an interaction that computer sim- a house and putting the kids in a better
ulations failed to consider. In experiments using containers with very smooth school,Ó he laments. ÒAll because we
walls, the convection was weakened. In further tests the workers used a con- have this nagging weight on our back
ical container of their own design. In this case, the beads flowed in the oppo- that we might not be able to stay.Ó More-
site direction, confirming that convection accounted for the separation. “This over, 200 residents in the area sold their
is a new mechanism for this kind of size separation,” Nagel says. homes to make room for SSC buildings.
Interest in the results extends beyond nut-maven circles. The findings Bill now has second thoughts about
could help the pharmaceutical, construction and agricultural industries, his occupation. ÒThe reason why I was
which rely on keeping different-sized grains uniformly mixed. Understand- attracted to particle physics is that I
ing the mechanics of “demixing” could also elucidate the motion of landslides, might help to uncover some of the fun-
avalanches and magnetic flux lines in superconductors. damental rules by which nature plays,Ó
Many questions remain unanswered, however, such as determining the real he explains. ÒIf I had perceived that
shape of the flow in three dimensions. “It’s brute force, painstakingly putting there would be no funding in my life-
in some tracer particles and then seeing where they go,” Nagel says, describ- time for the instruments that could in-
ing current methods. “We’d love to have a better way.” How about gambling vestigate those rules, I probably would
with a computer again? —Kristin Leutwyler have gone into a diÝerent Þeld.Ó
ÑTim Beardsley and Russell Ruthen

JANE LUU University of California, Berkeley, and DAVID JEWITT University of Hawaii
COMET SHOEMAKER-LEVY reveals its multiple personality in the fragments seen here are about five kilometers across; they
this false-color image. Astronomers estimate that the largest of should begin colliding with Jupiter on or around July 20, 1994.
Jovian Jolt approach, Shoemaker-Levy whizzed a actual moment of contact. Yeomans

scant 100,000 kilometers from the plan- predicts that the pieces of Shoemaker-
A comet heads for a et. The fragments continued along the Levy will hit JupiterÕs southern hemi-
smashup with Jupiter same path, gradually separating from sphereÑon the side facing away from
one another. Based on his most recent the earth. By one estimate the impacts
observations of the compound comet, would shine 100 times brighter than
W
ant to see some Þreworks that Shoemaker estimates that the largest Venus, rivaling the full moon in intensi-
are literally out of this world? of the eight sizable fragments are about ty, if only the comet struck the earth-
If you are in the neighborhood Þve kilometers in diameter. ward side. Instead observers will have
of Jupiter on the 20th of July next year, Further study of Shoemaker-Levy has to settle for watching the light from
keep your eyes open, because nature turned up additional surprises. Brian G. the impacts reßected oÝ JupiterÕs large
has scheduled some rather spectacular Marsden of the Harvard-Smithsonian satellite, Io. That eÝect, though far less
pyrotechnics. Around that day Comet Center for Astrophysics and others de- spectacular, should be visible through
Shoemaker-Levy 9 will almost certainly termined the cometÕs orbit and showed small telescopes, using no fancy equip-
crash into Jupiter at a speed of about that it is circling Jupiter, not the sun, ment. ÒIf I were an amateur astrono-
60 kilometers a second, annihilating it- and so could be considered a new satel- mer, IÕd be looking with my eyeball,Ó
self as it plows through the thick Jovian lite of the planet. Then, on May 22, Mars- Chapman says.
atmosphere. The energy unleashed by den dropped a bombshell: the comet is Fortunately, human eyes will not
Shoemaker-LevyÕs catastrophic demise on a collision course with Jupiter. be the only ones watching Jupiter. The
should approximate that of the devas- A hailstorm of electronic-mail mes- Galileo probe, cruising toward a 1995
tating asteroid impact on the earth sages ensued as astronomers raced to rendezvous with the giant planet, will
thought to have killed oÝ the dinosaurs. predict the eÝects of the impact and to be situated so that it will see Shoemak-
ÒItÕs a once-in-a-millennium event,Ó mar- Þnd ways to observe this extraordinary er-Levy crash. Chapman, a member of
vels Eugene M. Shoemaker of the U.S. event. ÒI havenÕt seen anything like this the Galileo imaging team, is leading
Geological Survey, who discovered the since the great Swift-Tuttle scare,Ó jokes an eÝort to take maximum advantage
comet this past March 24 with his wife, Yeomans, referring to the (since retract- of the spacecraftÕs favored location. Al-
Carolyn, and veteran comet hunter Da- ed) prediction that a tremendous comet though Galileo will be more than 200
vid H. Levy. might strike the earth in 2126. million kilometers from Jupiter at the
From the start, the three astronomers This time, however, there is little dis- time of the collision, the craftÕs cameras
realized they had bagged no run-of-the- agreement that a collision will occur; should produce images comparable to
mill comet when the Þrst photographs Yeomans places the probability at those visible through the eyepiece of
showed it to have a bizarre elongated around 95 percent. Moreover, Shoemak- a decent ground-based telescope. The
shape. A better image revealed the rea- er points out that ÒweÕre going to have potentially sensational pictures should
son for the cometÕs odd appearance: it a succession of eventsÓ as the various show a brilliant blast lasting some tens
consists not of a single nucleus but of pieces of Shoemaker-Levy successively of seconds.
21 or so bits of frozen gas and dust, crash into Jupiter. What those events will Shoemaker reports that the Voyager
stretched out in a line like a string of look like remains the subject of much 2 spacecraft also would be able to ob-
celestial pearls. speculation. ÒItÕs something thatÕs nev- serve the demise of Shoemaker-Levy,
Donald K. Yeomans and Paul Chodas er been seen before,Ó comments Clark albeit from its distant location at the
of the Jet Propulsion Laboratory in R. Chapman of the Planetary Science edge of the solar system. He hopes the
Pasadena, Calif., calculate that the comet Institute in Tucson. ÒOne wants to be National Aeronautics and Space Admin-
was probably rent by JupiterÕs powerful careful about raising expectations.Ó istration will reactivate Voyager 2Õs high-
gravitational Þeld during its last pass Indeed, the comet has already dashed resolution camera on the grounds that
by Jupiter in July 1992. During that astronomersÕ hopes of witnessing the Òwe donÕt want to pass up this amazing

opportunity.Ó NASA has not yet made a
decision; Yeomans judges that Òit would
take a Herculean eÝortÓ to assemble the
money and manpower to switch Voy-
ager 2 back on.
Although earthbound observers will
miss the main event, they may be treat-
ed to many stunning repercussions.
Shoemaker-Levy will probably blast a
hole in JupiterÕs thick deck of banded
clouds; when the area of impact rotates
into view, about two hours after the
collision, signs of disruption may still
be visible. Moreover, the amount of en-
DENISE APPLEWHITE Princeton University

ergy contained in each blast will be Òso
enormous that it should produce long-
term eÝects in the atmosphere,Ó Chap-
man says. Some researchers go so far as
to speculate that the comet could induce
the formation of a huge storm system,
like JupiterÕs famed Great Red Spot.
The comet may aÝect Jupiter in other
ways as well. A vast cloud of cometary
dust might circle the planet, leading to
the formation of widespread hazes and FOR SEVEN YEARS, Andrew J. Wiles secretly sought a proof of FermatÕs theorem.
to a cooling of the stratosphere in ways
that could alter JupiterÕs highly visible
weather systems. Some dust could es- FermatÕs MacGuffin Within hours the news had ßashed
cape into the Jovian magnetic Þeld, via electronic mail to mathematicians
forming a glowing halo around the plan- A great math problem is around the globe. Experts warned that it
et. If some parts of Shoemaker-Levy ac- finally (probably) conquered could take a year or more to ensure
tually miss the planet (which is still a that WilesÕs 200-page paper is free of
possibility, given the uncertainties in the errors that have tripped up count-
A
astronomersÕ understanding of its or- lfred Hitchcock coined the word less others over the centuries. But
bit), they could form a ring. ÒThere will ÒMacGuÛnÓ to describe some WilesÕs reputation for cautionÑand his
be eÝects that amateurs can observe,Ó sought-after thingÑa fabulous proofÕs rich provenanceÑquickly per-
Yeomans expects. emerald, say, or a blueprint for an atom- suaded the cognoscenti that this was
For the moment, however, Chapman ic bombÑthat propels a plot forward. the real thing. ÒThe world at large, the
warns that Òanything you write has to Mathematics, too, has its MacGuÛns. competent worldÑperhaps I should say
be full of caveats.Ó Indeed, some astron- Perhaps the greatest of all is the follow- the world at smallÑis convinced,Ó says
omers have argued that, based on its ing proposition: the equation X N + Y N = John H. Conway of Princeton.
orbit, Shoemaker-Levy may not be a Z N has no solutions in positive integers The theoremÕs namesake was Pierre
comet at all but rather a disintegrated for N greater than 2. de Fermat, a 17th-century lawyer and
asteroid, a distinction that would strong- Mathematicians have been striving to polymath who is considered a founder
ly inßuence the eÝects of the collision. prove this proposition, better known as of number theory, the study of whole
Measurements of the cometÕs composi- FermatÕs last theorem, for more than numbers. One of FermatÕs inspirations
tion, now being made using the Hubble 350 years. What has made it so com- was a translated edition of Arithmetica,
Space Telescope and other instruments, pelling? ÒTwo things,Ó answers Andrew written by the Greek sage Diophantus
will soon pin down Shoemaker-LevyÕs J. Wiles of Princeton University, a 40- in the third century A.D. If Fermat was
true identity. year-old mathematician lured into his the father of number theory, Diophan-
At present, scientists have derived on- profession by a youthful obsession with tus was the grandfather. In his honor,
ly an average orbit for the cometÕs cen- FermatÕs theorem. ÒOne, it is something equations whose solutions must be in-
ter of mass. To reduce the uncertain- a child can understand, and the other tegers are called Diophantine.
ties, Shoemaker is conducting a series is that it has a history. The fact that so One page of Arithmetica discusses
of observations to determine the exact many people have tried and failed has how to Þnd integral solutions to X 2 +
sizes and locations of its various com- turned it into a treasure hunt.Ó Y 2 = Z 2, which form the sides of a right
ponents. Yeomans promises that once Wiles smiles, and no wonder. In June triangle. In the margin, Fermat scrib-
better observational data come in, he this slight, soft-spoken Englishman an- bled in Latin that no solutions exist for
will be able to predict the times of colli- nounced that he had found the treasure. exponents greater than 2. ÒI have dis-
sion to Òwithin a few minutes.Ó Wiles presented his proof during a three- covered a truly marvelous demonstra-
The excitement about Shoemaker- day series of lectures he delivered at the tion of this proposition that this mar-
Levy is all the greater because astrono- University of Cambridge. He did not ad- gin is too narrow to contain,Ó he added.
mers genuinely do not know what they vertise his achievement in advance, and FermatÕs claim, discovered after his
will see. ÒI expect that most of the his argument was so novel that only a few death in 1665, was hard to ignore. Carl
worldÕs telescopes will be pointing at listeners suspected his destination. Final- F. Gauss sniÝed that the theorem was
Jupiter on the 20th and 21st of July,Ó ly, he pointed outÑÒalmost as an after- not particularly interesting, but only af-
Chapman says. Nobody wants to miss thought,Ó one participant recallsÑthat ter he had tried and failed to solve it.
Þreworks like these. ÑCorey S. Powell his lectures represented a proof of ÒFLT.Ó The 18th-century Swiss mathematician

Leonhard Euler generated a proof for that the Taniyama conjecture was cor-
N = 3. In 1847 the German Ernst E. Kum- rect for all semistable elliptic curves,
Malignant Mimicry
mer proved the theorem for all but one could also prove FermatÕs theorem. False estrogens may cause
three N Õs less than 100. Techniques Wiles remained skeptical of FreyÕs cancer and lower sperm counts
employed in these proofs have become Òastounding ideaÓ until 1986, when
standard tools in number theory, which Kenneth A. Ribet of the University of
P
has itself become vital to cryptogra- California at Berkeley proved it. Wiles ollutants resembling crucial hu-
phy, error-protection codes and other immediately devoted himself to prov- man hormones may be short-cir-
applications. ing FermatÕs theorem by way of the cuiting some of the bodyÕs most
In recent decades, computer-assisted Taniyama conjecture. Most mathemati- important control mechanisms. The sub-
proofs have ruled out any solutions for cians still considered the conjecture stances that worry researchers most
N Õs up to four million, a very large ex- too steep to scale, but that suited Wiles. are the usual suspects Þngered in pol-
ponent indeed; astrophysicists have es- ÒI have a preference for working on lution reports: polychlorinated biphenyls
timated the total number of particles in things that nobody else wants to or (PCBs), dioxins, DDT and some pe-
the universe at a paltry 10300. But in- that nobody thinks they can solve,Ó he troleum by-products, among others. To
Þnity is inÞnity, and mathematicians explains. ÒI prefer to compete with na- varying degrees, all these chemicals can
would never be satisÞed until the theo- ture rather than be part of something mimic the eÝects of estrogens on cells.
rem was proved for all numbers. That fashionable.Ó Some recent work has turned up hints
goal seemed increasingly elusive. Many For seven years, Wiles virtually stopped that a lifetimeÕs subtle overexposure to
professionals took the same attitude as writing papers, attending conferences such potent physiological signals could
the eminent German David Hilbert, who or even reading anything unrelated to be responsible for cancers, birth defects
declared in 1920, ÒI havenÕt that much his goal. He never took seriously the and reproductive problems.
time to squander on a probable failure.Ó suggestion of some mathematicians that In a report scheduled to appear in
Meanwhile legions of amateurs have the problem might be intractableÑor, Environmental Health Perspectives, for
persisted in searching for the demon- in the jargon of computer science, Òun- example, Devra Lee Davis of the De-
stration they believed Fermat himself decidable.Ó ÒI certainly had periods partment of Health and Human Servic-
had found. Some claimed to have ex- where I felt stuck, but I expected that,Ó es and her colleagues conjecture that
tracted the proof from the Frenchman he remarks. PCBs and similar compounds might be
directly by contacting him through a The last piece fell into place this past causing many cases of breast cancer.
medium. One mathematician who re- May, when Wiles came across a century- Davis, who has previously made con-
viewed a proof submitted by a self-pro- old numerical technique in a paper by troversial assertions about rising can-
claimed parapsychologist notes: ÒEi- Mazur that helped him complete a Þnal cer rates, notes that most of the known
ther this guy was a fraud, or Fermat re- calculation. The proofÕs centerpiece was genetic risk factors for breast cancer
ally wasnÕt that smart. Take your pick.Ó a novel method of counting both the inßuence the bodyÕs estrogen metabo-
Wiles spent his teenage years in Ox- semistable elliptic curves and their hy- lism. Many of the suspect compounds
ford (where his father taught theology) perbolic counterparts so as to demon- have that same eÝect or have an aÛni-
trying to rediscover FermatÕs proof us- strate a one-to-one correspondence be- ty for the receptors on cells that normal-
ing only 17th-century methods. Although tween them. The correspondence proved ly bind to estrogens. The chemicals
he became a number theorist after re- TaniyamaÕs conjecture for all semistable might therefore increase a womanÕs life-
ceiving his doctorate from Cambridge elliptic curves. QED FLT. time exposure to estrogens. Because
in 1980, Wiles did not focus on Fer- Wiles calls his proof Òin some sense some cells in the breast respond to es-
matÕs theorem, since he could see no a collaboration,Ó because he built on the trogens by multiplying, the chemicals
route to a solution. achievements of so many others. But ex- could trigger rapid, inappropriate cell
Actually, the foundation for WilesÕs perts call it a brilliantly original synthe- divisions like those in tumors.
achievement had been laid when he was sis of ideas that has opened up whole Women may not be the only victims
still an infant. In 1954 the number the- new realms of inquiry. Ribet praises of estrogenic pollutants. This past May
orist Yutaka Taniyama posed a conjec- WilesÕs counting method, in particular, in the Lancet, Richard M. Sharpe of the
ture involving elliptic curves, which are as Òrevolutionary.Ó Harold M. Edwards University of Edinburgh and Niels E.
generated by Diophantine equations and of New York UniversityÕs Courant Insti- Skakkebaek of the University of Copen-
can be represented by the surface of a tute of Mathematical Sciences has only hagen hypothesized that environmen-
doughnut-shaped object called a torus. one regret. He fears that the proof will tal estrogens might be damaging menÕs
Taniyama conjectured that for certain trigger Òan upsurge in cranksÓ claiming reproductive systems. ÒWhen I was go-
elliptic curves there are corresponding they have found FermatÕs original proof. ing to medical school [in the 1960s],Ó
structures in the hyperbolic plane, a ÒI would have preferred that Wiles had Skakkebaek recalls, Òmore than 60 mil-
non-Euclidean surface in which parallel proven FermatÕs theorem was wrong,Ó lion sperm per milliliter was normal.
lines can converge (or diverge). ÒIt was Edwards says dryly, Òso I could just And then it was changed to 40, and
a very, very bold guess,Ó says Barry C. dismiss them.Ó some years ago the World Health Orga-
Mazur of Harvard University. Wiles now believes that if Fermat tru- nization set a line of 20 million.Ó
The next big step was taken in the ly had a proof, he would have written it Skakkebaek and his Danish colleagues
mid-1980s. Gerhard Frey of the Univer- down. Wiles does think his own proof have found evidence that those shifting
sity of Essen in Germany proposed that can be simpliÞed, ideally in such a way standards reßect a shocking nosedive
if there were solutions violating FermatÕs that the Taniyama conjecture is proved in sperm counts during the past half
theorem, they would generate a class for all elliptic curves, not just semi- century. They looked at 61 papers on
of so-called semistable elliptic curves stable ones. Will Wiles take on this task? male fertility published between 1938
that could not be represented in the ÒIÕm afraid IÕve made this so fashion- and 1990, covering data on almost
hyperbolic plane and would thus vio- able that I may have to move on to 15,000 men from around the world.
late the Taniyama conjecture. Converse- something else,Ó he replies. Time for a According to their analysis, the mean
ly, Frey speculated, if one could prove new MacGuÛn. ÑJohn Horgan sperm count had declined from 113 mil-

to millions of women for more than 20
years beginning in the 1940s to pre-
vent miscarriages. Use of the drug end-
ed with the discovery that the daugh-
ters of DES mothers are unusually like-
ly to develop a rare form of vaginal
cancer. Later studies showed that they
also often have reproductive and uro-
logic abnormalities that impair their fer-
CUSTOM MEDICAL STOCK

tility. Many sons of DES mothers suÝer
from related problems, including unde-
scended testicles, deformities of the pe-
nis and low sperm counts. Some re-
searchers fear that the sons have an el-
evated incidence of testicular cancer as
well, although that issue is still under
ABNORMAL SPERM may be caused by scrutiny. The women who took DES face
pollutants that mimic estrogen. a one third higher risk of breast cancer.
John A. McLachlan, director of intra-
mural research at the National Institute
lion per milliliter in 1940 to only 66 of Environmental Health Sciences, has
million per milliliter in 1990. Moreover, studied the eÝects of DES and other es-
the volume of semen in a single ejacu- trogenic chemicals for two decades. Ex-
lation had also fallen from 3.40 to 2.75 perience with DES, he says, shows that
milliliters. Those Þgures suggest that, on Òwhat may look like a perfectly func-
average, men now produce less than half tioning organ may have developmental
as many sperm as did men 50 years ago. abnormalities at the molecular or chem-
At the same time, other abnormali- ical level that appear only later in life.Ó
ties of the male reproductive tract have Whether pollutants with weaker estro-
increased. Skakkebaek says rates of genic eÝects than DES can have similar
testicular cancer in Europe and the U.S. eÝects at environmental concentrations
have risen between twofold and four- remains to be seen.
fold. Many urologists also believe un- Conducting those tests may prove
descended testicles and other male re- diÛcult. McLachlan notes that Òsome of
productive abnormalities have become the environmental chemicals that have
more common, although the diagnosis estrogenic activity also seem to have a
and reporting of these conditions are long half-life and can bioaccumulateÓ
less thorough. ÒI think these data are in the bodyÕs fat. One group, he ex-
less substantiated, but there is a trend,Ó plains, looked at the effects of kepone,
Skakkebaek remarks. an insecticide that is only weakly estro-
He and Sharpe argue that chemicals genic. At Þrst, female rats exposed to
with aÛnities for estrogen receptors on part-per-billion levels of kepone showed
cells could cause all these phenomena. no eÝects, but after about nine weeks
Animal studies have shown that if male of exposure the chemical reached po-
fetuses are exposed to high doses of es- tent levels, and the animalsÕ reproduc-
trogens, they may develop with many tive systems locked into a perpetual
female characteristics. Lower doses may ovulatory state. The World Wildlife Fund
alter the diÝerentiation and multiplica- has gathered evidence that some sea-
tion of the germ cells that eventually gulls, Þsh and other creatures in pollut-
give rise to sperm, the researchers note. ed areas exhibit abnormal reproductive
Hormonal meddling during this sen- behavior or physiology.
sitive stage of development could also Nevertheless, it is by no means cer-
predispose some testicular cells to be- tain that the health consequences in hu-
come cancerous. Research previously mans are caused by mimicry of estro-
published by SkakkebaekÕs laboratory gen. Karl T. Kelsey of the Harvard School
has suggested that cellular abnormali- of Public Health points out that Òal-
ties associated with testicular cancer though PCBs and DDT metabolites have
may originate during fetal life. ÒAnd the been shown to have estrogenlike activi-
semen quality of men with testicular ty, other compounds such as birth-con-
cancer is reduced,Ó Skakkebaek ob- trol pills that have orders of magnitude
serves. ÒSo there is evidence that estro- more activity have not been deÞnitively
gens can cause all these changes. The associated with breast cancer. So itÕs
question is whether what we are seeing hard to understand how these com-
is caused by estrogens.Ó pounds could be active when those oth-
If pollutants are acting as estrogens, ers are not.Ó Unfortunately, the estrogen
their eÝects may parallel those of the pathway is just one of many that toxi-
notorious drug diethylstilbestrol (DES). cologists will need to explore in search
This powerful estrogen was prescribed of the answers. ÑJohn Rennie

Fads and Feds
Holistic therapy collides
with reductionist science
P
olitics makes strange bedfellows.
The National Institutes of Health
serves as the latest vindication of
that truth. For almost a year now, the
various institutes of the bastion of main-
stream biomedical research have been
cohabiting uneasily with a new entity on
the Bethesda, Md., campus: the OÛce
of Alternative Medicine. Proponents of
oÝbeat therapies and their supporters
are delighted with the arrangement.
ÒThere are lots of valuable things out
there,Ó asserts Berkley Bedell, a former
Iowa congressman, who was one of the
political forces behind the establish-
ment of the oÛce. ÒIÕm optimistic some
of them will prove out.Ó Bedell main-
tains that he was cured of what he de-
scribes as a possible recurrence of pros-
tate cancer by an unconventional Òni-
trogen enhancementÓ therapy.
Opinions on BedellÕs treatment ap-
parently vary: Canadian authorities have
tried to shut down the practitioner
who supplies it. Likewise, opinions on
the alternative medicine oÛce are di-
verse. Opponents complain that it will
divert resources from research that is
more likely to yield beneÞts. ÒItÕs a tragic
thing when a few politicians can dic-
tate scientiÞc priorities,Ó growls John
H. Renner, president of the Consumer
Health Information Research Institute
in Kansas City, Mo. Renner, a former
chairman of the department of family
medicine and practice at the University
of Wisconsin, has received a special ci-
tation from the Food and Drug Admin-
istration for combating health fraud.
The medical establishment has by and
large adopted an attitude of bemused
indiÝerence. The American Medical As-
sociation, for example, takes the view
that although most alternative thera-
pies are never proved and some are
fraudulent, they should be evaluated.
But critics charge that the establishment
of the oÛce has thrown a mantle of le-
gitimacy over a spectrum of practices
that range from folk remedies to out-
right quackery. The $2 million spent by
the oÛce so far, Renner says, Òis worth
$100 million in free advertisingÓ for al-
ternative practitioners. According to
Stephen Barrett, publisher of Nutrition
Forum and an authority on medical
fraud, ÒEveryone with an unscientiÞc
approach is saying, ÔWeÕre alternative.Õ
They suggest this indicates recognition
by the scientiÞc community.Ó
Indeed, interest in the new program
runs high among purveyors of every-
Copyright 1993 Scientific American, Inc. SCIENTIFIC AMERICAN September 1993 39

thing from visualization therapy to a randomized trial.Ó Yet the small bud-
herbal cures for infection with the AIDS get of JacobsÕs oÛce means that it can
virus. Frank D. Wiewel, a member of support only 20 outside grants this
the 26-member advisory panel to the year, each for $30,000. And $30,000 is
oÛce and an advocate of several un- far too little an amount to conduct a
CORRESPONDENCE conventional cancer therapies, says randomized trial.
mainstream medical science has Òa Was the OÛce of Alternative Medi-
problem of lack of innovation in meth- cine even necessary? Some of the insti-
Reprints are available; to order, write ods of evaluation as well as in kinds of tutes were already investigating ap-
Reprint Department, SCIENTIFIC AMERI- therapies.Ó The oÛce will, he declares, proaches that might be termed Òalter-
CAN, 415 Madison Avenue, New York, pioneer alternatives. nativeÓ when the new oÛce came along.
N.Y. 10017-1111 or fax inquiries to The establishment of such an oÛce The National Cancer Institute has eval-
(212) 355-0408. constitutes a triumph for Wiewel, who uated more than 30,000 natural prod-
is president of an Iowa-based organiza- ucts in recent years for activity against
Back issues: $6 each ($7 outside U.S.) tion called People Against Cancer. Two cancer and the AIDS virus. ( Taxol was
prepaid. Most numbers available. Cred- years ago he, together with Bedell, took one result.) The cancer institute also
it card (Mastercard/Visa) orders for the case for the new bureau to Senator evaluates Òbest-case seriesÓ oÝered by
two or more issues accepted. To order, Tom Harkin of Iowa. Harkin, who has practitioners of alternative therapies.
fax (212) 355-0408. lost two sisters to cancer, was sympa- Under that program, it examines case
thetic and inserted a provision in the studies to determine whether there is
Index of articles since 1948 available NIHÕs 1992 appropriation bill. The agen- any evidence that a therapy has pro-
in electronic format. Write SciDex™, SCI- cy then had little choice but to comply. duced a beneÞt.
ENTIFIC AMERICAN, 415 Madison Ave- The oÛce is now gearing up a program Champions of folk remedies and un-
nue, New York, N.Y. 10017-1111, or fax to investigate Òalternative or unconven- conventional therapies are quick to
(212) 355-0408. tionalÓ treatments. voice disapproval of quackery. But Ja-
Joseph J. Jacobs, its director, says he cobs even declines to oÝer a deÞnition
Photocopying rights are hereby grant- has received more than 800 Òletters of of what constitutes honest Òalternative
ed by Scientific American, Inc., to li- intentÓ to apply for grants. Jacobs, who medicine.Ó The closest he gets to it is
braries and others registered with the as a child was given herbal remedies by when he notes that unconventional
Copyright Clearance Center (CCC) to his Mohawk mother, holds establish- practitioners are generally not schooled
photocopy articles in this issue of SCI- ment credentials, including a medical in collecting valid case data. Jacobs
ENTIFIC AMERICAN for the fee of $3.00 degree from Yale University. He insists wants to teach those who want to learn
per copy of each article plus $0.50 per that his oÛce will encourage Òrigorous how to do so. And he is particularly in-
page. Such clearance does not extend scientiÞc testing,Ó adding that ÒI bring a terested in the placebo eÝect. ÒTake
to the photocopying of articles for pro- fair amount of skepticism to this job.Ó prenatal careÑwe accept that it lowers
motion or other commercial purposes. Jacobs is quick to assert that grants infant mortality, but no one can tell you
Correspondence and payment should supported by his oÛce will go through how it does it,Ó he suggests.
be addressed to Copyright Clearance normal NIH review procedures. But Critics fear that Jacobs will be unable
Center, Inc., 27 Congress Street, Sa- some scientists there wonder how a to defend the scientiÞc line against the
lem, Mass. 01970. Specify CCC Ref- proposal to investigate a therapy with unabashed advocates of unconvention-
erence Number ISSN 0036-8733/93. scant supportive evidence could go al therapies who dominate the oÛceÕs
$3.00 + 0.50. against a conventional research pro- advisory panel. ÒI donÕt think heÕs go-
posal in a fair competition. R. Michael ing to be able to bring objective stan-
Blaese, a gene therapy researcher at the dards to quackery. I think thereÕs a big-
Editorial correspondence should be NIH who admits to misgivings about ger danger that scientists will become
addressed to The Editors, SCIENTIFIC the alternative medicine oÛce, points quackiÞed,Ó Renner argues. ÒIf Jacobs
AMERICAN, 415 Madison Avenue, New out that the NIH can already support doesnÕt pick the really silly stuÝ to eval-
York, N.Y. 10017-1111. Manuscripts just a small fraction of the research pro- uate, he wonÕt satisfy the enthusiasts,
are submitted at the authorsÕ risk and posals it receives. and then he will become politically un-
will not be returned unless accompa- Wiewel says he and other supporters acceptable to them.Ó
nied by postage. of the oÛce want it Òto look at thera- The transformation may, Renner
pies that are outside the medical main- fears, already be taking place. For ex-
Advertising correspondence should stream.Ó And he sympathizes with the ample, the NIH has not required mem-
be addressed to Advertising Manager, unwillingness of some patients to par- bers of the alternative medicine oÛceÕs
SCIENTIFIC AMERICAN, 415 Madison Av- ticipate in double-blind, placebo-con- advisory panel to refrain from using
enue, New York, N.Y. 10017-1111, or trolled trials. He argues instead for out- that aÛliation to advertise businesses.
fax (212) 754-1138. come studies, which simply compare The reason, according to the NIH, is the
patients who receive a particular thera- White House moratorium on new pub-
Subscription correspondence should py with others, often after the fact. lic advisory committees. The panel has
be addressed to Subscription Manager, Unfortunately, that approach is weak. therefore been given ad hoc status and
SCIENTIFIC AMERICAN, P.O. Box 3187, The National Cancer Institute, in guide- is not subject to normal regulations.
Harlan, IA. 51537. The date of the last lines it has published for alternative Panel members are already using the
issue of your subscription appears on practitioners, advises that studies of name of the oÛce to promote their be-
each monthÕs mailing label. For change the kind Wiewel advocates can usually liefs and services, Barrett says.
of address notify us at least four weeks at best suggest when a treatment war- The American Cancer Society wants
in advance. Please send your old ad- rants further examination. For most that changed. Its committee on ques-
dress (mailing label, if possible) and therapies, the institute states that ÒeÛ- tionable methods of cancer manage-
your new address. cacy must be assessed in the context of ment has passed a motion protesting

the NIHÕs decision, says William T. Jarvis,
a member of the committee and presi-
dent of the National Council Against
Health Fraud in Loma Linda, Calif.
A four-day meeting that JacobsÕs of-
Þce, along with two independent orga-
nizations, sponsored in May stimulates
further concern that the NIH is suscep-
tible to being ÒquackiÞed.Ó The confer-
enceÑÒAlternative Medicine, Wellness,
and Health Care Reform: Preparing for
a Sustainable FutureÓÑwas held at the
Walter Reed Army Medical Center. Its
venue was its only reassuring feature.
According to Barrett, one practitioner
claimed to have cured people infected
with the AIDS virus using herbs. Yet
session chairs, unwilling to sully the eu-
phoric atmosphere, did not ask for the
evidence supporting such an extraor-
dinary claim.
Indeed, critical thinking seems to have
taken a complete holiday. Contradic-
tions between diÝerent dietary theories
were simply ignored, Barrett and oth-
ers maintain. When Barrett asked mem-
bers of a panel their opinion on immu-
nization, they were unwilling to give it
a general endorsement. ÒThis is not sci-
ence,Ó Barrett protests.
Victor Herbert, a New York physician
and lawyer who has been an expert wit-
ness for the government in successful
prosecutions of medical frauds, says
he is not surprised that JacobsÕs oÛce
has been drawn into such spectacles.
Jacobs Òis trying to do an honest job,Ó he
asserts, but Òthere are professional scam
artists on his advisory committee.Ó
Many of the putative therapies the
OÛce of Alternative Medicine will be
called on to investigate, Herbert points
out, have already been examined by the
congressional OÛce of Technology As-
sessment (OTA). Yet the OTA found that
in most cases proponents were unable
or unwilling to produce data that would
permit an evaluation. ÒOne of the ma-
jor rifts separating supporters of un-
conventional treatments from those in
mainstream medical care and research
is a distinct diÝerence in what they ac-
cept as evidence of beneÞt,Ó the OTA
reported.
Wiewel insists he values scientiÞc ev-
idence and blames the OTA for failing
to do evaluations. The alternative med-
icine oÛce will, he predicts, remedy the
deÞciency. But in the incurably opti-
mistic world of alternative medicine,
where any improvement is evidence of
beneÞt, it could be a Sisyphean task.
ÒYou shouldnÕt evaluate something if
no credible evidence has been adduced
that it has any value,Ó Herbert contends.
ÒNo government has the resources to
study all the theories people come up
with.Ó ÑTim Beardsley

PROFILE : RICHARD E. SMALLEY
The All-Star of Buckyball conductor and even a superconductor

at the reasonably high temperature of
about 40 kelvins. Buckyballs have been
I
am peering into a binocular micro- problem of how 60 carbon atoms could envisaged as a substrate for microelec-
scope, and all I see is white. For a assemble themselves in such a stable tronics, a lubricant and a drug delivery
moment, I consider humoring Rich- way. The name comes from the appear- compound. A paper published in August
ard E. Smalley. After all, he and one of ance of the molecule and its relatives, by Craig R. Hill of Emory University
his graduate students have been fuss- which contain other quantities of car- and his colleagues even shows that car-
ing with the samples for several min- bon: they resemble R. Buckminster Ful- bon 60 can inhibit the AIDS virus. Now,
utes now, cleaving chunks and reject- lerÕs geodesic dome designs. if only it could stop baldness.
ing them. But he saves me. ÒI may have Smalley wants me to look into the Despite the amount of fullerene re-
moved it,Ó he says, scooting over in his microscope to see a variation of bucky- searchÑabout 1,400 papers have been
wheeled desk chair to have another balls: bundles of buckytubes, each about published to dateÑcommercial appli-
peek. It seems to be a lot of trouble to a nanometer in diameter. I can see them cations are still a few years away. The
look at bits of soot. after he repositions the sample. They main problem is price: puriÞed carbon
But Smalley is a determined individu- look like collections of pencil lead em- 60 costs up to $1,000 a gram. ÒIf the
al. His thin, white beard and his mea- bedded in an outcropping of sedimen- material is to make a substantial im-
sured, deliberate tones give him a rather tary rock. If he could grow these tubes pact, it has got to be sensationally im-
ponderous presence, one that masks to macroscopic lengths, he might have portant, like a drug is, or it has got to
intensity. ÒFrankly, IÕm not a very good the strongest and thinnest Þbers known be cheap,Ó Smalley says.
scholar. I donÕt like to go through metic- to exist. The possibility of nanoengineering
ulously what has already happened,Ó Such a success would end a nagging with carbon is part of the reason Smal-
the 50-year-old Rice University chemist question: What good are the fullerenes? ley became excited about results re-
confesses. ÒI like to compete. I like be- That query pops up with considerable ported this past June. In separate arti-
ing on the team that did it Þrst.Ó frequency, especially since the 1990 re- cles in Nature, Sumio Iijima and Toshi-
Without his sense of competition, he port by Wolfgang KrŠtschmer of the nari Ichihashi of NEC Corporation and
might never have been on the team that Max Planck Institute for Nuclear Physics Donald S. Bethune and his colleagues
Þrst discovered and characterized buck- in Heidelberg and Donald R. HuÝman at the IBM Almaden Research Center
minsterfullerene, or buckyball for short. of the University of Arizona and their described how they were able to pro-
This collection of 60 carbon atoms, ar- colleagues. In that paper, they described duce consistently uniform batches of
ranged in the shape of a soccer ball, the carbon-arc technique, which could single-walled carbon nanotubes. Previ-
constitutes the third form of carbon, make fairly large quantities of bucky- ous methods had often yielded tubes
after graphite and diamond. In an oft- balls easily. of diÝerent sizes and tubes within
told anecdote, Smalley stayed up one Their recipe has enabled workers to tubes. SmalleyÕs group has been trying
night, after several daysÕ worth of ex- investigate the properties of fullerenes. to grow continuous Þbers. The problem
periments and group discussions. With Besides tubes and Þbers, the molecule was that the team has not been able to
a pad of paper and tape, he settled the can be made into a conductor, a semi- start with perfect buckytubes to act as
seeds. The new work may just provide
that needed feedstock. ÒItÕs a very im-
portant advanceÑmore important than
they allude to in the papers,Ó Smalley
comments.
Smalley stays on top of the activity
in his lab by holding group discussions
every morning, always making the stu-
dents justify their approach to solving
a problem. He will quickly end their
projects if he does not think the re-
search will work. The intensity and in-
volvement of his crewÑcurrently an
all-male castÑgive the lab a kind of lock-
er-room atmosphere. According to Smal-
ley, outsiders have described the en-
DAN FORD CONNOLLY
semble Òas a bunch of guys snapping

towels at each other.Ó Smalley laughs
and protests: ÒI think this is unfair.Ó
(The label Òfat old lady,Ó written on a
chalkboard by a student to describe an
overgrown carbon tube, does not help.)
FULLERENE FINDER Richard E. Smalley holds a model of carbon 60, the buckyball. Smalley received early lessons in prob-
He hopes that Òdown the road, some of these babies are off doing good things.Ó lem solving and engineering in his up-

per-middle-class neighborhood in Kan- study for his Ph.D. at Princeton Univer- calls mentioning Buckminster FullerÕs
sas City, Mo. ÒAs a preadolescent, I was sity. SmalleyÕs love of cluster science work as well as describing a Òstar dome,Ó
a quiet kid. I spent most of my time and nanoengineering was evident even a soccer ballÐshaped toy sphere paint-
working in my fatherÕs basement work- then. ÒIn those days, I wanted to be- ed with stars that Kroto kept in his
shop.Ó That is where he achieved one come a quantum chemist. I was always home in England. Smalley does not re-
of his Þrst great successes: keeping the taken with the notion of being able to member exactly when ÒFullerÓ came up
family collie out of the rose patch by sit down at a computer and tell the in their meetings, but he became suÛ-
rigging the garden so that any intruder computer what elements you had, where ciently upset with the dispute that Heath
would set oÝ Þreworks. ÒBruce never you were going to put them, and then returned to the lab last year to help re-
went back to the place again.Ó see what the computer thought of it as construct events from human memo-
Despite his demonstrated ingenuity, a molecule.Ó He joined a group headed ries and research notebooks.
Smalley was a fairly erratic student. Neither individual probably would
Not until his junior year in high school, have discovered buckyballs had they
the year he took chemistry, did his ÒI like to compete,Ó not collaborated, and both agree that
grades turn around. ÒChemistry was Smalley says. ÒI like it was a serendipitous Þnding. Al-
the Þrst time I did well academically.Ó though they remember the events slight-
He had some priming: his aunt was a being on the team ly diÝerently, each now seems willing
professor of organic chemistry. ÒShe that did it first.Ó to leave it at that. ÒThe whole issue is
was someone whom I really admired,Ó really sort of silly,Ó Smalley remarks.
Smalley says. Because of his aunt, ÒI ÒThe simple fact is, carbon has been
never quite understood why so many by Elliot R. Bernstein, now at Colorado making this structure for millions of
people think a woman may not be as State University. ÒHe was doing experi- years. Nothing particularly special has
good a scientist as a man.Ó ments that I found completely inscru- to happen. All you have to do is vapor-
Those high school years coincided table, so I decided that I must do that, ize it.Ó Indeed, in 1984 workers at Ex-
with the beginning of the space race. because they must be very neat.Ó Un- xon had detected buckyballs hidden
ÒIt was the time of Sputnik,Ó Smalley der BernsteinÕs tutelage, he trained as a among other clusters of carbon, but
recalls. ÒAn engineer-scientist came into condensed-matter spectroscopist. they did not recognize the signiÞcance.
an assembly, and I remember sitting in After Þnishing his thesis on spec- ÒIt wasnÕt because one of us was Albert
the audience, still pretty convinced that troscopy, Smalley went to the Universi- Einstein and conceived the truncated
an engineer was someone who drove ty of Chicago for postdoctoral work icosahedra [a fancy way of saying soc-
trains.Ó But after hearing the speaker, with Donald H. Levy. There he met Len- cer ball] for the Þrst time in the history
Smalley changed his mind. ÒMy bud- nard Wharton, who helped to trans- of man.Ó
dies and I, nerds of the school, got form SmalleyÕs basement construction The awards and honors Smalley has
turned on by the idea. The most roman- skills into laboratory ingenuity. With received almost parallel the explosion
tic thing you could possibly be in those Levy and Wharton, Smalley pioneered in fullerene research. Will Smalley win
days was a scientist or engineer. This one of the most powerful techniques in the Nobel Prize in chemistry or physics?
was where the action was.Ó chemical physics: supersonic jet laser ÒThis topic comes up a lot,Ó he ac-
By SmalleyÕs estimation, it took many beam spectroscopy. For the Þrst time, knowledges. ÒI donÕt know if itÕs going
years before he cultivated the skills es- researchers had the ability to isolate to happen. But if it does, the impact on
sential to be a scientist. On his auntÕs and study clusters in the gas phase. A my life could very well be quite nega-
recommendation, he went to Hope Col- laser vaporizes a small bit of the sam- tive,Ó says Smalley, who spends a vast
lege in Holland, Mich. But after his fa- ple, which is cooled in helium and amount of time speaking about ful-
vorite professor there died of a heart ejected into an evacuated chamber. The lerenesÑby his estimate, 150 talks in
attack and the chairman of the organic jet of clusters expands supersonically, the past six months. ÒOn the other
chemistry department retired, he trans- cooling the clusters to near absolute hand, it makes institutions happy with
ferred to the University of Michigan at zero and stabilizing them for study in themselves. And IÕm sure my mother
Ann Arbor. Distracted by what he terms a mass spectrometer. would be very happy.Ó
a self-destructive relationship with a The instrument proved crucial to the Financial gain does not motivate Smal-
woman at Hope, he achieved only me- discovery of buckminsterfullerene. In ley, either. Although he feels a bit dumb
diocre grades at Michigan. 1985 Smalley, his Rice colleague Robert for having failed to patent the teamÕs
Weary of academic pursuits, he went F. Curl and Harold W. Kroto of the Uni- method of making fullerenes, he does
to work for Shell Chemical in New Jer- versity of Sussex, together with gradu- not seem to regret it too much. ÒIn
sey, where he received an industrial de- ate students James R. Heath and Sean C. principle, there could be a lot of money
ferment that kept him out of the Viet- OÕBrien, placed carbon in SmalleyÕs laser involved, but when you go into basic
nam War. ÒI think the only thing impor- vaporization device. Only two weeks research, your motives do not include
tant about it was that we were making later, after many experiments, several getting rich.Ó
polypropylene, and thatÕs what is used long discussions and plenty of Mexican Then what does the buckyball celebri-
to make sandbags.Ó Marriage and the food, the team discovered and charac- ty want? ÒMostly I just would like to
birth of a son guaranteed he would not terized carbon 60. It probably would have more time,Ó Smalley admits. ÒI
be drafted. have happened even more quickly had have enough money to get a ranch, buy
Shell also enabled Smalley to start any of them been soccer aÞcionados. a boat, buy an airplane and go around
developing as a scientist. With virtually The discovery of carbon 60 created the world, but I donÕt want to do that. I
unlimited access to the laboratory, he some controversy. At issue were the care more about my babies,Ó Smalley
learned the analytic methods of chem- naming and the explanation of its shape. says of fullerenes and his other achieve-
istry. ÒI realized, gee, I can really do ÒRobert and I were surprised at times ments. ÒWhat I want most is to see that
this stuÝ. I began to enjoy science real- to hear HarryÕs account of the story,Ó x number of years down the road, some
ly for the Þrst time.Ó Smalley says, Òalthough Harry was sur- of these babies are oÝ doing good
In the fall of 1969, he quit Shell to prised to hear our account.Ó Kroto re- things.Ó ÑPhilip Yam

Life, Death
and the Immune System
By defining and defending the self, the immune system
makes life possible; malfunction causes illness and death. Study
of the system provides a unifying view of biology
by Sir Gustav J. V. Nossal
W
hat did Franz Schubert, John sponse. This work also provides a sci- destroy pathogenic microbes that enter
Keats and Elizabeth Barrett entiÞc framework for examining the the body, can attack cancer cells and
Browning have in common? chemical organization of living systems hold them in check, at least tempo-
Each was a creative genius, but each and integrating that information into rarily. Other experiments showed that
also had his or her life tragically short- an understanding of how the organism those same lymphocytes can also be-
ened by a communicable disease that functions as a whole. have in less desirable ways. For exam-
today could have been prevented or I am a little ashamed to admit that I ple, they can act against the foreign
cured. Progress in the treatment of such did not immediately recognize the un- cells in transplanted organs and cause
diseases undoubtedly ranks as one of derlying importance of immunology. As graft rejection. If the regulation of the
the greatest achievements of modern a medical student in the 1950s, I be- immune system breaks down, lympho-
science. Smallpox has been completely came interested in viruses, hoping that cytes can attack cells belonging to the
eradicated, and poliomyelitis and mea- the analysis of their growth might reveal very body that they should be protect-
sles may be problems of the past by the the most profound details of the life ing, leading to a potentially fatal auto-
end of the century. So great has been process. I aspired to study under Sir immune disease.
the headway against infectious diseas- Frank Macfarlane Burnet, the promi- All these Þndings intensiÞed interest
es that until the current AIDS pandem- nent Australian virologist, at the Walter in one of the most central and baÝling
ic, industrialized countries had placed and Eliza Hall Institute of Medical Re-
them on the back burner among major search in Melbourne.
national concerns. After my graduation and hospital
SIR GUSTAV J. V. NOSSAL is director
Such staggering improvements in training, I was lucky enough to be ac-
of the Walter and Eliza Hall Institute of
public health alone would justify tre- cepted. Burnet wrote, however, that he Medical Research and professor of medi-
mendous eÝorts to understand the hu- had become interested less in viruses cal biology at the University of Melbourne
man immune system. Yet the Þeld of than in exploring the human immune in Australia. He earned his medical de-
immunology embraces more than just system. I was utterly dismayed. To my gree at the University of Sydney in 1954
the nature and prevention of infections. thinking, the early giantsÑLouis Pasteur, and his Ph.D. in immunology from the
Immunologic research is pointing to- Paul Ehrlich and Emil A. von BehringÑ University of Melbourne in 1960. He has
ward new approaches for treating can- had already discovered the fundamen- worked at Stanford University, the Pas-
teur Institute and the World Health Or-
cer and diseases that result from laps- tal truths about immunity. Public health, ganization; he has held his present post
es or malfunctions in the immune re- the major application of immunology since 1965. Nossal is a foreign associate
research, seemed the dullest of the sub- of the U.S. National Academy of Scienc-
jects in the medical curriculum. es, a fellow of the British Royal Society
Since then I have learned how wrong I and a past president of the International
WIDESPREAD VACCINATION of infants
was. Just as I began my graduate work, Union of Immunological Societies. His
in Nigeria and in other developing coun- contributions to cellular immunology,
tries has drastically reduced the inci- a series of immune-related discoveries
particularly the Òone cell, one antibodyÓ
dence of diseases such as diphtheria began ushering in an extraordinary
rule and the discovery of antigen-captur-
and poliomyelitis. That worldwide as- chapter in the history of biomedicine. ing mechanisms, have been recognized
sault on infectious disease has been one Researchers observed that the white by honors from 12 countries.
of the triumphs of modern immunology. blood cells called lymphocytes, which

mysteries of the immune system: how Francis Crick deduced that, in biologi- identical heavy chains and two identi-
it is able to recognize the seemingly cal systems, information ßows from cal light chains. An intertwining light
inÞnite number of viruses, bacteria and DNA to RNA to protein. For this rea- chain and heavy chain form an active
other foreign elements that threaten son, antigen proteins could not deÞne site capable of recognizing an antigen,
the health of the organism. In most new antibody proteins: the information so each antibody molecule has two iden-
biochemical interactions, such as the for the antibody structures had to be tical recognition sites. Knowing that two
binding of a hormone to a receptor or encoded in the genes. Those Þndings chains contribute to the binding site
the adhesion of a virus to its host cell, raised a puzzling question: If genes dic- helps to explain the great diversity of
eons of evolution have reÞned the tate the manufacture of antibodies, antibodies because of the large number
chemistry involved so that each mole- how can there be speciÞc genes for each of possible pair combinations.
cule unites with its partner in a precise, of the millions of diÝerent antibodies A set of experiments initiated by Su-
predetermined way. The immune sys- that the body can fabricate? sumu Tonegawa of the Basel Institute
tem, in contrast, cannot anticipate what In 1955 Niels K. Jerne, then at the for Immunology led to the deÞnitive
foreign molecule it will confront next. California Institute of Technology, had description of how the immune system
already hit on a possible explanation can produce so many diÝerent anti-
O
ne of the crucial elements that for the incredible diversity of antibod- body types. He found that, unlike near-
helps the immune system meet ies. He suggested that the immune rely all other genes in the body, those that
that challenge is antibody, a sponse is selective rather than instruc- contain the code for the heavy chains
large protein molecule discovered in tiveÑthat is, mammals have an inher- do not preexist in the fertilized egg. In-
1890 by von Behring and Shibasaburo ent capacity to synthesize billions of stead the code resides in four sets of
Kitasato. Antibodies latch onto and neu- diÝerent antibodies and that the arrival mini-genes located in widely separated
tralize foreign invaders such as bacte- of an antigen only accelerates the for- parts of the nucleus. Antibody diversi-
ria and viruses; they also coat microbes mation of the antibody that makes the ty springs from the size of these mini-
in a way that makes them palatable to best Þt. gene families: there are more than 100
scavenger cells, such as macrophages. Two years later Burnet and David W. kinds of V (variable) genes, 12 D (diver-
Each type of antibody acts on only a Talmage of the University of Colorado sity) genes and four J (joining) genes.
very speciÞc target molecule, known as independently hypothesized that anti- The C, or constant, genes vary in ways
an antigen. Consequently, antibodies bodies sit on the surface of lympho- that aÝect only the function of the an-
that attack anthrax bacilli have no eÝect cytes and that each lymphocyte bears tibody, not its antigen aÛnity.
against typhoid. For decades, biologists only one kind of antibody. When a for- During the development of an anti-
thought of the antigen as a kind of tem- eign antigen enters the body, it eventu- body-forming cell, one member from
plate around which the antibody mole- ally encounters a lymphocyte having a each set of mini-genes jumps out of its
cule molded itself to assume a comple- matching receptor and chemically original position and links with the
mentary form. This theory, Þrst clear- stimulates it to divide and to mass-pro- other jumpers to form a complete
ly articulated by Felix Haurowitz in the duce the relevant antibody. In 1958 V-D-J-C gene. This genetic rearrange-
1930s and later espoused by Linus Paul- Joshua Lederberg, then visiting the Hall ment allows for 4,800 diÝerent vari-
ing, held sway until about 1960. Institute, and I demonstrated that when eties (100 × 12 × 4 × 1) of heavy chains.
By the mid-1960s the template mod- an animal is immunized with two dif- The same process occurs in the assem-
el was in trouble. Gordon L. Ada of the ferent antigens, any given cell does in bly of the light-chain genes, except that
Hall Institute and I demonstrated that fact make just one type of antibody. they have only V, J and C segments, so
antibody-making cells did not contain Soon thereafter Gerald M. Edelman there are about 400 basic combinations
any antigen around which to shape an of the Rockefeller University and Rod- for them. The diversity of heavy and
antibody. Studies of enzymes showed ney R. Porter of the University of Ox- light chains allows for the existence
that the structure of a protein depends ford discovered that antibodies are of 4,800 × 400, or 1,920,000, antibody
only on the particular sequence of its composed of four small proteins called genes. Moreover, special enzymes can
amino acid subunits. Furthermore, chains. Each antibody possesses two insert a few extra DNA coding units at
ANTIGEN AND ANTIBODY Þt together tightly, like two hands side), as happens on the surface of a B lymphocyte. Separat-
shaking (left). This computer simulation, based on x-ray crys- ing the two molecules by a distance of eight angstroms re-
tallography data collected by Peter M. Colman and William R. veals their complementary surfaces (right). The variable part
Tulip of CSIRO in Melbourne, shows an antigen from an of the heavy protein chain is shown as red, the correspond-
inßuenza virus (left side) interacting with an antibody (right ing part of the light chain as blue.

ANTIGEN-PRESENTING CELL ANTIGEN
MHC
PROTEIN
PEPTIDE
MHC
PROTEIN
PEPTIDE
T CELL
RECEPTOR
B LYMPHOCYTE
T LYMPHOCYTE
LYMPHOKINES
ACTIVATED ACTIVATED
T LYMPHOCYTES B LYMPHOCYTES
(PLASMA CELLS)
How the Immune System Defends the Body
T he body is protected by a diverse army of cells and molecules that work in

concert. The ultimate target of all immune responses is an antigen, which is
usually a foreign molecule from a bacterium or other invader. Specialized antigen-
presenting cells, such as macrophages, roam the body, ingesting the antigens
they find and fragmenting them into antigenic peptides. Pieces of these pep-
tides are joined to major histocompatibility complex (MHC) molecules and are
displayed on the surface of the cell. Other white blood cells, called T lympho-
cytes, have receptor molecules that enable each of them to recognize a different
peptide-MHC combination. T cells activated by that recognition divide and secrete
lymphokines, or chemical signals, that mobilize other components of the im-
mune system. One set of cells that responds to those signals comprises the B lym-
phocytes, which also have receptor molecules of a single specificity on their sur-
face. Unlike the receptors of T cells, however, those of B cells can recognize parts
of antigens free in solution, without MHC molecules. When activated, the B cells di- ANTIBODIES
vide and differentiate into plasma cells that secrete antibody proteins, which are
soluble forms of their receptors. By binding to antigens they find, the antibodies
can neutralize them or precipitate their destruction by complement enzymes or by
scavenging cells. Some T and B cells become memory cells that persist in the cir-
culation and boost the immune system’s readiness to eliminate the same antigen if
it presents itself in the future. Because the genes for antibodies in B cells mutate
frequently, the antibody response improves after repeated immunizations.

The Decentralized Defenses of Immunity
B ecause infectious agents can enter the body at any

point, the tissues and organs of the lymphatic sys-
tem—the wellspring of immunologic defense—are widely
ondary lymphoid organs, such as the lymph nodes,
spleen and tonsils. They then exit the bloodstream
through specialized blood vessels called high endothelial
scattered. The lymphocytes, which are responsible for venules. Although the lymphocytes become rather tight-
specific immunity, are born in the primary lymphoid or- ly packed (each gram of lymph node contains a billion of
gans: the thymus makes T cells, and the bone marrow them), they can still move about freely. Consequently, the
makes B cells. After leaving those organs, the cells circu- nodes are excellent places for lymphocytes to become ac-
late in the blood until they reach one of the numerous sec- tivated by antigens and antigen-presenting cells entering
through the afferent lymphatic vessels. T cells gener-
ally become activated by antigen in the paracortex; acti-
vated B cells become antibody-producing plasma cells in
areas such as the germinal centers of the lymphoid
follicles. Activated lymphocytes flow out of the nodes
ADENOIDS through the efferent lymphatics and travel through the
fluid in the lymphatic vessels until they reach the blood-
TONSILS stream and spread their protective influence around the
body. Eventually the lymphocytes flow into other lymph
LYMPH NODES nodes, and the cycle begins again.
THYMUS
SPLEEN
PEYER’S PATCH ON SMALL INTESTINE
APPENDIX
LYMPHATIC VESSEL
BONE MARROW
LYMPH NODE
AFFERENT
LYMPHATIC
HIGH
ENDOTHELIAL
VENULE
GERMINAL
CENTER
CORTEX
PARACORTEX
EFFERENT
LYMPHATIC

ANTIGEN ANTIBODIES
MITOSIS
CLONAL SELECTION enables the immune system to react to a myriad of possible

pathogens. Lymphocytes having any one of millions of diÝerent surface antibodies
constantly roam the body. When the antigen on the surface of a foreign entity
meets a lymphocyte having a matching antibody (top), the lymphocyte swells and
begins to divide rapidly (right). Once they reach maturity, B cells secrete antibod-
ies that attack the invader (bottom ); T cells generate lymphokines, chemicals that
boost the activity of other cells in the immune system.
the junctions between the V and D or D has a unique receptor, but unlike B cells,
and J segments when they interlink, T cells cannot ÒseeÓ the entire antigen.
which further increases the number of Instead the receptors on T cells recog-
possible antibody constructions. nize protein fragments of antigens, or
Despite their enormous versatility, an- peptides, linear sequences of eight to
tibodies alone cannot provide full pro- 15 amino acids. T cells spot foreign pep-
tection from infectious attack. Some tide sequences on the surface of body
diseases, such as tuberculosis, slip in- cells, including bits of virus, mutated ACTIVATED B
LYMPHOCYTE
side their host cells so quickly that they molecules in cancer cells or even sec-
can hide from antibody molecules. In tions of the inner part of a microbe. A
these cases, a second form of immune molecule known as a major histocom-
response comes into play. When the in- patibility complex (MHC) protein brings
fected cells become inßamed, lympho- the peptide to the cell surface, where
cytes attack them so as to conÞne the the T cell can bind to it.
infection. This defense mechanism is T cells and antibodies make perfect
known as cell-mediated immunity, in partners. Antibodies respond swiftly to
contrast with the so-called humoral im- toxin molecules and to the outer sur-
munity mediated by antibodies. faces of microbes; T cells discover the
antigens of hidden inner pathogens,
I
n the early 1960s Jacques F.A.P. which makes them particularly eÝective
Miller, then at the Chester Beatty at tracking down infectious agents. For
Research Institute in London, and instance, a virus might be able, through
Noel L. Warner and Aleksander Szen- mutation, to change its outer envelope
berg of the Hall Institute determined rapidly and in this way frustrate neu-
that lymphocytes fall into two diÝerent tralization by antibodies. That same vi-
classes, each of which controls one of rus might contain within its core sever-
the two types of immune response. al proteins that are so essential to its
Cell-mediated immunity involves a type life process that mutations are not per-
of lymphocyte that originates in the mitted. When that virus replicates in-
thymus and is thus called a T cell. Hu- side cells, short peptide chains from
moral immunity occurs through the ac- those viral proteins break oÝ and trav-
tion of antibodies, which are produced el to the cell surface. They serve as ripe
by the lymphocytes known as B cells targets for the T cell, which can then
that form in the bone marrow. attack the infected cell and inhibit the ANTIBODIES
T cells and B cells diÝer not only in spread of the virus.
their function but also in the way they So far I have described T and B lym-
locate a foreign invader. As Talmage phocytes as though they operate inde-
and Burnet hypothesized, B cells can rec- pendently, but in actuality they form a
ognize antigens because they carry anti- tightly interwoven system. T cells make
bodies on their surface. Each T cell also close contact with B cells, stimulate

them into an active state and secrete crete chemicals that kill infected cells, phokines from T cells, B cells can switch
lymphokines, molecules that promote limiting the spread of a virus. Because from one isotype of antibody to anoth-
antibody formation. T cells also can of their murderous nature, CD8 T cells er within a day or so.
suppress antibody formation by releas- are also referred to as cytotoxic T cells.
B
ing inhibitory lymphokines. B cells undergo an especially stunning oth B and T lymphocytes get a
B cells, in turn, process antigens into transformation once activated. Before helping hand from various other
the form to which T cells most readily it meets antigen, the B cell is a small cells and molecules. When anti-
respond, attach the antigens to MHC cell having a compact nucleus and very bodies attach to a bacterium, they can
molecules and display them on the cell little cytoplasmÑa head oÛce without activate complement, a class of en-
surface. In this way, B cells help to stim- much happening on the factory ßoor. zymes that kill bacteria by destroying
ulate T cells into an active state. Re- When the cell springs into action, it di- their outer membranes. Some lympho-
searchers have observed that B cells vides repeatedly and builds up thou- kines send out a chemical call to macro-
can also inhibit T cell responses under sands of assembly points in its cyto- phages, granulocytes and other white
experimental conditions. Such highly plasm for the manufacture of antibod- blood cells that clean up the mess at an
regulated positive and negative feed- ies, as well as an extensive channeling infected site by gobbling up germs and
back loops are a hallmark of the orga- system for packaging and exporting the dead cells. Such tidiness is enormously
nization of the immune system. antibodies. One B cell can pump out important: a patient having no granulo-
The specialization of the immune sys- more than 10 million antibody mole- cytes faces grave risk of death from the
tem does not end with its division into B cules an hour. infectious bacteria that feed on cellular
and T cells. T cells themselves comprise My co-workers and I routinely culti- corpses. Clearly, all the white blood
two subpopulations, CD4 (helper) and vate a single B cell to grow a ÒcloneÓ cells work together as a well-orchestrat-
CD8 (killer) T cells. CD4 cells recognize comprising hundreds of daughter cells. ed team.
peptides from proteins that have been After one week, those clones can gener- Amid all the complex operations of
taken up by macrophages and other ate 100 billion identical antibody mole- the immune defenses, it is utterly cru-
specialized antigen-capturing cells. CD8 cules to study. Such clonal cultures have cial that lymphocytes remain consistent-
cells react to samples of peptides origi- enabled us to witness another of the B ly benign toward the bodyÕs own cells,
nating within a cell itself, such as a seg- cellÕs remarkable talents. B cells can commonly referred to as self, while re-
ment of a virus in an infected cell or switch from making one isotype, or acting aggressively to those that it rec-
mutant proteins in a cancer cell. Each functional variety, of antibody to an- ognizes as foreign, or nonself. Burnet
variety of T cell utilizes its own form of other without changing the antigen to postulated that self-recognition is not
MHC to make the peptides noticeable. which the antibody binds. Each isotype genetically determined but rather is
When CD4 T cells encounter the prop- of an antibody derives from a diÝerent learned by the immune system during
er chemical signal, they produce large form of the C mini-gene. the organismÕs embryonic stage. He sug-
amounts of lymphokines to accelerate Each antibody isotype has its own pe- gested that a foreign antigen introduced
the division of other T cells and to pro- culiar advantage. One isotype serves as into an embryo before the immune sys-
mote inßammation. Some CD4 cells spe- a Þrst line of defense; another special- tem had developed would trick the lym-
cialize in helping B cells, others in caus- izes in neutralizing toxins; a third suf- phocytes into regarding the foreign mol-
ing inßammation. Activated CD8 cells fuses mucus and so helps to create a ecule as self. BurnetÕs attempts to prove
produce much smaller amounts of lym- barrier against infectious agents at- his theory by injecting an inßuenza
phokines but develop the capacity to tempting to enter through the nose, vaccine into chick embryos did not elic-
punch holes into target cells and to se- throat or intestines. In response to lym- it the expected null response, however.

T CELL B LYMPHOCYTE in its resting state is little more than a nucleus surrounded by a
thin enclosure of cytoplasm (left). Once a B cell meets a matching antigen, it de-
velops an extended body (center ) containing polyribosomes, which make antibod-
ies, and an elaborate channel system for exporting those antibodies. T lympho-
cytes can regulate the behavior of B cells by administering lymphokines through
an intimate junction somewhat like a nerve synapse ( right). During these interac-
tions, the B cell can also inßuence the activity of the T cell .
antibodies on the bodyÕs innumerable B of surgery, preempting a lymphocyte

cells suggested the mechanism by which attack. Most organ transplants provoke
lymphocytes learn to ignore cells of the such a strong T cell response that the
self. An immune reaction represents the doses of drugs needed to prevent organ
activation of speciÞc lymphocytes se- rejection are even higher than those
lected from the bodyÕs varied repertoire. used to treat autoimmune diseases. For-
It seemed logical that tolerance of self tunately, those dosages can be reduced
could be seen as the mirror image of im- after a few months. Newer, more pow-
munity: the systematic deletion of those erful immunosuppressive drugs are
cells that respond to self-antigen. leading to good success rates for trans-
Genetic inßuences and environmen- plants of the kidney, heart, liver, bone
LYMPHOKINES
tal triggers can cause the usual immu- marrow, heart-lung and pancreas; re-
nologic rules to break down. In those in- cently a few small-bowel transplants
stances, B cells or T cells, or both, may have taken. Researchers are also striv-
respond to self-antigens, attacking the ing to develop targeted drugs that
bodyÕs own cells and leading to a dev- dampen the organ rejection response
B CELL
astating autoimmune disease. Some while still allowing the body to react to
such disorders result from misdirected infectious diseases.
antibodies: in hemolytic anemia, anti- Transplantation has become so suc-
In 1953 Rupert E. Billingham, Leslie bodies attack red blood cells, and in cessful that doctors often confront a
Brent and Sir Peter B. Medawar, work- myasthenia gravis, antibodies turn on a shortage of organs from recently de-
ing at University College, London, suc- vital protein on muscle cells that re- ceased donors. Workers therefore are
ceeded where Burnet had failed. The ceives signals from nerves. T cells play renewing their eÝorts to perform xeno-
three men were exploring ways to trans- the villainÕs role in other autoimmune transplantation, the transplantation of
plant skin from one individual to an- diseases: in insulin-dependent diabetes, organs from animal donors. Tissue
otherÑin order, for instance, to treat a T lymphocytes destroy insulin-produc- from endocrine glands can be cultured
burn victim. Medawar had previously ing cells in the pancreas, and in multiple so that it loses some of its antigenic
discovered that the body rejected such sclerosis, they direct their fury against punch, raising the possibility that in-
skin grafts because of an immune re- the insulation surrounding nerve Þbers sulin-secreting cells from pigs will one
sponse. When he came across BurnetÕs in the brain and spinal cord. day be grafted into diabetics. Chemical
theoretical writings, Medawar and his Treating autoimmune diseases neces- treatments may be able to ÒhumanizeÓ
colleagues set about injecting inbred sitates abolishing or at least restraining crucial molecules in animal organs so
mouse embryos with spleen-derived cells the immune system. Immunosuppres- as to ameliorate the ferocity of im-
from a diÝerent mouse strain. Some em- sive and anti-inßammatory drugs can mune rejection. Nevertheless, xeno-
bryos died as a result of this insult, but achieve the desired eÝect, but such a transplantation faces formidable tech-
those that survived to adulthood ac- blunderbuss approach suppresses not nical and ethical obstacles.
cepted skin grafts from the donor strain. only the bad, antiself response but also
I
A patch of black fur growing on a white all the desirable immune reactions. For- mmunologic attacks on tissues in
mouse dramatically showcased the dis- tunately, researchers are making some the body need not be horriÞc; they
covery of actively acquired immunolog- progress toward the ideal goal of re- could actually be beneÞcial if direct-
ic tolerance; for the Þrst time, lympho- establishing speciÞc immunologic tol- ed against cancers. Indeed, one contro-
cytes were fooled into recognizing non- erance to the beleaguered self-antigen. versial theoryÑthe immune surveillance
self as self. Burnet and Medawar shared One kind of therapy involves feeding theory, Þrst articulated by Lewis Thomas
a Nobel Prize for their work. the patient large quantities of the at- when he was at New York UniversityÑ
Subsequent research clariÞed why Bur- tacked self-antigen; surprisingly enough, holds that eliminating precancerous
netÕs experiment had gone awry. Med- such an approach can selectively restrain cells is one of the prime duties of the
awarÕs group used living cells as an anti- future responses to that antigen. Re- constantly patrolling lymphocytes.
gen sourceÑspeciÞcally, cells that could searchers have achieved similar results People whose immune system has
move into critical locations such as the by administering antigens intravenous- been suppressed by drugsÑmostly re-
thymus and the bone marrow. As long ly while the T cells are temporarily cipients of organ transplantsÑdo in fact
as those donor cells lived, they contin- blindfolded by monoclonal antibod- experience a higher incidence of leu-
ued to make antigens that inßuenced ies that block their antigen receptors. kemias, lymphomas and skin cancers
the emerging lymphocytes. BurnetÕs in- Some treatments for autoimmune dis- fairly soon after transplantation than
ßuenza vaccine, on the other hand, had eases based on these approaches have do similar individuals in the general
been rapidly consumed and broken down reached the stage of clinical trials. population. After three decades of ob-
by scavenger cells; not enough antigen Successful organ transplantation also serving kidney transplant patients, phy-
reached the immune system to induce requires shutting down an undesired sicians Þnd that those individuals also
a signiÞcant degree of tolerance. aspect of immune response. In princi- experience a somewhat elevated sus-
The realization that immune response ple, the surgeon can begin supplying ceptibility to many common cancers,
depends heavily on the vast diversity of immunosuppressive drugs at the time such as those of the lung, breast, colon,

uterus and prostate. These findings hint family of proteins collectively called easy in advanced cases of cancer. And
that immune surveillance may act to MAGE , which has been extensively stud- yet experimental vaccines have shown
hold at least certain cancers in check. ied by Thierry Boon at the Ludwig Insti- tantalizing signs of success. In tests on
Alternatively, drug-associated cancers tute for Cancer Research in Brussels. In patients who had several forms of wide-
may be the result of some mechanism laboratory experiments, a peptide de- spread cancer, such as melanoma, kid-
other than immunosuppression. rived from MAGE can provoke a strong ney cancer and certain forms of leuke-
Further evidence of the immune sys- attack from cytotoxic T cells. If re- mia, roughly one Þfth of them experi-
temÕs role in preventing cancer comes searchers could learn how to manipu- enced a dramatic regression of their
from studies of mouse cancers induced late the antigen properlyÑperhaps by tumors in response to these vaccines.
by viruses or by chemical carcinogens. injecting a patient with MAGE or its Little is known about why those people
Those cancers often provoke strong im- constituent peptides, along with mole- responded and others did not.
mune responses when transplanted into cules designed to strengthen immuni- Many workers believe cancer vac-
genetically identical mice, which proves tyÑthey might be able to create an ef- cines will come into their own as weap-
that the cancerous cells bear antigens fective therapy for melanoma. ons against the few mutant cells that
that mark them as abnormal. Sponta- Another way to Þght cancers involves persist in the body after cancer sur-
neously arising cancers in mice, which boosting the immune response to aber- gery, chemotherapy or radiation thera-
are likely to be more akin to human rant forms of a class of proteins known py. These surviving cells can cause a
cancer, provoke little or no immune re- as mucins. Normal mucins consist of recurrence of the cancer even after an
sponse, however. a protein core almost completely en- apparently successful primary therapy.
Yet even spontaneous cancers may veloped by a shell of sugar molecules. In principle, killing the few million can-
carry some tumor-speciÞc antigens that Many cancerous cells, most notably cer cells that remain after a primary
could arouse a reaction from the im- those associated with tumors of the gas- treatment should be easier than elimi-
mune system if other chemical signals trointestinal tract, lung or ovary, con- nating the hundreds of billions that ex-
are present. One highly potent trigger tain altered mucins whose cores are exist beforehand.
molecule is known as B7. When insert- posed. Workers have identiÞed peptides Despite the promise of such innova-
ed into the cells of a tumor, B7 can from the core proteins in mucins to tive techniques, new and improved vac-
convert deadly, uncontrollable cancer which T cells strongly respond. Vaccines cines against infectious disease contin-
cells into ones that T cells attack and constructed from those peptides may ue to be the most urgent and immediate
destroy. B7 is not itself an antigen, but be able to induce cytotoxic T cells to at- application of immunologic research. In
it evidently helps antigenic molecules tack the naked core proteins and there- this arena, the World Health Organiza-
in the tumor cell to activate T cells. by kill the cancerous cells. tionÕs Expanded Program on Immuniza-
The discovery of immunostimulating Devising cancer vaccines presents a tion ( EPI ) has stood out as a laudable
molecules such as B7 has renewed in- diÛcult challenge. Tumor cells have a triumph amid the generally troubled
terest in the possibility of developing great capacity to mutate, which allows global public health scene. With won-
anticancer vaccines. Such treatments them to avoid destruction by discard- derful help from UNICEF, the World
might be eÝective against malignant ing or changing their distinctive anti- Bank, Rotary International and the de-
melanoma, the cancer arising from pig- gens. Killing every single tumor cell, as veloping countriesÕ health authorities,
mented moles. These cancers contain a must be done to cure cancer, will not be EPI provides protection against six ma-
RECOGNITION
RECOGNITION AND
SIGNAL ONLY ACTIVATION SIGNALS
DESTRUCTION
OF CANCER CELL
CD28
T CELL
CD28
B7
CANCER B7
CELL
CANCER CELLS can elude attack by lymphocytes even if they the body to Þght tumors by inserting the molecule B7 into
bear distinctive antigens. That absence of immune response cancer cells (center ). When B7 engages CD28, a complemen-
may occur because cancerous cells lack the proper costimu- tary molecule on the surface of T cells, it generates a signal
latory molecules (left). Researchers are attempting to induce that instigates an assault on the cancer cells (right).

fections in monkeys. It will take several
years, however, to determine whether
any of the present clinical trials hold
real promise.
The AIDS crisis has so enhanced pub-
lic awareness of immunology that when
I attend social or business functions and
reveal that I am an immunologist, peo-
ple commonly respond, ÒOh, then you
must be working on AIDS!Ó They are of-
ten surprised to hear that immunology
is a vast science that predates the iden-
tiÞcation of AIDS by many decades.
And yet the interdisciplinary nature
of immunology has had, I believe, a sig-
niÞcant salutary eÝect on all the biolog-
ical sciences. When I was young, many
researchers worried that as the special-
ties and subspecialties bloomed, scien-
tists would discover more and more
about less and less, so that the research
enterprise would splinter into myriad
fragments, each bright and shiny in its
own right but having little connection
to the others.
Rather a new, integrated biology has
arisen, built on the foundation of molec-
ular biology, protein chemistry and cell
biology, encompassing Þelds as diverse
EMIL A. VON BEHRING (right) studied the eÝects of antitoxins that appear in the as neurobiology, developmental biolo-
bloodstream after an infection; he coined the term ÒantibodyÓ to describe them. gy, endocrinology, cancer research and
Von BehringÕs experiments on inducing immunity in laboratory animals led to the cardiovascular physiology. A fundamen-
development of an antibody serum to prevent diphtheria. In 1901 he received the tal Þnding made within one discipline
first Nobel Prize in medicine for that work. spreads like wildÞre through the others.
Immunology sits at the center of the
action. The cells of the immune system
jor diseasesÑdiphtheria, whooping tive. No generally available vaccine ex- constitute ideal tools for basic biological
cough, tetanus, poliomyelitis, measles ists for many common diseases, such as research. They grow readily in the test
and tuberculosisÑto over 80 percent pneumonia, diarrhea, malaria and can- tube, display a rich diversity of chemical
of the more than 100 million children cers caused by human papillomavirus receptors and manufacture molecules
born every year in the Third World. and glandular fever virus. Furthermore, of great speciÞcity and power; conse-
Last year EPI added hepatitis B vac- rich and poor countries alike face the quently, the lymphocyte is perhaps the
cine to its list, although cost considera- practical problems of delivering the vac- best understood of all living cells. More-
tions have limited the number of doses cine to those who need it and making over, immunology embraces many inter-
available. In many Asian and African sure that it is used. The World Health linked molecular and cellular systems
countries, 5 to 10 percent of the popu- Organization badly needs extra funds and considers how they aÝect the or-
lation become chronic carriers of the to sustain its marvelous thrust in re- ganism as a whole. As a result, the im-
hepatitis B virus; a signiÞcant propor- search and deployment. mune system has become an instruc-
tion of these acquire severe liver disease Devising a vaccine against AIDS is tive model of the life process. Enough
and Þnally liver cancer. An infant who one of the most urgent and daunting of the master plan has been revealed to
receives the vaccine at birth does not tasks facing immunology researchers. provide a sturdy springboard for future
become a carrier and is protected from There are now at least 10 million peo- research, but enough remains hidden to
the virus. Mass vaccination against hep- ple around the world infected with the challenge the most intrepid explorer.
atitis B is worthwhile even in Western human immunodeÞciency virus (HIV),
countries, not only because of the risk which causes AIDS; most of these peo-
faced by homosexual men but also be- ple live in developing countries. HIV FURTHER READING
cause many of these countries now in- manifests a dizzying capacity to mu-
A HISTORY OF IMMUNOLOGY. Arthur M.
clude signiÞcant Asian or African-de- tate, and it can hide from the immune Silverstein. Academic Press, 1989.
rived populations. system inside lymphocytes and scaven- IMMUNOLOGIC TOLERANCE: COLLABORA-
ger cells. Still, there are some encourag- TION BETWEEN ANTIGEN AND LYMPHO-
E
ncouraging though the trends are, ing signs that the virus can be defeat- KINES. G. J.V. Nossal in Science, Vol. 245,
an enormous amount remains to ed. HIV often lies dormant in humans pages 147Ð153; July 14, 1989.
be done in the realm of immuni- for years, which suggests that immune ESSENTIAL IMMUNOLOGY. Seventh edition.
zation. EÝective vaccines against sever- processes hold the virus in check for I . M. Roitt. Blackwell ScientiÞc Publica-
tions, 1991.
al forms of meningitis are not yet in long periods. Antibodies can neutralize
THE AUTOIMMUNE DISEASES. Noel R. Rose
widespread use. The available vaccines HIV, and cytotoxic T cells can kill at and Ian R . Mackay. Academic Press,
against typhoid, cholera, tuberculosis least some of the virus-carrying cells. 1992.
and inßuenza are only partially eÝec- Vaccines have prevented AIDS-like in-

How the Immune
System Develops
Environmental and genetic signals cue cells
as they di›erentiate into the many lineages that
recognize foreign antigens and fight o› invaders
by Irving L . Weissman and Max D. Cooper
T
he marvelous array of deftly in- The current understanding of how ly that some bone marrow cells can
teracting cells that defend the the various components of the immune give rise to progeny of several diÝerent
body against microbial and viral system develop is almost completely at typesÑbut not necessarily all. These
invaders arises from a few precursor odds with beliefs that researchers held parents can be deÞned by their indi-
cells that Þrst appear about nine weeks only three decades ago. We now know vidual characteristics and by the char-
after conception. From that point on- that all immune systems derive from a acteristics of their lineages (all cells
ward, the cells of the immune system relatively small number of progenitors arising from one precursor are said to
go through a continuously repeated cy- in the bone marrow and thymus. Be- belong to a single clone). Workers can
cle of development. The stem cells on fore the 1960s, immunologists thought grow cells from many diÝerent clones in
which the immune system depends all the diÝerent kinds of cells required culture to provide enough cells at each
both reproduce themselves and give for an immune response were produced stage of diÝerentiation for analysis.
rise to many specialized lineagesÑB locally in lymphoid organs such as the In 1961 Ernest A. McCulloch and
cells, macrophages, killer T cells, helper spleen, appendix and lymph nodes, James E. Till of the Ontario Cancer In-
T cells, inßammatory T cells and others. which are distributed throughout the stitute in Toronto found evidence that
The cells of the immune system are body. That view began to change as a a single cell of the proper kind could in
not isolated in a single space or arrayed result of animal experiments and clin- theory reconstitute an entire blood sys-
in the form of a single organ; instead ical observations of immune system tem. They injected bone marrow cells
they exist as potentially mobile entities, dysfunction. into irradiated mice and noticed that
unattached to other cells. This character- Perhaps the earliest of the pivotal many of the mice developed bumps on
istic is not only crucial to their function events leading to the modern theories their spleens. Each bump contained sev-
but also confers a boon on researchers, of immune cell origin were the atomic eral distinct cell types. The two workers
who can isolate immune cells in relative- bomb attacks on Hiroshima and Naga- and their colleagues showed that all the
ly pure form at every stage of diÝerenti- saki. Many people exposed to radiation cells in a bump were derived from a sin-
ation. Experimenters can thus deter- released by the explosions died 10 to gle progenitor. They proposed the exis-
mine the properties of cells and con- 15 days later from internal bleeding or tence of a relatively rare population of
struct cellular Òfamily trees,Ó or lineages. infection. Animal experiments conduct-
The information gained in this way ed to explore what happened to such ca-
serves biologists attempting to under- sualties revealed that whole-body radia-
stand the general subject of how cells tion kills the generative cells in blood- IRVING L. WEISSMAN and MAX D.
develop and diÝerentiate, a process forming and lymphoid organs. Without COOPER have been investigating the
development of the immune system for
that starts with a fertilized egg and cul- the cells responsible for clotting and for
more than 25 years. Weissman, a profes-
minates in the consummate complexity Þghting invaders, the body dies. sor of pathology, developmental biology
of an adult organism. Even more im- Investigators found that the radia- and biology at Stanford University, stud-
portant in the short run, this knowl- tion syndrome could be treated by in- ies T and B lymphocytes, the central cells
edge makes possible attempts to treat jecting a small sample of bone marrow of the immune system. His laboratory
the many diseases that can arise when cells from a genetically identical donor. was the Þrst to isolate stem cells in mice
immune cells either fail to develop nor- Further work with mice demonstrated and later collaborated in the isolation of
human stem cells. Cooper is a Howard
mally in the fetus or deviate from their that the entire blood and immune sys-
Hughes Medical Institute Investigator at
proper pattern of growth later in life. tems of mice that recovered from radi- the University of Alabama at Birming-
ation were derived from donor cells. A ham, where he charts the early develop-
fraction of the newly reconstituted bone ment of the immune system in verte-
marrow from these irradiated mice brates and practices clinical immunolo-
B LYMPHOCYTE prepares to enter a
could in turn save other mice exposed gy. He received a bachelorÕs degree from
blood vessel and leave the bone marrow, the University of Mississippi in 1954 and
where it was produced. Immune cells to radiation. Clearly, the bone marrow
contained cells capable both of diÝer- an M.D. from Tulane University in 1957.
mature in the thymus and in the bone Weissman received a bachelorÕs degree
marrow, then circulate through the body entiating into all blood cell lineages and
from Montana State University in 1961
and lymphoid organs such as the spleen of reproducing themselves. and an M.D. from Stanford in 1965.
and lymph nodes. Immunologists discovered fairly ear-

cellsÑhematopoietic stem cellsÑthat Clinical observations provided com- other blood cells). One consists of the B
could both reproduce themselves and plementary evidence for the existence cells, which originate in the bone mar-
also generate all blood cell types. of two lymphoid lineages. In some in- row and produce antibodies that bind
The establishment of the crucial part fants the thymus developed normally, to foreign proteins and mark them for
played by bone marrow cells was fol- but the bone marrow malfunctioned. attack by other cells. They act against
lowed by discovery of a similarly es- These children had lymphocytes in their extracellular pathogens such as bacte-
sential role for the thymus. Removal of peripheral tissues but suÝered from a ria. The other, the T cells, arises in the
the thymus from newborn mice com- congenital deÞciency of plasma cells. thymus. T cells handle such intracellu-
promised the development of lympho- Conversely, infants born without a thy- lar pathogens as viruses in addition to
cytes elsewhere in the body. (Lympho- mus but with normal bone marrow such intracellular parasites as tubercu-
cytes are white blood cells that attack produced plasma cells but only a small losis. T cells also secrete molecules
bacteria and other foreign matter.) The number of lymphocytes. known as lymphokines, which direct the
mice from which the thymus had been Studies of lymphoid malignancies reactivity of B cells, other T cells and oth-
removed experienced severe lifelong vealed the same developmental pattern. er parts of the immune system.
immunodeÞciency. Many kinds of lymphoid tumors in mice Once formed, cells of both types mi-
In another important group of ex- were found to originate in the thymus, grate to the spleen, lymph nodes and in-
periments, researchers removed a lym- and early removal of the organ prevent- testinal lymphoid tissues. There they can
phoid organ called the bursa of Fabri- ed the development of lymphomas else- encounter antigen, the molecular signa-
cius from chicks (the bursa plays the where. Meanwhile a diÝerent lymphoma ture of microbial or viral invaders, and
role in chickens that bone marrow does in chickens could be cured by removing be called into action. Lymphocytes con-
in humans). That operation did not af- the bursa of Fabricius. Apparently, the tinuously circulate through the bodyÕs
fect the same lymphocyte lineages that two lymphoid organs have distinct, es- vascular and lymphatic systems, stop-
removal of the thymus did; instead it sential functions. Each seems responsi- ping periodically in the lymphoid or-
stopped production of cells that ma- ble for a diÝerent class of immune cell. gans as they patrol for foreign antigens.
tured to become plasma cells, which se- By the late 1960s, it had become clear
A
crete antibodies. The chicks thus exhibit- that stem cells give rise to two broad lthough the existence of the stem
ed immunodeÞciency of a diÝerent kind. lineages of lymphocytes (as well as the cell was Þrst posited in 1961, re-
searchers made little progress
in identifying actual examples until the
OTHER BLOOD CELL LINES early 1980s. At that time, biologists es-
tablished speciÞc assays for B, T and
myeloid precursors. They could then
STEM CELL isolate bone marrow cells to determine
THYMUS BONE MARROW which surface proteins were present or
absent on particular clone-forming cells.
In mice, scientists in one of our labora-
tories (WeissmanÕs) found progenitors
for B, T and other blood cells in only a
THYMIC STEM CELL small fraction of the total population of
PRO-B CELL bone marrow cells, about one in 2,000.
These turned out to be stem cells.
The search for human stem cells re-
quired the same kinds of techniques
that had proved so useful in mice. In the
THYMIC TRANSITIONAL CELL course of this search, Joseph M. Mc-
Cune and his colleagues at Stanford
University developed a technique that
turned out to allow the testing of this
fraction of bone marrow cells to deter-
mine whether it contained true stem
IMMATURE T CELL PRE-B CELL
cells that could reproduce themselves.
McCune and his colleagues implanted
human fetal thymus, liver, bone marrow
and lymph nodes into a strain of mice
that had no immune system of their own.
They succeeded in establishing a func-
tioning human blood-forming and T
cellÐdeveloping system. Since doing this
work, McCune has founded a biotech-
nology company, SyStemix (with which
Weissman is associated).
HELPER INFLAMMATORY KILLER B CELL NATURAL Researchers at SyStemix injected can-
T CELL T CELL T CELL KILLER CELL didate human stem cells into these mice
and showed that they could thereby
reconstitute the blood-forming and im-
CELL LINEAGES of immune and blood cells all begin with the stem cell . Stem cells mune systems. Interestingly, the hu-
that diÝerentiate to generate B cells reside in the bone marrow, and those that pro- man-derived thymus cells also proved
duce T cells reside in the thymus. vulnerable to infection with the human

immunodeÞciency virus ( HIV ), which STEM CELL INTERLEUKIN-7
causes AIDS; the infection depleted the PRO-B CELL RECEPTOR
same kind of circulating human im- INTERLEUKIN-7
mune cells that are destroyed in AIDS. SURROGATE
Stem cells diÝerentiate into B or T lin- LIGHT CHAIN
eages in response to cues (many of them HEAVY CHAIN
still unknown) from their environment.
This phenomenon can be seen in the LIGHT CHAIN
PR
embryo, where the distinction between ALPHA AND
E-
BETA CHAINS
B
B and T cells becomes clear. Early in fetal
CE
life, stem cells migrate from the blood- COMPLETE
LL
ANTIBODY
S
forming organs to the thymus in dis-
tinct waves. Once in the thymus, these
cohorts of stem cells divide and diÝer-
entiate. They give rise to successive STROMAL CELL
kinds of T cells that populate the lining
(epithelium) of the skin, various oriÞces DEVELOPMENT OF B CELL starts with
(such as the mouth and vagina) and the stem cells in the bone marrow. These
organs that connect with them (the gas- cells reproduce themselves and also
trointestinal tract, uterus and so forth) spawn lineages that pass through pro-B
before producing the later generations and pre-B stages to become B cells. Stro-
that circulate to the lymphoid organs. mal cells generate chemical signals that
These cells can be distinguished by B cells must receive to develop success-
the molecules (known as TCRs, for T fully. The cells reshuÜe their antibody
cell receptors) they carry on their sur- genes and then produce the light and
face. Moreover, they appear to be pro- heavy chains that make up a receptor. B
cell development culminates in the plas-
duced in a very speciÞc order. Early B CELLS
ma cell , which secretes antibodies to
cells carry receptors whose components
stimulate further attack of invaders by
consist of so-called gamma and delta the immune system.
chains, whereas later ones carry recep-
tors made of alpha and beta chains.
In mice, for example, the Þrst wave and red blood cells are formed. Early in
of cells appears between the 13th and embryonic life they are produced in the
15th days of gestation and carries a TCR liver, but later the stem cells migrate to
type known as gamma 3. These cells the bone marrow.
emigrate to the skin, where they may B cells generated in the fetal liver may
serve as sentinels that recognize and de- diÝer from those formed later in the
stroy skin cells that have become in- bone marrow. The earlier cells make an-
fected, cancerous or otherwise damaged. tibodies that can bind to a wide variety
The next wave, which appears be- of antigens but with relatively low af-
tween the 15th and 20th days of gesta- Þnity. The later cells, in contrast, carry PLASMA
CELL
tion, takes up residence mainly in the antibodies that react much more strong-
lining of the reproductive organs in ly but with only one or two antigens. It
females and in the epithelium of the appears that the mechanisms that B
tongue in both sexes. These cells carry a cells employ to produce a full range of ronment. When the late Cheryl Whit-
TCR called gamma 4. Subsequent waves antibodies come into play only near the lock and Owen N. Witte of the Universi-
emigrate for the most part to the spleen time of birth. Each B cell in the mature ty of California at Los Angeles Þrst dis-
( gamma 2) and to the lining of the in- organism bears on its surface a unique covered how to raise B cells in long-term
testinal tract ( gamma 5). antibody receptor complex that it uses cultures, they found that stromal cells
The Þrst and second waves of these to recognize a speciÞc antigen. (large, veil-like cells in the bone mar-
cells are made only in the fetal thymus. row) are essential for culturing B cells.
S
Later in development and throughout cientists have learned a great deal The stromal cells interact with progeni-
life, the stem cells that settle in the thy- about how a few stem cells can tor B (pro-B) cells by means of surface
mus diÝerentiate predominantly into T produce this enormous diversity molecules. They also make soluble pro-
cells carrying alpha-beta receptors, the of B cells. To trace the process, experi- tein factors (such as interleukin-7 ) that
so-called helper and killer T cells. menters have learned to recognize the bind to receptors on the pro-B and pre-
The order in which stem cells gener- many surface proteins that cells express B cells, signaling them to divide and to
ate these waves of progeny matches the as they divide and progress along the B diÝerentiate.
order in which DNA encoding the dif- cell path of diÝerentiation. These molec- As they divide, pro-B cells begin the
ferent gamma-chain types appears on ular markers are a primary means by process that will culminate in the ex-
the TCR gene. It appears that the stem which cells interact with nearby cells; pression of a unique antibody receptor
cells Òread outÓ a development program consequently, a B lymphocyte will dis- complex. First, they rearrange the gene
that depends on the age of the animal. play diÝerent proteins as it matures. fragments that encode the light and
Early development of the B cell sys- The signals that tell a stem cell daugh- heavy immunoglobulin chains that will
tem proceeds along similar but less ter to enter the B cell pathway instead form an antibody molecule. These genes
complex lines. The stem cell progeny of becoming a red cell or another type are actively transcribed as soon as re-
that enter the B cell path do so in the of white cell appear to come primarily arrangement is complete.
same tissues in which other white blood from other cells in the immediate envi- The order in which the gene frag-

ments begin functioning is crucial to ever, light-chain genes are rearranged their light-chain genes early, thus pro-
the later development of the B cell. The Þrst. Hiromi Kubagawa of the Universi- ducing nonsurrogate light chains at an
genes directing the construction of the ty of Alabama at Birmingham uncov- early enough stage to substitute for the
heavy chains are typically shuÜed and ered this fact when he infected early B missing receptor.
begin functioning Þrst. ( The cells are lineage cells with Epstein-Barr virus, cre- Other B cells die not because they fail
then called pre-B cells.) The genes en- ating a self-reproducing culture whose to receive a kiss of life but rather be-
coding light chains are then rearranged immunoglobulin genes were frozen at cause they carry a kiss of death. Some
and also start functioning [see ÒHow the that early stage of development. He rearrangements of a B cellÕs gene frag-
Immune System Recognizes Invaders,Ó found pre-B cells that had rearranged ments will make antibodies that react to
by Charles A. Janeway, Jr., page 72]. only their light chains; their joints con- the bodyÕs own cells. Lineages carrying
These cells also commence to pro- tained new sequences, suggesting that these antibodies must be eliminated.
duce two additional proteins, immuno- the shuÜing had taken place before The negative selection process begins
globulins alpha and beta (Ig alpha and transferase activity stopped. when newly formed B cells Þrst inter-
beta), which span cell membranes. The act with their environment. Self-reactive
T
immunoglobulin heavy chains and their hus far we have been discussing cells rapidly encounter large quantities
light-chain partners associate with Ig B cell development as if it were of antigen to which their antibodies
alpha and Ig beta to form an antigen a path that all cells follow to the can bindÑmolecules on the surfaces of
receptor unit that migrates to the cell end once they have embarked on it. That their neighbors. If the binding is strong
surface. There it can interact with anti- is not the case. When Dennis G. Os- enough, the antibody receptor will trans-
gens and send appropriate signals back mond, now at McGill University, count- mit signals into the cell, causing it to
to the nucleus. Cells that reach this stage ed the number of cells in the pro-B, pre- commit suicide in what is known as
of diÝerentiation are called B cells, and B and B stages in mouse bone marrow, apoptosis (programmed cell death). Im-
they enter the bloodstream en route to he found that half or more of the cells mature B cells that do not react strong-
peripheral tissues. apparently die during the pre-B stage. ly to self-antigen survive and mature.
The B cell population can respond to Researchers theorize that pre-B cells Later they can respond to antigenic
an extremely diverse range of antigens. die unless they receive a survival sig- stimulation from nonself molecules.
To guide the manufacture of its light nalÑsome kind of molecular messen- This general principle was Þrst demon-
and heavy chains, each cell selects one ger from nearby cells. The Òkiss of lifeÓ strated in chicks and mice treated with
combination of its gene fragments out may bind to a receptor that appears on antibodies against the IgM receptors on
of more than a million possibilities. In the surface of late-stage pre-B cells. This immature B cells: early administration
addition, each developing cell can mod- receptor is composed of heavy chains of receptor antibodies aborted B cell
ify the gene-splicing sites to further in- paired with a so-called surrogate light- development, whereas doses given lat-
crease variability in the DNA encoding chain complex. The surrogate complex, er stimulated it. Early in development
the antigen-binding site. AndÑas if that unlike the antigen receptors produced the signal transmitted by the antibody
diversity were still insuÛcientÑthe cell by mature B cells, is encoded by genes receptors induces apoptosis by activat-
can even insert new nucleotide sequenc- that do not require rearrangement for ing enzymes that cleave nuclear DNA.
es at the joint between fragments as it their expression. Virtually no reactive B cells survive to
splices them together. When Daisuke Kitamura and his col- maturity.
The cell rewrites its genetic code by leagues at the University of Cologne Clones that survive the selection pro-
means of the enzyme terminal deoxynu- prevented the expression of these re- cess can migrate to the peripheral lym-
cleotide transferase. This enzyme is ex- ceptors, they found that the produc- phoid tissues. There they Þnally begin
pressed only in the nucleus of pro-B tion of B cells fell to less than a tenth the working phase of their life history.
cells, where heavy-chain gene rearrange- its normal level. The B cells that survived Eventually, after being stimulated by
ment usually occurs. Sometimes, how- may have been ones that rearranged both antigens and T cells, they may re-
CLASS II
MHC
KILLER
POSITIVE
SELECTION
AUTOIMMUNE DEAD
T CELLS CELL
CLASS I
MHC
HELPER
POSITIVE
SELECTION
STEM CELL
NO POSITIVE SELECTION
CD4 CD8 T CELL RECEPTOR DEAD CELL
T CELLS are produced in the thymus by stem cells that have called helper T cells, and those whose receptors bind to class
migrated from the bone marrow. The maturing cells go II MHC molecules will for the most part become killer T cells.
through stages that can be distinguished by the surface pro- ( MHC is a molecule that cells use to present antigens to T
teins they express. Those whose receptors bind to class I cells.) Those that do not bind to any MHC or that bind to the
MHC molecules on adjacent cells will eventually become so- bodyÕs own antigens will die.

turn to the bone marrow to undertake
their Þnal maturation into antibody-se-
creting plasma cells. CAPILLARY
T
he T cell pathway is somewhat STEM CELLS
more complex. Stem cells in the
thymus that commit to this line BONE
of development may eventually mature
into several diÝerent kinds of T cells,
including helper and killer.
Developing T cells pass through a PRO-B CELLS
number of winnowing points. The Þrst
challenge tests their ability to recognize STROMAL CELL
antigens presented to them by other
cellsÑan essential attribute for a func-
tioning immune cell. Molecules of the
so-called major histocompatibility com- PRE-B CELLS
plex ( MHC ) hold fragments of protein
antigens for presentation to T cells.
MHC molecules are divided into two
types, class I and class II. Developing
cells in the thymus scan their environ-
ment to determine whether they rec-
SINUSOID
ognize any self-MHC. If they can, they
survive; if not, they die.
Once the maturing T cells have sur-
vived this challenge, the next step is
the destruction of the cells bearing re-
ceptors that react too well to the bodyÕs STROMAL CELL
own tissues ( just as with B cells). Ulti-
CENTRAL SINUS
mately, only T cells with receptors that
can recognize both foreign peptides
and self-MHC survive to leave the thy-
B CELLS ENTERING CIRCULATION
mus and take up residence throughout
the body.
Immunologists trying to Þll in the
BLOOD SUPPLY
details of this picture started by trac- TO BONE MARROW
ing the line of descent from stem cell
to emigrant T cell. To test lineage rela-
tionships, researchers used stem cells
and progeny bearing clearly recogniz-
able markers. They introduced these INTESTINES
cells, at diÝerent stages of maturation, BONE MARROW LYMPH NODES
into the thymuses of mice whose cells
SPLEEN
bore no such markers. By waiting hours
or days, the workers could then deter-
mine what oÝspring their transplants
had spawned. PEYER’S PATCHES
Thymic cells transplanted at the earli-
est stage of development express virtu-
CIRCULATORY SYSTEM
ally none of the common T cell markers
on their surfaces: little or no CD4 co-re- BILLIONS OF CELLS
PER DAY
ceptor protein and neither T cell recep-
tor structures nor the co-receptor pro-
tein known as CD8. (CD8 binds to class IMMUNE SYSTEM CIRCULATION commences in the bone marrow, where B cells
I MHC, whereas CD4 binds to class II mature (top). Cells leaving the marrow (bottom) take up residence in the spleen,
MHC.) A day after transplantation, how- lymph nodes and PeyerÕs patches of the intestines. B and T cells circulate continu-
ever, these large cells have reproduced ously through the body, patrolling for antigens that could signal infection.
themselves and given rise to other large
cells bearing CD8 but no CD4 or TCR
(human thymic cells at a similar stage ment may explain why HIV so virulent- ing their surface proteins, they are also
of development express CD4 but not ly depletes T cells: the virus is believed rearranging their genes to produce T
CD8 or TCR). These cells in turn divide to bind to CD4 molecules, and so it may cell receptors. In the mouse, for exam-
into progeny that bear CD4, CD8 and attack these primitive thymic progeni- ple, assembly and surface expression of
small amounts of TCR. This stage is the tors, cutting oÝ the entire line of their TCR chains begin at or before the stage
Þrst at which a T cell progenitor express- progeny [see ÒAIDS and the Immune at which they express both CD4 and
es TCR on its surface. The expression System,Ó by Warner C. Greene, page 98]. CD8. These progenitors are poised to
of CD4 at these early stages of develop- While the cells are dividing and chang- interact with MHC-bearing cells in the

Dendritic cell
presents antigen
to T cells
T CELL
Other B cells make
antibodies that bind
instead to the body’s
DENDRITIC own proteins; they die
CELL
KILLER
T CELL
HELPER
T CELL
CYTOKINES
B cells proliferate and
RELEASED mutate; some make
Some mature into antibodies that bind
killer cells strongly to the foreign
antigens and proliferate
further
Others become helper
cells and stimulate
B cells to mature into
plasma cells PLASMA CELL
B CELL
IMMUNE RESPONSE takes place in lymph nodes, where T and T and B cells to produce both killer T cells (left) that leave
B cells congregate. Dendritic cells present antigen to T cells the lymph node in search of infected tissue and plasma cells
(center). These T cells, called helper cells, interact with other (right) that secrete antibodies.
thymus. Most of those binding to class Most of the remaining stages in the de- immune responses. Yet other B cells
I MHC molecules will become killer velopment of both kinds of cells take become so-called memory cells. They
cells. Those binding to class II develop place once their receptors have been will not participate immediately in the
mainly into helper cells, although some triggered by encounters with a foreign bodyÕs defense but rather will retain a
also become killer cells. (Cells that do substance. molecular record of past invaders to
not bind to any MHC shrink and die.) Inside the lymphoid organs, T and B speed response in the future.
Once they have become committed cells that have matured but are not yet
A
to one path, the intermediate-stage cells engaged in immune responses reside in lthough the immune response is
shut down production of the receptor separate domains. After immune cells orchestrated within the lymphoid
type they will no longer use (either CD8 have been stimulated by antigens, the organs, lymphocytes do not
or CD4) and express additional TCR. cells that will participate in antibody merely reside there waiting to be called
They also acquire Òhoming receptorsÓ production undergo a complex set of in- on. James L. Gowans and his colleagues
that enable them to leave the blood- teractions to form new structures called at the University of Oxford demonstrat-
stream and enter the peripheral lym- germinal centers. ed in 1959 that immune cells circulate
phoid organs. Finally, they leave the Three kinds of cells congregate in between the bloodstream and the lym-
thymus. these germinal centers at the interface phoid organs. This traÛc provides each
Not all potential T cells, of course, com- between T and B domains: activated lymphoid organ with a rapid sampling
plete this line of development. Some un- helper T cells, B cells and dendritic cells, of all lymphocytes that might possess
dergo negative selection, in which sig- a type of antigen-presenting cell. A few receptors for the foreign antigens cur-
nals from other cells (those carrying self- B cells proliferate in response to the an- rently attracting the bodyÕs attention.
antigen attached to self-MHC ) cause tigen; soon their clones make up most Circulating lymphocytes pass into lym-
apoptosis. Cells in the thymus can sup- of the population in the centers. phoid organs by means of a specialized
posedly trigger positive or negative se- While they are proliferating, the B kind of blood vessel, the HEV (high en-
lection depending on the layer of prim- cells also diÝerentiate and mutate. They dothelial venule, named for the blocky
itive fetal tissue from which they derived: modify the DNA in their gene fragments surface of its walls). Only lymphocytes
endoderm, mesoderm or ectoderm. The to make antibodies similar to those can pass through the HEVs; they ex-
thymus is unusual among lymphoid or- that bound to the antigen in question press homing receptors that match
gans in containing cells from all three (but perhaps even more reactive). Some counter receptors on the HEV walls.
sources. of the B cells interact with helper T These receptors appear to come in two
At this point, the cellular pathways cells and then give rise to plasma cells. varieties: one that homes in on lymph
that diverged when particular stem cells There are several kinds of plasma cells; nodes, and another that matches sur-
began diÝerentiating into B or T cells the antibodies they generate all react to face molecules expressed by lymphoid
come together in the peripheral tissues. the same antigen but elicit diÝerent organs in the gastrointestinal tract.

When T and B cells are activated, they dividing. AÝected infants lack T and B To overcome this complex defense,
quickly stop producing their usual hom- cells and so cannot defend themselves the malignant sequence of mutations
ing receptor molecules and revert to against infection (hence the term Òse- must usually begin in the stem cells or
making another integrin that they pro- vere combined immunodeÞciency dis- their immediate clonal progeny to per-
duced early in their development. This ease,Ó or SCID). Armed with an under- mit the gradual evolution of a malig-
molecule binds to the vascular-cell adhe- standing of the function of stem cells, nant clone of cells that can elude all
sion molecule, VCAM-1 (which also ap- Robert A. Good and his colleagues at these monitoring mechanisms. Even if
pears on stromal cells in the bone mar- the University of Minnesota Medical a person inherits a gene predisposing to
row and epithelial cells inside the thy- School showed that SCID could be cured malignancy, the aÝected cells must ac-
mus). As a result, these activated cells no by transplanting compatible bone mar- quire additional mutations during their
longer pass through the walls of normal row from a healthy sibling, but unfor- life span to become malignant. Once
lymphoid-organ HEVs when they are tunately most patients lack a suitable one mutation favoring growth or sur-
released into the bloodstream. Instead donor. Michael R. Blaese and his co- vival occurs, however, the odds increase
they home in on blood vessels serving workers at the National Cancer Insti- that a cell will persist long enough to
infected, inßamed and antigen-bearing tute, however, have succeeded in insert- suÝer another growth-promoting mu-
tissues. The vessels in these inßamed ar- ing a functional ADA gene in deficient T tation and thus a third or fourth.
eas may express VCAM-1, whereas those lymphocytes, thereby repairing one es- This principle can be seen in follicu-
elsewhere do not. By returning to a cel- sential limb of the immune system. lar lymphoma, an extremely slow grow-
lular expression of their early develop- During the Þrst half of this year, re- ing malignancy of B cells in germinal
ment, the cells fulÞll their ultimate task. searchers found the genes responsible centers. Virtually all follicular lympho-
for three other immunodeÞciency dis- mas contain a translocation of a gene
T
his simpliÞed version of how the eases. All are on the X chromosome and called bcl-2, which produces a messen-
cells of the immune system de- aÝect boys (who have only one copy of ger that prevents programmed cell death.
velop and mature does not tell the XÕs genetic information), but each The gene is usually turned oÝ when an
the entire story. For example, a number aborts immune system development at activated B cell fails to recognize anti-
of other adhesion molecules are in- a diÝerent level. One, a mutation in a gen or reshuÜes its mini-genes so as
volved in interactions between lympho- protein kinase gene essential for trans- to make self-reacting antibodies, but in
cytes and endothelial or stromal cells. mitting signals for pre-B cell growth and follicular lymphoma cells it resides
Indeed, researchers still have much to development, causes a gross deÞcit of next to an antibody gene that is turned
learn about the means by which cells mature B cells and the antibodies they on in B cells and so remains active
receive the signals that cause them to secrete. Another is the consequence of indeÞnitely.
undergo programmed death, to contin- a mutation in the gene for one of the The multistep path to malignancy
ue living or to grow and diÝerentiate. three chains that make up the receptor may also explain why B cell malignan-
One important question is how stem for the growth factor interleukin-2. This cies are four times as common as those
cells choose between reproducing them- defect sabotages the development of involving T cells. Stem cells in the bone
selves and producing oÝspring commit- helper T cells, which in turn prevents B marrow produce B cells throughout life
ted to a particular lineage. This problem cells from maturing into plasma cells. (and thus have many years over which
is of more than theoretical signiÞcance: The third disorder to be elucidated is to accumulate mutations). Most T cells,
if stem cells prove useful in the restor- caused by a defect in the gene encoding in contrast, are produced early in life;
ation of congenital or acquired immuno- the surface molecules through which T the thymus withers as people age, leav-
deÞciencies, methods that increase their and B cells interact. Boys in whom the ing fewer thymic stem cells and their
numbers either in the test tube or in the CD40 molecule or its receptor is mal- offspring to mutate.
body might improve patientsÕ chances formed produce only IgM antibodies; Once developmental and molecular
for recovery. Stem cells are also an obvi- they lack the signal that causes B cells biologists unravel the signals that guide
ous target for gene therapy that might to divide and make high-aÛnity anti- stem cells and their intricate lines of
either replace a defective gene or en- bodies of other classes. progeny, they may be able to manipu-
dow the cellsÕ progeny with abilities to IdentiÞcation of these genes could late the development of the immune
survive in a hostile environment, such lead to gene replacement therapy for system from without. Clinicians will then
as a body carrying HIV. these deÞciencies. These three gene de- be able to strengthen responses to in-
In addition, as researchers under- fects were discovered almost simulta- vaders, mitigate the damage that im-
stand more fully the path from stem cell neously by several groups of investiga- mune cells do to self, and correct or elim-
to activated B or T cells, they will make tors; knowledge of the development and inate those cell lines that would other-
headway in treating diseases where that function of the immune system may wise propagate families of malignancy.
development goes dangerously wrong. have reached a level at which the genet-
Inherited or acquired defects in genes ic basis for other immune disorders
essential for the growth and diÝeren- may soon also be found. Consequently,
tiation of immunocompetent cells can clinical beneÞts may accrue rapidly. FURTHER READING
result in immunodeÞciency or lym- Although lymphoid malignancies also HOW THE IMMUNE SYSTEM LEARNS ABOUT
phoid malignancies. result from genetic malfunctions, they SELF. Harald von Boehmer and Pawel
Inherited defects can block develop- diÝer in a number of ways from immu- Kisielow in ScientiÞc American, Vol. 265,
ment of T or B cells at many diÝerent nodeÞciency diseases. Most important, No. 4, pages 74Ð81; October 1991.
stages, depending on the product of the malignancy requires the accumulation THE STEM CELL. David W. Golde in Scien-
gene in question. For example, a defect of several mutations, all of which favor tiÞc American, Vol. 265, No. 6, pages
in the gene encoding the enzyme adeno- excessive cell growth and survival at 86Ð93; December 1991.
LYMPHOCYTE DEVELOPMENT. Klaus Ra-
sine deaminase (ADA) allows toxic meta- the expense of maturation and natural
jewsky and Harald von Boehmer in Cur-
bolic products to accumulate in the bone death. Complex multicellular organ- rent Opinion in Immunology, Vol. 5, No.
marrow and thymus, preventing lym- isms have evolved many checkpoints 2, pages 175Ð176; April 1993.
phocytes from synthesizing DNA and for monitoring cell growth and survival.

How the Immune System
Recognizes Invaders
Cells of the immune system recombine gene fragments
to create the millions of receptors needed to identify and attack
the myriad pathogens encountered throughout life
by Charles A. Janeway, Jr.
T
hirty-six years ago an article enti- ease, the mechanisms of recognition ment can also kill cells and bacteria by
tled ÒAgammaglobulinemiaÓ ap- and response are the same. Recogni- punching pores in their lipid membrane.
peared in this magazine. One of tion mechanisms are therefore crucial The holes allow water to rush in, a pro-
the authors was my father. In the piece, to understanding how the immune sys- cess that destroys the cell. Complement
he described an illness resulting from a tem works and how it fails. protects against such diseases as bac-
defect in the bodyÕs defenses against In this article, I shall describe the two terial meningitis and gonorrhea.
infection, a failure in the immune sys- main systems by which the body iden- Yet this powerful attack system does
temÕs mechanism for detecting patho- tiÞes foreign material. The Þrst is the not destroy our own cells. Unlike mi-
gens. His work and that of Ogden Bru- innate immune systemÑinnate in the crobes, our cells are equipped with pro-
ton in identifying the Þrst known immu- sense that the body is born with the teins that inactivate complement. Thus,
nodeÞciency disease helped to break a ability to recognize certain microbes at this simplest of levels, innate immu-
path that has led to a deep and useful immediately and to destroy them. The nity distinguishes the molecules that
understanding of how the immune sys- second is the adaptive immune system, make up the body, called self, from all
tem recognizes and distinguishes the in which antibodies play a leading role. other molecules, or nonself.
molecules of the body from those of an The receptors used in the adaptive im- Not all pathogens are so easily dis-
invading bacterium, virus or parasite. mune response are formed by piecing posed of by the complement system.
People who have agammaglobulin- together gene segments, like a patch- Some have devised ways of avoiding at-
emia cannot make antibody molecules. work quilt. Each cell uses the available tack by complement. The bacteria that
These specialized proteins, found in pieces diÝerently to make a unique re- cause pneumonia and strep throat have
the blood and extracellular ßuid, nor- ceptor, enabling the cells collectively to capsules, coats made up of long chains
mally bind to the bacteria or viruses recognize the infectious organisms con- of sugar molecules (polysaccharides).
that cause infections and serve as a sig- fronted during a lifetime. Understanding These capsules prevent complement
nal to the attacking molecules and cells the genes, molecules and cells that make from acting directly on the bacteria.
of the immune system. The ability of up the immune system has enabled The innate immune system has two
molecules such as antibodies to identify researchers to determine the etiology ways of coping with these types of bac-
foreign molecules and so to guide the of diseases, including agammaglobulin- teria. First, throughout the tissues of the
bodyÕs defenses confers important ad- emia, and to start work on cures. body are the large phagocytes called
vantages. It enables us to eliminate in- macrophages. Macrophages have recep-
O
fections, to resist reinfection and to be ur innate immune system can tors for some of these polysaccharides,
protected by vaccination. destroy many pathogens on Þrst and they use these receptors to bind to
Some of these same mechanisms, un- encounter. An important com-
fortunately, can trigger disease instead ponent of the innate response is a class
of controlling it. The immune system of blood proteins known as comple-
might, for example, react to a harmless ment. Their name comes from their CHARLES A. JANEWAY, JR., is profes-
foreign substance, such as pollen, pro- ability to assist, or complement the ac- sor of immunobiology and biology at
ducing allergy. Events can take a more tivity of, antibodies in Þghting infec- Yale University and an Investigator at the
Howard Hughes Medical Institute at Yale.
serious turn when an immune attack fo- tion. Discovered by the Belgian bacteri-
He studied at Harvard University, earning
cuses on the bodyÕs own tissues, leading ologist Jules Bordet in 1900, comple- a B.A. in chemistry and, in 1969, an M.D.
to an autoimmune disease. But wheth- ment can act in many ways. One type degree. He trained in medicine at Peter
er they contribute to health or to dis- of complement protein, when chemi- Bent Brigham Hospital in Boston and in
cally stimulated, can bind to any pro- immunology at the National Institute for
teinÑthose on bacteria as well as those Medical Research in England, the National
on our own cells. The bound protein Institutes of Health and Uppsala Univer-
T CELLS ( yellow), a kind of lymphocyte, sity in Sweden. Janeway has been on the
use special receptors on their surface to triggers the activity of the other com-
Yale faculty since 1977. With Paul Trav-
detect an infected macrophage (blue). plement molecules. These bound mole- ers of Birkbeck College, University of Lon-
These T cells represent only part of the cules attract phagocytes, amoebalike don, he has written a textbook on immu-
repertoire the immune system has to cells that engulf and digest microbes nobiology, to be published next year.
recognize pathogens. wearing a complement coat. Comple-

1 One type of complement 1 After detecting an infection, 1 B cells are activated if they
molecule, called C3, can a macrophage secretes bind to the bacterium and are
bind to any protein, such interleukin-6 stimulated by a so-called helper
as those on bacteria. Self- T cell
BACTERIUM
cells are protected by proteins
that inactivate this molecule MACROPHAGE B CELL
INTERLEUKIN-6 BACTERIUM
COMPLEMENT C3
HELPER
T CELL
BACTERIUM 2 Carried through the
bloodstream, interleukin-6
reaches the liver, causing
it to secrete mannose- 2 The binding stimulates the
binding protein B cell to proliferate and to
secrete antibodies
ANTIBODY
MANNOSE-
BINDING
LIVER
PROTEIN
B CELL
2 Once bound to the microbe,

the C3 molecule causes other
complement molecules to
bind to the bacterium 3 The antibodies bind to the
3 Mannose-binding protein bacterium and activate a comple-
binds to the capsule of the ment protein called C1q, which
bacterium. This protein then activates other complement
triggers the complement cascade molecules
C1q
COMPLEMENT
COMPLEMENT
COMPLEMENT ACTIVITY can be triggered in three ways. Com- as a result of infection can also activate complement (right).
plement can act directly on bacteria (left), or it can be activat- Complement then kills the bacteria or recruits other immune
ed by mannose-binding protein (center ). Antibodies produced system cells, such as phagocytes.
and ingest bacteria. Second, macrophag- means to evade the inherited immune cytes, or B cells for short, manufacture
es that meet bacteria can secrete inter- defenses of humans and other species antibodies and display them on the cell
leukin-6, a protein that in turn stimu- that evolve more slowly. To compen- surface. The antibody then serves as a
lates the liver. Interleukin-6 instructs the sate, vertebrates have a unique strategy receptor. Each B cell makes a diÝerent
liver to secrete a new protein, one that of immune recognition: adaptive immu- receptor, so that each recognizes a dif-
binds to sugar residues called mannose. nity. Adaptive immunity enables the body ferent foreign molecule. Armed with
These residues protrude from the bac- to recognize and to respond to any mi- these receptors, the B cells act as sen-
terial capsule. After this mannose-bind- crobe, even if it has never faced the in- tries, always on the lookout for mi-
ing protein binds to the bacteria, it vader before. crobes. If a B cell Þnds such an intrud-
changes its shape so that it activates Adaptive immunity operates by the er, it divides rapidly. Because all the
the complement cascade and turns on process of clonal selection, an idea for- daughter cells come from one parent,
phagocytes. In this way, mannose-bind- mulated in the 1950s by Sir Frank Mac- they are known as a clone (hence the
ing protein tells the body which parti- farlane Burnet of the Walter and Eliza term Òclonal selectionÓ). All the cells in
cles must be bound. Hall Institute of Medical Research in each clone have the same receptor.
Innate immunity, however, cannot Australia and now widely accepted. In These cloned B cells then differentiate
protect against all infections. Microbes clonal selection, cells of the adaptive into cells that secrete antibodies, which,
evolve rapidly, enabling them to devise immune system, known as B lympho- like the B cell receptor, bind to the mi-

crobes. Once ßagged as foreign by the or ßuid component, of the blood. Be- These cells can be rapidly reactivated
antibodies, the microbes are removed cause this new antibody is speciÞed by when the same types of microbes enter
from the body by phagocytes and by the genes that created the receptor on the body, and their antibody products
the complement system. the original B cell, it has the identical prevent a recurrence of the disease. ( In
A critical question in understanding speciÞcity. But a B cell and its progeny contrast, the innate system does not
adaptive immunity is how B lympho- can produce a diÝerent kind of varia- discriminate one microbe from another
cytes generate so many diÝerent recep- tion on the antibody molecule. It can and so aÝords neither more nor less
tors. More speciÞcally, how could the do this by altering the so-called con- protection after an infection.)
millions of diÝerent receptors neces- stant part of the heavy chain, again by The beneÞts of adaptive immunity
sary to recognize all microbes be en- rearranging genes. This second type of are partially oÝset by two drawbacks.
coded in a limited genome? A person gene manipulation creates antibodies First, it takes more than Þve days to
has only about 100,000 genes, but the that go to diÝerent places in the body. develop an antibody response, given
10 trillion B cells in an individual can These antibodies still recognize the that the B cells need to proliferate and
make more than 100 million distinct same antigens. After binding to a mi- differentiate before they can make an-
antibody proteins at any one time. We crobe, these antibody types can begin tibodies. The body must rely on the in-
obviously cannot inherit the genes nec- the complement cascade, activate phago- nate immune system to hold infections
essary to specify all these proteins. cytes or cause allergic reactions. in check during this period. Second, be-
The answer was discovered in recent Adaptive immunity also is the source cause any large molecule, such as a
years, as investigators identiÞed the of immunologic memory. That is, we protein or a polysaccharide, can be rec-
genes that encode antibodies and B cell resist infections we have already expe- ognized by an antibody, the adaptive
receptors. One key was discovered in rienced far more eÛciently and force- immune system on occasion makes an-
1976 by Susumu Tonegawa, then work- fully than we do infections faced for the tibodies against the bodyÕs own cells.
ing at the Basel Institute for Immunolo- Þrst time. We have this memory be- These antibodies activate complement
gy. He showed that antibody genes are cause the body retains lymphocytes so eÛciently that the system that pre-
inherited as gene fragments. These frag- that responded in the initial infection. vents complement from attacking the
ments are joined together to form a
complete gene only in individual lym-
phocytes as they develop. HEAVY CHAIN LIGHT CHAIN
The joining process itself generates
still more diversity. In 1980 Fred Alt and
David Baltimore of the Massachusetts
Institute of Technology showed that
the enzymes that combine gene seg-
VARIABLE
VARIABLE
HEAVY
ments add random DNA bases to the CHAIN LIGHT
ends of the pieces being joined. As a CHAIN
result, new genes, each encoding a pro-
tein chain, are formed. Further diversi-
DISULFIDE
ty results from the assembly of protein BOND
)
EN
chains into a complete receptor. Anti-
AN AIN
G
V DOMAIN
bodies are made from two pairs of pro-
TI
tein chains: a heavy chain and a light TO OM
DS D
IN V
chain. The heavy chains are connected

DIVERSITY
to form a Y, with the light chains locat-

(B
ed on the upper branches, alongside the

COMPLEMENT AND PHAGOCYTES)
heavy chains. Each B cell produces just JOINING

DNA REARRANGEMENT
DNA REARRANGEMENT
one kind of light chain and one kind of

C DOMAIN (ACTIVATES
heavy chain, so that each B cell makes a

unique antibody receptor. In fact, 1,000
JOINING
diÝerent chains of each type can in

theory form a million combinations. All
these random joining processes can
create more distinct antibody mole-
CONSTANT
cules than there are B cells in the body.

As if these processes did not gener-
ate suÛcient diversity, the genes for RNA
receptors of B lymphocytes mutate ex- RNA
CONSTANT
C DOMAIN
tremely rapidly when the B cell is acti-

DNA
vated by binding to a foreign substance
or antigen. These ÒhypermutationsÓ cre- ANTIBODY
ate additional receptors. In eÝect, the
immune system is constantly experi-
menting with slight variations on suc-
cessful receptors in pursuit of an opti- DNA
mal immune response. ANTIBODY MOLECULE is made up of a pair of heavy chains and a pair of light
Once a B lymphocyte binds antigen chains. The chains are encoded by genes that consist of diÝerent DNA segments.
to its receptor, it diÝerentiates and se- These segments rearrange to make genes for chains that are diÝerent in each B
cretes antibody moleculesÑa soluble cell. The joining is variable, so that only a few gene segments generate the esti-
form of the receptorÑinto the plasma, mated 100 million distinct antibodies the body is capable of producing.

bodyÕs cells is overwhelmed. Autoim- en when a mobile bit of DNA, called a
mune disease is the result. The attack transposon, was inserted into an intact
on self is normally avoided through tol- V exon. This insertion split the V exon.
erance, a process that eliminates self- Split genes are inactive; they could man-
reactive cells [see ÒHow the Immune Sys- ufacture antibodies only once the inter- CD8 KILLER T CELL
tem Recognizes the Body,Ó by Philippa vening transposon is removed and the
Marrack and John W. Kappler, page 80]. gene segments are joined to re-form
the intact exon. Just such a removal
D
espite these drawbacks, the strat- mechanism exists in our bodies when B
egy of rearranging genes in adap- lymphocytes generate their receptors.
tive immunity has put in place Thus, V gene rearrangement does more
T CELL
an ingenious protection system. How than generate diversity in antibodies. It CD8 RECEPTOR
could such an elaborate process emerge is also crucial in forming the genes that PROTEIN
in vertebrates, and how did it become encode antibody proteins. Without re-
the keystone in adaptive immunity? As arrangement, no protein can be made 5
DESTROYS CELL 4
with all evolutionary issues, this ques- from these genes.
tion can be answered only in terms of Gene rearrangement has proved to
models and not with certainty. Never- be such a powerful means of express-
theless, our knowledge of receptors does ing just one of many related genes that
suggest a plausible scenario. at least one pathogen uses it to avoid
RIBOSOMES PRODUCING CLASS I MHC
An important clue lies in the fact that detection by the immune system. The MOLECULE
VIRAL PROTEINS
all immunologic receptors are built trypanosome, a protozoan parasite that
from similar blocks of protein. Each causes sleeping sickness, has a single
block is encoded in a chunk of DNA protein in its coat against which the in- 1
known as an exon, or coding sequence. fected host makes antibodies. These
Exons are divided by introns, noncod- antibodies eliminate most of the try- VIRAL
PROTEIN
ing DNA that is transcribed into RNA panosomes, but a few of the parasites
and then later removed by the process change their coats by rearranging the TRANSPORT
of RNA splicing. As a result, the coding coat protein gene. These variant trypan- VESICLE
blocks form a continuous message. osomes escape detection by the Þrst
Each protein component of an anti- onslaught of antibodies and continue
body has a structure called the immuno- to grow. The host makes antibody to
globulin fold. This general structure is each variant, but new forms keep aris-
2
used in many proteins besides antibod- ing and growing, causing a relapsing
ies; it forms a compact domain of pro- pattern of infection. Here, as in the RIBOSOMES
tein comprising strands of amino acids case of immunologic receptors, rear- PRODUCING
MHC MOLECULES
that lie side by side. In antibodies, these rangement controls gene expression.
domains form the heavy and light chains, ENDOPLASMIC
3 RETICULUM
S
connected by a couple of sulfur atoms, o far we have discussed how the
a disulÞde bond. innate immune system, which re-
Immunoglobulin domains are of two
types, called V for variable and C for
lies on inherited recognition mol-
ecules, and the adaptive system, which V iral proteins produced by an infect-
ed cell (1) are broken down into
peptides (2). The peptides are taken to
constant. The V domains in antibodies relies on gene rearrangement to gener-
pair to make the site that recognizes ate novel receptors in lymphocytes, the endoplasmic reticulum, where class
antigens. They are followed by pairs of work together to identify microbes. This I MHC molecules form around them (3).
C domains that mediate function in the dual approach is successful only against Each complex goes to the cell surface.
molecule, such as complement binding. pathogens in the bodyÕs ßuids. Many There it can be detected by a killer T
The V domains consist of partial genes: microbes slip inside the bodyÕs cells be- cell, which expresses a CD8 protein (4).
a V gene segment, a J (for joining) seg- fore antibodies can be made. As water- The T cell then secretes compounds
ment and sometimes also a D (for di- soluble proteins, antibodies can perme- that destroy the infected cell (5 ).
versity) gene segment. The unique vari- ate the extracellular ßuid and blood, but
ability of V domains results from gene they cannot venture across the lipid
rearrangement, which generates the di- membranes of cells.
versity of receptors in humans. Consequently, the immune system bind to peptides, small fragments of
Some proteins, however, have do- has evolved a special mechanism to de- protein that have been degraded inside
mains that resemble the V domains of tect infections within cells. This mecha- the cell. After binding to peptides, these
antibodies but are not produced by nism acts in two steps. First, it Þnds a transporter molecules migrate to the
gene rearrangement. In these proteins, way to signal to the body that certain cell surface.
a single exon speciÞes the entire V do- cells have been infected. Next, it mobi- These transporters are proteins of
main. An example of one such protein lizes cells speciÞcally designed to rec- the major histocompatibility complex
is the CD4 molecule, which plays a role ognize these infected cells and to elim- ( MHC ) of genes. They were discovered
in immune recognition and is also the inate the infection. by the late British geneticist Peter Gor-
target of the AIDS virus. Such intact V The initial step, signaling that a cell er and by George D. Snell of Jackson
genes are in fact found in some primi- is infected, is accomplished by special Laboratory in Bar Harbor, Me., as the
tive vertebrate antibody genes as well. molecules that deliver pieces of the mi- cause of graft rejection; hence their
Our rearranging antibody V genes crobe to the surface of the infected cell. long-winded name, derived from the
likely evolved from these intact V genes. These molecules, which are synthesized Greek word for tissues (histo) and the
Gene rearrangement could have aris- in the endoplasmic reticulum of cells, ability to get along (compatibility). These

Delivering Peptides to the Cell Surface
CD4 INFLAMMATORY T CELL CD4 HELPER T CELL
CD4 ANTIGEN
CD4
5 PROTEIN
PROTEIN
5 ACTIVATES 1
4
ACTIVATES CELL 4 CELL
ANTIBODY
BACTERIA
1 3
3 2
CLASS II MHC CLASS II MHC

INACTIVATING MOLECULE MOLECULE
PROTEIN
2
B CELL
MACROPHAGE
T he bacteria that infected a macrophage reside in the

cell’s vesicle (1). A class II MHC molecule, produced in
the endoplasmic reticulum, is transported to the vesicle (2).
A n antibody on the surface of a B cell serves as the B
cell’s receptor. If the antibody discovers a foreign anti-
gen in the bloodstream, it binds to it (1) and delivers the
A protein chain (black line) keeps the molecule inactive un- antigen to a vesicle inside the cell. The antigen is broken
til it reaches the vesicle. In the vesicle the chain falls away, down into peptides (2 ). A class II MHC molecule, which is
enabling the class II MHC molecule to bind to any peptides produced in the endoplasmic reticulum, migrates to the
there (3). The complex then moves to the cell surface, vesicle, where it grabs a peptide (3 ). The MHC molecule
where a so-called inflammatory CD4 T cell binds to the transports the peptide to the cell surface (4 ). A CD4 helper
peptide (4 ). The T cell then activates the macrophage, sig- T cell binds to the antigen and makes molecules that tell
naling it to destroy the material in its vesicle (5 ). the B cell to proliferate and to produce antibodies (5 ).
MHC molecules can be divided into two they fold into very similar shapes [see lymphocyte, the T cell. The structure of
classes, unimaginatively designated class illustration on next page]. Each MHC the receptor on T cells is basically the
I and class II MHC molecules. Class I molecule has a deep groove into which same as that of the membrane-bound
molecules are found on almost all types a short peptide, or protein fragment, antibody molecule that acts as the re-
of body cells. Class II molecules appear can bind. Because this peptide is not ceptor on B cells. But T cell receptors are
only on cells involved in an immune re- part of the MHC molecule itself, it can specialized to recognize only foreign
sponse, such as macrophages and B cells. vary from one MHC molecule to the peptide fragments bound by MHC mol-
Although both types of MHC mole- next. On healthy cells, all these peptides ecules. When a T cell receptor binds to its
cules are structurally distinct, studies come from self-proteins. It is the pres- speciÞc foreign peptideÐMHC complex,
published this past July by Jerry H. ence of foreign peptides in the MHC the T cell can act to cure or to kill the
Brown and Don C. Wiley of Harvard groove that tells the immune system infected cell.
University and their colleagues, as well that the cell is infected. The two diÝerent classes of MHC mol-
as earlier work by Pamela J. Bjorkman, The foreign peptideÐMHC complexes ecules present peptides that arise in dif-
now at the California Institute of Tech- displayed by an infected cell are recog- ferent places within cells. Class I mole-
nology, and her colleagues, showed that nized by receptors on a distinct type of cules bind to peptides that originate

from proteins in the cytosolic compart- proteins that are broken down into The genes that encode MHC mole-
ment of a cell. These proteins are di- peptides within the vesicles. These cules are the most variable ones in hu-
gested inside the cell as part of the nat- peptides bind to class II MHC mole- mans. This unusual feature of the MHC
ural process by which a cell continually cules, which then migrate to the vesi- molecule system may have allowed
renews its protein contents. James Shep- cles from their origin in the endoplas- Homo sapiens to survive so many path-
herd, working in my laboratory at Yale mic reticulum. ogens. Unlike antigen receptor genes,
University, recently showed that the Unlike class I MHC molecules, which which vary from cell to cell in one per-
short peptide fragments that result must mature around a peptide, class II son, MHC genes are the same in all of
from this process are pumped by a dis- molecules remain primed for action an individualÕs cells but differ from
tinct transporter from the cytosol into once they are synthesized. Peter Cress- person to person. Each variant of an
the endoplasmic reticulum. well, now at Yale, showed that a special MHC molecule will bind diÝerent pep-
Here the class I MHC molecules are chain of amino acids in the endoplasmic tides, because the genetic alterations af-
synthesized as long chains of amino reticulum holds the binding ability of fect mainly the structure of the groove
acids that must fold to yield the ma- class II MHC molecules in check until that holds the peptide.
ture class I MHC protein. This folding the molecules move to the vesicles. This The genetic variability of MHC mole-
can occur only around a suitable pep- extra chain then falls away, enabling the cules means that at least some individ-
tide, much as a pearl in an oyster de- class II MHC molecules to grab hold of uals will have MHC molecules that bind
velops around a grain of sand [see illus- any peptides they Þnd. to the peptides of any pathogen, even
tration on page 76]. The peptides trans- The class II MHC molecule then deliv- as the structure of microbial proteins
ported there, then, make natural seeds. ers the peptide to the surface of the cell. evolves. Indeed, A. V. Hill of the Univer-
The folding of a class I MHC mole- There the peptide can be recognized by sity of Oxford has recently studied a
cule around a peptide signals it to car- T cells that have the CD4 protein on population exposed over many hun-
ry the peptide to the surface and hold their surface. Unlike CD8 T cells, CD4 T dreds of years to Plasmodium falci-
it there. If the peptide is foreignÑstem- cells do not directly kill the cell. Rather parum, the parasite that causes fatal
ming from, say, a virus infecting the they activate the cells that have dis- malaria. He found that the percentage
cellÑthen a passing T cell will recognize played the peptide. For instance, one of people whose MHC molecules bind
it. The T cells that act in this way are kind of CD4 T cell, called inßammatory particularly strongly to peptides from
those with CD8 proteins on their surface. T cells (or Th1), can stimulate a macro- the parasite increased over that time. T
These CD8 T cells will mount an im- phage to kill the Mycobacteria inside cells can also recognize these genetic
mune response against the cell by re- its own vesicles. It is the loss of this diÝerence in MHC molecules, which ex-
leasing chemicals that destroy the en- class of CD4 T cells that makes pa- plains why tissue grafts are rejected: T
tire cell. Because CD8 T cells are pro- tients who have AIDS so susceptible to cells in the host regard the peptides
grammed to kill cells that display foreign diseases such as tuberculosis. bound by a diÝerent MHC molecule as
peptides, they are sometimes referred Another kind of CD4 T cellÑhelper T foreign and so kill the grafted tissue.
to as killer T cells. This response is the cells (or Th2)Ñguides the activity of B
T
only eÝective way to prevent the creation cells. When a protein binds to the B he binding of antigen to receptor
of more viruses by the infected cells. cellÕs receptor, the protein is taken to a is actually only the beginning of
Of course, not all microbes grow in the vesicle, where it is cleaved into peptides the immune response. For a B cell
cytosolic compartment of cells. Some that bind to class II MHC molecules. to produce antibodies, or a T cell to re-
bacteria, such as the Mycobacteria that These complexes are then delivered to lease its killer or helper molecules, the
cause tuberculosis, grow in vesicles in- the cell surface, so that they can be rec- nucleus of the cell must know that
side a cell, which are sealed oÝ from ognized by the helper T cells. The help- binding has occurred at the cell sur-
the rest of the cell by a membrane. er T cells tell the B cell to start making face. Lymphocyte receptors are made
Cells infected in this way tend to be antibody, turning on only those B cells of several proteins that interact to de-
macrophages, which engulf bacteria that have bound to antigen. Thus, even liver a biochemical message to the
and naturally form a home for such in- antibody production is ultimately con- cellÕs interior. When a receptor binds to
fections. Bacteria in cell vesicles make trolled by MHC molecules and T cells. an antigen, it causes other proteins in
the cell membrane to turn on enzymes
inside the cell referred to as kinases.
Active kinases add compounds called
phosphate groups to other proteins in-
side the cell. The added phosphate
groups change the activity of these pro-
teins so that they ultimately signal the
cell to grow and diÝerentiate. The CD4
and CD8 proteins on T cells, as well as
a protein on B cells known as CD19,
are examples of membrane proteins
coupled to kinases inside cells. Anoth-
er kind of molecule that goes into ac-
tion is CD45, an enzyme that helps to
mediate lymphocyte activation by re-
moving phosphates from certain pro-
MAJOR HISTOCOMPATIBILITY COMPLEX , or MHC for short, makes two kinds of teins, thereby deactivating them.
molecules in cells: class I (left) and class II (right). The images present the view- But kinase-mediated signals cannot
point of a T cell receptor. Class I MHC molecules can hold only short peptides by themselves activate lymphocytes.
(red ), because the binding site is closed oÝ. In contrast, class II MHC molecules can Lymphocytes must receive a second sig-
bind to peptides of diÝerent lengths, because the binding site is open at both ends. nal derived from other cells in the body

NO ANTIGEN ANTIGEN ONLY ANTIGEN PLUS B7
MACROPHAGE B7
MHC
PROTEIN
BACTERIAL
ANTIGEN
T CELL INFECTION
FIRST
RECEPTOR CD28 SIGNAL SECOND
SIGNAL
T CELL
INACTIVE T CELL INACTIVE T CELL T CELL GROWTH

AND DIFFERENTIATION
STIMULATION by two molecules is needed to activate lymphocytes. The diagrams
depict a CD8 T cell and a macrophage. Without the presence of antigens, the T cell
is dormant (left). Yet antigen alone cannot induce T cell function (center ). In this
way, a response to the bodyÕs own antigen does not occur; in fact, this Þrst signal
turns oÝ the T cell . If the macrophage is infected, it will produce a molecule called
B7, which acts on the T cellÕs CD28 surface protein (right). Only when an antigen
and the B7 molecule are present on the same cell does the T cell proliferate.
to grow. These messages are often in which antibodies are not made? The
called costimulatory signals. B cells re- answer has only recently been discov-
quire helper T cells not only to recog- ered [see ÒHow the Immune System De-
nize antigen but also to make a pro- velops,Ó by Irving L. Weissman and Max
teinÑCD40 ligandÑthat binds to the D. Cooper, page 64]. It turns out that
B cell molecule CD40. T cells rely main- during the development of B cells in
ly on so-called B7 molecules as costim- healthy individuals, the rearrangement duction is necessary for health. Treat-
ulatory signals; such molecules are ex- of receptor genes is carefully regulated. ment of these patients with immuno-
pressed by the same cells that present In other words, the antibody receptor globulins pooled from donors provides
antigen. While working in my labora- must be manufactured accurately. The them with antibodies and allows a
tory, Yang Liu, now at New York Uni- V gene for each chain has to be rear- nearly normal life. But this therapy is
versity Medical Center, showed that B7 ranged in the right sequence, and the only a temporary repair for a genetic
is expressed when the innate immune receptor cannot be completed until all disease that can now, in theory, be cor-
system recognizes that microbes are the rearrangements are correctly made. rected by inserting the normal gene into
present, that is, usually during the ear- a patientÕs bone marrow cells. Contin-
T
ly phases of infection. In eÝect, the in- hus, to form correct receptors, ued strong support for basic research in
nate system may prime the adaptive the cell must determine the state immunology, genetics, cell biology, can-
system for action. In this way, costimu- of its receptor genes as develop- cer and molecular biology is needed to
latory signals may also assist the adap- ment proceeds. A heavy-chain V gene conquer this and the other more preva-
tive immune response in diÝerentiating is rearranged so that a cell can make lent diseases discussed in this issue.
infectious microbes from self-tissues. the heavy chain of its receptor Þrst.
Lymphocytes that bind to antigen but This chain goes to the cell surface. The
do not receive costimulation are not ac- presence of the heavy chain at the cell
tivated. As a result, self-antigens alone surface signals the B cell to stop rear- FURTHER READING
would not be able to initiate an immune ranging heavy-chain genes and to start SEPARATION OF SELF FROM NON-SELF IN THE
response. rearranging light-chain genes. A kinase COMPLEMENT SYSTEM. John P. Atkinson
Once a lymphocyte binds to antigen seems to deliver this crucial message and Timothy Farries in Immunology To-
and receives costimulation, it diÝeren- from the cell surface to the interior. day, Vol. 8, Nos. 7Ð8, pages 212Ð215;
tiates and becomes active. (The active In agammaglobulinemia, heavy chains July/August 1987.
versions of lymphocytes are sometimes are made, but light chains are not. In STRUCTURE OF THE HUMAN CLASS I HISTO-
called eÝector cells, as they actually these patients, a kinase has recently COMPATIBILITY ANTIGEN, HLA-A2. Pamela
J. Bjorkman et al. in Nature, Vol. 329, No.
mediate the immune response.) Once been found to be defective. (Interesting-
6139, pages 506Ð512; October 8Ð14, 1987.
activated, the cell no longer requires the ly, absence of a related kinase found in T CELL ANTIGEN RECEPTOR SIGNAL TRANS-
costimulatory signal. Thus, although T cells has an identical eÝect on T cell DUCTION: A TALE OF TAILS AND CYTO-
only cells that express costimulators development.) Apparently, the gene de- PLASMIC PROTEIN-TYROSINE KINASES. Ar-
can elicit an immune response, any cell fect described by my father in these thur Weiss in Cell, Vol. 73, No. 2, pages
or molecule can be targeted. This re- pages 36 years ago has Þnally been 209Ð212; April 23, 1993.
sponse is important because it enables identiÞed, and we should soon under- PHYLOGENETIC DIVERSIFICATION OF IM-
MUNOGLOBULIN GENES AND THE ANTI-
B and T cells to attack any cell that has stand how it works.
BODY REPERTOIRE. Gary W. Litman et al.
become infected, regardless of its type. Meanwhile the kinds of infection that in Molecular Biology and Evolution, Vol.
So what is wrong in patients who occur in people with agammaglobulin- 10, pages 60Ð72; January 1993.
have agammaglobulinemia, a condition emia have taught us why antibody pro-

How the Immune System
Recognizes the Body
The human immune system has developed several
elegant processes that allow it to repel foreign invaders
and yet not attack the body itself
by Philippa Marrack and John W. Kappler
O
rganisms have various mecha- in the thymus or bone marrow, it is ble-strand RNA provoke mammalian
nisms of distinguishing between usually killed or inactivated. A mature cells to produce proteins called inter-
themselves and everything else. lymphocyte will usually suÝer the same ferons, which in turn stimulate a series
Many plants, for example, have hard fate if it responds to a self-product of reactions that help the host resist
outer shells that not only protect them and does not receive a second chemi- further viral infection.
against invaders but also deÞne the cal message. These basic strategies that Although these nonspeciÞc respons-
plantsÕ outer limits. Yeasts have mat- the body uses to eliminate self-reacting es to chemicals made by bacteria and
ing-type genes that code for proteins cells have many variations because viruses are an absolutely crucial part of
that prevent mating between similar there are many diÝerent types of lym- the immune system, vertebrates also re-
cells. Sponges have a collection of genes phocytes and many diÝerent kinds of quire mechanisms for identifying specif-
whose products can be used to detect self-products. ic invaders. The immune system must
and repel alien colonies. Despite the safeguards of the im- be able to recognize foreign products
The human body has evolved one of mune system, some self-reacting lym- whose chemistry is only slightly diÝer-
the most elaborate mechanisms for phocytes are not inactivated or killed, ent from its own molecules.
distinguishing invaders from itself. The and they can cause one of several ill- The immune system has evolved three
cells of the immune systemÑthe lym- nesses known as autoimmune diseases. very sophisticated methods of recogniz-
phocytes, macrophages and othersÑ Immunologists are well aware that if ing foreign chemicals, or what are termed
must learn to tolerate every tissue, every they understood all the mechanisms for antigens. The basis of these mecha-
cell, every protein in the body. They tolerance, they might be able to prevent nisms is the three kinds of so-called re-
must be able to distinguish the hemo- autoimmune diseases. Furthermore, such ceptor proteins found on lymphocytes.
globin found in blood from the insulin insights might help surgeons in their The Þrst method requires B cells that
secreted by the pancreas from the vit- continual search for reagents that can have receptor proteins known as im-
reous humor contained in the eye from prevent the immune system from re- munoglobulins; the second relies on T
everything else. They must manage to jecting such transplanted tissues as cells that have a receptor protein called
repel innumerable diÝerent kinds of kidneys, hearts and lungs. alpha-beta, and the third utilizes T cells
invading organisms and yet not attack that have the protein gamma-delta.
H
the body. igher vertebrates have many Many receptors are attached to the
Immunologists have always been ways of detecting and destroy- surface of each lymphocyte, and they
preoccupied with the issue of how the ing invaders. Some of these are will, in speciÞc circumstances, bind to
body learns to tolerate itself, but only relatively nonspeciÞc and depend on antigens. Each receptor is made up of
during the past decade or so have they the fact that groups of infectious or- two diÝerent polypeptide chains; immu-
discovered the details of what prevents ganisms make chemicals that are not noglobulins consist of so-called light
the all-important lymphocytesÑthe T produced in large amounts by higher and heavy chains; the alpha-beta pro-
cells and the B cellsÑfrom attacking vertebrates. For example, mammals can tein is made of an alpha chain and a
their host. Many immature lymphocytes detect the presence of invading bacte- beta chain, whereas the gamma-delta
have the potential to respond to self- ria because bacteria produce peptides
products and therefore pose a threat. that begin with an unusual amino acidÑ
The body tries to rid itself of all such formyl methionineÑwhereas mammals
cells by resorting to several ingenious produce only small amounts of such PHILIPPA MARRACK and JOHN W.
processes. If an immune cell reacts to peptides. Indeed, in mammals, high con- KAPPLER have pioneered new techniques
a self-product while it is developing centrations of peptides with formyl me- for studying tolerance in immune cells.
thionine attract white blood cells called Since 1986 they have both been investi-
neutrophils, which then consume the gators at the National Jewish Center for
Immunology and Respiratory Medicine
T CELLS develop in the thymus, but if bacteria producing the peptides. Simi-
in Denver, part of the Howard Hughes
one reacts to a protein made by its host larly, mammals can detect some viruses Medical Institute Research Laboratories.
before it matures, it will die. The pro- because viruses produce much greater Marrack and Kappler have been married
cess eliminates many T cells that have quantities of double-strand RNA than for 19 years.
the potential to attack the body. mammals do. Large amounts of dou-

blood. Later Sir Peter B. Medawar, Rupert
E. Billingham and Leslie Brent of the
National Institute for Medical Research
in London showed that if blood cells
were transferred from an adult mouse
into an unrelated, newborn mouse, the
newborn could accept a skin graft from
the adult later in its life. Hence, the in-
troduction of blood cells at birth could
aÝect the ability of the individual to ac-
cept not only blood but also skin.
Most important, this work and OwenÕs
research led to the same broad conclu-
sion: the immune system is not born
with all the instructions needed to rec-
ognize the products of its host ; rather
it learns what is self as it develops.
O
ne of the Þrst ideas that ex-
plained how the immune sys-
tem learns tolerance to self was
put forward by Joshua Lederberg, now
at the Rockefeller University. In 1959
he suggested that immature lympho-
cytes may not react to antigens in the
IMMATURE T CELLS are killed when their receptors bind to peptides, as shown by same way that mature lymphocytes do.
experiments with genetically engineered mice. The mice were designed to harbor Usually if something binds to the im-
T cells whose receptors could recognize a peptide made only in male mice. In the munoglobulin of a mature B cell, the
female mice, T cells developed normally. In the male mice, T cells were absent be- lymphocyte changes into an antibody-
cause the young T cells apparently bound to the peptide and died. secreting cell ; if a molecule attaches
to the receptors of a mature T cell,
the lymphocyte becomes either a cyto-
protein has, as you might guess, a gam- cause the composition and structure of kine-secreting cell or a killer cell. Led-
ma chain and a delta chain. Each chain receptors are determined somewhat erberg postulated that if an antigen
can vary in sequence from one cell to at random, some receptors are likely binds to the receptor of an immature
another. For example, the alpha and to be able to bind to the chemicals of cell, the cell might die instead of be-
beta chains of any given T cell will al- their host. coming active.
most certainly diÝer from those of any Randomness is introduced in at least LederbergÕs hypothesisÑnow called
other T cell. The receptors of any given two ways. First, the receptors of lym- clonal deletion theoryÑprovides a
T cell, therefore, will probably bind to phocytes are made by random combi- mechanism for eliminating lymphocytes
a diÝerent set of materials than those nations of specialized gene segments. that react to self-products. The process
of other T cells. Human beings have as The alpha and beta chains of T cells, works in the following way. T and B
many as a million million T cells and for example, are created by a random cells are produced constantly through-
consequently have many diÝerent al- mixture of gene segments known as V- out the lifetime of the individual, even
pha-beta molecules available to recog- alpha, J-alpha, V-beta, D-beta and J- though the production of T cells may
nize foreign material. beta. Second, short, random segments slow down after adolescence. Regard-
Indeed, when one considers the vast of DNA are introduced into the assem- less of when they are produced, T and
number of alpha-beta receptors of T bling genes for the alpha-beta receptor. B cells will always develop surrounded
cells as well as the many immunoglob- Thus, the organism has no absolute by a sea of materials produced by the
ulin molecules of B cells and the many control over the complete amino acid host. Those immature cells whose re-
gamma-delta receptors of T cells, it is sequences of the receptors. ceptors recognize self-products are de-
no small wonder that none of the lym- Control must be exerted in some stroyed, according to the theory; conse-
phocytes recognizes products of its other way, at some other stage. One quently, only lymphocytes that are not
own host. This remarkable phenomenon of the Þrst researchers to test this self-reactive will develop to maturity.
has intrigued investigators for decades, hypothesis was Ray D. Owen of the Cal- To be sure, the immature lymphocytes
and many theories have been put for- ifornia Institute of Technology. In 1945 will also die if they bind to a foreign an-
ward to explain how the human immune he was studying the inheritance of blood tigen, but an immune response will be
system learns to tolerate the cells of types in cattle. He found that twin cows carried out by those lymphocytes that
the body. that shared a placenta were very likely matured before the infection.
One of the Þrst ideas was that ani- to have the same blood type. This corre- Some time after the clonal deletion
mals simply cannot make lymphocyte lation was even seen in one case where theory was proposed, researchers came
receptors that are self-reactive. In partic- the twins had diÝerent fathers. Owen up with two other plausible explanations
ular, humans might not have the genes concluded that the correlation between for why the immune system is tolerant
necessary to create alpha-beta recep- blood types was a consequence of the to its host. One suggestion was that a
tors that could react with human pro- exchange of lymphocytes and other blood developing lymphocyte might be inac-
teins. Immunologists have known for cells in utero. Furthermore, he suggest- tivated permanently, instead of dying,
many years that this explanation is not ed that this early exchange prevented when its receptors were engaged. ( Im-
right. Nowadays we realize that be- the cows from rejecting each otherÕs munologists describe an inactive lym-

IMMATURE T CELL T CELL DIES
CARRIER CELL
PROTEIN
MHC
PEPTIDE T CELL DIES
THYMUS CELL IMMATURE T CELL
NO BINDING
CARRIER CELL
IMMATURE T CELL T CELL RESPONSIVE

TO SELF-PRODUCTS
NO BINDING
IMMATURE T CELL T CELL RESPONSIVE

KIDNEY THYMUS TO FOREIGN ANTIGENS
DEATH OF YOUNG T CELLS that bind to self-proteins helps to others are carried there, from organs such as the kidney, by
prevent the immune system from attacking the body. T cells traveling cells. Those young T cells whose receptors bind to
are exposed to most self-products as they develop in the thy- self-products die. Because some self-products never reach
mus. Some self-proteins are made in the thymus, whereas the thymus, some self-reactive cells reach maturity.
phocyte as Òanergic.Ó) The other hy- ogists say, is somewhere around one pha-beta receptor play a role in binding
pothesis stated that self-reactive T and in a million. Indeed, the frequency is the MHC protein and its captured for-
B cells might be kept at bay by lympho- so low that it would be impossible to eign peptide. To recognize a speciÞc an-
cytes called suppressor cells. distinguish the few lymphocytes that tigen, a T cell must have a receptor with
For many years, researchers strug- might recognize self-products from the exactly the right combination of vari-
gled to distinguish among these three many that do not. able segments.
hypotheses. Lymphocytes are clearly Nevertheless, researchers have recent- Superantigens are a diÝerent story.
very good at recognizing foreign tissue. ly developed two experimental tools Like their ordinary counterparts, super-
For example, a human being will reject that circumvent this problem. The Þrst antigens will attach to a particular type
skin grafts from an unrelated person requires a peculiar type of antigen of MHC molecule, but they will then
very rapidly, whereas an individual will called a superantigen, whereas the sec- bind to a speciÞc V-beta segment of an
accept skin tissue transplanted from ond relies on genetically altered ani- alpha-beta receptor, almost regardless
one part of the body to another. Like- mals known as transgenic mice. Both of the structure of the rest of the re-
wise, in culture dishes, lymphocytes fail the superantigen techniques and the ceptor. Because the number of diÝerent
to be activated by other cells from their experiments with transgenic animals types of V-beta segments is small com-
host but react violently to lymphocytes deserve to be described in some detail. pared with the number of diÝerent al-
or cells from another individual. Yet pha-beta receptors, many more T cells
W
the outstanding issue remained : Does hether a superantigen, or an- are capable of recognizing a particular
the immune system fail to respond to tigen, will bind to a lympho- superantigen than are able to identify a
self-products because the potentially cyte depends ultimately on the speciÞc antigen. In mice, for example,
reactive lymphocytes are simply not composition and structure of the recep- the number of different V-beta seg-
there or are inactive or are being sup- tor. The alpha-beta receptor, for exam- ments totals about 20, and thus any
pressed by other cells? ple, is a somewhat random assembly particular V-beta can be found in about
To resolve this question, workers at- of such segments as V-alpha and V-beta. one in every 20 T cells that have alpha-
tempted to devise methods for identi- The receptor is designed mainly to rec- beta receptors.
fying lymphocytes that recognized par- ognize foreign peptides, that is, anti- Most important, because so many T
ticular antigens but did not necessarily gens made by breaking down proteins cells respond to a speciÞc superanti-
respond by dividing. The development from invading organisms. The recep- gen, researchers can observe the reac-
of these techniques turned out to be a tor, however, will bind only to a foreign tion. To do so, they Þrst obtain an anti-
daunting task. If the T and B cells of an peptide that has already been attached body that can bind to the V-beta target
animal have never been exposed to a to one of the major histocompatibility of a superantigen. The antibody is then
speciÞc antigen, only a small fraction complex (MHC) proteinsÑspecialized tagged with a molecule that ßuoresces
of the lymphocytes should have the po- molecules found on the surface of or- under ultraviolet light. Hence, the ßuo-
tential to react to that antigen. The Òfre- dinary cells. As far as researchers can rescent antibody will attach to T cells
quencyÓ of reacting cells, as immunol- tell, all the variable segments of the al- that respond to the superantigen, and

workers can identify the cells using a research teams began to examine the ef- alpha-beta receptors to their surfaces.
microscope or a ßuorescent-activated fects of the superantigen made by MTV- As we discovered, however, an im-
cell sorter. 7, a strain of mammary tumor virus that mature thymocyte will die in the thy-
To test this technique, investigators has naturally integrated into the DNA mus if it recognizes the superantigen
Þrst used a superantigen produced by of some mice. This superantigen reacts produced by integrated MTV-7. Many
the mouse mammary tumor virus. Mice with certain V-beta segments on the re- diÝerent experiments on diÝerent ani-
become infected with the virus through ceptors of mouse T cells. SpeciÞcally, mals have now shown that superanti-
the milk of their mothers. The virus in- the superantigen binds to the segments gens cause the death of immature thy-
vades the lymphocytes of mice by man- known as V-beta 6, V-beta 7, V-beta 8.1 mocytes about halfway through their
ufacturing a superantigen and stimulat- and V-beta 9. development.
ing the lymphocyte. The mouse mam- Working with Uwe Staerz, then at the
A
mary tumor virus, like the virus that Basel Institute for Immunology, we fo- lthough these results oÝered
causes AIDS, is a retrovirus. Such virus- cused on the eÝects of the MTV-7 super- strong support for the clonal de-
es contain genes made of RNA, but they antigen on V-beta 8.1. We found that in letion theory, immunologists
reproduce by making DNA copies of mice whose DNA is free of MTV-7, as were forced to entertain the possibility
their RNA. This DNA is inserted into much as 8 percent of T cells have V-beta that superantigens, which have so many
the DNA of infected cells. The viral 8.1 as part of their receptors. On the special properties, do not aÝect T cells
DNA then gives rise to viral RNA and other hand, mice whose DNA includes in the same way as normal antigens do.
proteinsÑmaterials that assemble to MTV-7 did not harbor any mature T Harald von Boehmer and Michael Stein-
form new infectious viruses. cells with V-beta 8.1. At the same time, metz and their collaborators at the Uni-
Occasionally, retroviruses infect the a Swiss research teamÑincluding H. versity of Basel and HoÝmannÐLa Roche
cells that produce sperm or eggs. If that Robson MacDonald of the Ludwig Insti- therefore approached the problem of
happens, the virus may become part of tute for Cancer Research in Lausanne self-tolerance in a completely diÝerent
the DNA of the oÝspring and may cease and Rolf M. Zinkernagel and Hans Hen- way. They used transgenic mice, which
to be an infectious organism. In fact, gartner of the University of ZurichÑre- are produced by the injection of DNA
nearly all mice have one or more mam- ported that T cells bearing V-beta 6 are into fertilized mouse eggs. Such DNA is
mary tumor viruses integrated into their also missing in mice whose DNA has frequently incorporated into the DNA
DNA. These viral integrants then gener- MTV-7. More recently Edward Palmer of the developing embryo and is passed
ate proteins that are, for all intents and and his colleagues at the National Jew- on to progeny.
purposes, self-products. The viral pro- ish Center obtained similar results for Using this technique, von Boehmer
teins are made constantly throughout V-beta 9, and we discovered the same and his colleagues created mice in
the life span of the animal, just as gen- for V-beta 7. which most of the T cells had the same
uine self-proteins are. All these experiments showed that alpha-beta receptor. To understand how
We and our colleagues at the Nation- the superantigen made by integrated they accomplished this, one must know
al Jewish Center for Immunology and MTV-7 somehow leads to the disappear- that as a precursor T cell develops in an
Respiratory Medicine in Denver used ance of T cells that can react with the ordinary mouse, the cell actually builds
the superantigens produced by these superantigen. So, in this case, T cells the DNA that yields a particular alpha-
viral integrants to test how the immune that can recognize self-products are beta receptor. Pieces of the DNA cod-
system responds to self-products, since, neither inactivated nor suppressed by ing for the receptor are contained with-
as far as the mouse is concerned, the other cells; the T cells are simply not in the DNA of all mouse cells, but only
proteins made by the integrant are self- there and must have died at some in developing T cells are the pieces rear-
products. In 1988 we and several other stage in their development. ranged into functional genes. Von Boeh-
T cells begin as precursor cells. Dur- mer isolated DNA that coded for a spe-
ing the fetal stage of animal develop- ciÞc alpha-beta receptor gene, which
ment, the precursors originate in the had already been rearranged. He then
yolk sac or liver, whereas young and injected mouse eggs with the rear-
adult animals spawn precursors in their ranged DNA. As the mice developed,
bone marrow. These cells migrate to the the rearranged DNA took precedence
thymus where they start to build the over the unrearranged receptor genes.
genes that contain the instructions for Hence, most T cells in the transgenic
making alpha chains, beta chains and mice bore the receptor created by the
other receptor-related proteins. Soon injected genes.
after, as alpha-beta receptors start to The receptor that von Boehmer chose
appear in small quantities on the sur- to make was one that would bind an
face of the cells, the precursors be- antigen present only in male mice, pro-
come immature thymocytes. Such cells vided that the antigen was accompa-
then go through a mysterious stage of nied by the MHC protein D b. In those
development referred to as positive se- mice that made D b, he and his co-work-
lection. In this stage the immature thy- ers found, as expected, an undeniable
mocytes add an increasing number of diÝerence between the females and
males. In the female mice, many T cells
had the introduced receptor on their
SUPERANTIGEN binds to only one part
surfaces. In the male mice, however,
of a T cellÕs receptor, in this case the re- cells bearing the receptor were almost
gion known as V-beta. Before the super- completely missing; they had appar-
antigen attaches to the receptor, it must ently been destroyed at an early stage
bind to a major histocompatibility com- of their development in the thymus.
plex protein on the surface of a cell . These Þndings show that Lederberg

IMMUNE SYSTEM has a safety mechanism that prevents a The second is typically the secretion and binding of a pro-
mature T cell from mounting an immune attack against its tein, B7, for example (left). If a T cell is exposed to a self-pro-
host. Before a T cell can attack, it must receive two signals. tein that is presented on a nonstimulatory cell, the T cell will
The Þrst is the binding of an antigen to the T cellÕs receptor. die or become inactive (right).
was right when he proposed the clonal cells are thus incapable of transporting animals but become anergic. Further-
deletion theory. Immature lymphocytes the peptides of other cells to the thy- more, in other experiments Susan Webb
go through a stage when binding of mus. Immature T cells in the thymus are and her collaborators at the Scripps Re-
their receptors causes them to die. Self- not exposed to some cytoplasmic pro- search Institute in La Jolla, Calif., have
reactive cells are killed before they have teins and so have no way of learning to shown that under some conditions, ma-
a chance to proliferate and damage their tolerate them. Some other mechanism ture T cells die when exposed to self-
host. The immune system does indeed must be at work that either kills, inacti- antigen.
use clonal deletion to establish toler- vates or suppresses mature T cells. Immunologists do not know exactly
ance to self. what causes death rather than inactiva-
S
Unfortunately, the clonal deletion the- cientists have searched for a tion of mature T cells. Perhaps the in-
ory does not address the problem of mechanism by which mature T active cells are just intermediates on
how the immune system learns to tol- cells could learn tolerance. Several their way to the grave. In any case, the
erate self-products that the thymus ei- diÝerent experiments have now shown important outcome is that these cells
ther does not make or produces in ex- that when mature T cells encounter cannot respond. Indeed, researchers
tremely small quantities. This concern self-products, they may either die or have now gathered so many examples
applies not only to proteins that are become inactive. of antigensÕ causing the death or inacti-
relatively sequestered, such as those One such experiment was conducted vation of T cells that they are quite
made in the brain or eye, but also to by Jacques F.A.P. Miller and his col- puzzled about why and when antigens
proteins that are made only in certain leagues at the Walter and Eliza Hall In- from invading organisms cause T cells
specialized tissues. stitute of Medical Research in Austra- to become active. T cells with alpha-
In fact, many of these unusual self- lia. They worked with a gene for a class beta receptors seem to have been de-
antigens are transported to the thy- I MHC protein known as K b. They intro- signed so that they will not usually be
mus. Monocytes and B cells can take duced this gene into a mouse in such a activated when their receptors are en-
up a protein in one part of the body way that the gene was controlled by the gaged. The question is, therefore, how
and carry it to anotherÑto the thymus insulin gene. Hence, the mouse made a mature T cell decides whether to di-
in particular. This kind of process ac- K b only in its cells that normally make vide, become inactive or die when its
counts very well for how the immune insulin, that is, the beta cells of the receptors react to something.
system learns to tolerate many self- pancreas. Because these cells are im- The issue was resolved in part by a
products that are not generated in the mobile, K b could not Þnd its way to the classic experiment performed some 30
thymus. thymus of these animals, and, not sur- years ago by David W. Dresser, then at
Yet this scheme does not apply in all prisingly, the thymocytes of these mice the Medical Research Council Laborato-
cases; for instance, it does not explain could bind to K b. Mature T cells could ries in England. At the time, investiga-
how T cells learn to tolerate peptides not respond, however, unless they were tors were well aware that the immune
that bind to class I MHC proteins. Such confronted with K b under very special system responds vigorously to aggregat-
MHC proteins attach only to peptides circumstances. These results showed ed preparations of foreign protein or to
that are derived from proteins made that sometimes mature T cells that can protein mixed with an adjuvant, such
within the cell itself. Monocytes and B recognize self-antigens can survive in as dead bacteria in mineral oil. Dress-

er found, however, that the immune reformulated the idea into its currently T cell gets two signals: one through its
system fails to respond to soluble for- accepted form. In immunologic terms, receptor and another through CD28. If a
eign proteins. In fact, once the immune T cells need two signals to be stimulat- T cell is confronted with an antigen on
system is exposed to a soluble foreign ed by an antigen: the Þrst signal comes a cell that does not have functional B7,
protein, it will subsequently fail to re- from the binding of the alpha-beta re- it will get the receptor signal without
act to any preparation of that protein. ceptor, and the second is from some- the CD28 signal. The T cell is thereby
The system learns to tolerate soluble thing else. inactivated. This Þnding lends strong
foreign proteins, at least in part, be- The task of identifying this second support for the theory that T cells re-
cause it eliminates the T cells that can signal has preoccupied immunologists quire two signals to respond to an anti-
respond to such proteins, as was dis- for the past decade. One clue came from gen. ( It is worth emphasizing, however,
covered in 1971 by Jacques M. Chiller the work of Ronald H. Schwartz and his that CD28-B7 is only one of many pos-
and William O. Weigle of the Scripps collaborators at the National Institutes sible secondary signals.)
Clinic and Roger Taylor of the MRC of Health [see ÒT Cell Anergy,Ó by Ron- Of course, the way the CD28-B7 signal
Laboratories. ald H. Schwartz; SCIENTIFIC AMERICAN, is blocked in the laboratory is not the
Evidently, T cells can recognize the August]. In 1987 his group demonstrat- way it happens in the immune system.
form of the antigen, although how they ed that antigens bound to MHC pro- Researchers are still Þguring out what
do so was not clear until recently. Al- teins will not provoke cultured T cells cells can present antigens on MHC pro-
pha-beta receptors do not have a direct to divide if the cells that bear those teins but fail to deliver the C28-B7 sig-
way of detecting in what form the for- MHC proteins are prepared in a certain nal. The answer may be B cells, as sug-
eign protein was introduced into the way. Not only did the T cells fail to re- gested by such investigators as David
body. As long as a peptide is attached spond, but they were also unable to di- C. Parker of the University of Massachu-
to an MHC protein, it can bind to an al- vide several days later when confronted setts at Worcester and Polly C. Matzing-
pha-beta receptor regardless of wheth- with antigens bound to MHC proteins er of the National Institute of Allergy
er the peptide came from a protein in on live, unprepared cells. The prepared and Infectious Diseases. Most B cells in
solution or in an adjuvant. Something cells bearing the MHC proteins had animals bear very little, if any, B7. Only
besides the alpha-beta receptor must somehow inactivated the T cells. after the B cells have been stimulated
be giving the T cell information about Later work has shown that the mech- themselves do they increase their pro-
the form of the antigen. anism of inactivation involves CD28, a duction of B7 to measurable amounts.
In 1970 Peter A. Bretscher and Mel- protein on the surface of T cells. When Therefore, if T cells encounter antigen
vin Cohn of the Salk Institute for Bio- CD28 binds to a protein known as B7 or on B cells, they may be inactivated be-
logical Studies suggested a solution to BB1Ñwhich resides on the surface of B cause they receive one signal without
the problem in an early form, and Þve cells and macrophagesÑit delivers a sig- another. At the present, this theory seems
years later Kevin J. LaÝerty and Ali- nal to the T cell. Normally, a T cell binds plausible, but it has not been proved.
stair J. Cunningham of the John Curtin an antigen and an MHC protein and a Most likely, only certain specialized
School of Medical Research in Australia B7 at the same time. Consequently, the cellsÑmacrophages, dendritic cells and
perhaps activated B cellsÑcan deliver
both the Þrst and second signals to T
cells, thereby activating them.
T
he body has many ways to deal
with a self-reactive T cell that has
an alpha-beta receptor. If the cell
is still developing in the thymus and its
receptor binds to a self-product, it will
die. On the other hand, a mature cell
whose receptor binds to a self-product
will be inactivated or killed if it fails to
receive a second message, such as the
CD28-B7 signal. Investigators are less
certain about how B cells and T cells
with gamma-delta receptors respond to
self-products.
The immune system seems to han-
dle self-reactive B cells and their immu-
noglobulin proteins in much the same
way as it takes care of self-reactive
T cells with alpha-beta receptors. For
example, in 1976 Norman R. Klinman
and his colleagues at the University of
Pennsylvania and Ellen Vitetta and her
co-workers at the University of Texas
Southwestern Medical Center at Dallas
YOUNG B CELLS become inactive when they bind to something, as shown by ex-
independently showed that immature B
periments with transgenic mice. A group of mice was engineered to produce a pro- cells in tissue culture could be made
tein found in chicken: hen egg lysozyme ( HEL ). Other mice were designed to make tolerant to antigen much more easily
B cells with receptors that bind to HEL . The two groups of mice were mated, pro- than mature B cells could. Later, Sir
ducing mice that produced HEL and B cells sensitive to HEL . B cells in these ani- Gustav J. V. Nossal and his collabora-
mals could not be activated by reagents that usually stimulate such cells. tors at the Hall Institute showed that

QUINTUPLET COWS gave some of the Þrst evidence that the shared a single placenta in their motherÕs womb and exchanged
immune system learns to tolerate self-products. The fetal cows blood. As a result, the calfs accepted blood from one another.
this phenomenon could involve B cell bone marrow. In those mice, the B immune system makes mistakes, and T
anergy as well as B cell death. cells died. cells and B cells that can respond to
Recently researchers have been able to Why are the immature B cells some- self-antigens sometimes appear. These
demonstrate this phenomenon in animals times inactivated and sometimes killed cells damage the body they occupy,
rather than in tissue culture dishes, us- by contact with self-antigen? Investiga- leading to such diseases as rheumatoid
ing transgenic mice. For the experiments, tors have found that the form of the arthritis, multiple sclerosis and lupus.
they injected fertilized mouse eggs with antigen determines the fate of the cells. At the moment, physicians treat these
fully rearranged, mature genes for a par- Soluble antigens, such as hen egg diseases by waging a full-scale battle
ticular immunoglobulin, thereby intro- lysozyme, are more likely to inactivate against the immune cells that cause
ducing the genes into the mouse DNA. immature B cells that bind to them. On them. Powerful anti-inßammatory drugs
As B cells matured in the developing the other hand, cell-bound aggregated and chemicals that kill or slow down
mice, the introduced genes caused al- antigens, such as D b, are more likely to activated T and B cells are used to keep
most all the B cells to produce the spe- kill immature B cells. the autoimmune response in check.
cific immunoglobulin on their surface. All in all, tolerance mechanisms for B Sadly, these methods are not always ef-
cells are very similar to those for alpha- fective and in some cases have unwant-
A
mong the Þrst researchers to try beta T cells. Immature B cells die or are ed side eÝects. Immunologists hope
this technique were Christopher inactivated when their receptors bind that if they continue to study how the
C. Goodnow and his colleagues to something. Whether tolerance can immune system learns to tolerate the
at the University of Sydney. The work- also be imposed on mature B cells, as body, they will Þnd ways to improve
ers created two groups of transgenic it can on mature T cells, remains to be the treatment of autoimmune diseases.
animals. One contained the genes for determined.
an immunoglobulin that binds to the In contrast to B cells, T cells that
foreign protein hen egg lysozyme. The have gamma-delta receptors are a mys-
other group contained a gene that in- tery. In humans and mice, there are FURTHER READING
structs cells to produce hen egg lyso- about as many of these cells as B cells ACTIVELY ACQUIRED TOLERANCE OF FOR-
zyme. When mice from one group were or alpha-beta T cells, and the gamma- EIGN CELLS. R. E. Billingham, L. Brent and
P. B. Medawar in Nature, Vol. 172, No.
allowed to mate with mice from the delta T cells are clearly very important.
4379, pages 603Ð606; October 3, 1953.
other group, they produced oÝspring Yet scientists have only an incomplete T CELL TOLERANCE BY CLONAL ELIMINA-
whose DNA contained both types of picture of how these cells contribute TION IN THE THYMUS. J. W. Kappler, N.
gene. Hence, the oÝspring had the abil- to the immune system. Gamma-delta T Roehm and P. Marrack in Cell, Vol. 49,
ity to make both hen egg lysozyme and cells seem to respond to products that No. 2, pages 273Ð280; April 24, 1987.
the immunoglobulin that binds to hen are made by the host when, for exam- A CELL CULTURE MODEL FOR T LYMPHO-
egg lysozyme. The investigators found ple, tissue is abraded, overheated, ex- CYTE CLONAL ANERGY. R. H. Schwartz
that B cells in the oÝspring were inacti- posed to dangerous metals or attacked in Science, Vol. 248, pages 1349Ð1356;
June 15, 1990.
vated, conÞrming the results found in by invading organisms. The receptors
THE NEED FOR CENTRAL AND PERIPHERAL
tissue culture dishes. on these cells appear to have been de- TOLERANCE IN THE B CELL REPERTOIRE.
A similar experiment was performed signed particularly to bind to certain C. C. Goodnow, S. Adelstein and A. Bas-
by David Nemazee, then at the Basel In- components of self. If this is true, inves- ten in Science, Vol. 248, pages 1373Ð
stitute for Immunology, and Kurt Buer- tigators are then faced with the prob- 1379; June 15, 1990.
ki of Sandoz Pharma. They made trans- lem of how these self-reactive cells are ABLATION OF ÒTOLERANCEÓ AND INDUC-
genic mice with a gene for an immu- kept under control. At the moment, TION OF DIABETES BY VIRUS INFECTION
IN VIRAL ANTIGEN TRANSGENIC MICE.
noglobulin molecule that binds to the they have no idea.
P. S. Ohashi et al. in Cell, Vol. 645, No.
MHC protein D b. Some of the transgen- A healthy immune system does not 2, pages 305Ð317; April 19, 1991.
ic mice naturally produce D b in their attack its own host. Unfortunately, the

Infectious Diseases
When bacteria, viruses and other pathogens infect the body,
they hide in di›erent places. Each component of the immune
system is most adept at rousting trespassers from one location
by William E. Paul
T
hroughout the world infectious Perhaps the key to further success that live outside human cellsÑin, say,
diseases have always been the lies in a keener appreciation of how the the blood or the ßuid surrounding lung
leading cause of human death. immune system responds to infectious cells. The white blood cells known as
Malaria, tuberculosis, infectious diar- agents. The highly sophisticated immu- CD4 T lymphocytes are of central im-
rhea and many other illnesses still ex- nologic defenses seen in humans and portance in defeating the bacteria and
act an awful toll in suÝering and mortal- other higher organisms were shaped other parasites that live within cells, es-
ity, particularly in the developing world. through evolution by the perpetual strug- pecially those found in the organelles
For a time, it was widely assumed that gle between diverse, extremely mutable that are their pathway of entry into the
infectious diseases had been brought microorganisms and their hosts. The cells. Another class of white blood cells,
under control in at least the industrial- struggle is reenacted within each indi- the CD8 T lymphocytes, routs patho-
ized nations. Yet the appearance of vidual: a personÕs immune armament gens such as viruses that associate even
AIDS and the recent resurgence of tu- meets innumerable challenges in a life- more intimately with the cellular ma-
berculosis, including the evolution of time, foiling countless opponents, and chinery of the host.
strains resistant to many drugs, vividly a fatal infection often represents the
O
illustrate that the monster was not slain only unqualiÞed loss in a generally vic- f course, this view of the im-
but merely asleep. torious campaign. mune system is a vast oversim-
Notwithstanding those grim truths, An individualÕs immune response can pliÞcation; the most protective
the power of the immune system to be tailored to the challenges that per- immune responses involve all the sys-
deal with infection is remarkableÑpar- son encounters because its mechanisms, temÕs components acting in concert. In
ticularly when enhanced by modern like its foes, are diverse and speciÞc. practice, each part may be involved, di-
vaccine technology. Because of a con- Lymphocytes can detect invading organ- rectly or indirectly, in repelling almost
certed global vaccination eÝort, small- isms because they are equipped with any type of infection. The CD4 T cells,
pox has been completely eradicated: the surface receptor molecules; the genes for example, are often loosely called
last case from a natural infection oc- for those receptors can be shuÜed and helper T cells because they secrete sub-
curred in Somalia in 1977. There is hope varied to produce structures that match stances that amplify and control virtu-
for a similar success in the control of po- virtually any foreign substance. In addi- ally all aspects of immunity. Neverthe-
lio. The World Health Organization has tion, the varied cells that make up the less, this simpliÞed scheme does aÝord
set a goal of eradicating polio by the immune system specialize in their func- insights into the principal responses in
year 2000; the disease may have already tions. These specializations endow ver- the battle against pathogens.
been eliminated from the Western Hemi- tebrates with the capacity to recognize
sphere. Those triumphs underscore the and eliminate (or at least control) mi-
need to use the vaccines we now possess croorganisms that establish themselves
to their full eÝectiveness and to develop in diÝerent microenvironments within WILLIAM E. PAUL is chief of the labora-
vaccines against those diseases that still the body. The complexity of the immune tory of immunology at the National Insti-
remain great public health problems. responseÑthe very feature that gives it tute of Allergy and Infectious Diseases.
Paul graduated with honors from Brook-
extraordinary ßexibility and cloutÑpos-
lyn College in 1956 and four years later
es daunting challenges to those who received his M.D. from the State Univer-
would decipher it. sity of New York Downstate Medical Cen-
MALARIA and other infectious diseases With that in mind, it is instructive to ter. During his distinguished career as a
continue to be major scourges, partic- describe the current understanding of researcher, he has held positions at the
ularly in developing nations. Here a the immune response in relation to var- National Cancer Institute and the New
woman at the border between Thailand York University School of Medicine. Paul
ious types of infection. In a broad sense,
and Cambodia cares for a girl suÝering has served as president of the American
each of the immune systemÕs compo-
from cerebral malaria. When bacteria, Association of Immunologists and of the
parasites and viruses colonize diÝerent nents appears to be directed against American Society for Clinical Investiga-
environments inside the body, they rely agents that infect one niche in the hu- tion. He is a recipient of the 3M Life Sci-
on a variety of tricks to evade the im- man body. The immunologic proteins ences Award and is a member of the Na-
mune system. The immune system, in called antibodies, for example, are espe- tional Academy of Sciences.
turn, has developed countermeasures. cially eÝective at destroying bacteria

PNEUMOCOCCI are bacteria that can
cause potentially fatal infections by col-
onizing spaces inside the lungs. With-
out assistance from antibodies and com-
plement proteins, macrophages cannot
destroy pneumococci, because complex
sugar molecules in the capsules sur-
MACROPHAGE
PNEUMOCOCCI rounding the bacteria prevent the mac-
rophages from adhering to them.
Ultimately, this cascade of reactions

prompts the B cells to divide and to
secrete antibodies against the capsule
polysaccharides. (Certain chemical sig-
nals, or cytokines, supplied by helper T
cells also seem to be essential to the
OTHER BACTERIA full mobilization of the B cell defense.)
The antibodies released by an acti-
vated B cell bind to the capsule around
the pneumococci and improve the abil-
ity of phagocytes to ingest them. The
A look at the infection that causes the polysaccharide capsule of S. pneu- precise means by which this result is
pneumococcal pneumonia highlights moniae. Because the molecular struc- achieved depends on the structural and
the protective importance of antibodies. tures of the polysaccharides are repeti- chemical characteristics of the antibody
When the bacterium Streptococcus pneu- tive, the same capsule antigens appear molecules. Antibodies belonging to the
moniae (also referred to as the pneumo- frequently. Consequently, many recep- immunoglobulin G ( IgG) class of pro-
coccus) enters the lungs, it colonizes the tors on a single B cell will latch onto teins have a region designated Fc-gam-
space in the alveoli, the microscopic sacs the capsule simultaneously, which brings ma. Macrophages and other phagocytes
where oxygen is transferred into the them into proximity on the cell surface. have receptor molecules that bind spe-
blood and carbon dioxide is removed. Such receptor aggregation is essential ciÞcally to the Fc -gamma region and
The pneumococcus multiplies there, for the activation of the B cells in re- that, when engaged, signal the macro-
causing tissue damage and inßammation sponse to polysaccharide antigens, and phage to ingest the attached particle.
that can impair breathing. If the bacteri- it elicits a potent B cell response. These antibodies thus give the phagocytes
al infection goes unchecked, complica- Once a B cell has been activated in the ÒhandholdsÓ they need to attack the
tions can develop, and in a substantial this way, rapid biochemical events oc- pneumococci and end the infection.
fraction of cases the patient will die. cur within it. Enzymes called tyrosine Polysaccharide-bound antibodies can
Because they live outside of cells and kinases catalyze changes in intracel- also make the pneumococci more vul-
very near the bloodstream, pneumococ- lular signal molecules, such as some nerable by activating a cascade of cir-
ci would seem to be easy prey for the proteins associated with the receptors. culating enzymes referred to as the
macrophages, neutrophils and other
phagocytic cells of the immune system
that scavenge the body for bacteria and How the Immune System Attacks Pheumococci
debris. Instead the pneumococcal bac-
teria escape detection because they are PNEUMOCOCCI
surrounded by capsules of complex sug- Because of their receptors,
ar molecules, or polysaccharides. Phago- certain B cells can bind to
cytes cannot bind to these polysaccha- polysaccharides in the
rides and consequently cannot ingest bacterial capsule and
S. pneumoniae. become activated
T
he capsular polysaccharides oÝer
IMMUNOGLOBULIN
a much more attractive target, RECEPTOR
however, for the antibody-pro-
ducing white blood cells called B lym-
phocytes. The surface membranes of B
cells bristle with receptors for certain
determinants of foreign substances, or
antigens. Each B cell carries receptors
for only one kind of antigenic determi-
nant. But because the body produces
billions of B cells, most with receptors B CELL
of distinct structure and speciÞcity, the
chances are good that at least some B
cells will bear receptors that can bind
to the antigens presented by a micro-
bial invader.
Invariably, then, some B cells have re-
ceptors for antigenic determinants of

complement system. Fragments of one bodies specialize in nabbing conspicu- cellular pathogens. The T cells provide
of the enzymes, known as C3, can bind ous invaders. The resistance to infec- the main defense against both types of
Þrmly to the bacterial surface. Recep- tion that develops in people who have infections, although the means by which
tors on the phagocytes can then recog- been vaccinated or previously exposed they control or eradicate each one are
nize the C3 fragmentsÑmuch as the Fc- to an infectious agent also depends pri- quite diÝerent.
gamma receptors bind to IgG antibod- marily on the antibody response. Perhaps the simplest and clearest il-
iesÑand augment their action against lustration of how T cells Þght intracellu-
M
the pneumococci. Because the binding any microbes, however, estab- lar infections can be drawn from studies
of even one antibody to the pneumo- lish infections inside cells, where involving the parasitic protozoa Leish-
coccal capsule can set oÝ complement antibodies and complement can- mania. The principal diseases caused
reactions, antibodies act as a powerful not reach them. Antibodies may have a by Leishmania, visceral and cutaneous
amplifying signal for inducing phagocy- chance to control such an invader while leishmaniasis, may be less well known
tosis. Furthermore, researchers have re- it is en route to its intracellular destina- to Western readers than is tuberculosis,
cently shown that the presence of com- tion, but that response may not be but they are common ailments in much
plement fragments on an antigen also prompt or vigorous enough to prevent of the developing world. Patients who
markedly increases the eÛciency with the pathogen from gaining entry to have visceral leishmaniasis, or kala-azar,
which B cells will be stimulated by that cellsÑespecially if the host has never as it is often called, suÝer from enlarged
antigen, which means that the comple- before been exposed to the pathogen. spleens and livers and low white blood
ment system also increases the produc- The situation calls for diÝerent protec- cell counts; they lose their appetites and
tion of antibodies. Because of the positive strategies, ones that can recognize begin to waste away. Left untreated, the
tive feedback inherent in this arrange- a covert attack. disease can be fatal. Cutaneous leish-
ment, the line of defense oÝered by Such intracellular infections can be maniasis is marked by ulcerated skin
antibodies is extraordinarily rapid and thought of as taking two forms. In one, lesions that generally heal but that may
eÝective. the infectious microorganisms are found take a year or more to do so. In some
The antibody response is in many re- within the membrane-bound organelles cases, the lesions may spread to the mu-
spects the simplest in the immune sys- (endosomes and lysosomes) through cous membranes of the nose and throat,
temÕs repertoire. It is a straightforward which they entered the cell. This behav- with disÞguring consequences.
race between antibody production and ior is typical of the bacteria that cause The primary target of the Leishmania
pathogen replication, a case of Òthe tuberculosis and leprosy. In the other parasite is the macrophage. During their
quick or the dead.Ó The response is well form of infection, the microorganism routine scavenging in the bloodstream,
suited to Þghting pneumococcal pneu- gains access to the ßuid part of the cell macrophages engulf Leishmania organ-
monia and other infections caused by (the cytosol) and the cell nucleus. Virus- isms and package them in vacuoles.
extracellular bacteria ; B cells and anti- es are the most common of these intra- Those vacuoles fuse with others that
Some bound antibodies activate the system

of complement enzymes. A fragment of the
C3 component can bind to receptors on the MACROPHAGE
macrophages, leading to phagocytosis of
the pneumococci
ACTIVATED
B CELL
COMPLEMENT
PROTEINS
C3
Activated B cells divide into daughter

cells that secrete antibodies specific
for the capsule carbohydrates
Fc-GAMMA Fc-GAMMA
RECEPTOR
Antibodies of the IgG type

have a region called
Fc-gamma. Using their
Fc-gamma receptors,
macrophages can bind to
IgG antibodies on the MACROPHAGE
ACTIVATED capsule and ingest
B CELL the bacteria

LEISHMANIA and many other parasites
LEISHMANIA
proliferate inside the organelles of cells,
where they are beyond the reach of
PARASITE antibodies. Macrophages ingest Leish-
IN ENDOSOME mania organisms and hold them in ves-
icles called endosomes. Many organ-
isms trapped in endosomes are later de-
stroyed by enzymes from lysosomes.
Leishmania parasites, however, survive
LYSOSOMES and multiply in the endosomes.
the type of response by the CD4 T cells

can vary, thereby signiÞcantly altering
the eÛcacy of the protective reaction.
Much of the detailed work on Leishma-
nia infections has been conducted in
PARASITES MULTIPLY mice, which are susceptible to the para-
MACROPHAGE
IN ENDOSOME site L . major. In most strains of mice,
experimental infections with L . ma-
jor are transitory: the animalsÕ immune
system can purge them. Their CD4 T
contain proteolytic (protein-splitting) tion. All the receptors on a T cell are cells, when activated by leishmanial an-
enzymes that can kill and digest most identical, as are those on B cells, but tigens, produce gamma-interferon. Yet
microbes. Leishmania, however, diÝer- the great diversity of receptors made some inbred mice, such as those be-
entiate into a new form that not only by the T cell population ensures that a longing to the BALB/c strain, cannot
can endure this chemical assault but match can be found for virtually any control Leishmania infections: instead
actually can thrive during it. The para- peptide-MHC combination. Thus, with they develop progressive lesions and
sites multiply inside the vacuole until the help of MHC molecules, T cells can eventually succumb. The reason for that
the infected macrophage host can no recognize antigens from pathogens that failure seems to be that, when stimu-
longer sustain them all and dies. hide inside cells. lated, their CD4 T cells predominantly
This recognition event develops into secrete the cytokines called interleukin-
F
ortunately, the body has a meth- an immunologic response if the macro- 4 and interleukin-10, and not gamma-
od for eliminating intracellular phage also provides an additional sig- interferon. The combination of those
parasites sequestered in this way. nal to the T cell. One surface molecule two interleukins is an especially power-
Vertebrate organisms possess sets of that can provide this Òaccessory func- ful blocker of the microbe-killing activ-
molecules that bind to peptides pro- tionÓ is B7, which macrophages and ities that gamma-interferon induces.
duced within the cell and bring them to similar cells express when they become
the cell surface, where they can be recog- infected. B7 is recognized by a separate
nized by the immune system. These ma- protein, CD28, on the T cellÕs surface.
jor histocompatibility complex ( MHC ) Interactions both between the T cell re-
molecules have a groove in their struc- ceptor and the peptideÐclass II com-
ture that can bind to a range of anti- plex and between B7 and CD28 are
genic peptides, or protein fragments. necessary for the CD4 T cells to mobi-
There are two classes of MHC mole- lize an optimal response. PEPTIDE
cules; in the case of Leishmania infec- Indeed, in the absence of the acces-
tions of macrophages, it is the class II sory B7 signal, a CD4 T cell may be-
MHC molecules that pick up peptides come anergized, or inactivated, by its PARASITES CLASS II
from the microbes. exposure to the antigenic peptide. There- MHC MOLECULE
Class II MHC molecules are imported after, that cell may be unable to re-
into the vacuoles containing the Leish- spond to the antigen. The induction of
mania organisms and other extracellu- B7 expression on macrophages display-
lar antigens ingested by the macrophage. ing foreign antigens seems to be very
The MHC molecules become loaded important for eliciting protective im-
with peptides shed by the parasites or mune responses by CD4 T cells against
cleaved from them by the proteolytic intracellular pathogens.
enzymes. Not all the peptides present
W
will be able to associate with the class hen a CD4 T cell does receive 1
II MHC molecules, but from an antigen the dual signal, it releases cy- Class II MHC (major histocompatibility
as complex as Leishmania, at least sev- tokines that increase the macro- complex) molecules produced by
eral will. These complexes of MHC mol- phageÕs ability to destroy the enemy the infected macrophage bind to
ecules and peptides then move to the within. The most critical of these cy- peptides from the parasites.
macrophageÕs outer membrane. tokines, gamma-interferon, prompts the The MHC molecule carries the
Once displayed on the surface, the macrophage to produce other cytokines, peptide to the cell surface
complexes can alert passing CD4 T such as tumor necrosis factor, and
cells to the presence of the intracellular chemicals such as nitric oxide and tox-
infection. These T cells have receptor ic forms of oxygen, which lead to the
molecules that can recognize one par- microbeÕs destruction.
ticular peptideÐclass II MHC combina- Studies have revealed, however, that

Clearly, which cytokine the T cells may contribute to the severity of the menters might be able to coax the anti-
ÒchooseÓ to make in response to intra- infections. gen-challenged T cells to produce the
cellular infection is critical to the course A similar divergence seems to be at protective gamma-interferon. Experi-
of the disease. Subsequent research has work in leprosy. In tuberculoid leprosy, ments have shown that if susceptible
revealed details about how CD4 T cells the milder of the two major forms of mice receive an injection of monoclon-
make that decision. In general, when T the disease, the skin lesions contain few al antibodies against interleukin-4 at
cells in culture are exposed to antigenic if any bacilli. The T cells of people who the onset of a Leishmania infection, the
peptides displayed on macrophages or have tuberculoid leprosy vigorously animals can control the spread of the
other presenting cells, they are stimu- produce gamma-interferon. In contrast, parasite. The monoclonal antibodies
lated to develop into cells that can se- those with the severe lepromatous form seem to neutralize the interleukin and
crete large amounts of gamma-interfer- of the disease have lesions containing allow the T cells to diÝerentiate into
on and interleukin-2, a cytokine that vast numbers of intracellular bacilli; gamma-interferon producers.
prompts T cell proliferation, but little their immune responses are dominated Conversely, when Leishmania-resis-
or no interleukin-4. Yet if interleukin-4 by the production of interleukin-4. tant strains of mice have been injected
is present in the growth medium when Detailed investigations of such re- simultaneously with the parasite and in-
the T cells Þrst recognize the displayed sponses in tuberculosis patients have terleukin-4, the animals develop more
antigens, they produce more of that cy- not yet been completed. It is nonethe- severe infections. Good vaccine strate-
tokine instead of gamma-interferon. The less well known that most individuals gies should therefore be aimed at max-
choice between making interleukin-4 or can stave oÝ the infections because imizing the production of gamma-in-
gamma-interferon seems to involve a their highly eÝective immune response terferon at the time of immunization
commitment by the lymphocyte. Once prevents the tuberculosis bacilli from and either blocking or eliminating the
a cultured T cell has responded to an spreading beyond small lesions ringed action of interleukin-4. Recently the
antigen by producing one of these cy- by white blood cells. Only in a minority newly described cytokine interleukin-
tokines, it and its progeny will not proof patients does the disease progress 12 has been shown to increase striking-
duce the other. and become fatal if left untreated. It is ly the capacity of CD4 T cells to devel-
Those observations may partially ex- tempting to speculate that the out- op into gamma-interferon producers.
plain why the outcomes of some infec- comes of those infections may be de- The use of interleukin-12 in vaccines
tious diseases diÝer from one person termined in part by whether the re- therefore deserves study.
to the next. Leishmania infections in hu- sponse of their CD4 T cells is dominat- Like many bacteria and parasites
mans take divergent courses. Most peo- ed by the release of protective gamma- such as Leishmania, viruses establish
ple are able to control the parasite interferon or of macrophage-incapaci- infections inside the cells of the body,
without becoming sick, but in a few the tating interleukin-4 and interleukin-10. beyond the reach of antibodies. Unlike
infection develops into leishmaniasis. Insights from this work could some- Leishmania, however, viruses live in
Evidence now being collected suggests day be a boon to vaccine researchers. the ßuid interior of the cell and not in-
that diÝerences in the patterns of cy- By blocking the eÝects of interleukin- side a vacuole. They interact freely with
tokines produced by a patientÕs T cells 4 at the time of inoculation, experi- many cellular components. Viruses use
How the Immune System Fights Leishmania
INFECTED
MACROPHAGE 3
The activated T cells secrete certain
cytokines that bind to receptors on
the macrophage. In response, the
macrophage produces tumor necrosis
factor, nitric oxide and other factors CYTOKINES
that kill the parasites
RECEPTOR
NITRIC OXIDE
AND OTHER
FACTORS
2
CD4 T cells that have complementary
CD4 B7 receptor molecules are activated by
the peptide–class II complex and by
the B7 molecule on the surface of
the macrophage
CD28
RECEPTOR
DEAD
CD4 T CELL PARASITES

the protein-synthesizing apparatus of tumor necrosis factor. Those molecules
human cells, for example, to manufac- limit viral replication inside a cell, while
ture their own proteins. Consequently, also attracting macrophages and other
the viral proteins intermingle with the phagocytes that can destroy the cell.
normal cellular proteins instead of stay- The control of viral infections through
ing within a neat vacuole bundle and so the destruction of the bodyÕs own cells
present a less easily isolated target for has some powerful advantages. If the
the molecules of the immune system. recruitment of antigenic peptides by
Despite the intimacy of this arrange- the class I MHC molecules and the sub- PEPTIDES
ment, MHC molecules in all the bodyÕs sequent T cell response are fast enough,
cells can still Þnd and display peptide the infected cells can be destroyed even CLASS I
fragments from viruses. The process is before the viral particles inside them VIRAL MHC MOLECULE
fundamentally similar to the one that have been completely assembled. Any PROTEIN
VIRUS
reveals Leishmania infection, but it has virus particles that may be released
some important diÝerences. First, the when the cells are killed will not be ca-
MHC molecules that can bind to pep- pable of infecting other cells, and so INFECTED CELL
tides from the cytosol are class I pro- the infection will be terminated before
teins, which diÝer in structure from the it can propagate.
class II molecules. When viral and cellu-
O
lar proteins are fragmented in the cyto- n the other hand, the immuno- 1
sol, transporter molecules carry them logic response mediated by CD8 Class I MHC molecules pick up
into the organelle called the rough en- T cells carries the potential for viral peptides and carry them to
doplasmic reticulum. There the peptides extensive harm to the host. If a virus the surface of the infected cell
are loaded onto the class I MHC mole- multiplies and radiates quickly, the im-
cules. After further processing, the pep- mune systemÕs attempts to contain it
tideÐclass I MHC complexes are shipped may do no more than leave a path of
to the cellÕs surface in secretory vesi- destruction in the wake of the virus,
cles. Once they are inserted into the while never quite catching up to it. The
outer membrane, the complexes can be tissue damage associated with the infec-
CD8 T CELL
examined by T cells. In this case, how- tion would therefore result from the ef-
ever, the lymphocytes are CD8 T cells, fects of both the virus and the immune
which bear receptors speciÞc for the reaction. In general, the amount of tissue
class I complexes. damage caused by such an infection will cells. In these cases, the disease stems
When CD8 T lymphocytes detect anti- be largely determined by how fast the not from the virus at all but rather from
genic peptides, they often act, directly immune response occurs in relation to the immune response.
and indirectly, to kill the infected cells. the rate of spread of the virus. One experimental demonstration of
These T cells can destroy their infected The antiviral immune response be- the harm that such immune responses
targets by secreting perforin and other comes even more problematic when can do comes from work with the lym-
proteins that disrupt the integrity of the the viral infection itself does little or phocytic choriomeningitis virus (LCMV),
cellular membrane. Recent work indi- no damage to the cellsÑand many virus- which infects tissues in the nervous
cates that the killer T cells may also act es do indeed infect cells without seri- system but has relatively little intrinsic
by producing molecules that elicit a ously impairing cellular function. Such pathogenicity. If newborn mice are in-
form of cell death called apoptosisÑin noncytopathic infections can still pro- oculated with LCMV, the infection dis-
eÝect, these signals tell the infected voke forceful reactions by CD8 cells. If perses speedily through their tissues
cell that it should kill itself. In addition, the harmless virus spreads relatively but causes no evident disease. The rea-
activated CD8 cells release potent cy- quickly, the T cells may end up attack- son is that their immature immune sys-
tokines, including gamma-interferon and ing a very large number of the hostÕs tems learn to tolerate the viral antigens
as harmless constituents of the body;
consequently, their T lymphocytes ig-
VIRUS nore the LCMV-infected cells. If cyto-
toxic T cells that respond to LCMV an-
tigens are injected into these mice, how-
ever, the immune response is drastic and
often kills the animals.
A variety of noncytopathic human in-
CELL fections show a similar pattern of tis-
VIRAL GENOME sue injury. Chronic carriers of the hep-
VIRUSES invade cells by binding to cer-

tain surface molecules and penetrat-
ing the membrane. Once within a cell,
the viruses then use many components
of the cell to replicate themselves. Cyto-
pathic viruses damage and sometimes
kill their cellular hosts through these
REPLICATION AND RELEASE
processes. Immune defenses that are
OF NEW VIRUSES
eÝective against other types of infec-
VIRAL GENOME REPLICATION tions may not work against viruses.

How the Immune System Fights Viral Infections
3
The activated T cells release
cytokines that inhibit the replication
of the virus and cytotoxins that kill
the infected cell. The host cell dies,
but the cycle of viral infection halts
CYTOKINES
PERFORIN AND OTHER

CYTOTOXINS
VIRUS
CANNOT
INFECTED REPLICATE
CELL DIES
CD8
2
CD8 T cells with complementary
receptors bind to the displayed
peptide–class I complex and
RECEPTOR become activated
atitis B virus, for example, typically suf- lack of an answering immune response gens continue to pose to human immu-
fer liver damage even though it is a fair- will protect against disease. nity. The tremendous diversity and mu-
ly harmless pathogen. The destruction tability of infectious agents ensure that
S
of the infected liver cells is almost cer- uch examples illustrate the fallibil- such challenges will not abate. Never-
tainly a consequence of actions waged ity of this elegant but imperfect theless, the understanding of the mo-
by cytotoxic T cells, which can be found defense system: the very mecha- lecular basis of cellular responses is de-
in both the blood and the liver of the nisms that provide protection against veloping rapidly and promises to illu-
patients. certain kinds of disease will sometimes minate new ways to minimize tissue
There are indications that the im- abet the pathology of others. Perhaps damage and to control infection. Har-
mune system may sometimes subvert the cruelest demonstration of this prin- nessing our knowledge to boost immune
its own reaction to viral infections if ciple comes from viral infections that responses will be critical to eÝorts to
that response would hurt the host more exploit the cells and interactions of the conquer the present and future micro-
than the pathogen. Investigators have immune system to propagate them- bial threats to humanity.
shown that if mice are injected with selves. In such infections the immune
overwhelming numbers of LCMV, the response actually assists the replica-
CD8 T cells that should mobilize against tion of the virus rather than limiting it.
the infection become activated but then That is exactly what happens when FURTHER READING
die. Indeed, it seems likely that such people become infected by the human
THE PATHOGENESIS OF INFECTIOUS DIS-
cell deaths are the common result of a immunodeÞciency virus (HIV) that caus-
EASE. Cedric A. Mims. Academic Press,
highly exuberant T cell response to an es AIDS. The virus resides preferentially 1987.
antigenic stimulus. in CD4 T lymphocytes and other cells of VACCINES. Gordon L. Ada in Fundamen-
The elimination of those antigen-spe- the immune system. As it turns out, ac- tal Immunology. Edited by William E.
ciÞc T cells leaves a strategic hole in tivated T cells are much more hospitable Paul. Raven Press, 1989.
the immunologic defense. Against a non- to growing viruses than are resting T REGULATION OF IMMUNITY TO PARASITES
cytopathic virus, this deÞciency may be cells; consequently, the more agitated BY T CELLS AND T CELLÐDERIVED CYTO-
KINES. A. Sher and R. L. CoÝman in An-
to the hostÕs beneÞt because it allows the immune system becomes, the better
nual Review of Immunology, Vol. 10,
the cells harboring the virus to survive. the conditions for viral replication. In pages 385Ð409; 1992.
One might argue that the elimination addition, cytokines such as tumor necro- ROLES OF ab AND gd T CELL SUBSETS IN
of these T cells after an exposure to sis factor, which T cells produce when VIRAL IMMUNITY. P. C. Doherty, W. Al-
overwhelming numbers of a virus is an they detect viral antigens, can actually lan, M. Eichelberger and S. R. Carding in
adaptation of the immune system to an stimulate the replication of viruses in Annual Review of Immunology, Vol. 10,
infection that it cannot control without CD4 T cells. Thus, HIV uses the most so- pages 123Ð151; 1992.
causing irreparable injury to the host. phisticated defenses of the immune sys- IMMUNITY TO INTRACELLULAR BACTERIA.
Stefan H. E. Kaufmann in Annual Re-
As long as the persistence of the virus tem to further its own survival.
view of Immunology, Vol. 11, pages
does not lead to the death of its host Diseases such as AIDS are a painful 129Ð163; 1993.
cells or to malignant abnormalities, the reminder of the challenges that patho-

AIDS and the Immune System
The AIDS virus exploits the immune
system to replicate itself. New findings are showing
how it wreaks havoc on the body’s defenses
by Warner C. Greene
I
t is now 12 years since acquired im- cent of the worldÕs present population. than does HIV-1, the more common
munodeÞciency syndrome sprang To be certain, other diseases, such form elsewhere. It is even possible that
into medical and public awareness as malaria, kill more people than AIDS some rare strains are benign. Some ho-
as a fatal disease of the immune sys- does. But the rapid spread of HIV, to- mosexual men in the U.S. who have
tem. The term ÒAIDS,Ó or its equivalent gether with the lack of a vaccine or sat- been infected with HIV for at least 11
in other languages, has since become isfactory treatment, makes this disease years show as yet no signs of damage to
recognized around the world. Other ill- uniquely alarming. New infectionsÑthe their immune systems. My colleagues
nesses besides AIDS cause inappropri- majority now from heterosexual con- Susan P. Buchbinder, Mark B. Feinberg
ate immune responses, as numerous tactÑcontinue at the estimated rate of and Bruce D. Walker and I are studying
examples in this issue illustrate. Yet one every 15 seconds. No country or these long-term survivors to ascertain
AIDS warrants special consideration. social group is immune. Currently HIV whether something unusual about their
First, it is now tragically clear that is spreading quickly in East Asia, a re- immune systems explains their response
the virus that causes AIDS, the human gion that was largely spared in the ear- or whether they carry an avirulent strain
immunodeÞciency virus (HIV), is one ly years of the pandemic. Worldwide, of the virus.
of the principal threats to human life women now account for some 40 per-
T
and health worldwide. In an article cent of AIDS cases; about 10 percent are he great majority of investiga-
about the epidemiology of AIDS pub- children born to infected mothers. Pub- tors believe not only that HIV is
lished in ScientiÞc American in October lic education campaigns aimed at reduc- the primary cause of AIDS but
1988, Jonathan M. Mann, James Chin, ing transmissionÑmainly exhortations also that HIV infection alone will usual-
Peter Piot and Thomas Quinn estimat- to the sexually active to use condoms ly cause profound immune dysfunction
ed that more than 250,000 cases of the and to drug users to sterilize needles over time. No other speciÞc pathogen
disease had then occurred worldwide and syringesÑhave had limited success. is known to be necessary. It does seem
and that between Þve and 10 million The second reason for discussing HIV likely that other infections in a person
people were infected with HIV. Five is that it is the most intensively stud- carrying HIV may hasten immune deÞ-
years later the situation is far worse. ied virus in history. We already have an ciency ; this area is being actively inves-
The Global AIDS Policy Coalition, outline sketch of how the genes and tigated. Such opportunistic infections,
which Mann coordinates, now estimates proteins in the HIV virion, or virus par- which frequently complicate the clinical
that the actual number infected by the ticle, operate. We still lack, however, a course of HIV-infected patients, are of-
end of 1987 was about seven million; it clear understanding of what controls ten the eventual cause of death. Never-
places the number infected by the end its replication and how it destroys the theless, if we are to understand AIDS,
of 1992 at 19.5 million, almost three human immune system. we must understand HIV.
times the earlier Þgure. Although anti- I must emphasize that all responsi- High-resolution electron microscopy
viral and other medications may mod- ble opinion holds that HIV is indeed the has shown the HIV virion to be rough-
estly prolong the lives of those infect- primary cause of AIDS. A small num- ly spherical and about one ten-thou-
ed, the great majority of them will, bar- ber of cases of people with immune de- sandth of a millimeter across. Its outer
ring some major advance, eventually Þciency who are not infected with HIV coat, or envelope, consists of a double
die of an AIDS-related illness. More than received inappropriately widespread
three million people have developed publicity last year, which fostered the
full-blown AIDS; most have already died. unsubstantiated notion that there is an-
Responsible estimates of the number other cause of AIDS not detected by cur- WARNER C. GREENE is director of
the Gladstone Institute of Virology and
of cases of HIV infection likely to have rent blood tests. This unfortunate epi-
Immunology and professor of medicine,
occurred by the year 2000 range from sode only fueled the paranoia that sur- microbiology and immunology at the Uni-
40 million to more than 110 million. rounds the disease. In fact, there is little versity of California, San Francisco. He
The second number is about 2 per- reason to believe that the condition of earned his M.D. and Ph.D. in 1977 at
these patients was caused by any virus Washington University School of Med-
or that it is becoming more common. icine. He has worked at the National
Yet there are many diÝerent strains Cancer Institute and at Duke University,
T LYMPHOCYTE infected with the hu- where he taught and was an Investigator
man immunodeÞciency virus (HIV) dis- of HIV, and epidemiological and labo-
for the Howard Hughes Medical Insti-
plays a characteristic lumpy appearance. ratory studies suggest that some are tute. His research has focused on T cell
The protuberances colored green in this deadlier than others. HIV-2, for exam- activation and growth and on abnormal-
electron photomicrograph are virus par- ple, which is prevalent in West Africa, ities induced by retroviral infection.
ticles in the process of budding. seems to produce less severe disease

ANATOMY OF HIV:: electron microscopy and other techniques
have led to a consensus on the complex structure of the AIDS
virus (above). The truncated cone-shaped core in a spherical
envelope is the dominant feature. The micrograph (right)
shows HIV particles in an intracellular space inside a cul-
tured human macrophage. Cores can be discerned in mature
virions; they are lacking in immature virus particles.
layer of lipid molecules similar to and of the immune system, particularly killer ducing HIV is tinyÑabout one in 40. In
taken from the membranes surround- T cells (which attack virus-infected cells) the early stages of chronic infection, few-
ing human cells. This bilayer is stud- and B cells (which produce antibodies). er than one in 10,000 T4 cells in blood
ded with proteins, including some of are doing so. If the virus were killing
O
human origin. These proteins, the so- nce an HIV virion has entered the cells just by directly infecting them,
called class I and class II major histo- a cell, a complex sequence of it would almost certainly have to infect
compatibility complex molecules, are, events follows that, if complet- a much larger fraction at any one time.
in their normal location, important in ed, leads to the budding of new vi- Another clue that a more complicat-
controlling the immune response. rus particles from the infected cell. But ed process is involved comes from a
The coat of the virion also bears nu- when a person acquires an HIV infec- recent experiment done by Donald E.
merous viral protein ÒspikesÓ that pro- tion, he or she initially mounts a vigor- Mosier and his colleagues at the Scripps
ject into the external medium. Each ous immune defense. During this acute Research Institute in La Jolla, Calif. They
spike probably consists of four mole- phase of the infection, B cells produce found that strains of HIV that kill T4
cules of a protein called gp120 on the antibodies that neutralize the virus, and cells most eÝectively in culture are not
outside and the same number of gp41 activated killer T cells multiply and de- necessarily those that cause the biggest
embedded in the membrane. (Gp stands stroy infected cells, much as they would depletion of T4 cells in genetically en-
for glycoproteinÑthe proteins are linked in many other diseases. Although it is gineered mice that lack their own im-
to sugarsÑand the number refers to the possible that the immune system may mune system and have been transfused
mass of the protein, in thousands of successfully Þght oÝ HIV at a very ear- with human CD4 cells.
daltons.) These envelope proteins play ly stage, by the time antibodies to HIV If direct attack by the virus is not
a crucial role when HIV binds to and are found in the blood, infection is gen- the only reason for the decline of T4
enters target cells. erally permanent. cells in blood, what are the other pos-
Underneath the envelope is a layer of The clinical picture in acute HIV infec- sibilities? A variety of plausible theo-
matrix protein called p17, which in turn tion is that of a mild, ßulike illness, typi- ries exist, although none has yet been
surrounds the core, or capsid. It has cally with fever and muscle aches, that proved, and indeed several diÝerent
the shape of a hollow, truncated cone usually lasts no more than a few weeks. mechanisms may be at work. One theo-
made of another protein, p24, which During this time, large amounts of the ry is that uninfected killer T cells might
contains the genetic material of the vi- virus are present in the bloodstream, start destroying infected immune sys-
rus. Because HIV is a retrovirus, its ge- and transmission is probably relative- tem cells, including helper T cells. Oth-
netic material is in the form of RNA, or ly easy. Then the immune response is er proposals are more complex. Anti-
ribonucleic acid, rather than the more mounted and begins to eliminate infect- bodies that recognize gp120 and gp41
usual DNA, or deoxyribonucleic acid. ed cells and circulating viruses. A pro- in the viral envelope might also attach
Two strands of RNA, about 9,200 nu- portion of infected cells remains, how- to and interfere with histocompatibili-
cleotide bases long, Þt within the viral ever, eluding the hostÕs defenses, and ty antigens on healthy cells, impairing
core. They are attached to molecules of the virus continues to replicate in low- immune function. This could happen,
an enzyme, reverse transcriptase, which er numbers for as long as a decade. For some researchers have suggested, be-
transcribes the viral RNA into DNA most of this period of chronic infection, cause gp120 and gp41 have character-
once the virus has entered a cell. Also the patient is usually quite well. Only istics similar to the histocompatibility
present with the RNA are an integrase, after several years does the virus so antigens. Alternatively, those similari-
a protease and a ribonuclease, enzymes signiÞcantly damage the immune sys- ties could mean that gp120 triggers an
whose functions I shall describe later. tem that opportunistic malignancies immune attack on healthy T4 cells.
Two other proteins, p6 and p7, are pres- and infections appear. Another hypothesis rests on the fact
ent as well. Ideas about how the damage takes that T cells are normally stimulated to
The gp120 envelope protein can bind place have shifted considerably in the divide when receptors on their surfaces
tightly to CD4, a protein found in the past two years. When Michael S. Gottlieb recognize a foreign protein on another
membranes of several types of immune of the University of California at Los An- cell. Complexes of gp120 and gp41 that
system cells. This property makes such geles Þrst described in 1981 the clinical become detached from HIV, together
cells vulnerable to HIV infection. When syndrome that came to be known as with antibodies, may bind to the CD4
the gp120 of a virion binds to a cell AIDS, he noted that his patients had molecules on T4 cells and so prevent
bearing CD4, the membranes of the very low numbers of T4 lymphocytes in them from dividing, a phenomenon
virus and the cell fuse, a process gov- their blood. Studies have since demon- called anergy [see ÒT Cell Anergy,Ó by
erned by the gp41 envelope protein. strated that these cells decrease grad- Ronald H. Schwartz; SCIENTIFIC AMERI-
The virus core and its contents are ually in number during the long sub- CAN, August].
then brought inside the cell. clinical phase of chronic infection, from Recent experiments point to yet an-
Some CD4-bearing cells, known as about 1,000 per cubic millimeter to less other possibility. In people with HIV in-
dendritic cells, are present through- than 100. The observation naturally sug- fection, many T cellsÑeven those that
out the bodyÕs mucosal surfaces and gested that the decrease in T4 cells was are not infectedÑcommit cellular sui-
elsewhere; it is possible that these are responsible for the decline in immune cide when they are stimulated by for-
the Þrst cells infected by HIV in sex- function that happens over the same eign proteins, rather than dividing as
ual transmission. Immune system cells period. they should. This genetically controlled
called macrophages and monocytes also For a while, it seemed possible that function, known as apoptosis, or pro-
carry the CD4 molecule and are simi- HIV causes the decrease in numbers of grammed cell death, normally occurs in
larly vulnerable. Macrophages, in par- T4 cells solely by infecting and killing the thymus gland and serves to elimi-
ticular, may carry HIV to other parts of them. Most researchers now believe the nate T cells that would attack the bodyÕs
the body, including the brain. But HIVÕs process is more complex. Even in pa- own tissues. But Joseph M. McCune and
principal targets are the CD4-bearing tients in the late stages of HIV infection his colleagues at SyStemix have found
helper T lymphocytes, or T4 cells. These with very low blood T4 cell counts, the evidence that HIV infection triggers
cells help to activate other components proportion of those cells that are pro- widespread apoptosis in mice that, lack-
LIFE CYCLE OF HIV begins when virus
particles attach to CD4 receptors on the
cell membrane (1) and are drawn into
the interior of the cell. The viral core
then partially disintegrates (2) as reverse
transcriptase (purple) produces DNA
(blue) from the viral RNA (red ). The vi-
ral DNA enters the nucleus, where it is
integrated into host chromosomes (3).
Host cell proteins bind to the DNA , ini-
tiating transcription (4 ). Short RNA mol-
ecules leave the nucleus (5 ) and make
viral regulatory proteins. Later, medi-
um-length and long RNAs leave the nu-
cleus and generate structural and enzy-
matic proteins (6 ). Viral protease ( yel-
low) becomes active as RNA and viral
proteins (orange) enter the budding new
virus (7 ). Core and other components
form after the virus has budded (8 ).
ing an immune system, have had trans-

plants of human fetal thymus and liv-
er cells.
The researchers found that HIV
caused a rapid loss of CD4 thymus cells
in the implanted tissue, together with
characteristic signs of apoptosis. A sim-
ilar process might occur in infected
humans. That could explain why AIDS
progresses speedily in infants, whose
immune systems are developing. The
mechanisms that might trigger exces-
sive apoptosis are, however, unknown. tion, the amount of viral RNA in the Such thinking gains further support
Whatever the mechanisms, important blood is very low. In fact, it is often from the observation that even before a
clues have emerged about where much impossible to detect by conventional patientÕs T4 cells start to decline, a sub-
of the damage to the immune system techniques. As symptoms develop, the set called memory T cells, which are re-
is occurring. Researchers now know that amount rises rapidly and may approach sponsible for remembering foreign pro-
T4 cells in the blood are not the main the peak levels present during the ini- teins, begins responding abnormally to
site of viral replication during the chron- tial acute phase, prior to the immune stimulation. Ultimately, these cells dis-
ic asymptomatic phase of infection. Giu- response. A few investigators have sur- appear. Other changes also occur. These
seppe Pantaleo and Anthony S. Fauci mised that some type of signal sets oÝ phenomena could be a consequence of
and their colleagues at the National In- a late wave of rapid viral replication that pathology in the lymph nodes.
stitute of Allergy and Infectious Dis- heralds the onset of full-blown AIDS.
T
eases have shown convincing evidence Recent technical advances in our ability he declining T4 cell count in the
that much of the HIV is replicating not to detect small amounts of the virus blood might, then, be at best an
in the blood but in the scores of lymph make this seem unlikely. indirect indicator of damage tak-
nodes found throughout the body. The Rather it is now clear that the vi- ing place elsewhere in the body. If so, it
lymph nodes are where T4 cells, as well ral burden is substantial and increases underscores the importance of stop-
as other immune cells such as B cells, steadily throughout most of the chron- ping the virus from multiplying even in
cluster to respond to foreign invaders. ic asymptomatic phase of infection. the earliest stages of infection. One
Pantaleo and his associates have doc- The abrupt rise in blood levels of viral strategy being tried is to release Òde-
umented that HIV gradually destroys RNA in the last stages of infection can coyÓ CD4 receptor molecules into the
the lymph nodes. The Þnding suggests most likely be attributed to the Òburn- blood. These, it is reasoned, should at-
that the decline in the number of T4 ing outÓ of the lymph nodes. These or- tract HIV particles to stick to them ra-
cells in the blood could be a result of gans contain cells with delicate, Þn- ther than to CD4-bearing cells. Results
damage to the lymph nodes. In fact, swel- gerlike projections, known as follicular so far have been disappointing, partic-
ling of these organs has long been rec- dendritic cells, that normally present an- ularly against natural strains of the vi-
ognized as one early sign of infection. tigens to T4 cells but also Þlter out var- rus. It is likely that future interventions
Nevertheless, for convenience, research- ious infectious agents. Collapsing nodes will focus on stopping the virus from
ers have, perhaps mistakenly, usually fo- infected with HIV might no longer eÛ- replicating after it has entered a cell.
cused on the changing cell counts and ciently remove the virus, allowing its Thousands of meticulous experi-
amounts of viral RNAÑa marker for escape into the bloodstream. What pre- ments, many involving specially disabled
the virusÑin the bloodstream. cisely causes the death of the follicular strains of HIV, have demonstrated that
The central involvement of the lymph dendritic cells remains a mystery, but inside a cell infected with HIV there is
nodes could explain one puzzling ob- the process may be as important as the an intricate but elegant interplay among
servation. During early chronic infec- loss of T4 cells. proteins produced by viral RNA and
102 SCIENTIFIC AMERICAN September 1993

proteins produced normally in healthy infectionÑazidothymidine (also known their study, although clinical trials are
cells. SigniÞcantly for the development as AZT or zidovudine), dideoxycytidine proceeding. I suspect, however, that HIV
of therapies, it is clear that only if the (ddC) and dideoxyinosine (ddI)Ñall work will not easily succumb to drugs that are
right conditions are met will HIV com- by interfering with reverse transcription. aimed at a single step in its life cycle.
plete its life cycle and unleash scores of Each is somewhat similar to one of the
R
progeny that disseminate an infection. four nucleotides that reverse transcrip- ecent discoveries indicate oth-
The Þrst thing that happens to the tase connects together to build DNA. er ways in which the early stag-
two strands of HIV RNA in a newly in- When the enzyme incorporates one of es of viral replication might be
fected cell is that their encoded mes- these drugs rather than a genuine nu- thwarted. Irvin S. Y. Chen and his col-
sage is converted into DNA by the mul- cleotide into a growing DNA strand, leagues at the U.C.L.A. School of Medi-
tiple reverse transcriptase molecules the reverse transcriptase cannot extend cine have performed experiments indi-
attached to the viral RNA. The process it further. cating that reverse transcription can-
is the opposite of normal transcription, The problem is that the high rate of not be completed unless the host T cell
which makes RNA from DNA. Reverse mutation means that within months vari- is activated by a foreign protein. Oth-
transcriptase moves along the RNA, ant reverse transcriptases appear in the er results, from Mario Stevenson and
producing an equivalent chain of DNA body that can produce viral DNA even his co-workers at the University of Ne-
by stitching together the nucleotide in the presence of the drugs. This rapid braska Medical Center, suggest that it
building blocks. When the Þrst DNA Darwinian evolution occurring within is the next stage in the replication pro-
strand is completed, the reverse tran- patients, as well as the toxicity of the cess that is blocked in resting cells. In
scriptase starts constructing a second drugs, almost certainly explains why the this operation, the two DNA strands
DNA strand, using the Þrst one as a beneÞts of AZT are only temporary. produced by reverse transcriptase are
template. Other potential therapies aimed at integrated into the host cellÕs chromo-
The reverse transcriptase that HIV blocking reverse transcriptase are on somes by the integrase present in the
uses is not very accurate: on average the horizon. One of these is the Òcon- HIV virion.
it introduces an error, or mutation, ap- vergent triple therapyÓ devised by Yung- In either case, the remarkable impli-
proximately once in every 2,000 incor- Kang Chow and his colleagues at Har- cation is that something made in a T4
porated nucleotides. This intrinsic inÞ- vard Medical School. These researchers cell when it is activated is critical to the
delity underlies HIVÕs remarkable abili- had reported in Nature that the muta- virusÕs becoming integrated in the host
ty to become resistant to various drugs, tions reverse transcriptase undergoes cell. When unintegrated, HIV is unstable
because new variants of viral proteins in the presence of a mixture of AZT, di- in the cell, decaying after a few days.
are being constantly generated during deoxyinosine and one other drug, nevi- That could be a weakness worth exploit-
the course of an infection. rapine or pyridinone, are so extreme ing. Various immunosuppressive drugs,
The antiviral drugs that have been ap- that the enzyme becomes ineÝective. such as cyclosporine and FK 506, re-
proved in the U.S. for treatment of HIV The workers have since found a ßaw in duce the activation of T cells. A treat-
SCIENTIFIC AMERICAN September 1993 103

ment protocol that intermittently de- Some of the cellular signaling pro- copies of shorter sequences by cellular
creased T cell activation might pre- teins that bind to the enhancers in the splicing enzymes. When they reach the
vent HIV from being integrated and so HIV long terminal repeats are members cytoplasm, they are only about 2,000
prolong the asymptomatic phase of in- of an important family known as NF-kB/ nucleotides in length. These early-phase
fection. Such an approach would not Rel. Present in virtually all human cells, short transcripts encode only the virusÕs
be without risk, since we know that these regulatory proteins increase the regulatory proteins: the structural genes
a functioning immune system is vital transcriptional activity of many genes. that constitute the rest of the genome
for the initial containment of the virus. SigniÞcantly, cells step up production are among the parts that are left behind.
Experiments, perhaps employing mon- of some members of this family when One of the Þrst viral genes to be tran-
keys infected with the HIV-like simi- they are stimulated by foreign proteins scribed, tat, is encoded in the short tran-
an immunodeÞciency virus (SIV), could or by hormones that control the im- scripts and produces a regulatory pro-
delineate the relative beneÞts versus mune system. It appears that HIV utiliz- tein that speeds up transcription of the
the dangers of the approach. es the NF-kB/Rel proteins resulting from HIV provirus. This protein acts by bind-
Once the two strands of HIV DNA activation of immune cells to boost its ing to a speciÞc sequence within the vi-
have been integrated into the host cellÕs own transcription. ral RNA, called TAR. Once the tat pro-
chromosomes, they are known as the tein binds to the TAR sequence, tran-
T
provirus. As far as we can tell, infec- he virus does not have everything scription of the provirus by cellular RNA
tion of the cell is then permanent. But its own way : my colleagues Ste- polymerase II accelerates at least 1,000-
many processes still have to be com- fan Doerre and Dean W. Ballard fold. Ro 31-8959, a compound made by
pleted before the cell can bud new viri- and I have found that one cellular pro- HoÝmannÐLa Roche, is in a new class
ons. HIV is an extraordinarily complex tein, c-Rel, a member of the same NF- of drugs that have the ability to inhibit
virus. Whereas some retroviruses man- kB/Rel family, actually hinders HIV tran- the function of tat. It is now being eval-
age to get by with only three genes, scription. But it is made more slowly uated in clinical trials.
HIV has nine or more, and at least Þve than are the factors that stimulate tran- Another regulatory gene expressed in
of them are essential for replication. scription. Clearly, the virus succeeds in the early phase is called nef. Until quite
Before the provirusÕs genes can be ef- getting itself transcribed often enough recently, it was believed that nef Õs role
fective, RNA copies of them that can be to spread infection. At Þrst, the provi- was to suppress transcription, but new
read by the host cellÕs protein-making rus relies on NF-kB and other proteins experiments have cast doubt on that in-
machinery must be produced by for- present in the activated cell to initiate terpretation. Nef protein may somehow
ward transcription. This transcription its transcription into RNA. This pro- modify the cell to make it more suit-
stage is accomplished by the cellÕs own cess, though slow to begin with, can be able for manufacturing HIV virions lat-
enzymes, including RNA polymerase II. likened to the tumbling of a stone that er. In any event, it now appears that
But the process cannot start until the sets more and more stones rolling until production of nef protein is required
polymerase is activated by various mo- it creates an avalanche. for the development of AIDS, a Þnding
lecular switches located in two stretches The RNA transcripts from the pro- that could be important if a way can be
near the ends of the provirus: the long virus then undergo complex processing found to block its action.
terminal repeats. This requirement is by enzymes in the cell. Two distinct A third regulatory protein encoded
reminiscent of the need of many genes phases of transcription follow the in- in the early short transcripts is called
in multicellular organisms to be Òturned fection of an individual cell by HIV. In rev. We know that rev plays an essen-
onÓ by proteins that bind speciÞcally to the early phase, which lasts roughly 24 tial role in the life cycle of HIV. SpeciÞ-
controlling sequences termed enhanc- hours, RNA transcripts produced in the cally, this protein appears to be re-
er elements. cellÕs nucleus are snipped into multiple sponsible for switching the processing
of viral RNA transcripts to the pattern
that dominates once a cell has been in-
fected for more than 24 hours. Rev pro-
tein binds to viral RNA at a sequence
that is absent in the early short tran-
scripts. Longer transcripts that do con-
tain the rev-binding sequence are con-
Þned within the nucleus during the
early phase. Once the amount of rev
protein in the cell has built up to a high
enough level, splicing and movement
of the transcripts change to the pattern
characteristic of the late phase.
In this late phase, two new size
classes of RNAÑlong (unspliced ) tran-
scripts of about 9,200 bases and me-
dium-length (singly spliced) transcripts
of some 4,500 basesÑmove out of the
nucleus and into the cytoplasm. These
longer transcripts encode HIVÕs struc-
tural and enzymatic proteins. The cru-
cial function of rev as a switch that
turns on production of viral structural
LYMPH NODES are believed to be an important site of HIV replication. In this sec- and enzymatic proteins makes it an at-
tion of a lymph node from a patient with early-stage infection, the tissue has been tractive target for drug development.
stained to show the presence of HIV (white dots) in localized patches. Unfortunately, no substance that eÝec-
Promotes Required Viral-coat proteins Uncertain
Binding sites for host Nucleocapsid- infectivity for efficient mediating CD4 binding function
transcription factors core proteins of cell-free virus virion budding and membrane fusion
nef
gag vif vpu env
LTR
LTR
pol vpr tat
rev
Reverse transcriptase, Weak Potent

protease, integrase transcriptional transcriptional Regulator of structural
and ribonuclease activator activator gene expression
HIV GENES are indicated by the positions of colored bars ducing machinery of the host cell . Structural and enzymatic
along the DNA of the provirus. Genes that overlap utilize the genes are green; regulatory genes, purple; others, tan. Sec-
same region of DNA but are read diÝerently by protein-pro- tions called long terminal repeats ( LTRs) are yellow.
tively blocks revÕs action has yet been cade of the epidemic we will have anti- the cells resistant to HIV infection. This
identiÞed that is not unacceptably toxic. viral therapies substantially better than approach, a form of gene therapy that
Once the long and medium-length those now available. I strongly suspect Baltimore dubs Òintracellular immuni-
transcripts reach the cytoplasm, the that these will consist of combinations zation,Ó might be possible with the tech-
cellÕs protein-making machinery begins of drugs directed against diÝerent parts nology of the next century. Some mu-
constructing the components for new of the life cycle of HIV. tant HIV genes that confer immunity
virions. The viral gene called gag en- In contrast, I feel there is less cause on T cells in tissue culture have already
codes the core proteins; pol encodes for optimism about prospects for the been identiÞed.
the reverse transcriptase, protease, in- development of a practical prophylac- At present, we lack gene delivery and
tegrase and ribonuclease; and env en- tic vaccine for HIV in the near future. expression systems that could make
codes the two envelope proteins. Three The virusÕs ability to mutate quickly such techniques widely applicable. If
other proteins encoded in the longer and by other means to elude immune an injectable delivery system for protec-
transcripts are produced as well, en- responses poses a serious obstacle. Al- tive genes could be developed, the ap-
coded by the vpr, vif and vpu genes. though clinical trials have shown that proach might prove practical and cost-
They have as yet ill-deÞned eÝects on vaccines made from various viral pro- eÝective even in underdeveloped coun-
infectivity, and the last two may play a teins, chießy the envelope, can improve tries. This avenue merits investigation.
part in the assembly of new virions. human immune responses to the virus In the meantime, there is still much
But all three seem to be signiÞcant for in laboratory tests, this is a far cry from to be learned about HIV. For now, ef-
HIVÕs pathological properties. demonstrating useful protection against forts to educate people about the virus
The newly formed precursors of the natural infection. Even if a course of should be redoubled. In the Þnal analy-
proteins that will constitute the cores of vaccinations could increase immunity, sis, preventing transmission of HIV is
new virions aggregate in the cytoplasm, economic considerations may make the best strategy.
together with complete copies of the vi- such an approach unfeasible in the de-
ral RNA and the precursors of its asso- veloping countries of the world where
ciated enzymes. They all then move to HIV is now spreading most rapidly.
FURTHER READING
the surface of the cell and bud through There are some bright spots. Ron-
the membrane, where they acquire their ald C. Desrosiers of Harvard Univer- THE MOLECULAR BIOLOGY OF HUMAN IM-
lipid membranes and viral envelope pro- sity and his colleagues have been able MUNODEFICIENCY VIRUS TYPE 1 INFEC-
TION. Warner C. Greene in New England
teins. During this Þnal stage of assem- to make a vaccine that protects rhesus
Journal of Medicine, Vol. 324, No. 5,
bly, the viral protease becomes active, monkeys against infection from SIV. pages 308Ð317; January 31, 1991.
cutting up the precursors to complete Desrosiers used as his vaccine a live MOLECULAR INSIGHTS INTO HUMAN IM-
the core proteins and the enzymes. The strain of SIV that had its nef gene ar- MUNODEFICIENCY VIRUS TYPE-1 PATHO-
structure of the protease, like that of tiÞcially disabled. The resulting virus GENESIS. Mark B. Feinberg and Warner
the reverse transcriptase, is known in establishes a persistent low-level infec- C. Greene in Current Opinion in Immu-
detail, and drugs have been designed tion that stimulates a strong immune nology, Vol. 4, No. 4, pages 466Ð474;
August 1992.
to thwart its action. Trials of HIV pro- response but causes no illness. Perhaps
HIV INFECTION IS ACTIVE AND PROGRES-
tease inhibitors are under way at sev- it will be possible to do something sim- SIVE IN LYMPHOID TISSUE DURING THE
eral clinical centers; results should be ilar with HIV. Yet the safety problems CLINICALLY LATENT STAGE OF DISEASE.
available within a few months. surrounding the use of an attenuated Giuseppe Pantaleo et al. in Nature, Vol.
but live HIV vaccine are daunting. 362, No. 6418, pages 355Ð358; March
H
ope for the future should be Even bolder approaches may Þnd ap- 25, 1993.
tempered by the recognition that plication in HIV therapy. One idea has HOW DOES HIV CAUSE AIDS? Robin A.
it is still true in 1993, as it was been suggested by David Baltimore of Weiss in Science, Vol. 260, pages 1273Ð
1279; May 28, 1993.
Þve years ago, that no satisfactory treat- the Rockefeller University, who shared
SCIENTIFIC AND SOCIAL ISSUES OF HUMAN
ment for AIDS is yet in sight. Neverthe- a Nobel Prize in 1975 for discovering IMMUNODEFICIENCY VIRUS VACCINE DE-
less, I am encouraged by how much we reverse transcriptase. Baltimore pro- VELOPMENT. B. F. Haynes in Science, Vol.
have learned in the past 12 years, and I poses introducing into an infected per- 260, pages 1279Ð1286; May 28, 1993.
believe that by the end of the second de- sonÕs T cells a gene that would make
Autoimmune Disease
Misguided assaults on the self produce multiple
sclerosis, juvenile diabetes and other chronic
illnesses. Promising therapies are emerging
by Lawrence Steinman
N
ormally, the immune system is tolerance for myelin proteins, and a ge- stable, with transient strengthening of
able to distinguish friend from netically engineered monoclonal anti- her right hand and occasional periods
foe, ignoring the bodyÕs own body as well as a naturally occurring of improvement in her walking. She
components and attacking foreign in- substanceÑbeta-interferonÑhas inter- now uses a cane only when walking
vaders. Unfortunately, the immunolog- rupted the process of inßammation, in- outside her home. Her most recent
ic weapons can, like friendly Þre, some- hibiting relapses and thereby slowing magnetic resonance scan shows overall
times turn against the self, causing se- the progression of disease. Small amounts beneÞt, with noticeable regression in
vere illness and even death. of insulin, administered for the same many lesions and clear evidence of re-
Autoimmune diseases may involve purpose, have at least delayed and in pair of the white matter [see insets in il-
any organ system, although some are some cases perhaps prevented the on- lustration on opposite page]. Some new
aÝected more commonly than others: set of diabetes in children at high risk lesions have also appeared, however.
the white matter of the brain and spinal for the disease. These Þndings suggest
A
cord, in multiple sclerosis; the lining of that advances in the treatment of one s is the case with most autoim-
joints, in rheumatoid arthritis; the in- autoimmune disease may yield divi- mune illnesses, genetic factors
sulin-secreting cells, in juvenile diabetes dends for all the others. are evident: studies of monozy-
mellitus. Other forms of autoimmune The history of one of my patients, Kim gotic, or identical, twins show that when
disease ravage the connections between Kent, reveals many aspects of auto- one twin gets multiple sclerosis, the
nerve and muscle in myasthenia gravis, immune illness. She has multiple scle- other twin has about a 30 percent
stimulate the thyroid gland to produce rosis, a disease that aÝects 250,000 chance of acquiring it. The disease usu-
excessive amounts of thyroid hormone Americans, two thirds of them women. ally presents itself in early adulthood,
in GravesÕ disease, blister the skin in Kim is 26 years old and works as a often a few weeks after a routine ill-
pemphigus vulgaris or destroy the kid- travel agent in California. She Þrst not- ness. It also tends to ßare after preg-
neys and other organs in a condition ed symptoms Þve years ago, when she nancy. Periods of remission alternate
called systemic lupus erythematosus. felt tingling in her legs and pain in her with acute episodes of worsening in
Five percent of adults in Europe and arms. Her physicians diagnosed multi- about half of the patients; in the remain-
North AmericaÑtwo thirds of them wom- ple sclerosis when a magnetic resonance der, the disease follows a continuously
enÑsuÝer from an autoimmune disease, scan revealed damage to the white mat- progressive course.
many from more than one at a time. ter, which contains the long nerve Þbers A picture of the cause of multiple
The aÝected population may turn out that carry information to and from the sclerosis is at last coming into view.
to be far larger if, as some workers sus- brain. A year later she had a single epi- Self-reactive cells, which ought to be
pect, autoimmunity plays an important sode of double vision, lasting about a eliminated or silenced in the thymus
secondary role in atherosclerosis, the week, and the year after that she began
cause of half the deaths in the Western to have trouble keeping her balance while
world. Yet, if true, it might be good news, walking. She relied on a cane some-
for science is making great strides in un- times, particularly when tired. Her main LAWRENCE STEINMAN is professor of
derstanding autoimmunity. problems now are poor balance, tingling neurological sciences and pediatrics at
In the past year, clinical trials have in the legs and weakness of the right the Stanford University School of Medi-
produced promising results for three ex- hand, which makes writing diÛcult. cine. He is also chief scientist for immu-
nology at Neurocrine Biosciences, Inc., in
perimental treatments of multiple scle- In 1991 Kim began to participate in
La Jolla, Calif., which develops therapies
rosis. Oral doses of myelin have induced trials of a drug that eliminates a crucial based on the interactions of the immune,
actor in the autoimmune response. In nervous and endocrine systems. He earned
the Þrst month she received three in- his bachelorÕs degree in physics from
travenous infusions of a genetically en- Dartmouth College in 1968 and a degree
KIM KENT has multiple sclerosis, a crip- gineered antibody to CD4, a molecule from Harvard Medical School in 1973.
pling disease in which the bodyÕs im- Before joining his current departments,
on certain T cells. More recently she
mune system attacks the white matter he completed a postdoctoral fellowship
has undergone therapy once every four
in the central nervous system. A charac- in chemical immunology at the Weiz-
teristic lesion appears in a magnetic res-
months. As a result, the number of her mann Institute of Science in Israel and a
onance image of KimÕs brain (top ). Af- CD4 T cells has declined far below the residency in pediatric neurology at Stan-
ter treatment with an antibody against usual level. Yet other parts of the im- ford. He is a recipient of the Senator Ja-
CD4Ña molecule on the T cells that or- mune system continue to function nor- cob Javits Award from the National Insti-
chestrates the attacksÑthe inßamma- mally, and Kim has developed no infec- tute of Neurological Disorders and Stroke.
tion subsided (bottom ). tions. Her symptoms have remained
gland during development, instead es- ciÞc part in destroying the myelin sheath bridge have found complexes contain-
cape to the rest of the body. The thy- that insulates long nerve Þbers, giving ing Þve components of complement in
mus may fail to do its job because it them their white coloration. It turns the cerebrospinal ßuid of multiple scle-
does not come into contact with a suÛ- out, moreover, that the T and B cells rosis patients. The complexes fasten
cient quantity of self-antigens, particu- achieve these ends by diÝerent means. speciÞcally to the membranes of oligo-
larly proteins that are ordinarily seques- Two questions arose immediately: dendroglial cells, where they interfere
tered in a particular organ, such as the What were these cells doing to the white with the outward passage of calcium
brain. The possibility also exists that matter, and how did they penetrate the ions, thus destroying the cells.
the autoimmune response may be trig- blood-brain barrier, which normally ex-
T
gered by microbes that mimic the cludes agents of the immune system he function of the T cells was more
structure of self-antigens, especially if [see ÒBreaching the Blood-Brain Barri- diÛcult to elucidate because, un-
those antigens had not been presented er,Ó by Elaine Tuomanen; SCIENTIFIC like antibody, they recognize a
to the thymus during development. AMERICAN, February]? To answer the targetÑa peptide, or protein fragmentÑ
The self-reactive lymphocytes that are Þrst question, researchers have exten- only when it is bound in a strategic
thus created migrate from the thymus, sively studied the T and B cells, in par- pocket of one of the proteins referred to
lymph nodes and spleen to the blood- ticular the structures, called receptors, as human lymphocyte antigen, or HLA.
stream and thence into the organs of with which they recognize antigen. (Such proteins sit on the membrane of
the body, where they release chemicals Analysis of the antigen receptor on B the cell, presenting antigens to T cells
that damage speciÞc tissues. These in- cells revealed that the spinal ßuid of for the same reason soldiers give pass-
sights have already suggested a num- patients with multiple sclerosis had an words: to avoid being treated as an en-
ber of ways in which the self-destruc- increased content of antibody. Most of emy.) A problem arises here because
tive cells might be removed or silenced. the antibody had been produced by just HLA molecules are not normally ex-
Investigators had long wondered a few clones of B cells. In the early pressed in an appreciable manner with-
whether autoimmunity might be the 1980s Claude C. A. Bernard and his col- in the nervous system. In multiple scle-
cause of multiple sclerosis, but clear ev- leagues at La Trobe University in Aus- rosis, however, they are induced in the
idence came only in 1982, when Cedric tralia demonstrated that some of the white matter by the cytokine gamma-
S. Raine and his colleagues at the Al- antibodies precipitated the destruction interferon, one of the chemical signals
bert Einstein College of Medicine in of the major constituent of the myelin through which immune system cells
Bronx, N.Y., found immune cells in the sheath: myelin basic protein. communicate.
white matter of patients. There they ob- The B cellsÕ antibodies attack not the Physicians discovered this connec-
served a pattern indistinguishable from protein itself but the oligodendroglial tion by accident, while testing gamma-
simple inßammation: most of the im- cells in which it is made. The assault be- interferon as a therapy for multiple scle-
mune cells were T lymphocytes, derived gins when the antibodies combine with rosis. Instead of helping, the drug made
from the thymus; a few were B lympho- blood-borne enzymes known as com- matters worse by causing recurrent pa-
cytes, derived from the bone marrow; plement to form so-called attack com- ralysis, and the clinical trial was stopped.
the rest were scavenger cells, or macro- plexes. D. Alistair S. Compston and his Yet the results were instructive. They
phages. Each kind of cell plays a spe- associates at the University of Cam- showed that viral infection and other
DEMYELINIZATION proceeds on several planes. Macro- necrosis factor. They also induce B cells to produce antibod-
phages directly attack the myelin (left ), presenting fragments ies that destroy oligodendroglial cells, which normally repair
of the protein on their surface for T cells to recognize. T cells myelin. The resulting demyelination (center ) can be reversed
attack from a distance by secreting cytokines, such as tumor by transplanting new oligodendroglial cells (right ).
FOREIGN SELF-
HLA ANTIGENIC ANTIGENIC
PEPTIDE PEPTIDE
T CELL
FRIEND OR FOE: T cells recognize foreign antigens when they are presented by the HLA
molecules of the immune system. In some people, especially those who have certain
HLA types, a foreign antigen may resemble antigen produced by the body. Such molecu-
lar mimicry provokes the T cells to attack body tissues that contain the self-antigens.
stresses might aggravate the disease by at the Stanford University School of commonly employ to elude T cells. The
eliciting the secretion of gamma-inter- Medicine and Ann B. Begovich and Hen- answer appears to lie in molecular mim-
feron in the brain. HLA molecules then ry A. Erlich of Cetus Corporation. From icry, an evolutionary adaptation where-
appear in the cells of this region, where 1989 to 1992, we analyzed RNA from by viruses and bacteria attempt to fool
they are not normally expressed. lymphocytes at sites of inßammation the body into granting them free ac-
In 1983 Gian Franco Bottazzo of Mid- in the brains of patients with multiple cess. Such mimicry works by showing
dlesex Hospital Medical School and sclerosis. By sequencing a major set of the immune system stretches of amino
Marc Feldmann of University College, T cell receptors, we were able to infer acids that look like self. For example,
London, documented this process for the receptorsÕ target : the antigen com- adenovirus type 2 has amino acid se-
the brain, in multiple sclerosis; the plex formed when a particular frag- quences like those in the crucial frag-
joint lining, in rheumatoid arthritis; and ment of myelin basic protein binds to ment of myelin basic protein. In re-
the pancreas, in juvenile diabetes. Such a speciÞc part of the HLA receptorÑits sponding routinely to this virus, the
aberrant expression of HLA molecules DR2 molecule. We also found a se- immune system may become primed to
explained how gamma-interferon wors- quence of three amino acids in the re- attack the corresponding self-compo-
ened multiple sclerosis. It also provid- ceptor that seemed to bind to the anti- nentÑmyelin.
ed a rationale for further experimental gen complex. An autoimmune response can begin
therapies using agents that blocked the Independent work conducted at the even if the molecular mimicry is not
expression of HLA at the sites of au- same time by Daniel P. Gold of the San quite exact. Anand Gautam and Hugh
toimmune disease. Diego Regional Cancer Center and by O. McDevitt of Stanford were able to in-
Before such therapies could be de- Halina OÝner-Vandenbark and Arthur duce paralysis in mice by exposing
signed, however, it was necessary to A. Vandenbark of the Oregon Health them to a short stretch of 10 amino
identify what the T cells were attacking Sciences University School of Medicine acids, of which only Þve were actually
in the white matter. To do so, research- provided another crucial step. The re- identical to myelin basic protein. Robert
ers had to infer the structure of the T searchers found the same, rearranged T S. Fujinami and Michael B. A. Oldstone
cell receptor from the sequence of genes cell receptor gene, the same amino acid of the Scripps Research Institute dem-
that encode it. Unlike other genes, how- triplet at the binding site and the same onstrated that hepatitis B virus poly-
ever, those for the T cell receptor re- fragment of myelin basic protein in an merase shared a stretch of just six amino
arrange themselves with respect to the animal model of multiple sclerosis called acids with a part of the myelin basic
order inherited on the chromosomes. It experimental allergic encephalomyelitis protein molecule that causes EAE in
is therefore necessary to extract and (EAE). These results were signiÞcant be- rabbits. When they immunized rabbits
analyze genes from the individual T cause they proved the value of the with this part of the virus, the animals
cellsÑa daunting task until the mid- model, which is induced by autoimmu- developed inßammation in their brains.
1980s, when a researcher at Cetus Cor- nizing animals against myelin basic pro- This research suggests that molecu-
poration (now Roche Molecular Sys- tein and which produces the clinical lar mimicry between viruses or bacteria
tems) developed a powerful technique symptoms of multiple sclerosis: paraly- and self may be critical in initiating au-
of gene ampliÞcation known as the sis and demyelination. The model can toimmune responses. Scarring of the
polymerase chain reaction [see ÒThe thus test therapies for the human illness. heart valves in rheumatic fever may be
Unusual Origin of the Polymerase Chain a consequence of the cross-reaction be-
W
Reaction,Ó by Kary B. Mullis; SCIENTIFIC hat turns the T cells against tween myosin and a component of the
AMERICAN, April 1990]. the self? Infection often pre- cell-wall M protein in hemolytic strep-
This technique proved invaluable to cedes the onset of autoimmune tococcal bacteria. Inßammation of the
a team consisting of Bernard, Jorge R. disease, and so scientists have closely joints in rodents can be induced by im-
Oksenberg, Michael A. Panzara and me scrutinized the tactics that pathogens munization with Mycobacterium tuber-
How Multiple Sclerosis Progresses
The demyelination of neurons that occurs in multiple sclerosis results from a complex chain of
cellular interactions. Possible strategies for intervening in this disease process are described in red.
BLOOD-BRAIN
Phagocytosis by macrophage BARRIER
and presentation of viral ENDOTHELIAL CELL
antigen to T cell
Proliferation Adhesion
and and
activation penetration
T CELL
MACROPHAGE
T CELL
RECEPTOR BLOOD
VESSEL
Attack the T cell receptor or Block T cell penetration into the
other surface molecules with brain with monoclonal antibodies
antibodies produced in the that bind to adhesion molecules
laboratory by bacterial cloning or on the T cell or the endothelial
induced in the patient by vaccination cells lining the blood vessel
culosis. This disease resembles rheuma- healthy population carry both of them. must consist of more than the mere
toid arthritis and may arise from the Even the twins of persons with this dis- raising of an army of T cells: the cells
similarities in structure between a core ease acquire it only about 50 percent must also travel from the thymus and
protein of cartilage and tuberculosis. of the time. Systemic lupus erythem- spleen to the blood and thence to the
Obviously, not everyone responding atosus has also been associated with target organ. Three categories of mole-
to adenovirus type 2 mounts an im- certain HLA types, although here the cules are involved in this intricate hom-
mune response to myelin basic protein concordance rate in twins is only 25 ing mechanism. Movement through the
and develops multiple sclerosis. The percent. Some HLA types predispose to blood vessel wall appears to be the same
reason seems to rest for the most part several autoimmune diseases, explain- in autoimmune disease as in the nor-
with the diÝerences in individualsÕ HLA ing why those with myasthenia gravis, mal inßammatory response to infec-
types. The HLA molecules determine for instance, have a 30 percent chance tion. The process of homing in on the
exactly which fragments of a pathogen of acquiring GravesÕ disease as well. target is mediated by members of the
are displayed on the cell surface for pre- immunoglobulin supergene family and
G
sentation to T cells. One individualÕs HLA enes may also confer protection the T cell receptor, CD4 and CD8 [see
structure may bind a self-mimicking against autoimmune diseases. In ÒHow the Immune System Recognizes
fragment and present it to the immune 1987 McDevitt, John I. Bell and Invaders,Ó by Charles A. Janeway, Jr.,
system, whereas anotherÕs may bind a John A. Todd of Stanford observed page 72].
fragment unique to the pathogen that that resistance to juvenile diabetes cor- Here is how the process works. Once
does not mimic self. In the latter case, relates with the presence of the ami- they arrive at the target, leukocytesÑ
the pathogen is attacked, but self-toler- no acid aspartate at position 57 of the mainly T cellsÑget a foothold with the
ance is not violated. HLA-DQ beta chainÑone of two struc- help of intracellular adhesion molecules
People who carry HLA-DR4 are six tures in the HLA protein. Erlich made called integrins. These molecules, which
times more likely than others to ac- the same discovery independently. In- sit on the T cells, bear receptors that
quire rheumatoid arthritis. Those with terestingly, among the Japanese, most can be likened to Velcro fasteners.
HLA-DR2 are four times more likely of whom have precisely this HLA char- Counter receptors belonging to the im-
to inherit multiple sclerosis than those acter, the prevalence of juvenile dia- munoglobulin supergene family consti-
without it. Juvenile diabetes mellitus af- betes is just 5 percent of that observed tute the other half of the Velcro bond.
fects 0.2 percent of the U.S. population, in the U.S. In contrast, HLA-DQ beta The counter receptors grow from the
but it is about 20 times more common chains with serine, alanine or valine at endothelial lining of blood vessels at
in those white persons who have the position 57 are associated with a high points that have been exposed to such
HLA-DR3 and HLA-DR4 genes. risk for juvenile diabetes. These corre- cytokines as gamma-interferon and tu-
Yet, as is the case in all the autoim- lations between HLA and disease are mor necrosis factor.
mune diseases, the genes by themselves partly a result of whether a certain HLA These cytokines are produced on the
cannot cause the disease. Five percent molecule can present a fragment of a spot by activated T cells and macro-
of those who have juvenile diabetes pathogen that mimics a self-constituent. phages. Therefore, when a T cell rolls
lack the genes, and Þve percent of the Autoimmunity, however it begins, down a blood vessel and meets a coun-
NEURON
Mask peptides presented
to T cells by macrophages
or glial cells by administer- ANTIGEN-
PRESENTING
ing specific antibodies or GLIAL CELL
chemical decoys, such as AXON
peptides B CELL ANTIBODIES MYELIN
SHEET
MYELIN BASIC
PROTEIN
COMPLEMENT MEMBRANE
T cell reentry DAMAGE
into circulation ACTIVATED OLIGODENDRO-
COMPLEXES GLIAL CELL
CYTOKINES
Proliferation
and activation
of T cells
CYTOTOXINS
Head off inflammation TNF
with antibodies against
cytokines, such as gamma- CYTOKINES
interferon and tumor TNF GAMMA-
necrosis factor (TNF) GAMMA-INTERFERON INTERFERON
ter receptor, it sticks. The process of diseases the pattern of decline has been
sticking causes the T cell to secrete shown to correlate strongly with three
proteases, enzymes that help to create factors in the environment: female hor-
MACROPHAGE
a hole in the blood vessel and enable mones, infection and stress.
the T cell to tighten its cytoskeleton so It has long been noted that auto-
that it can squeeze through the tiny immune disease is generally worse in DEMYELINATION
hole. In this manner, leukocytes break women than in men. Recently Howard
through the blood-brain barrier to cause S. Fox of Scripps adduced a reason.
multiple sclerosis, penetrate the syno- He has shown that the female hormone
vial lining to cause rheumatoid arthritis estrogen stimulates a DNA sequence NAKED AXON
and so on for all the other autoimmune that stimulates nearby genes, which in
diseases. turn transcribe gamma-interferon. Es-
Destruction begins when a T cell en- trogen thus promotes the production
counters its antigen in the cleft of an of gamma-interferon, which, as we have
HLA molecule and releases proteins seen, helps to induce the autoimmune Because superantigens reactivate rogue
and peptides, including tumor necrosis process. T cells, they greatly intensify the inßam-
factor, a chemical relative called lym- mation. They have this broad effect be-
M
photoxin and gamma-interferon. These icroorganisms clearly cannot cause they bind to the T cell receptor
chemicals have been identiÞed as the worsen existing autoimmune at a point that lies outside the highly
proximate cause of demyelination. Mac- disease in the same way that speciÞc site that recognizes antigen
rophages then speed the process, part- they induce itÑmolecular mimicry will [see ÒSuperantigens in Human Disease,Ó
ly by secreting tumor necrosis factor not cause the body to be more sensitive by Howard M. Johnson, JeÝry K. Rus-
and partly by mounting a direct attack. to one of its own components than it al- sell and Carol H. Pontzer; SCIENTIFIC
Raine and John Prineas of the Univer- ready is. Some other microbial function AMERICAN, April 1992].
sity of Medicine and Dentistry of New must be culpable. Its nature was sug- Of course, only those T cells that are
Jersey have shown that macrophages gested by a study of EAE by Stefan primed for a self-antigen will Þnd their
actually strip fragments of myelin from Brocke and his colleagues at Stanford. way to the target. Brian L. Kotzin and
the sheath encasing the nerve axons When the workers administered staphy- Philippa Marrack of the National Jewish
[see illustration on page 108]. lococcal enterotoxin B to mice that had Center for Immunology and Respirato-
One might suppose that autoimmune recovered from EAE-induced paralysis, ry Medicine in Denver have shown, for
disease, once started, would proceed relapses occurred within 48 hours. instance, that certain T cells bearing a
without interruption. Yet in multiple scle- Staphylococcal enterotoxin B belongs speciÞc receptor are concentrated in the
rosis, rheumatoid arthritis, systemic lu- to the class of substances known as su- synovial ßuid of patients who have rheu-
pus erythematosus and myasthenia perantigens, so called because they ac- matoid arthritis. That concentration is
gravis, periods of deterioration usually tivate T cells that would otherwise re- mirrored by a corresponding depletion
alternate with remission. In all these spond only to diÝering, speciÞc antigens. of the same T cells in the bloodstream.
Kotzin and Marrack proposed that these ing of the neurons). These cytokines releasing factor in response to stress
autoimmune T cells were activated by may be augmented with others pro- are quite susceptible to experimentally
superantigens, so that they attacked the duced outside the brain and ferried induced arthritis. Gabriel S. Panayi of
lining of joints and then proliferated in into it through certain critical points in GuyÕs Hospital Medical School, Univer-
the synovial tissues, where they were the blood-brain barrier. (Such eÝects sity of London, has noted the same fea-
selected by an as yet undetermined are crucial in the etiology of simple tures in rheumatoid arthritis patients.
speciÞc antigen. fever: infection causes macrophages to These Þndings may provide a link be-
produce interleukin-1, which enters the tween the well-known clinical observa-
S
tressÑsuch as sickness or trau- hypothalamus through a breach in the tion that anxiety can worsen autoim-
maÑcan worsen autoimmune dis- blood-brain barrier in the preoptic mune disease.
ease by aÝecting two glands in area. There it triggers a rise in body If fear can produce relapses, then
the brain: the hypothalamus and the temperature.) even the fear of a relapse may become
pituitary. They then secrete hormones The nervesÕ possible involvement in a self-fulÞlling prophecy. Indeed, un-
that promote inßammation. In addi- immunity has long been suspected, but certainty about the future is perhaps
tion, nerves may play a role by directly hard evidence came only a few months the most bitter aspect of autoimmune
innervating lymph glands and immune ago. Richard D. Granstein and his col- disease. Remissions may last for months
cells resident in the organs. leagues at Massachusetts General Hos- or for years, disease may progress slow-
Inßammation stimulates the release pital were able to show that nerves can ly or rapidly, complications beyond the
of cytokines, which travel to the brainÕs release certain neuropeptides in the primary autoimmune process may or
glands and cause them to secrete corti- skin, thereby inßuencing the vigor of may not ensue. Moreover, the chances
cotropin-releasing factor. This neuropep- the local immune response. This local of developing another autoimmune con-
tide has two opposed eÝects: it height- regulation may Þgure in psoriasisÑ dition are much enhanced in those who
ens the activity of immune cells at the clearly an autoimmune diseaseÑa con- already have one.
site of inßammation and at the same dition that worsens when the patient Some of these secondary conditions
time stimulates the adrenal glands to becomes anxious. are fairly innocuous because they de-
produce glucocorticoids, which shut So far research has concentrated on stroy tissues whose function can be re-
down inßammation. One can block the the hormonal pathways that link stress placed. GravesÕ disease, for instance,
inßammatory eÝect of corticotropin-re- to autoimmune reactions. Recently Ron- can be treated by removing the overac-
leasing factor by using drugs, such as ald L. Wilder and George P. Chrousos tive thyroid gland and then supplying
antibodies, that bind to the factor, neu- and their colleagues at the National In- the missing hormone orally. Yet the cor-
tralizing it. stitutes of Health have demonstrated responding therapy for juvenile dia-
In multiple sclerosis, especially dur- that corticotropin-releasing factor is betesÑinsulin injectionsÑleaves some-
ing infection, such cytokines as tumor present in the synovial ßuid and tis- thing to be desired. Such injections can-
necrosis factor and interleukin-1 may sues of patients with rheumatoid ar- not fully reproduce the Þnely graded
be produced within the brain itself by thritis. They also showed that animals secretion of the beta cells, which con-
glial cells (which support the function- that fail to release enough corticotropin- trols the metabolism of glucose with
exquisite sensitivity. The glucose con-
centration in the blood therefore ßuc-
tuates excessively, exposing the diabet-
ic to a heightened risk of vascular com-
plications. (In June, a long-term study
sponsored by the National Institute of
Diabetes and Digestive and Kidney Dis-
eases concluded that patients can pre-
vent or delay complications by testing
their blood frequently and making ap-
propriate adjustments in diet and exer-
cise and insulin dosage.)
N
o substitute exists, however, for
the tissue attacked in myasthe-
nia gravis: the acetylcholine re-
ceptor at the junction between nerves
and muscle. Antibodies attack the
junction, causing weakness and paraly-
sis. Tolerance to the acetylcholine re-
ceptor is broken in the thymus gland,
where the acetylcholine receptor is ex-
pressed. In about half of the patients
the gland becomes enlarged, and it is
standard practice to remove itÑa pro-
cedure that often alleviates the disease,
especially in young patients.
Systemic lupus erythematosus is per-
haps the most devastating of the au-
CHARACTERISTIC RASH over the cheekbones and forehead is diagnostic of sys- toimmune diseases, capable of reach-
temic lupus erythematosus. The disease often begins in young adulthood and may ing virtually all the organs, sometimes
eventually involve many organ systems. one after the other, often with no warn-
ing at all. It aÝects about 250,000 peo-
ple in the U.S., displaying an extraordi-
nary imbalance in relation to sex: fully
Where Autoimmunity May Strike
90 percent of the patients are women.
DISEASE TARGET
The illness generally begins in young
adulthood when a characteristic skin Addison’s disease Adrenal gland
rash appears over cheekbones and fore- Autoimmune hemolytic anemia Red blood cell membrane proteins
head, producing the wolßike impres- Crohn’s disease Gut
sion from which the disease derives Goodpasture’s syndrome Kidney and lungs
its name [see illustration on page 112 ]. Graves’ disease Thyroid
Hair loss is common, as is severe kid-
Hashimoto’s thyroiditis Thyroid
ney damage, arthritis, accumulation of
ßuid around the heart and inßamma- Idiopathic thrombocytopenic purpura Platelets
tion of the lining of the lungs. In nearly Insulin-dependent diabetes mellitus Pancreatic beta cells
half of the patients the blood vessels of Multiple sclerosis Brain and spinal cord
the brain also become inßamed, leading Myasthenia gravis Nerve/muscle synapses
sometimes to paralysis and convulsions. Pemphigus vulgaris Skin
Why systemic lupus erythematosus
Pernicious anemia Gastric parietal cells
is so protean remains a mystery, al-
though the pathology in so many dif- Poststreptococcal glomerulonephritis Kidney
ferent tissues implies a general failure Psoriasis Skin
in self-tolerance. Recent experiments Rheumatoid arthritis Connective tissue
suggest an attractive explanation. Mice Scleroderma Heart, lungs, gut, kidney
with a lupuslike disease turn out to have
Sjögren’s syndrome Liver, kidney, brain, thyroid,
a mutation in the gene encoding Fas, a
molecule found on the surface of thy- salivary gland
mocytes and on activated T and B cells. Spontaneous infertility Sperm
The normal Fas molecule triggers pro- Systematic lupus erythematosus DNA, platelets, other tissues
grammed death in immune cells. If the
Fas-mediated death goes awry, self-re-
active T and B cells of all kinds may wreak
havoc in many diÝerent organ systems. sensitive antigens may be even more tumor necrosis factor. Feldmann and
Until quite recently, physicians have direct and potent. In the animal model R. Tini Miani and their associates at the
had to Þght these diseases in the dark, of multiple sclerosis, molecules similar Kennedy Institute for Rheumatology in
armed only with nonspeciÞc immuno- to HLA-DR present fragments of myelin London and at Centocor Corporation
suppressants, such as the corticoste- basic protein to T cells, which then at- have done so in a pilot trial. They pro-
roids, which help very little and some- tack the central nervous system. Mc- duced a monoclonal antibody that binds
times cause harm. In the past few years, Devitt and I and others showed that it with tumor necrosis factor and showed
however, our understanding of the path- is possible to make analogues of mye- that it can clear that cytokine from the
ogenesis of autoimmune disease has led lin that bind to the HLA molecules with circulation. A single dose will suppress
to the development of highly selective higher aÛnity than the native myelin the autoimmune response for Þve to
therapies, each of which intervenes at a and yet are nonimmunogenic. By mop- 10 weeks without damping the general
diÝerent point in the autoimmune pro- ping up all the HLA molecules, the ana- immune response to infection. The po-
cess. These therapies have achieved ex- logues serve as molecular decoys that tency of the treatment is matched only
cellent results in animal models, and prevent EAE and even reverse the asso- by its remarkable speciÞcity.
some of them are undergoing clinical ciated paralytic disease. Treatment with the antibody increased
trials. Indeed, a few drugs are now await- joint mobility and reduced the stiÝness
E
ing approval. ncouraged by these results, my associated with rheumatoid arthritis.
If HLA molecules in the white matter colleagues at Neurocrine Biosci- This strategy is also being contemplat-
are associated with attacks of multiple ences (where I serve as chief sci- ed to treat multiple sclerosis, in which
sclerosis, then it makes sense to block entist) are designing decoys that Þt tumor necrosis factor has been impli-
their expression. Beta-interferon has into the HLA cleft. They speciÞcally turn cated as an agent of destruction at the
this blocking eÝect, just as gamma-in- oÝ, or Òtolerize,Ó the T cells that de- scene of the disease in the white matter.
terferon works to increase expression. stroy myelin. Neurocrine Biosciences Yet another tactic is to distract the
Recently a large multicenter clinical trial holds the patent rights to this technol- lymphocytes from their targets. Ted A.
of beta-interferon was mounted by sci- ogy and is developing it, with my assis- Yednock of Athena Neurosciences, Nati
entists aÛliated with two collaborating tance, for clinical applications. There is Karin of Stanford and I have prevented
biotechnology enterprises, Chiron Cor- reason to believe this strategy can be the development of EAE in rats in this
poration and Berlex Biosciences. The applied to all the autoimmune dis- fashion. We administered a monoclon-
drug reduced the number of attacks by eases. Michael Sela and Ruth Arnon al antibody directed to VLA-4, one of
30 percent and actually shrank the ar- and their colleagues at the Weizmann the adhesive protrusions from the T
eas of inßammation in the white mat- Institute of Science in Israel have syn- cell. A T cell that has been treated in
ter. In July the Food and Drug Adminis- thesized a copolymer that resembles this fashion cannot attach to matching
tration recommended beta-interferon, myelin basic protein. This copolymer receptors on the wall of the blood ves-
making it the Þrst approved therapy for binds to HLA-DR2 and reduces the inci- sel. It therefore sails past its disem-
multiple sclerosis. dence of relapses in multiple sclerosis. barkation point without even attempt-
Other strategies aimed at blocking Another approach is to Þght one of ing to breach the blood-brain barrier.
the HLA molecules that present self- the T cellsÕ principal chemical weapons: Not only were the animals protected
from paralytic disease, their brains were tem that is self-destructive, while leav- London transplanted oligodendroglial
also completely devoid of inßammation. ing the rest intact to Þght infection. This cells into the brains of rodents with
Such an approach is soon to be ap- ideal may be more easily attained than EAE, the grafts wrapped the ravaged
plied in multiple sclerosis. We have al- researchers had originally thought be- regions with newly formed myelin [see
ready humanized the anti-VLA-4 mole- cause there is evidence that the T cells illustration on page 108].
culeÑthat is, we have substituted hu- that cause autoimmune disease use a
T
man components for those pieces that limited set of receptor molecules. The his research may bear even rich-
identify the moleculeÕs murine origins. importance a single molecule may have er fruits than anyone could have
A similar approach was taken in an an- was demonstrated most dramatically in anticipated, for autoimmunity is
imal model of rheumatoid arthritis by EAE in 1988. In independent experi- turning out to be surprisingly wide-
Ko Okumura and his colleagues at the ments, my colleagues and I at Stanford spread. It appears to complicate many
Juntendo University School of Medicine and Leroy E. Hood, then at the Califor- diseases whose primary cause has noth-
in Tokyo. They blocked lymphocyte mi- nia Institute of Technology, and his co- ing to do with immune response. In
gration to joints with an antibody to workers showed that the T cells that in- DuchenneÕs muscular dystrophy, for in-
ICAM-1, a molecule that enables the duce paralysis in EAE all had the V-beta stance, a defective gene enfeebles a ma-
cell to adhere to the blood vessel wall. 8 gene, which encodes one of the com- terial crucial to the strength of muscle,
Here, too, anti-ICAM-1 antibodies are ponents of the antigen receptor. We de- weakening the person and Þnally lead-
now undergoing preclinical trials for signed a monoclonal antibody directed ing to death from respiratory failure,
use in human patients. to the product of that gene and showed usually in the patientÕs twenties. When
that it reverses paralytic disease. the muscles were found to harbor T
A
n especially cunning approach In the early 1980s Irun R. Cohen of cells, immunosuppressive drugs were ap-
has been undertaken by Caro- the Weizmann Institute of Science had plied, prolonging the ability to walk by
line C. Whitacre of Ohio State demonstrated that one could vaccinate between three and Þve years.
University and Howard L. Weiner of individuals against their own rogue T Intriguing evidence suggests an even
Harvard University. They demonstrated cells and so prevent or even treat ex- more momentous connection. Athero-
that simply feeding myelin basic pro- perimental autoimmune encephalomy- sclerosis, the arterial blockage that caus-
tein to animals with EAE can prevent or elitis, experimental arthritis and exper- es stroke and heart attack, may also in-
reverse paralysis. The mode of admin- imental diabetes [see ÒThe Self, the World volve autoimmunity. Among the signs
istering the protein matters, it seems, and Autoimmunity,Ó by Irun R. Cohen; are autoantibodies bound to fatty de-
because the body is programmed to ac- SCIENTIFIC AMERICAN, April 1988]. posits in the arteries, histocompatibili-
cept most proteins ingested as food Clinical trials with T cell vaccination ty proteins expressed in aberrant fash-
and to attack most proteins that are have been initiated in multiple sclerosis ion, inÞltration of macrophages and T
presented directly to the tissues (as in and in rheumatoid arthritis. In 1989, in cells secreting cytokines. These cyto-
a puncture wound or a subcutaneous separate experiments, OÝner-Vanden- kines may induce the proliferation of
injection). Such oral tolerance therapy, bark and Vandenbark and Steven W. smooth muscle and endothelial tissue
as it is called, appears to induce T cells BrostoÝ of Immune Response Corpora- that adds to the blockage. Should the
that secrete cytokinesÑsuch as trans- tion successfully treated EAE by vacci- connection prove real, therapies to sup-
forming growth factor βÑthat counter- nating animals with a peptide from one press rogue T cells and their chemical
act the harmful eÝects of gamma-inter- of the T cell receptor molecules. Since messengers may one day reduce the
feron and tumor necrosis factor. then, OÝner-Vandenbark and Vanden- severity of cardiovascular disease, the
Weiner recently conducted a small bark have tested the technique in a cause of half the deaths in the industri-
clinical trial in which he fed bovine small number of multiple sclerosis pa- alized world.
myelin to multiple sclerosis patients tients, using a peptide found in a T cell
and signiÞcantly reduced the number receptor that reacts to myelin basic
of relapses in the men, but not the protein. Half of the patients exhibited
women. Because the beneÞts were far an immune response to these patho- FURTHER READING
more apparent in men than in women, genic T cell receptors. Trials are now MOLECULAR MIMICRY AND AUTOIMMUNE
the disparity perhaps can be linked to establishing whether this treatment al- DISEASE. M. B. Oldstone in Cell, Vol. 50,
the eÝect estrogen has on the produc- ters the course of the disease. No. 6, pages 819Ð820; September 11,
1987.
tion of cytokines. As highly selective therapies for these
T CELL RECOGNITION AS THE TARGET
A more direct approach to the treat- diseases emerge, scientists will shift FOR IMMUNE INTERVENTION IN AUTOIM-
ment of autoimmunity has aimed to re- their focus to the repair of damaged tis- MUNE DISEASE. David C. Wraith, Hugh
move speciÞc subsets of T cells in- sues. Some such repair may be expect- O. McDevitt, Lawrence Steinman and
volved in the pathogenesis of disease. ed to proceed spontaneously, once the Hans Acha-Orbea in Cell, Vol. 57, No. 5,
William J. Koopman and his colleagues autoimmune response is interrupted. pages 709Ð715; June 2, 1989.
at the University of Alabama at Birming- Moses Rodriguez and his colleagues at ADHESION RECEPTORS OF THE IMMUNE
SYSTEM. Timothy A. Springer in Nature,
ham have treated rheumatoid arthritis the Mayo Foundation have cited sugges-
Vol. 346, No. 6283, pages 425Ð434; Au-
with a monoclonal anti-CD4 antibody. tive data from an animal model of mul- gust 2, 1990.
The antibody increased the mobility of tiple sclerosis. When the workers treat- THE DEVELOPMENT OF RATIONAL STRATE-
the patientsÕ joints considerably. This ed the animals by blocking the relevant GIES FOR SELECTIVE IMMUNOTHERAPY
strategy is also being tested against T cells and HLA molecules, myelin was AGAINST AUTOIMMUNE DEMYELINATING
multiple sclerosis by W. Ian McDonald regenerated in the aÝected parts of the DISEASE. Lawrence Steinman in Advances
and his co-workers at the National Hos- brain. More aggressive therapies may in Immunology, Vol. 49, pages 357Ð379;
pital for Neurology and Neurosurgery help speed such regeneration or induce 1991.
MHC CLASS-II MOLECULES AND AUTOIM-
in London. it in cases where the damage is too
MUNITY. Gerald T. Nepom and Henry
The perfect treatment for autoimmu- profound to allow for self-repair. When Erlich in Annual Review of Immunolo-
nity would involve silencing or remov- Marc Noble and his associates at the gy, Vol. 9, pages 493Ð525; 1991.
ing only the part of the immune sys- Ludwig Institute for Cancer Research in
Allergy
In allergic individuals, parts of the immune system
misdirect their power at innocuous substances,
producing sometimes deadly symptoms
by Lawrence M. Lichtenstein
T
he allergic responseÑin which main to be deciphered, but recent dis- to parasites. Yet animal studies de-
certain components of the im- coveries are already generating exciting signed to test the proposal have been
mune system react strongly to new ideas for prevention and control inconclusive, and so the question of
a normally inoÝensive foreign sub- of allergic disorders. why allergy exists remains unsolved.
stanceÑaccounts for a good deal of the Before addressing these discoveries,
U
illness and medical expense in devel- it seems worthwhile to examine the nderstanding of the physiologi-
oped countries. Indeed, an estimated broader question of why natural selec- cal basis of the allergic response
20 percent or more of the U.S. population has allowed allergy to become so rests on a more substantial col-
tion is allergic to something. The largest widespread. An especially persuasive lection of evidence. I can therefore of-
group suÝers from allergic rhinitis (in- proposal derives from the observation fer a reasonably cohesive overview of
cluding hay fever) or asthma, sneezing that certain features of allergy occur in current knowledge. We know, for in-
or Þghting for air after inhaling partic- only one other circumstance: when the stance, that diÝerent allergens evoke
ular pollens or other ordinarily benign immune system attempts to eradicate disparate symptoms in part because
chemicals. Many children and some parasites. For instance, in the response they engage with the immune system
adults are allergic to foods. Others fall to both allergens and parasites, the at separate sites in the body. In the up-
ill after receiving such medicines as pen- body produces high quantities of mole- per airways the misdirected immune re-
icillin. Still others endure untoward lo- cules known as immunoglobulin E (IgE) sponse yields sneezing and nasal con-
cal or systemic reactions to bee stings. antibodies. In contrast, when the im- gestionÑin other words, allergic rhinitis.
Occasionally, allergic attacks are fatal. mune system combats other invaders, In the lower airways it can cause con-
Asthma alone accounted for an estimat- notably bacteria, it relies on diÝerent striction and obstruction of the bron-
ed $3.6 billion in direct medical expen- classes of antibodies. chi, thereby participating in the devel-
ditures in 1990 and for nearly 1 per- The hypothesis suggests that the opment of such asthmatic symptoms
cent of all health care costs. allergic response initially evolved to as wheezing. Likewise, immune activity
To ease the Þnancial, physiological help the body cope with parasites. Peo- in tissue of the gastrointestinal tract
and psychological burdens imposed by ple whose genetic endowment enabled may at times cause nausea, abdominal
the wayward immune response, many them to mount an eÝective immune at- cramps, diarrhea or vomiting.
researchers, including my colleagues tack against these organisms would Finally, if an allergen delivered via
and me at Johns Hopkins University, have enjoyed a survival advantage, liv- any route makes its way into the blood-
have long sought to expand existing ing longer than their counterparts who stream, it can induce anaphylaxisÑal-
therapeutic options. As part of this ef- lacked such a defense mechanism. They lergic reactions at sites distant from
fort, we are attempting to uncover each would thus have produced more oÝ- the port of entry into the blood. Severe
step in the process by which exposure spring, who in turn would have passed anaphylactic reactions can disturb nor-
to an allergic trigger, or allergen, leads the helpful genes to their own, numer- mal functioning throughout the body
to symptoms. It is now clear that a num- ous children. In consequence, the para- and may end in death.
ber of the cellular and molecular in- site defense system became common in Although the overt manifestations of
teractions constituting the allergic re- the human population. This defensive the allergic response can vary, the re-
sponse are often similar from person capability has remained useful wher- sponse is universally set in motion by a
to person, regardless of diÝerences in ever parasites are abundant. In people
the substances to which the individuals who no longer encounter these mi-
react and the symptoms they exhibit. crobes, however, the immune system is LAWRENCE M. LICHTENSTEIN is pro-
Many details of these exchanges re- now free to reactÑalbeit counterpro- fessor of medicine and director of the
ductivelyÑto other substances, such as Asthma and Allergy Center at Johns Hop-
ragweed pollen. kins University. He earned his M.D. from
SNEEZING triggered when an allergic in- the University of Chicago in 1960 and
dividual inhales pollen results from a In support of this thesis, epidemiolo-
gists Þnd that allergic disease is less completed doctoral studies in microbi-
complex chain of molecular and cellular ology at Johns Hopkins in 1965. He has
interactions in the nasal passages. Simi- common in developing than in devel- served at Johns Hopkins in various ca-
lar interactions underlie the symptoms oped nations, where public health mea- pacities ever since.
evoked by other allergens. sures have eliminated most exposure
silent process called sensitization. Sen- cell to release potent chemicals that di-
sitization may begin the Þrst time an rectly and indirectly generate allergic
allergen, typically a protein, enters the symptoms. (A number of triggers can Stages of an
body. In the airways or other tissues the independently elicit release of the same Allergic Reaction
allergy-inducing substance encounters chemicals, but the resulting response
scavenger cells, or macrophages. These typically is not classiÞed as allergic if 1. SENSITIZATION
cells engulf the foreign substance, IgE antibodies are not involved.)
The initial meeting of an allergen and
chop it into pieces and display the re- Among the released chemicals, mast
the immune system yields no symptoms;
sulting fragments on the cell surface. cells produce two well-studied, symp-
rather it may prepare the body to react
The sensitization process continues tom-causing groups referred to collec-
promptly to future encounters with the sub-
in the form of several incompletely un- tively as allergic mediators. One set is
stance. The sensitization process begins
derstood interactions. In essence, how- synthesized in advance of antigen bind-
when macrophages degrade the allergen
ever, leukocytes, or white blood cells, ing and is stored in microscopic gran-
and display the resulting fragments to T
called helper T lymphocytes recognize ules. IgE cross-linking induces granules
lymphocytes (bottom left). The steps that
certain of the displayed fragments and to fuse with the cell membrane and
follow are somewhat obscure, but in a pro-
bind to them. Binding spurs the T cells eject their contents.
cess involving secretion of interleukin-4 by
to secrete interleukin-4 and other chem- Histamine, Þrst described in 1911 by
T cells, B lymphocytes mature into plasma
icals that prod neighboring B lympho- Sir Henry Dale of the Wellcome Physio-
cells able to secrete allergen-specific mole-
cytes to mature into antibody-secreting logical Research Laboratories in En-
cules known as immunoglobulin E (IgE)
plasma cells. At some point, the plasma gland, is perhaps the most infamous of
antibodies. These antibodies attach to re-
cells switch from making so-called IgM these pre-formed mediators. It can stim-
ceptors on mast cells in tissue and on ba-
antibodies to producing IgE antibodies. ulate the production of mucus from the
sophils circulating in blood.
In common with other classes of anti- epithelium, thereby contributing to con-
bodies, these molecules are Y-shaped ; gestion of airways. It can cause smooth
2. ACTIVATION OF MAST CELLS
each ÒarmÓ is able to bind to one mole- muscles, which wrap like an elastic band
In later encounters between the allergen
cule of the allergen. around the bronchial airways and the
and the body, allergen molecules promptly
By the time the antibodies are made, intestines, to contract. Histamine can
bind to IgE antibodies on mast cells (top
days or weeks may have passed, and also dilate small blood vessels and in-
left). When one such molecule connects
the allergen that elicited their produc- crease their permeability, allowing ßu-
with two IgE molecules on the cell surface,
tion may be long gone. But the IgE mol- id to leak into tissues. These vascular
it draws together the attached IgE recep-
ecules do not disappear. They attach changes can give rise to redness and
tors, thereby directly or indirectly activat-
by the ÒstemÓ of the Y to IgE receptors swelling. If the changes are widespread,
ing various enzymes (green spheres) in
on two classes of immune system cells. they may contribute to a deadly condi-
the cell membrane. Cascades involving ty-
One class consists of mast cells, which tion termed hypotensive shock: a pro-
rosine kinase enzymes, phospholipase C,
derive from bone marrow and reside in found drop in blood pressure, accompa-
protein kinase C and an influx of calcium
tissues. Mast cells generally settle close nied by a dramatic reduction in the sup-
ions (black arrows) induce chemical-laden
to blood vessels and to the epithelium: ply of oxygen to the heart and brain.
granules to release their contents. These
the layer of epithelial and gland cells The second group of mediators, dis-
cascades also appear to promote the syn-
that covers the surfaces by which we covered decades later at the Karolinska
thesis and extrusion of chemicals known
make contact with the outer world. IgE Institute in Stockholm, consists of lip-
as cytokines (brown arrows). Other se-
antibodies also bind to basophils; these ids (fats)Ñmainly prostaglandins and
quences of molecular interactions ( green
cells, too, derive from bone marrow, leukotrienesÑthat are synthesized af-
arrows) end in the secretion of such lipids
but they diÝerentiate into white cells ter allergen molecules make contact
as prostaglandins and leukotrienes. The
that circulate in the bloodstream. with IgE antibodies on cells. Like hista-
various chemicals released by mast cells
Once IgE antibody production be- mine, both kinds of lipids cause con-
are responsible for many allergic symp-
gins, it apparently persists for months striction of the bronchial tubes and vas-
toms. The reaction pathways shown are
or, at times, many years. As a result, cular dilatation; what is worse, their ef-
simplified and but a sampling of those
IgE antibodies perpetually occupy IgE fects persist longer. Stimulated mast
thought to occur; many are also only part-
receptors on mast cells and basophils, cells additionally extrude a variety of
ly understood (broken arrows).
where they sit ready to react promptly potentially toxic enzymes. Evidence sug-
to the next encounter with an allergen. gests the cells release cytokines as well:
3. PROLONGED IMMUNE ACTIVITY
Thus, even in a person who will later small proteins that direct the activities
be revealed as allergic, the initial en- of other immune system cells. Some- Chemicals emitted by active mast cells
counter evokes no symptoms; rather it times, virtually all the symptoms of an (left) and their neighbors in tissue may in-
primes the immune system to react to allergic attack seem to stem from the duce basophils, eosinophils and other cells
a subsequent exposure. rapid release of mediators and other flowing through blood vessels (right) to
chemicals from mast cells. For example, migrate into that tissue. The chemicals fa-
cilitate migration by promoting the expres-
T
his later exposure initiates a swift activation of these cells is proba-
more visible stage of the allergic bly at fault in anaphylactic reactions or sion and activity of adhesion molecules on
response. Within seconds after an when a cat ownerÕs hospitality is met the circulating cells and on vascular en-
allergen meets human tissue, it binds to with sneezes and tears by a visitor al- dothelial cells. The circulating cells then at-
IgE antibodies on mast cells. When it lergic to feline dander. tach to the endothelial cells, roll along
engages at least two IgE molecules, it In most instances, though, the al- them and, eventually, cross between them
forms a bridge between them; this lergic reaction progresses to a third, of- into the surrounding matrix. These recruit-
cross-linking, in turn, draws the at- ten chronic, stage. At these times, it is ed cells secrete chemicals of their own (or-
tached IgE receptors close to one an- thought that activated mast cells lure ange speckles), which can sustain immune
other. Such aggregation of receptors other immune system cells from the activity and damage tissue.
activates the cell. That is, it induces the circulation into tissues. These attract-
ed cells include basophils (which, like phase reactionÑderives from experi- turn a few hours after that, paralleling
mast cells, contain granules) and gran- ments done in my laboratory at Johns the late-phase invasion of circulating
ular white cells known as eosinophils. Hopkins University and elsewhere. In a cells into the epithelium. Similarly, de-
They also include T lymphocytes and standard technique, investigators study livery of allergens into the skin evokes
monocytes (precursors of tissue mac- the eÝects of allergens by delivering an acute wheal-and-ßare reaction, or
rophages). The presence of large num- them directly to the airways or into the swelling and redness, followed later by
bers of basophils and eosinophils in an skin of allergic volunteers. At the cellu- prolonged return of the reaction. In the
inßammatory lesionÑtissue invaded by lar level, the acute phase (mast cell ac- course of daily living, people do not nec-
components of the immune systemÑ tivation in tissue) is followed hours lat- essarily experience delayed symptoms
constitutes another shared hallmark of er in many subjects by a late-phase in- after an acute allergy attack. But ongo-
allergy and parasitic infection. These ßammatory response: basophils and an ing exposure to allergens in sensitized
cells are virtually absent at sites of bac- army of other leukocytes invade the air- individuals may result in persistent late-
terial invasion, where leukocytes known ways or skin, generating a new wave of phase inßammation and in continuous
as neutrophils are more prominent. symptoms. Varied data make me sus- or easily evoked symptoms.
The recruited cells secrete substanc- pect that in the experimental situation,
M
es that can prolong and exacerbate the and probably in nature, basophils or- uch of what I have just de-
early symptoms and may injure local chestrate much of the late response; scribed has been established
tissue. For example, basophils (which the chemicals they secrete seem both for some time. It is in the Þlling
are activated in much the same way as to cause symptoms and to help sustain in of details, however, that new ideas for
mast cells) emit many of the pre-formed activity by the other cells. treatment arise. One area actively being
and lipid mediators also found in mast Within minutes after a patient in- studied focuses on an early part of the
cells. Eosinophils release toxic proteins; hales an allergen, the cellular activities allergic response: regulation of IgE anti-
one, major basic protein, can damage of the acute phase manifest themselves body synthesis. Why do allergic indi-
respiratory epithelial cells. as sneezing and congestion or wheez- viduals generate abnormally high levels
Current understanding of this third ing and shortness of breath. The symp- of IgE antibodies? ( The concentrations
stageÑoften referred to as the late- toms disappear within an hour but re- of non-IgE antibodies in the blood typi-
cally vary little from person to person,
whereas those of IgE antibodies can
vary considerably. In allergic individu-
Mediators of Allergic Reactions als, IgE levels remain much lower than
those of other antibody classes, but
Molecules released from activated mast cells and basophils account for they can be thousands of times higher
many allergic symptoms. This list includes a sampling of those chemicals than those in nonallergic people.)
and some of their effects, which can be redundant. Part of the explanation for the un-
usually high levels may rest with the
CHEMICAL ACTIVITY SYMPTOMS
nature of T cells active in allergic pa-
Constricts bronchial Wheezing; difficulty tients. Intriguing recent discoveries im-
airways breathing ply that the T cells in allergic lesions
Dilates blood vessels Local redness at sites include two varietiesÑTh1 and Th2Ñ
of allergen delivery; and that the Th2 type predominates. It
if dilatation is wide- is also known that Th2 cells secrete in-
spread, it can contrib- terleukin-4 and interleukin-5 but not
MEDIATORS FROM GRANULES
ute to a lethal drop in gamma-interferon, whereas Th1 cells

blood pressure (shock) secrete gamma-interferon and inter-
leukin-2 but not interleukin-4 and in-
Histamine Increases permeability Swelling of local tissue;
terleukin-5. Interleukin-4 encourages
of small blood vessels if change in
permeability is B lymphocytes to make IgE antibod-
widespread, it can ies rather than other types. Moreover,
contribute to shock gamma-interferon retards such synthe-
sis. These results suggest that an indi-
Stimulates nerve Itching and pain in skin vidualÕs mix of Th1 and Th2 cells deter-
endings mines whether B cells give rise to IgE
molecules or other types of antibodies.
Stimulates secretion Congestion of airways
of mucus in airways Further, drugs able to interfere with
the synthesis or activity of interleukin-
Constricts bronchial Same as for histamine 4 might help reduce IgE levels and thus
Platelet-activating airways prevent allergic reactions.
factor Many workers, focusing on the ef-
Dilates blood vessels Same as for histamine fects rather than synthesis of IgE anti-
bodies, are now attempting to trace the
LIPID MEDIATORS
Constrict bronchial Same as for histamine complex signal-transduction pathways

airways in mast cells and basophils: the series
Leukotrienes of steps by which cross-linking of IgE
Increase permeability Same as for histamine
of small blood vessels molecules at the cell surface leads to the
release of disease-inducing chemicals. In
Prostaglandin D Constricts bronchial Same as for histamine a critical breakthrough, the genes speci-
airways fying the three types of protein that
constitute the receptor for IgE antibod-
ies have been cloned, providing impor-
tant clues to the receptorÕs three-dimen-
sional structure. As the precise functions
of the receptorÕs subunits are discerned,
speciÞc blockade of their distinctive ac-
tivities, and hence of mediator release,
should be possible.
It is also clear that when an allergen
binds to two or more IgE molecules
and draws together the attached recep-
tors, receptor aggregation switches on
several separate biochemical cascades.
Researchers have realized for a while
that at least one cascade ending in the
extrusion of mediators from granules
depends on activity of the enzyme pro-
tein kinase C. They have found, too,
that the enzyme phospholipase A 2 is a
central player in the secretion of leu-
kotrienes and prostaglandins. More re-
cent evidence indicates that various ty- DUST MITE , invisible to the unaided eye, is a common cause of chronic allergic
rosine kinases (enzymes that add phos- rhinitis. The allergic response is triggered by inhalation of the miteÕs feces.
phate groups to tyrosine amino acids
on proteins) set oÝ additional cascades
that promote the disgorging of chemi- leukin-5 (cytokines made by T cells) ter tiny amounts of a suspected air-
cals stowed in granules. Because many and GM-CSF (another cytokine, made borne allergen are injected into the skin.
reaction pathways end in the same out- by endothelial cells, macrophages and Antihistamines generally prove effective
comeÑsecretion of particular media- other cell types) facilitate the migration and are still the standard treatment. The
tors and cytokinesÑtherapies that block of eosinophils and basophils and may newest versions of these drugs do not
a single pathway may be incompletely prolong their survival. A fourth cyto- pass across the blood-brain barrier read-
successful on their own. The interrup- kine, RANTES, made by T lymphocytes ily and so do not cause drowsiness.
tion of two or more pathways seems to and other cells, seems to regulate mi- When inßammation is severe and anti-
be synergistic, however. gration by eosinophils. histamines are ineÝective, compounds
Compounds that inhibit enzymes in- Apparently, then, many diÝerent cells more commonly prescribed to alleviate
volved in generating speciÞc mediators and molecules, not a single chemical, the chronic inßammation of asthma
are already in development. The proto- account for the presence of any given (that is, inhaled corticosteroids) are of-
typical therapeutic agent impedes ac- cell type in an allergic lesion. If the com- ten helpful. I anticipate that experimen-
tivity of an enzyme called 5-lipoxyge- binations of factors responsible for the tal drugs now being tested on asthmat-
nase and in so doing retards produc- accumulation of eosinophils and ba- ics, which I shall discuss later, could
tion of several leukotrienes. Early trials sophils in the allergic process can be oÝer added alternatives for allergic rhi-
of this inhibitor in asthmatic patients clariÞed, this step, too, should become nitis suÝerers.
indicate that this approach will reduce amenable to pharmaceutical control. For severe cases, immunotherapy
inßammation. (also called allergy shots or desensiti-
I
Beyond signal transduction, we must t is often useful to discuss allergy as zation), which was introduced in 1911,
explain how basophils, eosinophils and if it were a single disease, but inves- may provide relief. Physicians inject pa-
other white cells are recruited to sites tigators are also giving attention to tients with increasing doses of the aller-
where mast cells are active. The gener- the best ways to diagnose and treat spe- gens to which they are sensitive. I wish I
al consensus holds that stimulation of ciÞc allergic conditions. Of these, aller- could describe how immunotherapy
mast cells triggers the release of chem- gic rhinitis is the most prevalent, aÝect- confers resistance to an allergen, but no
icals that penetrate into local, small ing perhaps 15 percent of Americans. one has put forward a deÞnitive expla-
blood vessels and increase expression This disorder takes two forms. Peo- nation. Nevertheless, controlled studies
of adhesion molecules on circulating ple aÜicted with one variantÑhay by A. William Frankland of St. MaryÕs
leukocytes and on endothelial cells that feverÑundergo symptoms seasonally ; Hospital in London and Francis C. Low-
line the interior of the vessels. The se- they may react to pollens of trees and ell of Harvard University in the 1950s
creted chemicals include leukotrienes, grasses in the spring or to pollens of demonstrated that immunotherapy for
platelet-activating factor and probably weeds in the fall. In the perennial vari- grass and ragweed sensitivity can ame-
cytokines; the adhesion molecules have ant, symptoms are more likely to be liorate allergic rhinitis and asthma. My
such names as integrins, selectins and caused by indoor allergens, such as an- colleagues and I later conÞrmed this ob-
immunoglobulin adhesion molecules. imal danders or the ubiquitous dust servation, and others demonstrated that
Next, the leukocytes stick to the blood mite. Allergic rhinitis is never fatal but allergens produced by dust mites can be
vessel wall and roll along it. They then may lead to complications, such as si- useful as well. In all cases, however, the
migrate between endothelial cells and nusitis, polyps or asthma. It is also a dosage is critical; too little allergen pro-
out into the surrounding tissue. major nuisance and a cause of signiÞ- vides no protection. Moreover, protec-
There the mixture of chemicals pro- cant discomfort. Indeed, billions of dol- tion is rarely complete.
duced by diverse cell types controls lars are spent every year to prevent and Asthma is much more serious than
their migration route, how far they trav- assuage the symptoms. allergic rhinitis and is sometimes le-
el and whether they will die or thrive. Physicians conÞrm the diagnosis by thal. Roughly 5 to 10 percent of chil-
For instance, interleukin-3 and inter- observing a wheal-and-ßare reaction af- dren have the condition, about a third
of whom may display no symptoms af- ed activity, and some of which may not. bling those seen in the late-phase re-
ter adolescence. Conversely, another 5 One hallmark of the disease is so- sponse produced in the laboratory. Evi-
to 10 percent of people acquire asthma called twitchy airways. Compared with dently, chemicals released from mast
in adulthood; it may arise at any time, the bronchi of nonasthmatics, those cells and inÞltrating basophils combine
even in oneÕs eighties. of asthmatics contract in response to with toxic eosinophil proteins to pro-
As is true of allergic rhinitis, asthma much lower doses of bronchoconstric- mote mucus production, as well as to
is generally divided into two types. In tors (such as histamine or methacho- damage tissue, thicken airway walls and,
the extrinsic form, an oÝending aller- line) or of noxious substances (such as perhaps, increase bronchial hyperreac-
gen can be identiÞed; in the intrinsic ozone or tobacco smoke). In asthmat- tivity. When an allergen comes along,
form, symptoms cannot be traced to a ics, exercise and cold, dry air can bring the resulting constriction of the airways
substance capable of inciting produc- on symptoms as well. can then close the already partially oc-
tion of IgE antibodies. Actually, though, Asthmatics may also evince chronic cluded passages.
the deÞning features of asthma can but potentially reversible partial ob- Bronchodilators are the most com-
probably result from any of at least half struction of their lower airways. Much monly used drugs for asthma; they re-
a dozen diÝerent disease processes, of the obstruction is thought to arise lieve the symptoms generated by his-
some of which may involve IgE-mediat- from inßammatory processes resem- tamine and other bronchoconstrictors
After a Sting Dizziness, seizures, loss of

consciousness or death can arise
as a consequence of a severe
B ee sting in an allergic individual
can cause anaphylaxis: malfunc-
tioning of organs far from the site of
drop in blood pressure
Swelling of the lips and tongue

the sting. One or more of the symp-
occur frequently and can impede
toms shown here might arise in any swallowing and breathing
given person. Systemic reactions oc-
cur because venom diffuses into cir- Swelling of the larynx can cause
culating blood (inset), which can car- suffocation
ry it to sensitized mast cells located
throughout the body. Constriction of lower airways
can cause wheezing and other
asthmatic-type breathing
difficulties
Potentially fatal heart attacks

and arrhythmias can arise as a
consequence of a severe drop in
blood pressure
Dilatation of large blood vessels

can contribute to shock:
profound lowering of blood
pressure, leading to disturbance
of the heart and brain
Nausea, vomiting, abdominal

cramps and diarrhea occur
sometimes
Dilatation and increased

permeability of small blood
vessels can contribute to shock
Skin eruptions, such as hives,

are the most common symptoms
soon after exposure to an allergen. Yet
these drugs probably do not aÝect the
underlying inßammation. Further, over-
use of bronchodilators may cause Òre-
boundÓ constriction and actually de-
crease airßow. Prevailing wisdom favors
ongoing treatment of the inßammatory
process in addition to separate treat-
ment of acute episodes.
The approved anti-inßammatory
agents include corticosteroids and non-
steroidal drugs. Of these, the steroids
are the most potent. Until about a de-
cade ago, patients generally took the
steroids orally, and the side eÝects
(such as weight gain, osteoporosis and
ulcers) posed a major problem. More HUMAN MAST CELLS look quite diÝerent before (left) and after (right) activation.
recently many studies have shown that Activated cells retain very few granules (small black spheres) and display exten-
the inhaled, or topically administered, sive alteration of the surface. The large spheres in the cell at the left are lipid bod-
versions can achieve good control with- ies, which may participate in synthesizing the lipids secreted by stimulated mast
out producing signiÞcant unwelcome cells. Ann M . Dvorak of Harvard Medical School supplied the micrographs.
eÝects. On the other hand, inhaled ste-
roids may not attain full eÝectiveness
in people who undergo very frequent is not dramatically or completely eÝec- with a scalpel or even a table knife or
asthmatic attacks or who have perpetu- tive in most patients. A recent study the tip of a fountain penÑcan be life-
al breathing diÛculties. conducted by the National Institutes of saving. Other possible manifestations
This last problem has spurred a Health showed that ragweed immuno- of mast cell activity include asthmalike
search for anti-inßammatory agents that therapy could beneÞt asthmatics, but constriction of the lower airways. Skin
are more potent than corticosteroids the eÝect was modest. eruptions and itching are particularly
but also relatively nontoxic. Two of the Sadly, the incidence of asthma and common, whereas gastrointestinal dis-
more exciting classes of drug candi- the number of deaths it causes surged turbances occur rarely.
dates aim to block the activity of in- by more than 60 percent in the 1980s. Interestingly, in individuals who have
ßammatory cytokines and the adhe- The reasons for the rises are mysteri- undergone repeated episodes of ana-
sion molecules that facilitate migration ous, as is the explanation for why Amer- phylaxis, the particular set of symptoms
of immune system cells from the blood icans of African descent are three times suÝered almost always reproduces it-
into tissue. In theory, such products more likely than those of European de- self exactly. These symptoms may be
should ameliorate not only asthma but scent to die from the disease. Hypothe- preceded by an aura, in which the pa-
many allergic disorders, including some ses to explain the overall mortality Þg- tient may have a feeling of impending
that are not now amenable to treatment ures range from overuse or ineÝectual doom or, strangely, a feeling of great
(such as chronic skin allergies). These use of bronchodilators to an increase calm or peace. Whether severe anaphy-
drugs have not yet entered clinical trials in environmental pollutants and aller- laxis is occurring for the Þrst time or
for the treatment of asthma, but pre- gens. In the African-American popu- the Þfteenth, it is an emergency. Hence,
liminary studies in humans and other lation, poor access to care may also be treatment must focus on correcting the
primates are encouraging. at fault. most serious symptoms. Usually this
Research into experimental therapies strategy includes injection of epineph-
J
for asthma does not end there. In addi- ust as asthma can be deadly, so too rine (adrenaline), which inhibits media-
tion to developing drugs that should can anaphylaxis, which is frighten- tor release, opens airways and combats
block enzymes involved in signal trans- ing for both the patient and the dilatation of blood vessels. Naturally,
duction, pharmaceutical houses are de- physician treating it. It was Þrst de- the best treatment is avoidance. In the
vising new products that interfere with scribed in 2641 B.C.: a tablet describes case of bee stings, this strategy is often
the activity of mediators made by mast the death of the Egyptian king Menes impossible, and so immunization with
cells and basophils. For instance, sever- after an insect sting. In the U.S. today, the venom of the oÝending insect is
al companies are well into clinical trials millions of anaphylactic reactions prob- used to prevent reactions.
of substances that block the function- ably occur every year, although deaths Bee-sting immunotherapy has an in-
ing of leukotrienes. The drugs reduce apparently number in the hundreds. structive history that underscores the
symptoms and may work even better The symptoms, which can vary, re- importance of well-designed clinical tri-
when combined with antihistamines. sult from an acute, explosive release of als of new therapies. Back in 1930, in
(Antihistamines by themselves do not chemicals from mast cells. This explo- the Þrst volume of Journal of Allergy,
have much eÝect in asthmatics, presum- sion typically elicits one or more symp- Robert L. Benson and Herman Semen-
ably because inßammatory cells secrete toms within minutes, and it can kill ov of the University of Oregon de-
large amounts of leukotrienes and oth- promptly. Shock is a major cause of scribed a single case of a beekeeper
er redundant mediators.) death. People can also perish if the vo- who suffered an anaphylactic reaction
Investigators also continue to explore cal cords swell (as a result of blood to a sting. Searching for the allergens
the value of immunotherapy for asth- ßuid leaking into tissues) and close oÝ that might be delivered as a preventive,
matics. This treatment is oÝered more the trachea. This disturbance is one of they performed skin tests on this pa-
often by allergists than pulmonary spe- the few that is readily corrected, by tra- tient with bee venom (later identiÞed
cialists. When such a disparity exists in cheotomy. Making a hole in the trachea as the true allergen) and with ground-up
medicine, it means that the treatment just below the ÒAdamÕs appleÓÑbe it whole bees. They found that the pa-
league Hugh A. Sampson has demon- ful study of their method. As would be
strated that aÝected youngsters usual- expected from research demonstrating
ly are sensitive to proteins in milk, the need for relatively high doses, this
nuts or eggs. The symptoms, typically study failed to prove any eÛcacy. In
skin rashes, can be fairly subtle in chil- another odd practice, small amounts of
dren. To be sure of the diagnosis, at a potentially oÝending inhaled allergen
Johns Hopkins we perform a standard are placed under the tongue as a form
skin test. If that result is positive, we of Òdesensitization.Ó There is no evi-
do a double-blind food-challenge test : dence that this procedure works.
on one day a capsule of an allergen or
T
a placebo is fed to a child, and on an- hose of us conducting research
other day the alternate choice is given. by the standard scientiÞc meth-
At the time of the feeding, neither the od can feel heartened by the ex-
patient, the parent nor the physician tent of progress that has been achieved
knows whether a food or a placebo is to date. Even so, gaps remain. We need
being administered. to understand the mechanisms of sig-
In adults the cause-and-eÝect relation nal transduction in more detail, so that
between a food and symptoms is usual- we can develop drugs to block the re-
ly obvious because dramatic symptoms lease of mediators and their relatives
arise promptly. Most often, an individ- from immune cells. It is important to
ual will acquire hives (urticaria) or suf- determine precisely which circulating
fer a more serious anaphylactic reac- cells are involved in causing allergic
WHEAL-AND-FLARE REACTIONÑswell- tion within minutes after eating shell- diseases and to discern exactly how
ing and rednessÑindicates a person is Þsh or nuts. Hence, suspected allergy they are drawn into inßammatory le-
allergic to a substance that has been in- can be conÞrmed with a simple skin sions. And we need to understand
jected into the skin. In this case, the re- test. Probably dozens of people die ev- which of the many, redundant cellular
action on the arm indicates the individ- ery year because nuts or egg proteins secretions most contribute to distress-
ual is allergic to grass. unexpectedly show up in packaged or ing symptoms, so that we can develop
other foods. eÝective antagonists. I am conÞdent
Food allergies in adults are uncom- that the tools being honed by investiga-
tient responded equally to both these mon, aÝecting only 1 to 2 percent of tors in the pharmaceutical and biotech-
preparations. They therefore conclud- the population. Yet about 25 percent nology industries and in academia will
ed that allergic patients could be of Americans believe they are allergic help resolve these issues to a signiÞ-
helped with whole-body extracts, which to some food and that this sensitivity cant extent within the next few years.
were significantly less diÛcult and ex- engenders vague disturbances such as
pensive to produce than venom. depression, fatigue or extreme irrita-
Unfortunately, they failed to realize bility. I am perturbed by this phenom-
that beekeepers would test positive to enon because there are doctors who FURTHER READING
both venom and body parts of bees be- minister to these patients, using com- ASTHMA: PHYSIOLOGY, IMMUNOPHARMA-
cause they continually inhale the con- pletely unreliable tests to diagnose COLOGY, AND TREATMENT. Edited by
A. Barry Kay, K. Frank Austen and Law-
stituents of the dead insects and con- food sensitivity. I estimate that hun-
rence M. Lichtenstein. Academic Press,
sequently become sensitive to those dreds of millions of dollars are thus 1984.
constituents. Allergic individuals in the wasted on useless tests and treatments ALLERGY: PRINCIPLES AND PRACTICE.
general population encounter bees less every year. Edited by E. Middleton, Jr., C. E. Reed,
often and do not become so sensitized. These are not the most worrisome E. F. Ellis, N. F. Adkinson and J. W. Yun-
Based on this single case report, phy- doctors. One group, self-described clin- ginger. C. V. Mosby, 1988.
sicians ÒimmunizedÓ allergic patients ical ecologists, diagnose patients as be- THE VALUE OF IMMUNOTHERAPY WITH
with whole-body extracts of bees and ing ÒsensitiveÓ to their environment, VENOM IN CHILDREN WITH ALLERGY TO
INSECT STINGS. Martin D. Valentine et al.
yellow jackets for the next half centu- such as to minor contaminants in wa-
in New England Journal of Medicine,
ry, until my colleagues and I did a con- ter, food or air, even though these con- Vol. 323, No. 23, pages 1601Ð1603; De-
trolled study comparing the preventive taminants cannot, in fact, induce aller- cember 6, 1990.
value of a placebo, a whole-body extract gic responses. As before, these practi- ANAPHYLAXIS. Bruce S. Bochner and Law-
and venom. We found that the whole- tioners typically diagnose by unproved rence M. Lichtenstein in New England
body extract did not diÝer in effective- techniques; each method that has been Journal of Medicine, Vol. 324, No. 25,
ness from the placebo; in contrast, the examined in rigorous trials has been pages 1785Ð1790; June 20, 1991.
EFFECT OF H1 RECEPTOR BLOCKADE ON
venom was uniformly successful at fore- found wanting. Yet the clinical ecolo-
THE EARLY AND LATE RESPONSE TO CU-
stalling bee-sting anaphylaxis. Thus, be- gists and their patients are highly out- TANEOUS ALLERGEN CHALLENGE. E. N.
cause of the lack of a controlled study, spoken, and so I fear that already limit- Charlesworth, W. A. Massey, A. Kagey-
physicians treated their patients for ed federal research dollars will be allot- Sobotka, P. S. Norman and L. M. Lichten-
years with a totally worthless material. ed to the study of this so-called allergy stein in Journal of Pharmacology and
Today only venom is administered. to the environment. Experimental Therapeutics, Vol. 262, No.
Finally, many questionable types of 3, pages 964Ð970; September 1992.
THE PATHOPHYSIOLOGY OF ALLERGIC RHI-
F
ood allergies, which can cause lo- immunotherapy are oÝered. For in-
NITIS AND ITS IMPLICATIONS FOR MAN-
cal or systemic reactions, deserve stance, those who employ the Rinkel
AGEMENT. A. G. Togias and L. M. Licht-
special mention because of wide- technique inject tiny, homeopathic dos- enstein in The Mast Cell in Health and
spread misunderstandings about them. es of allergens. Years ago several of my Disease. Edited by M. A. Kaliner and
These allergies are not uncommon in colleagues collaborated with advocates D. D. Metcalfe. Marcel Dekker, 1992.
children. In deÞnitive studies, my col- of the Rinkel approach to plan a care-
The Immune System
as a Therapeutic Agent
New technologies and insights into the molecular
underpinnings of the immune system provide the basis
for novel approaches to vaccines and other therapies
by Hans Wigzell
T
he immune system is an alche- that is, selected T cells or antibodies re- munize people against smallpox eÝec-
mistÕs dream. Its multifaceted spond to a precise target: a foreign or- tively and safely.
methods of attacking such intrud- ganism or entity. The T cell form of ac- At the turn of this century, techniques
ers as bacteria or viruses oÝer research- tion is called cell-mediated; the anti- to make vaccines became somewhat
ers an abundance of compounds and body response is termed humoral. more precise. Researchers grew microbes
molecular strategies that can extend The second form of immune system in laboratories and administered small
the scope of medical intervention. Us- reaction is not antigen-speciÞc. This doses of the killed or attenuated organ-
ing our knowledge of the immune sys- type of response entails the actions of isms as vaccines. The improvements,
tem, we can strengthen its response to compounds known as cytokines, which however, did not always ensure the pu-
a given antigen, direct it to combat an resemble hormones, or those of antibac- rity of the product: disease sometimes
overlooked foe or, in cases of organ terial peptides. Such molecules can de- resulted, and reactions to vaccines were
rejection, forestall misguided attacks. stroy bacterial cell walls, prevent viruses not uncommon. After this advance,
When successful, these attempts give from replicating or interfere with the vaccine research proceeded at a pain-
rise to a kind of gold in therapies to biochemistry of pathogens in a number stakingly slow pace.
prevent and to treat disease. of other manners.
D
EÝorts are currently under way to Therapeutic uses of the antigen-spe- evelopments in the past decade
improve existing vaccines, to make them ciÞc strategy are familiar because they have revived such investigations.
more speciÞc and to eliminate any ad- include one of medicineÕs most potent Using molecular techniques, sci-
verse reactions that may accompany defenses: vaccines against infectious entists can now rapidly locate the ge-
immunization. These reÞnements and diseases. The key to vaccines lies in the netic component of a microorganism
a more thorough understanding of cer- immune systemÕs remarkable memory. that gives rise to an illness. They can
tain illnesses have suggested innova- Not only can it recognize and destroy isolate the protein, or series of proteins,
tive means of limiting immune system nearly any intruder, the immune sys- arising from these genes, manufacture
responses in cases of allergy, autoim- tem also can remember for decades it in pure form and in great quantity and
munity and organ rejection by pinpoint- most of its previous skirmishes. Thus, then vaccinate people with the speciÞc
ing and blocking the action of speciÞc when a person is given a weakened element rather than with the entire or-
molecules. In contrast, other therapies dose of an infectious agent such as the ganism. Furthermore, if any proteins in a
are being crafted to increase attacks on virus that causes polio, his or her body potential vaccine are found to be harm-
cancer and AIDS. Perhaps most exciting responds by making antibodies and T ful, they can now be easily deleted or
is the creative use of components of the cells that ultimately eliminate the virus. modiÞed.
immune system as biological mimics Once the organism has been obliterat- SpeciÞcity increases a vaccineÕs eÝec-
and as enzymes that can help in the ed, the responsible antibodies and T tiveness. Monoclonal antibodies can be
treatment of disease. cells remain on the alert and protect used to discover the neutralizing deter-
In general, there are two approaches the immunized individual against any minant, or vulnerable portion, of a bac-
to harnessing the immune system ther- later, and perhaps more virulent, en-
apeutically. Not surprisingly, these ap- counters with the same organism.
proaches reßect two aspects of immuno- Vaccinations of various kinds have
HANS WIGZELL is professor of im-
logic function. Certain reactions of the been used for hundreds of years. Pliny munology at the Karolinska Institute in
immune system are antigen-speciÞc, the Elder thought the livers of mad Stockholm, where he has taught since
dogs held a cure for rabies. And for cen- 1982. He is also director of the Swedish
turies, Asian physicians took dried crusts Institute for Infectious Disease Control.
from the lesions of smallpox patients After earning an M.D. and a Ph.D. at the
LIVER TRANSPLANT can cause the re- Karolinska Institute in 1967, Wigzell be-
cipientÕs immune system to reject the
and gave them to children to scratch
into their skin or to inhale nasally. Many came professor of immunology at Upp-
donor organ after surgery. Recent dis- sala University in 1972. In his spare time,
coveries in immunology are pointing to- children became immunized, but some
Wigzell grows tropical plants in the cold
ward ways in which the system can be developed smallpox. It was not until reaches of Sweden. So far his eÝorts
safely manipulated to thwart its own ef- 1796 that British physician Edward Jen- have not been fruitful.
forts to attack such grafts. ner used a related virus, cowpox, to im-
Events in the History
British physician Jenner uses Von Behring and Kitasato
Roman scholar Pliny the cowpox virus to vaccinate Louis Pasteur Shibasaburo successfully test
Elder suggests that livers effectively against smallpox vaccines for diphtheria and tetanus
of mad dogs could offer
protection against rabies
Asian physicians use Typhoid
smallpox crusts as form and cholera
of immunization– vaccines are
with mixed success produced
Pasteur develops
Edward Jenner a rabies vaccine Emil A. von Behring
A.D. 23–79 1500s 1796 1885 1890–1904 1900s
terium or virus. A large majority of the required that the vaccine be made of can serve as factories where antigens
antibodies that the body produces to live organism or virus, a sometimes are produced, processed and presented
conquer an organismÑsay, an inßuen- dangerous proposition. on the MHC molecules. The muscle cells
za virusÑare ineÝectual because they New adjuvants (substances used in make the foreign protein from the in-
target proteins that do not allow them the preparation of vaccines) can circum- jected DNA and then oÝer it up as anti-
to eradicate the organism. But the re- vent this problem because they can en- gen that is recognizable to the T cells.
maining minority of antibodies are fo- sure that an antigen will be ÒseenÓ by Although there is an autoimmune re-
cused on a weakness in the viral de- the correct immune system cell. Re- sponse against the muscle cells, it ap-
fenses. Therefore, if a person receives a searchers can insert an antigen into li- pears to be negligible.
vaccine composed of the protein or posomes, or tiny capsules made of fat- Despite these improvements in vac-
proteins that make up the neutralizing ty molecules. Once the liposomes are cines, many microorganisms maintain
site, his or her antibody production for in the body, macrophages devour them. their capacity to outwit the immune
that portion of the virus will increase, Like waiters bringing dinner to ravenous system. Elusive quarry, including the
and disease will be staved oÝ. diners, the macrophages and other im- malaria parasite, continuously alters
Such advances in vaccine design have mune system cells that have consumed its appearance as it rescrambles its ge-
been accompanied by more eÝective the antigen-laden liposomes Þnd them- netic systems. Although a more com-
ways to administer immunizations. For selves surrounded by T cells. plete understanding of the structure of
instance, killer, or cytotoxic, T cells Another fascinating way of obtaining these organisms or parasites will im-
cannot attack an antigen unless it has a killer T cell response entails injecting prove vaccine design, pathogens will al-
been taken inside a cell and presented DNA that encodes a foreign protein into ways exist that are capable of resisting
on a surface compound called the ma- skeletal muscle. Although this seren- immunization.
jor histocompatibility complex (MHC). dipitous Þnding is not entirely under-
T
In the past, ensuring this absorption stood, it seems that muscle cells, which he vaccines that I have just de-
and subsequent correct presentation are much larger than most body cells, scribed are prophylactic; they are
given before contact with a dis-
ease-causing organism. Vaccines that
may serve as remedies have also been
developed and have, like their cousins,
beneÞted from the recent advances in
molecular biology. Immunotherapy for
patients who have allergies to pollen or
to animal proteins, for instance, is un-
dergoing a transformation. Traditional
treatment of this problem involves the
repeated administration of an allergen,
say, cat hair, in highly dilute, gradually
increasing concentrations. Such classi-
cal therapy can reduce a personÕs sen-
sitivity to the allergen, but it works in
only some patients, and its methods of
action are constantly debated.
A more sophisticated alternative to
vaccine therapy would attempt to dis-
arm the antibodies involved in the re-
action. The form of immediate allergy
described above is usually caused by
the overproduction of antibodies, or
immunoglobulins, belonging to a class
called IgE. Thus, a logical treatment
would be to suppress IgE and IgE-relat-
HARLEM RESIDENTS wait in line to receive a poliomyelitis vaccine at a mobile clin- ed reactions.
ic in 1959. The unit was part of a health department drive to vaccinate everyone in It is known that two chemical mes-
New York City. Now that smallpox has been wiped out, World Health Organization sengers, interleukin-4 and interleukin-
oÛcials have targeted the polio virus for eradication. 5, produced by T cells augment the
of Vaccine Development
Salk and Sabin discover
Diphtheria and yellow different forms of poliomyelitis vaccine
Tetanus vaccine fever vaccines
becomes available are produced
Influenza and whooping
Tuberculosis cough vaccines are Measles and rubella
vaccine is made created vaccines are
made
Mosquito Jonas E. Salk Alfred B. Sabin
1914 1920s 1930s 1940s 1955 –1960 1960s
production of IgE. Because many al- the experiments resulted in a low but against CD4 or CD8 molecules of the T
lergy-inducing organisms have an un- speciÞc number of animals becoming cells that bind with antigens, others
usual ability to induce the formation of functionally tolerant illustrates the bio- against adhesion molecules on the T
these compounds, vaccines could be logical validity of the concept. cell surface and still others against re-
designed to block interleukin-4 and in- The most successful immune in- ceptors for interleukins. Reportedly,
terleukin-5. The potential success of tervention for transplantation directs several of these antibodies have been
this approach has been suggested in monoclonal antibodies against the cell- shown to be beneÞcial when used in
laboratory experiments on mice: ro- mediated part of the immune system. preliminary trials in patients.
dents unable to produce interleukin-4 In fact, the Þrst monoclonal antibody
I
are also unable to make IgE. Another to be registered as a drug is targeted n addition to blocking immune sys-
chemical messenger, gamma-interfer- against the constant part of the anti- tem attacks on foreign antigens,
on, brings about the production of mol- gen-binding receptor on T lymphocytes vaccines have the potential to thwart
ecules that inhibit the formation of in- that are causing the rejection of a kid- attacks on the self. The causes of many
terleukin-4 and interleukin-5. Therefore, ney transplant. ( The constant portion autoimmune diseasesÑincluding rheu-
vaccines developed to treat IgE-depen- remains the same in all T cells; the vari- matoid arthritis, in which T cells attack
dent allergies could include an agent able-gene portion changes, allowing an- joints, insulin-dependent diabetes, in
that would lead to the production of tigenic speciÞcity.) Unfortunately, al- which T cells attack insulin-making pan-
gamma-interferon. though the drug reduces the rejection of creatic cells, and multiple sclerosis, in
Curbing immune response is also the the kidney, it has a major disadvantage which T cells attack the fatty sheaths
secret to preventing organ transplant because it blocks all T cell function. around nerve cellsÑhave been general-
rejections and to treating autoimmune Monoclonal antibodies with more ly unknown. Animal models suggest
disorders. The goal in transplantation selective immunosuppressive activity that immunization with self-components
is to create speciÞc tolerance in the re- are being designed. Some are directed can induce the autoimmune disease.
cipient toward the antigens from the
donor or, in the case of a bone marrow
graft, to deter the lymphocytes produced
in the donor marrow from attacking the
recipient. We know this option is with-
in reach in humans because nonidenti-
cal twins, who shared blood circulation
during pregnancy, can accept tissue
grafted from each other.
A spectacular means to achieve toler-
ance would be to harness an autoim-
mune response. The recipientÕs immune
system could be used to identify and
then wipe out T cells carrying recep-
tors for the transplanted antigens. It
has indeed been possible to induce au-
toimmunity against T cells with a spe-
ciÞc antigen-binding capacity. I have
been involved in several experiments in
which rats from strain A were injected
with T cells that sought the antigens
from the tissue of rats from strain B.
We found that in a minority of ani-
mals the vaccination brought about
lifelong speciÞc tolerance against the B
antigens, without complications. These
exciting experiments have, however,
been frustrating because it has proved LABORATORY TECHNOLOGY has advanced dramatically in the past decade, there-
impossible to make these autoimmune by permitting the development of more selective and sophisticated vaccines. In
systems produce speciÞc tolerance in a this photograph, a researcher uses automated, computer-controlled equipment to
reproducible manner. Yet the fact that produce monoclonal antibodies.
Meningococcal diseases and Hepatitis B
chicken pox vaccines and a combination Vaccine for Hemophilus
Mumps vaccine are produced Pulmonary diseases vaccine for measles, influenzae, a cause of
is designed vaccine is developed mumps and rubella meningitis, is introduced
become available
1968 1970s 1978 1980s 1990
For example, an injection of rat collagen the case of human autoimmune dis- called sarcoidosis, 100 percent of the
can give rise to a rheumatoid arthritisÐ ease, the former are still not known. So patients of a similar genetic background
like disorder in the same animal. But one major strategy has been to elim- have an unusually large number of T
until recently, it was unclear whether inate selectively the T lymphocytes in cells with a characteristic receptor in
these models reßected what occurs in the aÝected tissue. (Most autoimmune their lungs.
humans [see ÒAutoimmune Disease,Ó diseases are cell-mediated.) In animal experiments, several
by Lawrence Steinman, page 106]. The tactic is essentially to use au- groups have been able to immunize
Regardless of etiology, enough is toimmunity to combat autoimmunity. against variable-gene products that
known about autoimmune disorders to When immunologists examine the local give rise to an identiÞable receptor. In
permit vaccine research. The antigen- T cell populations causing a disease, this way, one can block the activity of
speciÞc therapy for autoimmune dis- they often Þnd an enormous enrich- T cells having that particular antigen-
ease has only two possible targets: the ment of T cells that recognize a certain binding receptor. After such immuni-
disease-inducing agent, or antigen, and antigen at the site of the illness. For ex- zations, researchers have observed re-
the antigen-speciÞc lymphocytes, or T ample, my colleagues and I have seen duced numbers of T cells expressing
cells, that are attacking the tissue. In that for an autoimmune lung disorder the relevant variable-gene marker in
Researchers
isolate CD4
molecules
HIV Researchers
isolate gp160 UNINFECTED
T CELL WITH
GP160 CD4 MOLECULES
Gp160 injected
into asymptomatic HIV patient
CD4 molecules
injected
into monkey
Antibodies block HIV

infection but do not
interfere with normal
T cell activity
BEFORE INJECTION AFTER INJECTION
ANTIBODIES
TO GP160
CD4
ANTIBODIES
Monkey creates
antibodies
to CD4 molecules
THERAPEUTIC AIDS VACCINES of two varieties are currently the number of antibodies available to attack the whole virus.
being tested. The Þrst form (left) entails isolating a protein, The second type of vaccine (right) involves taking CD4 mol-
called gp160 (which is composed of gp120 and gp41), from ecules from T cells and injecting them into a macaque mon-
the human immunodeÞciency virus (HIV). Gp160 is injected key. The animal responds by producing antibodies to the
into an HIV-infected patient, causing the individual to make CD4 molecules; these antibodies bind to the CD4 molecules
antibodies to the circulating protein and thereby increasing and prevent the virus from entering the T cells.
addition to lowered immune function MACROPHAGE
in cells that did express this marker. MHC MOLECULE
Immunization also resulted in protec- ANTIGEN
tion against other autoimmune diseas-
es that are characterized by T cells car- T CELL T CELL
rying this same receptor. Several teams
have recently vaccinated patients with
human variable-gene products. It will
soon be known whether such immuni-
zations result in an autoimmune attack GAMMA-
against the relevant T lymphocytes and, INTERFERON
if so, whether this Þnding has clinical
applications.
I
n cases of autoimmunity, graft re-
jection and allergy, the immune
system reaction needs to be scaled
down and redirected. The opposite is
true for AIDS and for cancer: the im-
mune system attack needs to be scaled
up. The desperate situation brought
about by the human immunodeficien-
cy virus (HIV), which causes AIDS, has
prompted attempts to develop thera-
peutic vaccines, in addition to the on-
going eÝorts to design preventive vac- CHEMICAL MESSENGERS produced by the immune system, such as gamma-inter-
cines. These experimental forays have feron (small purple spheres at top right), can be used to increase attacks on an anti-
not yielded any clinical beneÞts, but gen. Before an antigen can be ÒseenÓ by T cells, it must be processed by a macro-
they have suggested intriguing avenues phage and presented on a major histocompatibility complex ( MHC ) molecule (top
for research. left). Gamma-interferon ampliÞes this process (bottom) by causing macrophages to
display more antigen, thereby enhancing T cell activity.
One attempt involves isolating enve-
lope proteins, called gp120 or gp160 (a
combination of gp120 and gp41), from the virus cannot gain entry, it cannot pressing the antigen protein. In mouse
HIV. The protein is given to HIV-infect- destroy the cells. Furthermore, immu- tumors, similar vaccines administered
ed individuals in whom symptoms have nization with recombinant CD4 mole- after viral infection block the appear-
not developed. As initially shown at the cules in SIV-infected monkeys caused a ance of tumors.
Walter Reed Army Institute of Research reduction or a disappearance of virus In other cancers, tumor-associated
and conÞrmed by my colleagues at the from the blood for up to four months. molecules that serve as antigens may
Karolinska Institute, this procedure can The frequent appearance of normal- be caused by mutations in genes. These
generate an enhanced immune response ly rare cancers, including KaposiÕs sar- genesÑoncogenes or suppressor genes
against HIV. The reaction includes in- coma, in AIDS patients has suggested for the oncogenesÑare involved in cel-
creased titers of antibodies that neu- to some researchers that the immune lular proliferation. Such mutations cre-
tralize the envelope protein and other system is able to combat such tumorsÑ ate new peptides, or antigens, against
HIV variants. Normally, levels of CD4 T although the role of the immune sys- which T cells may respond. Intensive
cells, which bind to HIV, drop in infect- tem in cancer suppression is hotly de- research is now under way to explore
ed patients. Although this observation bated. Nevertheless, this possibility, whether this latter strategy can be used
needs to be conÞrmed, there have been coupled with observations that the im- to produce vaccines capable of induc-
at least two reports that CD4 T cell de- mune system can sometimes overcome ing a therapeutic immune response
cline is curbed following vaccination common cancers, forms the basis of against already established tumors.
with the gp160 protein. some immunotherapeutic eÝorts to In general, killer T cells are more de-
A second interesting candidate for treat cancer. structive than antibodies. Unfortunate-
a therapeutic HIV vaccine is based on Augmenting the early immune rely, most T cells are ineÝective against
autoimmunity. In a series of experi- sponse to a tumor is pivotal. If the im- many tumor-associated proteins. In sit-
ments, Norman L. Letvin and his group mune system could recognize and at- uations where this is not the case, how-
at Harvard University injected macaque tack tumor-associated antigens before ever, T lymphocytes able to inÞltrate
monkeys with recombinant CD4 mole- a tumor reached a critical size, the the tumor tissue have been isolated.
cules in order to block infection. They chances to wipe out the disease would These cells have served as the germs
found that the animals made antibod- be greatly enhanced [see ÒTeaching the for large in vitro cultures and, once
ies against CD4. These antibodies ap- Immune System to Fight Cancer,Ó by mass-produced, have been infused back
pear to have no eÝect on normal CD4 Thierry Boon; SCIENTIFIC AMERICAN, into the patient. Despite this accom-
T cell function, yet they inhibit HIV and March]. This kind of early immune in- plishment, dramatic improvements have
SIV, the green monkey virus usually tervention is particularly promising for been observed in very few patients.
described as simian immunodeÞciency cancers in which viruses are implicat- Directing monoclonal antibodies
virus, from replication in vitro. Ostensi- ed. These tumors exhibit tumor-associ- against molecules present on the sur-
bly, the antibodies work because they ated antigens that are encoded by viral face of tumor cells is an alternative so-
disturb the viral binding site on the cells genes. When normal animal cells are in- lutionÑalthough this strategy, too, has
and thereby prevent the virus from jected with one of these viral genes, T achieved only limited success. Antibod-
binding and entering the CD4 T cells. If lymphocytes are able to kill all cells ex- ies against the interleukin-2 receptor,
which is normally found in cancers ies as antigens. Oudin called such anti- tion of several other molecules, includ-
caused by the AIDS-related virus HTLV- gens ÒidiotypicÓ and the antibodies that ing neurotransmitters and regulatory
1, can bring about remission. But in reacted with them Òanti-idiotypic.Ó The molecules in the immune system. Al-
other tumors, prior treatment to re- concept of antibodies and anti-antibod- though these Þndings have not yielded
duce the tumor massÑeither surgically ies was extended by the Danish Nobel clinically useful treatments, this situa-
or with other therapiesÑis a necessary laureate Niels K. Jerne into a vision of tion may change soon. In a remarkable
prerequisite for such success. immunologic networks. In such a sys- series of studies, it has been possible
Yet another promising line of attack tem, some anti-idiotypic antibodies re- to produce antibodies with enzymatic,
exists. Immunologists have been able act with the antigen-binding site of the or catalytic, capacity.
to elicit both the humoral and cell-me- idiotypic antibody and look like the an- These catalytic antibodies can extend
diated responses using hybrid mole- tigen itself. Although JerneÕs work was the range of antibody activity, allowing
cules: artiÞcial structures that combine initially treated with skepticism, it has them to do more than bind to a target.
the features of other immunologically now been shown that anti-idiotypic an- The enzymatic activities performed by
relevant molecules. One interesting hy- tibodies may indeed function like the such antibodies include the cleavage
brid consists of an antitumor antibody antigen they mimic. They can therefore of conventional peptide bonds, as well
and a superantigen. Superantigens are foster active and protective immunity as entirely new functions, such as the
proteins of mostly microbial origin that against an infectious disease. detoxiÞcation of highly poisonous mol-
have a unique ability to activate a sub- Antibodies may even be designed to ecules. Toward that end, a team led by
stantial proportion of T lymphocytes, take over functions of antigens or anti- Donald Landry at Columbia University
regardless of their antigen speciÞcity. genic molecules. One of the Þrst re- College of Physicians and Surgeons re-
The antibody part of the compound can ports of such an expanded function cently designed a catalytic antibody that
bind to antigens on the tumor surface. came from experiments on insulin anti- can break down cocaine in the blood-
The superantigen part of the molecule bodies. Antibodies that can arise against stream. Immunologists may soon be
recruits large numbers of T cells to at- insulin were used to produce anti-anti- able to create proteases with the ability
tack the tumor cells (the T cells ÒthinkÓ bodies. When these anti-antibodies were to split selectively an essential enve-
they are attacking the superantigen). In tested for biological activity, it was lope protein present on an otherwise
tests, such antibody-superantigen hy- found that they reacted with antibodies lethal virus such as HIV. Because anti-
brids have been able to bring about the against insulin, thereby blocking attacks bodies have a comparatively long half-
destruction of tumor cells. on insulin. Most important, they were life in vivo, enzymatically active anti-
In addition to protecting against dis- also found to bind to cellular receptors bodies could be used to replace a mis-
ease, antibodies can be converted into for insulin, and when given to animals, sing enzyme.
highly potent antigens capable of pro- they lowered blood glucose levels. In
A
voking a strong immune response. In other words, some of the anti-antibod- lthough the predominant ap-
the 1960s Jacques Oudin of the Pasteur ies functioned like insulin. proach to designing immuno-
Institute showed that some antibodies Antibody molecules were later shown therapies has been based on the
could be recognized by other antibod- to be capable of mimicking the func- antigen-speciÞc elements of the im-
mune systemÑantibodies and T cellsÑ
the picture is rapidly changing. The iso-
ANTIBODIES Researchers
TO INSULIN induce antibodies lation, cloning, expression and produc-
to antibodies tion of a great many pharmacologically
active polypeptides and proteins from
the more ancient, antigen-nonspeciÞc
Researchers isolate parts of the immune system have re-
insulin antibodies sulted in a novel channel for medical
investigations.
INSULIN During evolution, our immune sys-
MOLECULES ANTI-ANTIBODIES tem developed an intricate set of de-
vices to disarm infections. For instance,
small peptides, called cecropins, de-
fensins and magainins, are sometimes
found in the skin and mucous mem-
ANTI-ANTIBODIES branes of higher animals as well as in
TO INSULIN insects. These peptides destroy many
bacteria by inserting themselves into
INSULIN Anti-antibodies the bacterial wall and breaking it down.
RECEPTOR are isolated Investigators have recently deter-
and injected
mined that slight alterations in the com-
FAT CELL position of these peptides do not impair
their function. Peptides can be made
synthetically of amino acids that orient
to the right, referred to as D-amino ac-
ids, instead of to the left, as they nor-
ANTIBODIES TO ANTIBODIES can be used to mimic biological substances and to
curb immune responses. In some disease states, the immune system creates anti-
mally do. (L-amino acids, or those that
bodies to insulin (red Þgures at top left). Such antibodies can be harvested in the have a leftward orientation, are the bio-
laboratory (center) and used to provoke the production of anti-antibodies (purple logically active amino acids found in
Þgures at top right). When introduced into a patient (bottom), anti-antibodies block our bodies.) Surprisingly, these D-ami-
the antibodies that harm insulin. They also bind to the insulin receptor and cause no acid peptides have the same eÝects
blood glucose levels to drop. as their mirror images, are more stable
T CELL
ANTIGEN ANTIGEN
MHC SUPERANTIGEN
ANTIBODY MOLECULE
TUMOR CELL
MACROPHAGE
HYBRID MOLECULE
CANCER TREATMENT employs two aspects of immune re-

sponse: antibody recognition of an antigen (top left) and T cell
reaction to superantigens (top right). Superantigens are micro-
bial proteins that garner attack by many T cells. The therapeu-
tic strategy fuses an antibody recognizing a tumor antigen
with a superantigen to form a hybrid (middle). When the hy-
brid molecule meets the tumor (bottom), the antibody portion
binds to the antigen, and the superantigen attracts T cells. The
T cells carry out their functionÑto destroy the superantigenÑ
and kill the tumor in the process. The strategy is eÝective be-
cause T cells are more destructive than antibodies.
and less easily degraded. This discov- treatment in this disease has the oppo- factor-alpha and gamma-interferon, re-
ery suggests that the D-peptides are not site eÝect of deterioration. spectivelyÑare essential for parasite
binding to receptorsÑotherwise, they Although it is somewhat painful for a colonization. It is thus essential that
would not have any activityÑbut rather scientist to admit, the underlying eÝec- vaccines that induce immunity not only
to lipids speciÞc to the bacterial wall. tor mechanism used by interferons in enhance the production of some cy-
Therefore, researchers may be able to individual diseases is for the most part tokines but also avoid the induction
produce long-lasting self-based antibiot- unknown. Therefore, new applications of others. Our understanding of these
ics that can kill bacteria but not harm for interferons may stem from trial-and- powerful compounds will continue to
the cells of the host. error studies rather than from precise progress through studies of pure inter-
Other pharmacologically active pro- interventions based on scientiÞc knowl- leukins, transgenic mice that overex-
teins oÝer other possibilities for thera- edge. Nevertheless, I anticipate that in- press a single interleukin and so-called
pies. In particular, a family of proteins terferons will Þnd an increasing num- knockout mice that do not express an
called cytokines are of interest. This ber of applications in the clinic, espe- interleukin.
family comprises the interleukins, which cially in the Þeld of tumor treatment. The discovery of new forms of treat-
are produced by white blood cells, and ments, such as those that include cyto-
I
interferons, which stimulate the activi- t is beyond the scope of this article kines, shows us that the human immune
ty of lymphocytes and scavenger cells to enter into a thorough analysis of system has riches as yet unearthed.
that digest foreign particles. interleukins: the number of deÞned The complexity of this defensive sys-
Interferons were the Þrst such chem- interleukins is soon expected to exceed tem promises a wealth of proteins and
icals to be molecularly deÞned. They 20. But enough is known about several molecular strategies that can continue
received their name from the clinical of these chemicals so that some specu- to forge medical innovation. And, like
observation that a patient infected with lative predictions can be made. The in- miners equipped with brighter head-
one virus appeared to be protected clusion of some interleukins or their lights and sharper picks, immunologists
against a second one because some im- precursors in more conventional types can select and extract these treasures
munologic feature interfered with the of vaccines against infectious diseas- with increasing ease.
virusÕs reproduction. There are three es has, in experimental systems, been
major types of interferons: alpha, beta shown to have profound consequences
and gamma. on the composition and the intensity of
FURTHER READING
After a series of overenthusiastic the subsequent immune response. In
claims by researchers, interferons are some instances, the simultaneous pro- IDIOTYPE NETWORKS IN BIOLOGY AND
MEDICINE: PROCEEDINGS OF THE INTER-
now Þnding their place as more con- duction in the local tissue of the anti-
NATIONAL CONFERENCE ON IDIOTYPE NET-
ventional drugs to treat some viral dis- gens of the vaccine vector and the in- WORKS IN BIOLOGY AND MEDICINE. A. D.
easesÑamong them chronic hepatitis terleukin could synergize, inducing an Osterhaus and F. G. Uytedehaag. Else-
B and C, larynx papillomas and rela- enhanced and focused immune re- vier Science Publications, 1990.
tively rare tumors, such as hairy-cell sponse against the antigens. IMMUNOLOGY. Jan Klein. Blackwell Scien-
leukemias and carcinoids of the gut. The occurrence of interleukins in in- tiÞc Publications, 1990.
Lately some remarkably positive re- fectious disease is not an insigniÞcant VACCINES 93: MODERN APPROACHES TO
sults have emerged from the treatment issue. In two parasitic diseases, namely, NEW VACCINES INCLUDING PREVENTION
OF AIDS. Edited by Harold S. Ginsberg
of multiple sclerosis with beta-inter- schistosomiasis and African sleeping et al. Cold Spring Harbor Laboratory
feron, although the reasons for these disease, it has been found that induc- Press, 1993.
results are unclear. Gamma-interferon tion of two cytokinesÑtumor necrosis
Will We Survive?
As host and pathogen evolve
together, will the immune system
retain the upper hand?
by Avrion Mitchison
T
he human species has existed in about 20 percent of us have lived in
something like its present form modern industrial society, an artiÞ-
for about 200,000 years. During cial environment of our own construc-
that time, the immune system has pre- tion, notably free of parasites and many
sumably played a crucial role in our pathogens to which our immune sys-
ability to weather exposure to parasites, tem responds. Good news, perhaps. Yet
bacteria, viruses, toxins and other haz- questions arise concerning the effect
ards that assert themselves by interact- underemployment might have on our
ing with our biochemistry. The relation- defenses.
ship, one must note, has been an ongo- The immune system may no longer
ing, mutual one in which all parties have enjoy the luxury of time. Air travel, ma-
adapted to each other through a vari- jor population growth and the emer-
ety of means, from open warfare to ac- gence of megacities have vastly increased
commodation and even symbiosis. As the ease with which people can become
the relationship has proceeded, neither exposed to agents of disease. For their
we nor our cohabitants have stood still part, the microbes have not been rest-
in an evolutionary sense. Such a long ing on their laurels. New ones continu-
run should by itself give us conÞdence ally come into being. A virus now ex-
that our species will continue to sur- ists that attacks the very defenses on
vive, at least insofar as the microbial which we rely for survivalÑthe human
world is concerned. Yet such optimism immunodeÞciency virus (HIV). The Le-
might easily transmute into a tune whis- gionella bacterium, the Lyme disease
tled whilst passing a graveyard. spirochete and the Rift Valley fever vi-
Changes in some key aspects of hu- rus also exemplify natureÕs ability to
manityÕs conditions of existence have challenge the immune system radically.
created the uncertainty. As a result, our Even old pathogens invent new tricks.
immune system has never before faced Recently evolved drug-resistant strains
more daunting challenges. For perhaps of the tuberculosis bacillus have been
a centuryÑa trivial amount of time plaguing industrial urban centers. Will
from an evolutionary perspectiveÑ such developments change the comfort-
able deadlock? Will Homo sapiens and
the microbes continue to coexist, or will
one side win?
AVRION MITCHISON is scientiÞc di- An important part of the answer to
rector of Deutsches Rheuma Forschungs-
that question can be found in the evo-
zentrum in Berlin. Mitchison read zoolo-
gy as an undergraduate at Magdalen lutionary history of the immune sys-
College, Oxford, where his tutor was Sir tem. We need to look back over a few
Peter B. Medawar. Having won a Þrst- hundred million years to when the ear-
class degree in 1948, he earned his doc- liest vertebrates evolved from their in-
torate in 1952 and went to Indiana Uni- vertebrate ancestors, for at that time
versity and Jackson Laboratory in Bar the immune system Þrst appeared. The
Harbor, Me., as a Commonwealth Fund
Fellow. In the years that followed, he did
research, lectured and taught at Edin-
burgh University, Harvard University, CHALLENGE to the immune system is
Stanford University and University Col- presented by the rapid growth of the hu-
lege, London, where from 1971 until
man population, the crowding together
1991 he was professor of zoology and
of many individuals in large cities, such
headed that department. Mitchison has
received many honors, including the
as London (one of the cityÕs commuter
Paul Ehrlich Prize and the ScientiÞc Med- rail stations is shown here), and the ex-
al of the Zoological Society of London. He istence of high-speed, eÛcient means of
has published over 200 research papers. travel. Such factors change our relation-
ship to viruses, bacteria and parasites.
inquiry turns up a signiÞcant fact: the aberrant growth within the host do not system can prevent some forms of
immune system has always served the aÝect the immune systemÕs develop- sterility by warding oÝ the eÝects of
sole purpose of defense against infec- ment. Bubble babies and their animal paternal leukocytes. Yet mice that have
tion. No other external factor shaped it. counterpartsÑmice with a congenital a congenital thymus defect, if kept alive
This observation is demonstrated to- thymus defect, for exampleÑdo not have in a semisterile environment, reproduce
day by those rare experiments of na- a high incidence of most types of cancer. quite well.
ture in which infants are born with an These natural experiments eliminate The Þndings do not necessarily mean
immune system that does not function two other suggested functions. Some that the immune system cannot be made
because one critical gene has mutated. investigators have proposed that the im- to attack cancer cells or to facilitate re-
If left untreated, these infants will die mune system stimulates the growth of production. But one has to be realistic:
from infection. They can survive only red blood cells. Yet participants in the it will not be easy to persuade the sys-
in a sterile isolator, known as a bubble. natural experiment still make normal tem to perform chores to which it has
The same natural experiment shows numbers of erythrocytes. Other work- not grown accustomed in the course of
that tasks such as protection against ers have proposed that the immune evolution.

In addition to singleness of purpose,
consideration of the immune systemÕs
history reveals a second major feature:
the immune system appears to have
evolved through a process of elabora-
tion. It has achieved its protective pow-
er by incorporating a variety of defens-
es that existed in the invertebrates. It
did not merely override those mecha-
nisms and replace them with some-
thing better.
Among the perfectly serviceable sys-
tems that protect invertebrates are wan-
dering phagocytic cells as well as pro-
teins, ßoating freely in body ßuids, that
can bind to invading bacteria. These
defenses can perform most tasks of
the full-ßedged immune system, except
for mounting heightened responses
against organisms that are previous in-
vaders. The ancient defenses have no
speciÞc memoryÑa hallmark of the im-
mune system proper.
Having evolved in the presence of
these older, nonadaptive defenses, the
immune system incorporates some of
their elements for its own purposes.
It is not fanciful to trace the modern
complement system or antigen-present- HIV INFECTION
ing cells back to these ancestral forms. PER 1,000 PERSONS
One Þnds such ancient molecules as 0.0–0.1
complement receptors on modern lym-
phocytes. Our macrophages sport ma- 0.1–0.15
jor histocompatibility complex (MHC) 0.15–0.25
moleculesÑstructures derived from the
0.25–0.50
phagocytic cells of invertebrates.
The immune system seems to have 0.5–1.0
created its ability to recognize antigens 1.0–2.0
and to mount attacks against them by
2.0–3.5
evolving from and incorporating ÒdumbÓ
defensive proteins such as comple- 3.5–5.0
ment. The nervous system evolved in >15
much the same way. It probably be-
came more intricate to carry out more
complex functions. Thus, the oldest RAPID DIFFUSION OF DISEASE by air travel and other forms of transportation is a
part, the brain stem, mediates auto- fact of contemporary life. Serious, sometimes lethal, infectious diseases such as var-
matic functions, such as heartbeat and
breathing. The cerebellum governs com-
plex motor movements, whereas the its essential components to the exteri- Only for the immunoglobulins can
cerebrum functions as the seat of con- or world. we discern much of an evolutionary
sciousness, mediates perception and co- Unfortunately, we cannot trace most story. Presumably, the Þrst system com-
ordinates the whole. of the evolutionary steps that the im- prised but a single immunoglobulin-
The resemblance between the two mune system took. Virtually all the producing gene. It quickly re-created it-
systems extends to structure as well crucial developments seem to have self, establishing a series of duplicates,
as function. A cytoskeleton consist- happened at an early stage of verte- each making a diÝerent immunoglobu-
ing of its characteristic array of special- brate evolution, which is poorly repre- lin molecule. Then control mechanisms
ized proteins can be recognized in or- sented in the fossil record and from emerged that could direct the produc-
ganisms as primitive as yeast. The cy- which few species survive. Even the tion of separated gene segments that
toskeleton does more than passively most primitive extant vertebrates seem were able to recombine. Yet even hu-
support the cellÕs structure. In our neu- to rearrange their antigen receptor mans retain in a corner of their immune
rons, for example, it serves as the ma- genes and possess separate T and B system something of the primitive ar-
chinery that moves vesicles containing cells, as well as MHC molecules. Thus rangement: the genes that control the
transmitters from the cellular interior has the immune system sprung up ful- production of the lambda light-chain
to the synapse. In the immune system, ly armed. It is regrettable that so few of immunoglobulin, one form of which
antigen-presenting cells, using a simi- the evolutionary experiments of the consists of only two members.
lar method, are able to ingest foreign transition to vertebrates seem to have Molecules of immunoglobulin, the
material, break it down and present survived. proteins most characteristic of the im-

in bacterial cell walls. Molecules that
function as magainins do, such as the
squalamines of sharks and the cecro-
pins made by insects (and perhaps by
many other species) have been found
throughout the animal kingdomÑeven
in warm-blooded creatures.
The immune system, then, probably
passed much of its early life in a slug-
gish, relatively ineÛcient style, playing
a fairly minor role in defense. The sys-
tem came fully into its own only much
later on, after the revolution of warm-
bloodedness enabled our cells to multi-
ply rapidly.
A
s the immune system grew in
importance and complexity, it
underwent a series of internal
reorganizations, which involved com-
promises or trade-oÝs of one kind or
another. The fact that the metabolic
resources of an organism are not un-
limited makes such economic choic-
es necessary. Investment in eÝector
systems, the cutting edge where kill-
er cells and antibodies wallop bacteria
and viruses, must be balanced by in-
vestment in regulatory systems neces-
sary for keeping the entire enterprise
under control. Thus, in the human im-
mune system there are more regulato-
ry T cells, known as CD4 cells, than
any other kind.
One cannot avoid the language of
capitalism here, any more than one can
in discussing ethology. Immunologists
will surely follow in the footsteps of
SPREAD OF H3N2 INFLUENZA VIRUS, BY COUNTRY
those colleagues who have for quite a
BEIJING, NOVEMBER 1989 OCTOBER 1990–MARCH 1991 while been discussing the investment
NOVEMBER 1989–MARCH 1990 APRIL 1991–MARCH 1992 EPIDEMIC of deer in antlers or the balance of
APRIL 1990–SEPTEMBER 1990 AIRLINE ROUTES advantage to hummingbirds in Þnding
fresh ßowers. What a perfect microcosm
of the market the lymph nodes and
ious strains of inßuenza, AIDS and new, drug-resistant strains of tuberculosis spread spleen oÝer. In the germinal centers of
rapidly around the world, often from developing to industrialized countries. these organs, mutating B cells furiously
compete with one another for the tiny
amount of antigen needed for survival.
mune system, combine with antigen to mune system is that its proteins have di- The winners are assured the reward of
ßag its presence to other leukocytes or versiÞed and specialized to an extent un- massive replication. Cells that do not
to initiate destructive chain reactions precedented, except in the nervous sys- Þnd antigen die.
of complement. Such proteins can be tem. Only a very few of the molecules of Where nature fails to provide evidence
grouped into superfamilies. The fruit the immune system are really new. Nat- to support the inquiry into evolution,
ßy, Drosophila , has been found to em- ural selectionÑin Francis CrickÕs words, immunologists have borrowed a tool
ploy molecules that resemble those of the ÒtinkererÓÑneeds only a limited from economists: computer modeling.
the immunoglobulin superfamilies. Their number of parts in its erector set. Franco Celada of the Hospital for Joint
role, however, is not immunologic. As Recent research on the immune sys- Diseases in New York City and Philip
cellular adhesion molecules, they guide tems of Þsh and amphibians has iden- E. Seiden of the IBM Thomas J. Watson
the growth of neurons in larvae. tiÞed another interesting survival. These Research Center have formulated a cel-
Some immunologically signiÞcant mol- cold-blooded vertebrates have relative- lular automaton for closely modeling
ecules are even older. Bacteria, for ex- ly slow-acting immune systems, equipped the cellular events that take place with-
ample, have transporter proteins. These with poorly diversiÞed antigen recep- in the immune system. Sets of simu-
proteins are homologous to those that tors. The tadpole of the common frog, lated T cells, B cells and antigen-pre-
our own cells use to carry peptides to for example, makes only about 100 dif- senting cells appropriately endowed
MHC molecules. There the proteins load ferent antibody molecules. On the oth- with receptors and MHC molecules are
the peptides into the antigen-presenting er hand, frogs have potent defense pep- (metaphorically) shaken up with anti-
groove. The cogent feature of the im- tides, called magainins, that punch holes gen and then allowed to undergo a se-

ries of interactions. The automaton re- by balancing the advantage of being in the number of self-antigens. A corre-
sponds well to antigenic stimulation, able to present more and more peptide sponding number of T cells must there-
mounting recognizable primary and sec- against the disadvantage of deleting fore be deleted if autoimmunity is to
ondary responses. more and more of the T cell repertoire. be avoided. Furthermore, loss of MHC
More interesting results come when Recall that in addition to presenting types ultimately reduces the ßexibility
it is asked deeper questionsÑfor exam- antigen, the MHC molecule identiÞes tis- of response to invading organisms.
ple, how many MHC types per individ- sue as self. So an increase in the number After a few runs, the model comes
ual are optimal? The program answers of MHC molecules means an increase up with a number of between four and
eight, which agrees remarkably well
with what has been observed. Although
not the Þrst mathematical model of the
immune system, this is by far the most
user-friendly tool available for explor-
ing these evolutionary issues. Its real
test will come when it attempts to an-
swer questions to which the solutions
are not known.
A related problem is why the antigen-
presenting groove in MHC molecules
accommodates a sequence of just nine
amino acids [see ÒHow the Immune Sys-
tem Recognizes Invaders,Ó by Charles A.
Janeway, Jr., page 72]. The hard-nosed
biochemist might argue that this size is
an accident of the geometry of the MHC
molecule. The soft-nosed evolutionary
biologist would wonder whether that
explanation alone is suÛcient. Instead
he or she might argue that the length
of the groove may reßect a balance of
selective pressure between two oppos-
ing needs: on the one hand, to con-
serve as much of the T cell repertoire
as possible and, on the other, to pre-
vent parasites from building proteins
invisible to the T cell system. For exam-
ple, if a groove accommodated only six
amino acids, nearly all possible hexa-
peptides might be present in self-pro-
teins, with the result that nearly all T
cells would be deleted. But if a groove
accommodated 14 amino acids, para-
sites could evolve so as to avoid using
bindable peptides in their proteins.
One can imagine primitive vertebrates
trying out various lengths to Þnd out
which one suits best. Testing this pos-
sibility lies just beyond the range of
present computer models but will sure-
ly become possible in the future.
How can one reconcile this tremen-
dous need for economy, and indeed ev-
ident economy in so many aspects, with
features of the immune system that
seem so proßigate? Leukocytes, for in-
stance, occur in several repeated sets,
OPTIMAL NUMBER OF MHC TYPES derives from a balance between the need to re- each equipped with a more or less com-
spond to a large quantity, perhaps many millions, of invading organisms and the plete array of receptors for antigen. We
need to avoid autoimmunity. Observation, as well as computer simulations, such can make a fair guess that the advan-
as those run by Philip E. Seiden of IBM from which the information above is de-
tage of this repetition lies in allowing
rived, shows that the optimal number of MHC types is between four and eight. The
specialization. DiÝerent immunoglobu-
illustration at the bottom shows how the MHC molecule presents antigen to helper
T cells. The process begins when a macrophage encounters an antigen (1). The lins are needed to deal appropriately
macrophage engages the antigen and engulfs it (2, 3). When the antigen has been with diÝerent parasites ( IgA, say, is the
ingested, the cell breaks it down and combines it with an MHC molecule (4 ). The one most eÝective against worms in the
macrophage expresses the antigen-MHC combination on its outer membrane (low- gut), and each immunoglobulin requires
er right ), where it can be detected by a T cell, which alerts B cells to make antibod- its own clone of B cells. Similarly, cyto-
ies that mobilize either component of the immune system. toxic T cells provide an appropriate de-

fense against viruses such as inßuenza ual to another to such an extent that a so to speak [see ÒAutoimmune Dis-
and intracellular bacteria such as Liste- single combination is hardly ever du- ease,Ó by Lawrence Steinman, page 106].
ria. And the larger division into T cells plicated. This state of aÝairs reßects the Nowhere is the balance between the
and B cells reßects, at least in part, the fact that our parasites breed far more two kinds of control displayed better
advantage of giving to the former re- rapidly than we do and can therefore than in leprosy. The disease aÜicts more
sponsibility for self-tolerance and there- evolve more rapidly. than one million people in the tropics
by permitting the latter to indulge in As with other forms of polymor- throughout the world. It disappeared
hypermutation. It would never work to phism, such as that of wing color in from Europe only in the past few centu-
combine the two. Imagine the T cell butterßies, this diversity is presumably ries, for reasons unknown. (Some geo-
populationÕs getting purged of self-re- maintained by selection in favor of het- graphic signs remain. NATO nuclear
active cells in the thymus (which does erozygotes. Heterozygotes are individ- submarines are based at Lazaretto Point
happen) and then generating new re- uals that have diÝerent copies of each at Holy Loch, so called because of the
ceptors by hypermutation (which hap- gene, in this case the genes that con- leprosarium once located there.)
pens only to B cells); disastrous auto- tribute to the variability of antigen- Individuals infected with the leprosy
immunity would ensue! binding molecules. An individual clear- bacterium respond in various ways.
ly enjoys an advantage by having, in Tore Godal of the World Health Organi-
W
e can now begin to derive addition to the four to eight genetic zation found that most patients throw
some answers to our question. loci mentioned earlier, two diÝerent oÝ the infection and are left only with
I would like to do so by dis- genes at each locus. Such an arrange- traces of reactivity in their immune
pelling a possible misconception. So ment maximizes the chances of being system [see illustration on next page].
far this account of the evolution of the able to bind at least one peptide from Others acquire a ÒtuberculoidÓ infec-
immune system might suggest that the any one viral or bacterial protein. tion, in which the body makes a vigor-
process had mostly played itself out Polymorphism in the MHC is indeed ous but only partially eÝective T cell re-
long ago. In fact, the reverse is true. The more complex and more interesting sponse. A third group develops a Òlep-
human immune system is almost cer- than simple selection in favor of im- romatousÓ condition in which the T cell
tainly now evolving more rapidly from mune responses to parasites. The re- response is suppressed. The skin Þlls
generation to generation than ever be- verse also occurs: a vigorous process up with infective bacteria, but life can
fore. Much of this change aÝects poly- in all likelihood creates a rich vari- proceed more or less normally. It is in
morphic genes, genes that express many ety of genes whose products suppress those cases in which the response has
diÝerent forms of the same MHC or an- the immune response. Such genes are not been so fully suppressed, that im-
tibody molecule. Our immune system committed to limiting an immune re- munopathology tends to manifest itself.
is intensely polymorphic, much more action that directly damages the body RenŽ de Vries and his colleagues at
so than any other part of the body. in the course of responding to a path- University Hospital, Leiden, have amply
These molecules vary from one individ- ogenÑthey suppress Òfriendly Þre,Ó demonstrated that the MHC genes pri-
Agendas: Shared and Unshared
R ichard Dawkins of the University of Oxford has noted

that the relationship between pathogen and host can
range from complete compatibility to fatal divergence,
many mammal species, including the raccoon, carry a
significant complement of such benign and even useful
viral genes. The relationship between the rabies virus and
depending on the extent to which they share their agen- its host illustrates the opposite effect. The virus, which
das for survival. When a pathogen’s ge- spreads through contact with saliva, has
nome travels in the host’s gametes, little interest in host survival. The
the two share a common agenda historical trend in the relationships
and thus “agree” that the host between humans and their patho-
should be healthy and capable gens, the author believes, has
of reproduction. The gametes of been toward the shared agenda.

marily have control of the spectrum of for treatments that will mimic these in order to combat such autoimmuno-
responses. genetic eÝects. In taking this view, we logic diseases as rheumatoid arthritis
No doubt these immunosuppressive have been much inßuenced by the pio- [see illustration on opposite page].
genes survive in the industrial societies neering work of Howard L. Weiner of At the other end of the spectrum, nu-
for the most part as relics of chronic Harvard University on multiple sclero- merous viral DNA sequences have be-
infections such as leprosy. In doing so, sis, published earlier this year [see ÒAu- come integrated into the human genome
they provide us (albeit inadvertently) toimmune Disease,Ó page 106]. and are never expressed (most of the
with a measure of protection against The evolution of immunosuppressive coat-color varieties prized by fanciers
the autoimmune and allergic diseases. mechanisms is but one example of how of pet mice result from genesÕ having
Donald J. Capra and his associates at hosts and parasites aÝect one anoth- been knocked out by just such viral se-
the University of Texas Southwestern erÕs development through time; there quences). Or the sequences may get
Medical Center at Dallas conducted a are many others. Indeed, the more we used for purposes that have nothing to
large survey of people suÝering from learn about the molecules of the im- do with viral replication. For example,
insulin-dependent diabetes who re- mune system, the more striking such certain viral genes that encode endoge-
sponded to an appeal over the local ra- adaptations appear. Certain viruses, for nous superantigens have been retained
dio. They found far fewer MHC genes instance, use molecules of the immune in the genome of the mouse. From that
of a speciÞc type ( HLA-DQw1.2) within system for gaining access to host cells. location, they delete the products of
their sample than would have been ex- Exploitative in this way as pathogens other genes called V genes. V genes
pected from the frequency in normal are, their very cleverness can on occa- govern the production of proteins that
control individuals. Presumably, those sion be exploited by humankind. John serve as attachment sites for bacterial
genes suppress the immune response P. Tite and his colleagues at Wellcome superantigens [see ÒHow the Immune
that destroys the beta cells in a personÕs Research Laboratories in England have System Recognizes the Body,Ó by
pancreas. Similar observations have been deÞned a sequence within a bacterial Philippa Marrack and John W. Kappler,
made with other HLA genes in other invasin, a protein that facilitates inva- page 80].
immunologic diseases, such as rheu- sion of host tissue. The sequence binds One can begin to make sense of this
matoid arthritis and vasculitis. to an integrin, a hostÐcell surface pro- coevolution by considering the princi-
The protective eÝect seems hardly tein. TiteÕs group hopes to use this in- ple of the Òshared agendaÓ introduced
large enough to account for the sur- formation to build molecules that by Richard Dawkins of the University
vival of such genes (the diseases are might block invasin. of Oxford. The DNA of a dormant en-
rare and aÜict mainly an aged popula- Scientists at Immunex Corporation in dogenous virus has the same needs as
tion). They nonetheless excite consider- Seattle have been intrigued by the dis- the DNA of the host: they share the
able research interest. At Deutsches covery that certain viruses make cyto- same agenda almost completely. In
Rheuma Forschungszentrum in Berlin, kine-binding proteins. The proteins in- contrast, a virus that kills its host after
we believe protection is mediated by crease virulence, presumably by inhib- a short latent period has little shared
inhibitory cytokines such as transform- iting the immune response. Immunex agenda. One ought to add that full dor-
ing growth factor §. We are searching workers are building similar proteins mancy (incorporation into host DNA)
is rather unusual, as most viruses do
not make reverse transcriptase, the en-
zyme necessary for incorporation.
The need for transmission of the
parasite tends to enforce a common
agenda, and almost without exception
LEPROSY, a disease no longer endemic to Europe, shows a ßuid-Þlled blebs on the skin. In the patient at the center, an
range of pathology that is the result of the immune systemÕs eÝective immune response has caused no more than a lesion
ability to shut itself down when the danger exists that a re- at the hairline. The hand at the right belongs to a patient in
sponse will damage the host. In the patient at the left, genes whom a vigorous immune response has been mounted but in
are expressed that have led to a lack of eÝective response. whom not all the bacteria have been eliminated. In these inter-
Consequently, the leprosy bacillus multiplies and collects in mediate cases, the immune response causes tissue damage.
THERAPEUTIC STRATEGY for rheumatoid arthritis is sug-
gested by a defensive maneuver the pox virus uses against
inßammation. An inßammatory response begins when a mo-
lecular messenger exchanged between immune system cells,
called tumor necrosis factor (TNF ), locks onto its receptor (a ).
In order to block the inßammatory response, viruses lodged
in cells that would be destroyed by the reaction cause the
production of decoy receptors (b). The decoy receptor couples
with TNF before the messenger can dock with an immune sys-
tem cell . This response has suggested a therapy for rheu-
matoid arthritis, a disease caused by inßammation, to workers
at Immunex Corporation in Seattle. The researchers are devel-
oping a TNF decoy that consists of two artiÞcial receptors cou-
pled to an antibody fragment. They reason that the Y-shaped
assembly will compete eÝectively for TNF molecules, thereby
aborting the autoimmune inflammatory response (c ). Early re-
sults show success (curves at right ). The artiÞcial receptor
sTNFR : Fc inhibits response in cultured cells at much lower
concentrations than do other TNF receptors against which it
was tested, perhaps as a result of cross-linking.
that is the direction in which evolution The mixings of the maritime cen- sign that new ones will emerge ab ovo.
has moved. Only new forms of infec- turies are a second reason the immune Rising standards of living and the
tion, such as viruses that have recently system must be changing more speedi- consequent reduction of the impact of
been transmitted from another host ly than ever before. Robert C. Gallo of infection on natural selection will be the
species, bring with them their own sep- the National Cancer Institute has con- main forces producing rapid change. We
arate agendas. Seldom if ever does it vincingly argued that HIV probably had are likely to see in response to the pro-
pay a parasite to kill its host, a fact for its origins in a complex passage of the tean challenge of microorganisms var-
which we should be profoundly grateful. virus from simians to humans. There is iation in the relative frequency of such
little doubt that the worldwide inßuen- polymorphic genes as those of the
C
an we be conÞdent that this tra- za epidemics have the same kind of MHC. Later, full-scale gene replacement
dition of live and let live can origin, starting perhaps when a new va- will occur. Isolation from the complete
persist in the modern world? riety of virus crosses a species barrier range of pathogens also enables us to
Opportunities have never been great- and is then quickly spread around the conserve the storehouse of genetic var-
er for mixing hosts and parasites that world by travelers. iability that is our chief defense. As long
have no previous experience of one Although our cleverness in manipu- as polymorphisms are unused, they re-
another. About a billion human bengs lating the immune system continues to main available, at the ready, like mis-
join the worldÕs population each de- grow in sophistication, our best natural siles in their silos.
cade. Many of them crowd into the defense against most pathogens, new All these developments should bet-
megacities of the developing countries. and old, consists of the immune sys- ter Þt the system for its changing tasks
High-speed aircraft transportation fa- temÕs polymorphism. It enables us to in the modern world. We can conÞdent-
cilitates the easy movement of millions counteract the advantage that pathogens ly predict that these adaptations will on
of people around the globe. The recent enjoy because of their ability to evolve the whole be beneÞcial, although just
past oÝers illustrations of what can rapidly. So far our storehouse of vari- what they will be is unpredictable. We
happen when people meet a pathogen ability has enabled us to survive. can expect the loss of seemingly dele-
from which neither their evolution nor Might we count on more radical de- terious genes to be more conspicuous
their immune system protects them. fenses, such as a further elaboration than the acquisition of beneÞcial ones.
One need only recall the English ditty of structure? Might the control system, The possibility even exists that the
about the malaria-infested west coast for example, arrive at a qualitatively MHC genes that confer susceptibility to
of Africa: diÝerent level of complexity? We can- rheumatoid arthritis or multiple sclero-
not count on such a development as a sis might gradually disappear. This de-
The Gulf of Benin, the Gulf of Benin, possible further line of defense. All of velopment would have little to do with
Where few come out, the existing structures were anticipated any evolutionary eÝect the diseases
Though many go in. in earlier forms of life. And there is no might haveÑafter all they aÜict older
as much as one third to susceptibili-
ty to this disease and that the MHC is
the strongest single genetic factor. The
situation in diabetes is similar. We can
begin to discern a susceptible Òtype.Ó
In the future, we shall be able to draw a
much more complete proÞle of suscep-
tibility, which will no doubt take ac-
count of the MHC and other genes
as well as such other immunologic pa-
rameters as the pattern of cytokine pro-
duction. All this could be done for
healthy individuals, so that they would
know in what circumstances to expect
their responses to fail or to go too far.
They could then take steps to avoid or
prevent risk.
Has the immune system, then,
reached its apogee after the few hun-
dred million years it has taken to de-
velop? Can it respond in time to the
new evolutionary challenges? These
perfectly proper questions lack sure
answers because we are in an utterly
unprecedented situation. Even if we
knew how often in the past host spe-
cies had been wiped out by their para-
sites, that knowledge would tell us lit-
tle about ourselves as we stand at pres-
ent. Yet there are grounds for opti-
mism. Never before have we succeeded
in eradicating a disease simply by en-
hancing the activity of the immune sys-
NEW TUBERCULOSIS STRAIN is highly virulent and resists drugs. Such altered tem, as was done with smallpox less
forms of traditional pathogens as well as such new pathogens as the human than 20 years ago. Never before has sci-
immunodeÞciency virus ( HIV ) and Legionella , which causes LegionnairesÕ disease, ence been so sophisticated and so solid-
challenge and even undermine the human immune system. ly lined up against infections, thanks to
the World Health Organization (and
more particularly its special research
individuals who have had ample oppor- human evolution is now moving far programs) and to such national organi-
tunity to reproduce. It is more likely to faster than ever before. zations as the Centers for Disease Con-
happen because the infections that se- In comparison with this major trend, trol in Atlanta.
lected for the maintenance of these other evolutionary forces seem to exert But above all, I put my trust in the
genes have been eliminated. From the a relatively minor eÝect. Our growing powers of microevolution, in the capac-
point of view of an industrialized soci- ability to track the grossly damaging ity of polymorphism to pull new de-
ety, the genes seem harmful, although genes mentioned at the beginning of fenses out of its vast storeroom, and in
no doubt they served our infection-rid- this article and to eliminate them the ability of host and parasite ulti-
dled ancestors well. through genetic counseling and screen- mately to adopt a common agenda.
Because we know so little about which ing will have an eÝect that will be more
MHC genes are needed for which infec- signiÞcant for individual families than
tions, detailed predictions of this kind for the species as a whole. Contracep-
are diÛcult. At the start of the Iliad, tive vaccines are in the oÛng, such as FURTHER READING
Homer ascribes the plague among the those based on the pregnancy hor- THE EVOLUTION OF ACQUIRED IMMUNITY
Acheans to arrows shot by the irate mone chorionic gonadotropin. G. Pran TO PARASITES. N. A. Mitchison in Para-
Apollo. Would that the god could tell Talwar and his colleagues at the Na- sitology, Vol. 100, Supplement, pages
us about the inßuence of the MHC on tional Institute of Immunology in Delhi S27ÐS34; 1990.
SPECIALIZATION, TOLERANCE, MEMORY,
his choice of targets! have demonstrated how remarkably
COMPETITION, LATENCY, AND STRIFE
This overall trend toward a diminish- eÝective this form of contraception can AMONG T CELLS. N. A. Mitchison in An-
ing selection for infection-resistance be, but only in women who make the nual Review of Immunology, Vol. 10,
genes has obvious hazards. As we low- right immune response. pages 1Ð12; 1992.
er our genetic defenses against the old Genetic information used appropri- A WALK ROUND THE EDGES OF SELF TOL-
infections, we will almost certainly in- ately may serve as an even more pow- ERANCE. N. A. Mitchison in Annals of
crease our susceptibility to new ones. erful tool. The better we become at Rheumatic Diseases, Vol. 52, Supple-
We can comfort ourselves with the tracing the inßuence of destructive ge- ment 1, pages S3ÐS5; March 1993.
T-CELL ACTIVATION STATES: THE NEXT
knowledge that evolution has moved netic factors, the better placed we shall
BREAKTHROUGH IN SIGNALING? N. A.
slowly, maximizing the pros over the be to thwart them. Take rheumatoid ar- Mitchison in Immunologist, Vol. 1, No.
cons through many generations, al- thritis as an example. Studies with twins 3, pages 78Ð80; May/June 1993.
though we need also to remember that suggest that genetic factors contribute
SCIENCE AND BUSINESS
Crystal Light
Storing volumes of data
in four-dimensional spots
I
n July, IBM announced that its re-
searchers had packed Þve times the
usual amount of data onto an opti-
cal disk by shortening the wavelength
of their laserÕs light from infrared to
blue. That achievement is as much an
ending as a beginning. Further progress
in CD-ROM technology faces a funda-
mental limit: the pits that encode infor-
mation on the surface of a compact
disc can be no smaller than the wave-
length of the laser light used to read
them. The next giant leap in data den-
sity will have to come from elsewhere.
DOUGLAS L. PECK
A handful of scientists around the

world think it might come from crys-
tals that can remember and reproduce
patterns and colors of light. Where com-
pact discs store data in two dimensions,
these crystals make use of four: volume CRYSTALS doped with rare-earth ions store laser pulses as color patterns. Apparatus
and color, as well as area. Crystal stor- built by Ravinder Kachru of SRI International could pack 50,000 bits into a tiny dot.
age pioneers believe the technology has
cleared its theoretical hurdles and en-
tered the race to succeed current opti- cy principle. Simply put, it says that periments, an initial infrared ÒwriteÓ
cal and magnetic memories. light does not like to be pinned down. pulse paved the way for the brief but
The basic ideas of crystal memory To conÞne a laser pulse to a narrow intense data stream that followedÑ20
were worked out in 1975. Take a mate- frequency channel, you have to give it on-oÝ pulses representing the 1Õs and
rial that absorbs light over a wide range space (and time) to move around in. 0Õs of binary code, squeezed into the
of frequencies (that is, colors) and fo- That means using long pulses that read same time ordinarily required to burn a
cus a single-frequency laser on it to and write data slowlyÑso slowly that single spectral hole. Hitting the crystal
create a Òspectral hole.Ó Then change spectral holeÐburning could take eons with a ÒreadÓ pulse identical to the write
the frequency of the laser slightly and to Þll a marble-sized crystal with data. pulse caused its molecules to emit a
ÒburnÓ other holes at other colorsÑall in In 1982 physicist Thomas W. Moss- stream of light identical to the data sig-
the same physical spot inside the crys- berg, then at Harvard University, turned nal (though much fainter).
tal. With the right material and a sophis- HeisenbergÕs law from bane to boon. Early experiments, while encourag-
ticated (and costly) laser, a single, one- He suggested using ultrafast shutters ing, uncovered disturbing problems. To
cubic-micron spot inside a crystal might to chop the laser beam into very short get the pulsesÕ color to smear enough
be made to hold a million bits of infor- pulses corresponding to a data stream. to Þll the crystalÕs spectral memory,
mationÑone in each color channelÑ Pinned down in time, the packets of the light must be chopped into bits just
using just 100,000 atoms per bit. IBMÕs light spread out in colorÑthe ßip side picoseconds longÑ25,000 times shorter
new optical disk, by comparison, still of HeisenbergÕs rule. Each color-smeared than Mossberg could make with his
uses roughly 10 trillion atoms per bit. pulse interferes with its neighbors to acousto-optical shutters. Jamming all the
Density is not the sole goal, however. produce a distinctive color pattern. data into one intense stream required
ÒThe real problem is speed,Ó says Mi- When the light hits the crystal, Moss- powerful, expensive lasers. And all the
chael JeÝerson of the IBM Almaden Re- berg explains, Òthe atoms donÕt see each information in one storage cellÑpoten-
search Center. As processors grow fast- pulse; they see an interference pattern tially a million bitsÑhad to be written
er and begin working in parallel, slow that uniquely represents the whole se- or read all at once, at rates much faster
storage threatens to mire computer quence of data.Ó than todayÕs computers can work.
speeds. ÒMoving parts poop out at about By 1988 Mossberg had moved to the So Mossberg went back to the draw-
100 million bits per second,Ó JeÝerson University of Oregon and proved the ing board and theorized a solution: use
notes. Inertia thus imposes another lim- principles of the technique he had ÒchirpedÓ write and read pulsesÑlonger
it on disk-based storage. named Òtime-domain optical memory.Ó beams that steadily increase in frequen-
Spectral holeÐburning has its own He used crystals of yttrium oxide spiced cy as the data are sent. Chirping allows
speed limit, a law of quantum mechan- with a dash of europium ions for broad- slower communication rates and makes
ics called the Heisenberg indetermina- er and more lasting memory. In his exit possible to retrieve small chunks of
data by sending only part of the read
signal. Perhaps most important, it also Contented Cows?
works just as well with $13 diode lasers
as with $100,000 dye lasers.
Ravinder Kachru, a molecular physi-
cist with SRI International, recently
T his room is a big coil, that’s what it is,” says Javier Burchard, a veterinary
researcher at McGill University’s Macdonald campus. He is referring to a
stable owned by the university on the west end of the island of Montreal.
adapted MossbergÕs technique to record This bovine pied-à-terre, once used for metabolic experiments on cows, was
and recall 1,600 bits in a single spot. redecorated. The floor was dug up. Copper wiring, set in a new concrete
Kachru used random phase-shifting in- floor, was stretched up the walls and around the ceiling to form electric coils—
stead of chirping to achieve a similar with each loop placed every meter along the 14-meter length of the room. At
eÝect but with an added feature: natu- the same time, two charged metallic plates were suspended from the ceiling.
ral encryption. The data stored in the Animal-rights activists need not fret. The coils and plates are not for con-
crystal can be retrieved only by a read cocting rosbif. The controversy over the biological effects of electromagnet-
pulse that exactly matches the complex ic fields, which has become a subject of scrutiny for pregnant women who sit
shape of the initial write pulse. in front of personal computers and homeowners who live near high-power
KachruÕs record-breaking experiment lines, has now touched the holsteins of La Belle Province.
used a mere fraction of the crystalÕs Milk and electricity are big industries in Quebec. Hydro-Québec’s 735-kilo-
color capacity. By stepping the laser fre- volt power lines carry electricity from a hydroelectric complex on Hudson Bay
quency up 100 megahertz at a time, to the U.S. border for export. But Quebecois are attached to their farms. If
he found he could continue to write electromagnetic fields were affecting milk output from cows grazing below
1,600-bit packets in the same spot. All the utility towers, it would have ramifications for the entire provincial economy.
told, KachruÕs relatively simple appara- The McGill stable (below ), with a capacity for eight cows, is one of the
tus could Þll each 100-micron spot with most controlled environments for measuring the effects of electromagnetic
at least 50,000 bits, at the rate of 40 fields on a mammal. A current is applied to the coils to produce a magnetic
million bits per second. More sharply field of 30 microteslas, the equivalent of having a cow stand all day below a
focused lasers and faster liquid-crystal 735-kilovolt tower carrying electricity at peak capacity. The ceiling plates
shutters might soon increase that den- give off an electric field measuring 10 kilovolts per meter. The animals—
sity and rate 1,000-fold. four groups of eight cows have been used throughout the course of the
For all its promise, crystal memory is study—are exposed to the fields for a month, and then the current is turned
still far from practicalÑbut then so are off for another month to see if any variation in milk production ensues. Feed
its competitors. Erasing and rewriting intake and hormones and other blood chemicals are also monitored.
are still a problem, and crystals must Winding electric coils around the walls and ceilings of the stable proved to
be kept within 10 degrees of absolute be a tricky engineering feat. Construction, in fact, took eight months. “It was a
zero or they lose their memory. Moss- riot,” Burchard laughs. “The first generator blew up. Nobody knew how to
berg does not think this is a serious prob- generate a uniform magnetic field in such a big space.” Spacing between coils
lem: ÒClosed-cycle refrigerators the size had to be precisely measured, or the team of McGill and Hydro-Québec risked
of a ßashlight can now cool that low.Ó digging up the concrete floor anew to make adjustments. Hydro-Québec sup-
But Kachru suspects that the low-tem- plied about $625,000 for the research, which was undertaken because previ-
perature disadvantage, combined with ous studies of the effects of alternating-current fields on livestock had flaws.
the advantage of blazing speed, makes McGill has also proposed to the Canadian National Research Council an exper-
crystals more likely to replace silicon iment on the effects of electromagnetic fields on cows’ immune systems.
RAM than bulk storage technologies. So far the results of the present investigation, which will be completed
All agree that new materials are a pre- next year, suggest little cause for worry. The holsteins seem to be supply-
requisite. The Department of Defense, ing a normal quotient of milk. “I have the feeling we’re not going to find
crystal memoryÕs largest booster, host- anything,” Burchard says. If that is so, then the term “cow fields” may cease
ed a meeting in July to promote basic to have a double meaning. —Gary Stix
materials research for the technology.
With so little known about the molecu- RECTANGULAR COILS
lar resonance and excitation phenome- PLATES FOR MAGNETIC FIELD INSULATOR
na that make crystal storage work, Moss- FOR ELECTRIC
FIELD
berg says, Òit is not clear that there will
be any material that will make this
technique competitive. But neither is it
clear that there is no such material.Ó
Yet work continues. Kachru is record-
ing images in crystals. Masaharu Mitsu-
naga of JapanÕs NTT Basic Research Labs
has written data by spectral holeÐburn-
ing and then read it as a time-domain
signal. Researchers at the Swiss Federal
Institute of Technology reportedly have
recorded holographic movies using
time-domain techniques. ÒThis is the
LAURIE GRACE
most viable technology to take us to

the atomic level,Ó Mossberg says. Crystal
data storage may be in its infancy, he
adds, but so are the people who may
one day use it. ÑW. Wayt Gibbs
JapanÕs Ministry of Posts and
Tr•s Grande Alliance Telecommunications is spon-
Europe follows the U.S. soring development of a fully
into digital broadcasting digital HDTV satellite broad-
casting system that is intend-
ed to help that nation regain
I
ndustrial policy doesnÕt always pay its leadership role. ÒWeÕll make
oÝ. The European Community and a comeback,Ó declared Take-
television manufacturers together hiko Yoshino, a deputy direc-
have spent at least $750 million over tor of NHK Science and Tech-
the past eight years developing a pan- nical Research Laboratories.
European technical standard for satel- Progress in digital television
lite high-deÞnition television (HDTV) has the Europeans on the de-
AGENCE FRANCE-PRESSE
only to see the money go down the drain fensive, too. The European
when the project was canceled this CommunityÕs Eureka project
past spring. That is a fraction of the bil- mounted an HDTV oÝensive
lions spent by Japanese companies over intended to counter what was
the past decades to gain a dominant viewed in the mid-1980s as a
foothold in the market for television Japanese threat. Now the EC is
with motion pictureÐquality images. also talking 0Õs and 1Õs. This
Meanwhile the U.S., which lagged in new digital television project MICHEL PELCHAT, a French deputy, proposes that
entering the HDTV fray, may now have scraps any notion of pushing the U.S. and Europe agree on television standards.
taken the lead in the next generation of HDTV out into the market-
consumer electronics by pushing ahead place anytime soon. Instead it
in digital broadcasting technology. The gives top priority to digital broadcasts HDTV planners had not reckoned on
carefully laid plans of Europe and Japan of conventional television. EC planners the speed with which television broad-
were upset by the rapid arrival of meth- are promoting wide-screen television on casters would move to exploit techno-
ods for digital compression and modu- far cheaper low-resolution sets than logical advances in the marketplace.
lationÑand the announcement in late those needed for HDTV. To this end, the When Rupert MurdochÕs News Interna-
May of a Ògrand allianceÓ that joins the EC is making more than $260 million tional made its Sky Channel available
eÝorts of three competing consortia available over the next four years to en- as a direct-broadcast satellite ( DBS)
developing digital television for approval courage broadcasters to switch formats. channel in the late 1980s, it rejected
by a technical group advising the Fed- This amount, however, is far less than the ECÕs standard, called MAC (for mul-
eral Communications Commission (FCC). the now abandoned Þve-year, $965-mil- tiplexed analog components), in favor
The commissionÕs laissez-faire ap- lion HDTV proposal that went to the of PAL (phase alternation by line)Ña
proach to standards making is credited commission last year. cheaper alternative that yielded a low-
with fostering a technology that will The digital project marks an about- er-quality picture but one for which in-
likely supplant the hybrid systems of face for EuropeÕs television makers and expensive receivers were readily ob-
analog and digital components that were broadcasters. For years, they spurned tainable. By oÝering the service on a
laboriously developed in Europe and the notion of cooperating with their ri- lower-frequency communications band,
Japan. The mere existence of an openly vals abroad on common worldwide stan- Murdoch circumvented the ECÕs ban on
published technical standard does not dards for fear of opening the European non-MAC DBS transmission. The com-
endanger Japan and EuropeÕs position marketplace to television sets from mercial success of this venture and the
as the leading makers of both studio Japanese competitors. Now EuropeÕs failure of ventures that used MAC
production equipment and television manufacturers are turning to the same helped to seal the standardÕs demise.
sets. EuropeÕs big television manufac- standard for compressing the digital Soon after a reshuÜing of EC minis-
turersÑPhilips N. V. in the Netherlands signal that U.S. makers have largely in- ters in early 1993, the HDTV project
and Thomson Consumer Electronics in corporated into their television plans. was pronounced dead. And now even
FranceÑare, in fact, members of the The irony is all the more compelling be- the French, who in the past have been
grand alliance. But the digital technolo- cause these digital standardsÑcalled the most vociferous proponents of keep-
gy that is being shepherded in Wash- MPEG-2 (for Moving Picture Experts ing European standards European, are
ington, D.C., does provide a new open- Group)Ñwill not work with existing tele- embracing the hands-across-the-water
ing for U.S. companies to reassert them- vision sets without a special electronic approach. Michel Pelchat of the French
selves in consumer electronics, an ÒboxÕÕ to decode the signals. As a result, National Assembly recently put for-
opportunity created by the merging of broadcasters will have to ÒsimulcastÕÕ ward the suggestion that Europe and
television with the computer and tele- the new signals on top of the old ones. the U.S. agree on common standards
communications technologies that U.S. Philips and Thomson have little choice for MPEG compression as well as for
companies dominate. The standard Òap- but to embrace the spirit of coopera- modulation of the signals. PelchatÕs over-
pears to give the U.S. a decided lead tion. The failed HDTV policy has shak- tures led an FCC commissioner to quip
[that] could almost single-handedly re- en conÞdence in the old-style industri- that such an accord would have the
vive the moribund American electronics al policy-making, backed up by power- makings of a Òtr•s grande alliance.Ó
industry,Ó proclaimed an editorial in ful lobbying, that once worked so If the EC commission in Brussels fol-
Japan Times. reliably. ÒIn the past we tried to impose lows the French lead, Europe will try to
Although the Japanese have vowed to technology on the marketplace,ÕÕ says get the U.S. to adopt another technical
continue the deployment of their Hi-Vi- Robert Boyer, vice president for ad- standard for eÛciently modulating the
sion system, which has been transmit- vanced business development at Thom- transmission signal, called orthogonal
ting to a limited number of receivers son. ÒThis time we want to provide a frequency division multiplexing. Devel-
since 1991, Nikkei Weekly reported that service that customers want.ÕÕ oped in Europe for digital audio broad-
casting, it would make the best use of
the precious frequency spectrum for
television broadcasts in Europe. These
standards would allow for manufactur-
ing eÛciencies, but lingering technical
diÝerences would prevent sets made on
one continent from working on another.
EuropeÕs manufacturers and broad-
casters are scurrying behind the scenes
to put the new scheme in place. Once
again, the timetable is being set by
Murdoch. News International, together
with the French television station Canal
Plus, hopes to oÝer a digital television
service by 1995. In response, the same
manufacturers and broadcasters who
collaborated on the original HDTV proj-
ect have formed the European Launch-
ing Group for Digital Video Broadcast-
ing, which expects to publish digital
standards for terrestrial, satellite and
cable broadcasts by the end of this
year. That would give Murdoch and
company enough time to incorporate
the standards into their oÝering.
Back in the U.S., the vaunted grand
alliance risks becoming a great debate.
The coalitionÑbringing together Zenith,
AT&T, General Instrument, the Massa-
chusetts Institute of Technology, Phil-
ips, Thomson and SRI InternationalÕs
David SarnoÝ Research Center in Prince-
ton, N.J.Ñplans to submit a Þnished
system for Þnal testing by next May. In
the meantime, the computer industry
is leading an eÝort to press broadcast-
ers and equipment manufacturers to
fashion a technical standard that makes
television sets and studio equipment
fully compatible with computers.
Still, video equipment manufacturers
and some broadcasters argue for retain-
ing an interim technology that would
keep costs low and speed development,
perhaps in time for the 1996 Olympics.
ÒMost people donÕt want their television
set to look like a computer,Ó says How-
ard N. Miller, a senior vice president of
the Public Broadcasting System and a
member of a technical group evaluating
the HDTV proposals for the FCC. ÒMy
brother-in-law could not care less about
watching a computer.Ó
Computer executives and academics
point out that it is more important to
allow broadcast television to interact
seamlessly with a host of advanced dig-
ital technologies, from hand-held per-
sonal computing devices to cable televi-
sion. Compatible products, they assert,
could encourage vast new markets for
entertainmentÑand beyond, for edu-
cation, medical imaging and publish-
ing. Whether the consensus building of a
grand alliance can withstand the pull of
diverse marketplace demands remains
to be seen. ÑFred Guterl in London,
Robert Patton in Tokyo and Gary Stix
permeation and to dissolve at the same
speed as rabbit skinÑchange the color
of the detection ßuid.
After it was announced last Novem-
ber, Corrositex quickly garnered a pow-
erful fan club. Animal-rights activists,
led by People for the Ethical Treatment
of Animals, inundated the DOT with
more than 26,000 letters imploring the
department to allow Corrositex to re-
place rabbit tests. Dow Chemical, Mo-
bil, S. C. Johnson and Microbiological
Associates (a large contract laboratory)
volunteered to evaluate the product. And
the DOT, in a highly unusual move, invit-
ed IVI to apply for an exemption to the
new regulations.
InVitro did, and in May the DOT
stamped its imprimatur on Corrositex,
virtually guaranteeing IVI the lionÕs
share of a worldwide market that Por-
ter estimates to be worth $300 million
annually. IVI counts among its early
LARA JO REGAN SABA

adopters Exxon, Texas Instruments, Ato-
chem, Ciba-Geigy and numerous other
conglomerates in the U.S. and Europe,
where Òthe movement against animal
testing is much stronger than it is here,Ó
notes William J. Fisher, IVIÕs president.
TEST for corrosive chemicals, demonstrated by William J. Fisher, president of In- So far Corrositex has no competitors,
Vitro, is the only government-approved alternative to using live rabbits. and the exemption process ensures IVI
at least six monthsÕ early warning of
any rivalÕs approach.
In Vitro, In the Money in six months. It has since stabilized at Porter sees more than altruism be-
about $12 per share. hind the quickly approved exemption
A government-approved test InVitro owes its good fortune to the and the corporate rush toward in vitro
spares rabbits and snares bucks United Nations and the U.S. Depart- tests: ÒThere is a very simple explana-
ment of Transportation. Under new U.N. tionÑthis test is obscenely cheap.Ó In-
and DOT regulations that take eÝect on deed, IVIÕs in vitro kit costs about $300
W
hat does it take to get animal- October 1, all potentially corrosive sub- per sample and gives results in one
rights activists, testing labora- stances must be tested and classiÞed day, compared with $1,200 and one
tories, government regulators into one of four shipping categories. month for rabbit tests. Although nega-
and giant chemical companies to agree? Companies caught improperly trans- tive in vitro tests must still be veriÞed
One answer, apparently, is a unique porting caustic chemicals face Þnes of with rabbit tests, the speed and sim-
test introduced by a small Þrm just in up to $25,000 per shipment per day. plicity of the vial method allow busi-
time to save itself from bankruptcy. Perhaps even more persuasive is the nesses to check in-house many samples
Last fall, InVitro International (IVI) threat of class-action lawsuits if a ship- that they used to send out. Oddly
was sliding toward insolvency. The com- per knowingly breaks the rules. enough, Fisher says, this appears to be
pany, based in Irvine, Calif., had two in Until this past spring, the only govern- Þne with most laboratories. ÒEven hard-
vitro (nonanimal) eye and skin irritant ment-approved test for a corrosive chem- core animal-testing labs really oÝer an-
tests, which together earned $1.5 mil- ical was to apply it to the shaved backs imal tests for corrosives as a loss lead-
lion in annual sales to cosmetic and of six rabbits and observe the time nec- er; they feel that Corrositex will give
household products manufacturers. Af- essary for Òfull tissue destruction.Ó Af- them much better proÞts.Ó
ter spending a bundle on expensive ter the procedure, all the rabbits must InVitro stands to do quite well itself.
robotic production equipment, the com- be killed, regardless of the result. ÒItÕs Thanks to automated production and
pany found itself short of cash and ar- one of the most gruesome tests you can relatively cheap raw materials, Porter
ranged a stock oÝer, its second. But only conceive,Ó says Donald J. Porter, direc- conÞdes, Òtheir margins are astonish-
weeks before the sale, the Securities and tor of research for Lew Lieberbaum & ingÑ80 to 90 percent.Ó He predicts that
Exchange Commission charged IVIÕs in- Company, an investment Þrm. ÒIt is hor- IVI, which lost $5 million in 1992, will
vestment banker with securities fraud. rible, expensive and time-consuming.Ó see proÞts soar to more than $10 mil-
The deal fell through, leaving the com- And obsolete, since IVI came up with lion by the fall of 1994. The company
pany cashless and its investors very un- an alternative test called Corrositex. It is already working on a new product,
happy. IVIÕs stock price plummeted. consists of a vial Þlled with a mixture called Ecotox, which will test sewage
In December white knights rode in of chemical detectors, capped by a cel- and industrial waste for toxicity. If Eco-
and bought 3.4 million shares of InVi- lulose membrane that supports a gel- tox is as warmly received by the Envi-
tro at 50 cents apiece. By June their in- like artiÞcial skin three centimeters ronmental Protection Agency as Cor-
vestment was worth more than $42 mil- thick. Corrosives that completely de- rositex was by the DOT, IVI could really
lion as the stock shot up 2,500 percent stroy the skinÑit is designed to resist clean up. ÑW. Wayt Gibbs
Genome sequencing, artiÞcial evolu-
Natural Selection tion, small molecules: many analysts
Investors arenÕt buying into and executives agree these will play
Darwin MolecularÕs evolution starring roles in the next decade of
biotechnology. ÒDarwin symbolizes the
synthesis of these technologies,Ó says
N
othing succeeds like success,Ó JeÝrey W. Casdin, managing director of
runs the old chestnut. So bring- Oppenheimer & Co., an investment Þrm.
ing together executives with prov- Yet despite its attractive package, its
en track records and scientists of the all-star cast and a diligent, year-long
highest caliber to deploy advanced tech- search for investors, Darwin is still run-
nology to meet important market de- ning on seed money.
mands should all but guarantee that This is unsettling for a company that
money will soon follow. But these days, counts on raising $50 million in start-
biotechnology start-ups face a wary in- up capital, among the largest initial
vestment climate that often deÞes that Þnancing ever attempted in biotech-
expectation. nology. ÒOur game plan is grandiose,
Two years ago, for example, Darwin both in its nature and because of the
Molecular would have been as nearly a competition,Ó concedes Cape, DarwinÕs
sure thing as exists in biotechnology. chairman and one of just three early
Its founders include George B. Rath- investors. Advanced sequencing ma-
mann, CEO of ICOS and founding pres- chines, powerful computers and highly
ident of AmgenÑnow the largest inde- skilled personnel all come at steep
pendent biotech company in the world; prices, and Òwe need to hit the ground
Ronald E. Cape, founding president and running in order to compete with peo-
chairman of Cetus; and Leroy E. Hood, ple who already have a lot of money,Ó
coinventor of the DNA sequencing ma- Cape explains.
chine and head of molecular biotech- But the biotech boom of 1991 gave
nology at the University of Washington way early last year to doldrums that
School of Medicine. DarwinÕs president, have all but slammed the window shut
Mark L. Pearson, resigned as head of on companies hoping to go public. Stock
cancer research at Du Pont Merck. David prices of the 100 largest biotech com-
J. Galas, formerly director of health panies dropped 14 percent in the Þrst
and environmental research for the De- Þve months of 1993; the top 10 com-
partment of Energy, took charge of the panies saw their value plummet almost
companyÕs scientiÞc programs in July. 30 percent. Darwin has not escaped the
The list goes on. pinch. ÒWe have a long way to goÓ to
This constellation of luminaries reach $50 million, Pearson admits. ÒItÕs
formed to capitalize on a new method going more slowly than I anticipated.Ó
of drug discovery that incorporates Cape concurs: ÒItÕs pretty depressing.
several of the hottest trends in biotech- There is no question that 18 months
nology. Darwin believes it can develop ago this would have been relatively easy
faster ways to decode human genes and that now it is relatively diÛcult.Ó
and to identify those that may be help- Biotech executives and analysts have
ful for treating cancer, AIDS and multi- put a name to their pain: they call it the
ple sclerosis. Equipped with libraries of ÒHillary factor.Ó The Clinton administra-
molecular targets, the company can tionÕs assault on pharmaceutical prof-
then use directed molecular evolu- its and a growing suspicion that health
tionÑa vastly accelerated test-tube ver- care reform will quash the demand for
sion of the naturally slow process of expensive drugs have sobered investors
mutation, reproduction and selectionÑ considerably.
to pick the best drug candidates out of Casdin sees two other depressants. A
millions of possibilities quickly. string of disappointing clinical results
Although Darwin has shinnied out this year and last kept drugs developed
on a limb in pursuing unproved tech- by Xoma, Centocor and Synergen out
nologies, it is not there alone. Half a of the U.S. market and spooked much
dozen other start-ups were founded last of the biotech investment community.
year to do sequencing work, and Gil- But just as critical, he says, Òthe wave
ead Sciences, Nexagen, AÝymax and of biotech Þnancings in 1991 and early
Isis Pharmaceuticals have all started 1992 created a large number of needy
using artiÞcial selection to varying de- public companies, which are burning
grees. Pearson thinks that limb is wide about $1.5 billion a year in capital and
and strong enough for a number of com- which need more.Ó This burden will
panies. But he is also quick to point out likely increase before it eases. ÒBy the
DarwinÕs special branch: its drugs will end of this year, itÕs going to be very in-
be small molecules that, unlike more tense,Ó Casdin predicts.
complex peptides, oligonucleotides and Despite the gloomy forecast and the
proteins, can be given orally. fact that $50 million, while sizable, is
just a fraction of the $200 million to eral million in the company for a decade, gy,Ó he says, especially to raise capital
$500 million typically needed to devel- more or less. So far it has had little suc- beyond the start-up costs.
op a commercially eÝective drug, Dar- cess. Cape remains steadfastly opti- All agree that Darwin, despite its ad-
win has mustered enough self-conÞ- mistic, pointing to previous examplesÑ vantages, is as much at the mercy of
dence to close the door on one tradi- RathmannÕs ICOS started with roughly the market as other biotech start-ups.
tional source of investment: venture $30 million from private ÞnancingÑas ÒDarwin is a tiny leafÑnot even a shipÑ
capital funds. Pearson complains that proof of the principle. But Pearson is on that stormy sea, bouncing around
venture capitalists tend to undervalue already looking ahead to other sources under the inßuence of economic fac-
companies, seize too much control and of revenue. ÒWe expect to see some in- tors,Ó Pearson muses. If it weathers the
focus too Þxedly on the short term. come through strategic alliances and storm without recourse to venture cap-
ÒInvestors who are not in it for the long deals where we sell our leads to real ital, Darwin may establish a new pre-
haul cause us some concern,Ó he says. drug companies for development,Ó he ferred route for biotechnology Þnance.
Darwin is searching instead for says. Casdin is skeptical nonetheless. But Þrst it must Þnd a course around
wealthy individuals willing to sink sev- ÒThey may have to change their strate- Hurricane Hillary. ÑW. Wayt Gibbs
Blackballing the Inner City
A lan P. Sager still remembers the disappointment he ex-

perienced as an 11-year-old in 1958 when the Brook-
lyn Dodgers moved to Los Angeles. “I don’t think I ever re-
resents the owners of the 28 major-league teams, finds
little credence in Sager and Culbert’s findings. “We would
think that most clubs would have moved for economic
covered,” he laments. reasons,” says Richard Levin, a spokesman for the organi-
Years later as a health policy researcher, Sager exam- zation. Levin suggests that the advent of travel by jet and
ined the reasons that inner-city hospitals move or close. the fact that some cities were no longer able to support
The study, published in 1983 when Sager was a professor two teams were more likely explanations.
at Brandeis University, found a close correlation between If that were the case, Sager responds, attendance should
the hospitals’ decision and changes in the racial composi- have had a stronger predictive value in the analysis. He
tion of the neighborhood from white to black. Sager went adds that larger cities had two teams, so the average pop-
on to teach public health at Boston University. ulation per team was about the same as for cities that only
But all this time he never forgot that trauma from his lodged a single club.
youth. And he often considered the possibility of exploring Race, as Sager hypothesizes, also seems to serve as a
a similar parallel between race and the seemingly steady better variable than personal income or other factors that
exodus of urban baseball teams from inner-city neighbor- might suggest that fans feared venturing into a poor
hoods. Earlier this year he and Arthur J. Culbert, another neighborhood. He makes his case by listing examples of
baseball aficionado and associate dean of student affairs long-abandoned sports arenas that were always at the
at the Boston University School of Medicine, used vaca- very least blue-collar: “Sportsmen’s Park in St. Louis,
tion time to combine data from such authoritative sources Schibe Park in Philadelphia, the Polo Grounds in New
as The Sporting News Dope Book with U.S. census data York: these are areas surrounded by row houses, apart-
that had been incorporated in the original hospital study. ment buildings, densely packed dwellings. These are not
This compilation yielded information about stadium age, upper-income areas.”
team standing and average annual attendance as well as When Sager presented his paper, he said that few in the
race—variables that Sager and Culbert hypothesized might Cooperstown audience seemed surprised. Baseball has
have influenced a decision to relocate. carried its share of racial baggage: Marge Schott, the own-
At the Cooperstown Symposium on Baseball and the er of the Cincinnati Reds, is still under suspension because
American Culture in upstate New York—an academic fo- of disparaging remarks about blacks, and Al Campanis, a
rum at which papers are presented on such esoterica as Dodgers executive, was fired in 1987 after stating on tele-
the effect on baseball of the advent of night games—the vision that blacks were less fit than whites to hold man-
two academics put forth their findings. The most power- agement positions in the sport. Two people at the sympo-
ful statistical predictor among the four variables exam- sium remarked to Sager that the once-owner of the Min-
ined turned out to be race. nesota Twins, Cal Griffith, had said how glad he was to
The study noted that when the Boston Braves migrated have escaped a predominantly black city when the team
to Milwaukee in 1952, almost 50 years had elapsed since left Washington, D.C., in 1960.
the Baltimore Orioles had become the New York Yankees If they can find the time, Sager and Culbert plan to bring
in 1903, the last time a team had made such a move. In their research up-to-date. Sager muses that the original
contrast, from 1950 to 1970—a period when many blacks trend may have moderated somewhat as cities have pro-
were moving north—10 of the 16 baseball teams changed vided incentives for teams to stay—sometimes even in
neighborhoods or cities. black neighborhoods. Local and state coffers have paid for
By necessity, the sample was a small one, and it does the construction of massive stadiums surrounded by huge
not provide conclusive proof that race was the only rea- parking areas and expressways. The ballpark has become
son owners decided to take flight. Sometimes it clearly was less of a neighborhood fixture. “The number of residents
not: the Pittsburgh Pirates changed locale in 1970 because within a quarter mile of the stadium is vanishingly small,”
the land was sought by a nearby university. Sager says. “The nearest resident may not be able to walk
Management, of course, did not announce that teams to the stadium.” The arena might just as well be occupying
were pulling up stakes because a neighborhood was pop- the kind of sprawling suburban tract that has provided
ulated by blacks. In fact, Major League Baseball, which rep- refuge from urban change for other teams. —Gary Stix
THE ANALYTICAL ECONOMIST
The Greening of Garbage the U.S. Fishbein notes that the legisla-
tion forces companies to follow the life
of a product or a package and to scruti-
T
he industrial world is running out to garbage disposal fees because their nize more closely the choices they make
of places to dump its trash. In the preferences and their costs for other with regard to materials. Regulations
U.S., residents discard an average options are not the same. could also give rise to incentives to buy
of two kilos daily. LandÞlls in many ar- Depending on the kind of waste to recycled materials, thereby establishing
eas will reach their capacity soon after be minimized, charges could be target- a market for ÒgreenÓ products and fur-
the turn of the century. Meanwhile ened at either producers or consumers. ther reducing the global garbage pile.
vironmental and other opposition make ÒYou just pick the point where the price The German plan has recently been
opening landÞlls or building incinera- signal can have the most direct eÝect criticized because companies report
tors almost impossible. The solution, ac- on the economic actor, be that indus- that they are collecting more waste than
cording to the new economic-environ- try or the consumer,Ó says Roger C. they can handle and that it is costing
mental credo, is to use the market: eco- Dower of the World Resources Institute. them more than they expected. If com-
nomics has created this heap of trash; panies passed on the full charge to the
economics can cut it down to size. consumer, they would suÝer a sharp
The costs of waste disposal have tra- ÒJust pick the point where drop in sales (a reasonable event from
ditionally been hidden or underesti- the price signal can have the environmental point of view but
mated, economists note. Municipalities economically undesirable).
typically charge their citizens just for the most direct eÝect Fee-per-bag systems, however, raise
the present expense of operating land- on the economic actor.Ó questions of increased littering and il-
Þlls, even though every ton of garbage legal dumpingÑjust as the high price
hauled away hastens the day that high- of handling hazardous waste has
er-priced alternatives will become nec- The so-called fee-per-bag approach spawned a black market for toxic in-
essary. Furthermore, consumers pay the has been implemented in about 100 dustrial garbage disposal. Even simple
same amount in taxes whether they communities around the country. Be- requirements for recycling may cause
leave one bag of trash on the curb each fore 1981, the average Seattle house- resistance. New York City, for example,
week or 60. hold, for instance, threw away three 32- has decided to charge $100 for a bag
In addition, the prices of recycled ma- gallon containers of trash each week; Þlled with improperly sorted trash.
terials have been inßated. People have in 1989, 87 percent of those house- These issues are typically regarded
thus been given incentives to use virgin holds paid $13.75 a month to put out as mere ÒimplementationÓ problems.
or primary materials and to throw them one 32-gallon container each week (al- Many experts consider them unimpor-
away after a single use. Internationally though recycling also accounted for a tant compared with the crucial goal of
these materials are given favored treat- hefty fraction of the drop). Elsewhere, redeÞning the trash market. If any-
ment under the General Agreement on Dower says, charging $1.50 per contain- thing, they say, these hitches can help
TariÝs and Trade. As a result, says Al- er could cut waste by 18 percent. reÞne market rules and determine which
len Hershkowitz of the Natural Resourc- At the same time, a number of Euro- portion of the waste stream should be
es Defense Council, they are generally pean countries are trying to force com- dealt with by which user.
less expensive than recycled materials. panies to consider the amount and type If rules forcing manufacturers to take
Environmental economists are now of packaging they generate. Two years back used packaging and products do
pushing two strategies for compacting ago Germany passed a law mandating not reduce the ßow of garbage signif-
the trash heap. One would charge con- that by 1995 companies recover and icantly, then it may be time to intro-
sumers for each bag or bin of garbage reuse some 80 percent of their packag- duce bag fees that persuade consumers
they discard. The other would put the ing materials. The idea Òis to aÝect the more directly. Conversely, if bag fees
onus on industries by forcing them to people who make the waste and to im- do not lead to less wasteful products
take back and recycle packaging and pact the companies at the design stage,Ó on store shelves, recycling quotas for
other waste products. says Bette Fishbein of INFORM, an envi- manufacturers may help the greening
In a perfectly frictionless economy, ronmental research group. process along. Only about 13 percent
these two approaches would be identi- Producers, according to this rationale, of U.S. garbage is recycled today, at
cal: consumers would factor the expense have more alternatives for reducing least in part because there is often no
of disposal into their purchasing deci- waste than consumers (who can take market for recovered products.
sions, thus altering the competitive bal- or leave only whatever appears on their Meanwhile, as the mountains of refuse
ance among producers. Conversely, com- local marketÕs shelves). Companies can continue to grow, municipalities are in
panies would pass on their costs to also more easily coordinate the Þnancial eÝect gambling that alternative dispos-
consumers, inßuencing their choice of resources required to set recycling in al methods will appear before landÞlls
which products to buy. In practice, how- motion. Although recovery is limited to reach capacity. If none do, the price of
ever, as economist George S. Tolley of packaging, in the near future some Ger- dumping trash will balloonÑand even
the University of Chicago points out, man companies will be taking back cars, the most expensive of the current fee-
Òcompanies and households have a dif- computers and electronic equipment. per-bag plans will look in retrospect like
ferent set of production relationsÓÑ Waste experts argue that aspects of a massive subsidy for wastefulness.
that is, they will react in dissimilar ways the German system could be applied in ÑMarguerite Holloway and Paul Wallich
MATHEMATICAL RECREATIONS by Ian Stewart
moved. IÕll just call sweetly to my

A Shepherd Takes a Sheep Shot swans; theyÕre so well behaved.Ó
This plan proved acceptable to all
B
umps the swan girl and Grimes logical superiority to select some pret- save Fumble, who felt that chasing
the shepherd boy rested on the ty good moves. ÒWhat game do you sheep around a hillside on a perfect
grassy slope in the spring sun- have in mind? Ó day was a pretty stupid idea. But when
shine while Fumble the sheepdog slept ÒFive-in-a-row,Ó Bumps said deci- he tried to explain his point, it came
beneath a juniper tree. In the valley the sively. ÒOtherwise known as go-moku, out as Òwoof,Ó which it always did.
rams ran, the swans swam and the go-bang, pegotty or pegity. We need ÒWhat are the rules?Ó Grimes asked.
lambs . . . stumbled. It was idyllic. pieces of two diÝerent colors and a ÒWe each play one piece in turn,
ÒIÕm bored,Ó Bumps complained. ÒMy board.Ó putting it on a square. At most, one
brain is getting kind of fuzzy from all ÒNothing like that around here.Ó piece can go on any square, of course.
this sitting around. Why donÕt we play ÒWeÕll just have to improvise.Ó She The Þrst to get Þve in a row next to
a game? Ó stared across the valley. Farmer Quinn each other wins.Ó
Grimes shook his head. ÒI donÕt usu- had been preparing the ground for new ÒAre diagonal rows allowed?Ó
ally enjoy playing games with you. You drainage pipes, and it was marked out ÒNaturally, otherwise the game would
always win. Your mind is too logical with white lines into a grid of squares. always be drawn with perfect play,Ó
for me.Ó ÒThat Þeld over there can be the board. Bumps said.
ÒWell, what if we play a game with You use your black sheep as pieces, ÒHuh? Ó
no known strategy? That way I canÕt and IÕll use my white swans.Ó ÒOh, sorry, I forgot for a moment that
force a win by superior logic.Ó ÒItÕs a long way to go to move them. youÕre not a logician. IÕll explain later.
ÒOkay,Ó said Grimes, who had been And they wonÕt stay put.Ó LetÕs just agree that diagonal lines are
so lulled by the sun that he wasnÕt ÒYou can whistle up old Fumble and allowed, okay? Ó
thinking very clearly. Even without a get him to move your sheep by re- Bumps won the Þrst 20 games. But
winning strategy, Bumps could use her mote controlÑand make sure they stay Grimes was undaunted because he was
beginning to see how to improve his
play. For the Þrst few games, he had ig-
nored obvious and immediate threats
to win. Then Bumps started warning
him by shouting ÒshotÓ every time such
a position occurred, to remind him to
block it [see top illustration on opposite
page]. He did the same for Bumps,
though not as frequently.
16
He still ran into trouble when she
created two such possibilities simulta-
neously. She began warning him by
yelling Òshots,Ó but by the time she did,
5 12
it was too late, of course. So then she
had to warn him that she had reached
a position that guaranteed a shots po-
sition on her next move, and in that
3 14 4
case she shouted Òpot.Ó If either of
them created a pot and a shot at the
same time, they shouted Òpotshot,Ó
and so it went. This system made the
13 9 1 2
game a lot more fun and seemed to im-
prove their tactics. Grimes started yell-
ing ÒhotÓ when he had the chance of
11 10 6 8 creating a pot next time, and they col-
lapsed in giggles when Bumps achieved
a hotshot-hotpot.
Eventually the games got so long that
7 15 poor old Fumble ran completely out
of steam trying to control 20 or more
sheep at once, so they called a time-out
while the dog collapsed under the ju-
niper tree.
ÒBumps, why is Þve-in-a-row such a
GAME OF FIVE-IN-A-ROW is played on a large grid of squares. In the case above, diÛcult game? Ó
the swans beat the sheep on the 16th move. ÒWell,Ó Bumps explained, ÒletÕs think
SHOT cause the Þrst player has to give so drawn, youÕll probably need a diÝerent
much advance warning of his inten- approach from the Hales-Jewett one.Ó
tions that itÕs easy for the second play- Grimes settled back against the hill-
er to break up any row that is forming. side. ÒYes. When we play, the biggest
The diÛcult games are in between, and problems seem to be long-range eÝects.
the hardest seem to be Þve- and six-in- You put a piece a long distance away
a-row.Ó from where the action is, and 20 moves
ÒOkay,Ó Grimes said. ÒI can see that later it turns out to be crucial.Ó
SHOTS one-in-a-row is a win for the Þrst play- ÒExactly.Ó
er, because he wins on the Þrst move.Ó ÒFumble looks refreshed. LetÕs play
ÒBrilliant analysis, Grimes.Ó another game. IÕve just thought of a
ÒLook, IÕm just polishing oÝ the triv- new one. Same kind of rules, except
ial case Þrst, okay? He also wins with that to win you have to get four of your
two-in-a-row, on the second move, be- pieces in a two-by-two square.Ó
cause wherever the second player goes, Bumps thought about it for a mo-
thereÕs always a place to play next to ment. ÒI think I should warn youÑÓ
the Þrst piece. The opening move is a ÒNo! LetÕs play! I go Þrst! Ó
shots position.Ó ÒYou asked for it,Ó Bumps exclaimed.
ÒRight.Ó After 57 consecutive draws, Fumble
ÒWith three pieces the opening move crawled back into the shade of the tree,
is a pot position. Whatever the second and Grimes ßung himself to the
player does, the Þrst can create two in ground in frustration. ÒI thought it was
a row with both ends open. There are a good idea,Ó he said faintly.
several diÝerent cases, but itÕs still pret- ÒIt was, Grimes, but you didnÕt think
ty obvious.Ó it through properly. ThereÕs a simple
Bumps nodded and called to one Hales-Jewett pairing that proves the
of her swans that was getting a bit game is always a draw if played cor-
POT too interested in a tangle of blackber- rectly. Imagine covering a plane with
ry thorns. It squawked in protest but dominoes, two-by-one rectangles, ar-
backed away. ranged so that each layer is staggered
ÒIÕm having trouble with four-in-a- relative to its neighbors, like bricks in
row, though,Ó Grimes admitted. ÒI canÕt a wall. Pair oÝ every two squares of the
decide whether the opening move is a board to form a pattern of dominos.
hotpot-potshot or a whatnot.Ó The second playerÕs strategy is that
ÒIÕm not surprisedÑitÕs a hard prob- whenever the Þrst player occupies one
lem. Carlyle Lustenberger used a com- square of a domino, she immediately
POTSHOT puter to prove that itÕs a win for the occupies the other. You can check that
Þrst playerÑprovided the board is at however a two-by-two square is placed,
least four-by-30. Coming from the oth- it must include a domino. So the strate-
er direction, thereÕs a very beautiful gy prevents a two-by-two square of a
proof that the second player can force single color being formed.Ó
a draw in nine-in-a-row. The idea is to ÒI see. What about shapes other than
pair oÝ squares in a clever way [see il- two-by-two squares?Ó
lustration at right]. Whenever the Þrst ÒYouÕve reinvented a game proposed
player occupies one square of such a
pair, the second player immediately oc-
cupies the other. Here the pairs are ar-
ranged so that any row of nine pieces
must contain both members of some
pair. That means that no row of nine
pieces all the same color can ever be
formed, so itÕs a draw.
ÒThis kind of strategy is called a
Hales-Jewett pairing, after A. W. Hales
and R. I. Jewett, who used the same ap-
FOUR THREATENING MOVES: the sheep proach to prove that Þve-in-a-row is a
will win if the swans do not move imme- draw on a Þve-by-Þve board.
diately to occupy the gray squares. ÒA group of Dutch mathematicians,Ó
Bumps continued, Òusing the pseudo-
nym T.G.L. Zetters, proved that the sec-
about n-in-a-row, which has the same ond player can draw eight-in-a-row. Vic-
rules, but you win by getting n pieces tor Allis and his co-workers at the Uni-
in a rowÑhorizontally, vertically or diversity of Maastricht recently showed
STRATEGY shown in the diagram above
agonally. Roughly, if n is small, then that Þve-in-a-row can always be won on prevents an opponent from winning a
there is an easy win for the Þrst play- a board at least 15 by 15. Yet no one is game of nine-in-a-row. The thick lines
er because the task required is not very sure whether there is a winning strate- connect the squares in pairs. The strate-
hard anyway ; if n is large, the sec- gy with rows of six or seven. If youÕre gy is that gray must not allow white to
ond player can always force a draw be- going to prove that the game is always occupy both squares in a pair.
a b
WINNING SHAPES
BOARD
c
d e
TACTICS for the Polyomino game are represented by the trying to occupy four squares that form a larger square, for
green playing boards. The object of the game is to form one example, gray must superimpose the thick lines of pattern a
of the Polyominos at the right of each board. For all the Poly- on the playing board and then not allow white to occupy both
ominos shown, a player can always force a draw. If white is squares of any pair connected by lines.
by Frank Harary of New Mexico State Polyomino. Call the Polyomino a win- powerful idea,Ó Grimes said. ÒI donÕt
University. Choose some shape formed ner if the Þrst player has a winning suppose they solve any other prob-
by adjacent squaresÑknown as a Poly- strategy, that is, if he can always force lems of the same kind?Ó
omino, a registered trademark of Solo- a copy to occur among his pieces. Call ÒOh, dozens. For instance, Golomb
mon W. Golomb. Players take turns it a drawer if the second player can al- found a Hales-Jewett pairing for eight-
placing pieces, trying to form a copy of ways force a draw. Now, any Polyomino in-a-row in an eight-by-eight-by-eight
that Polyomino in their color. It doesnÕt that contains a drawer must itself be cube. Hales and Jewett themselves
matter if there are other pieces around, a drawer.Ó thought about n-in-a-row on a k-di-
of course, just that some set of pieces ÒWhy? Ó mensional n-by-n-by- . . . -n board. They
of their color is the same shape as the ÒBecause if you could force the occur- proved that if n is very large compared
rence of the big Polyomino, the same with k , the game is a draw, but if k is
strategy would force the occurrence of large compared with n, then the Þrst
the one contained in itÑwhich canÕt player can always win. If k and n are
happen since itÕs a drawer. There are roughly the same size, nothing is
12 basic drawers, and in every case known.Ó
that property can be proved by a Hales- ÒThatÕs getting rather esoteric, Bumps.
Jewett domino pairing [see illustration But it reminds me of the joke about the
above]. Every Polyomino that contains mathematician who walked in perfect
one of these 12 is also a drawer. Only circlesÑÓ Grimes never got to the
12 Polyominos are left. Of these, 11 are punch line, for at that moment Fumble
SNAKY known to be winners. The only un- began to bark. All the sheep had wan-
solved case is Ôsnaky,Õ which is pretty dered oÝ.
certainly a winner, but to my knowl-
edge thereÕs no absolutely rock-solid
proof. [Readers may enjoy working out
winning strategies in each case, and I FURTHER READING
would be happy to be told of any proofs REGULARITY AND POSITIONAL GAMES.
for snaky.] A. W. Hales and R. I. Jewett in Transac-
ÒOh, incidentally, youÕll notice that tions of the American Mathematical So-
WINNING STRATEGY exists when the ciety, Vol. 106, No. 2, pages 222Ð229;
object of the game is to form one of
one of the pairings excludes the Poly-
omino formed by Þve squares in a row. February 1963.
the shapes above, except for the one WINNING WAYS, Vol. 2: FOR YOUR MATHE-
known as snaky. Mathematicians have So that says Þve-in-a-row is a drawn
MATICAL PLAYS: GAMES IN PARTICULAR.
not proved whether a game whose ob- game if diagonal rows arenÕt allowedÑ E. R. Berlekamp, J. H. Conway and R. K.
ject is to form the snaky shape can al- as I told you when we started.Ó Guy. Academic Press, 1982.
ways be won or always drawn. ÒThose Hales-Jewett pairings are a
BOOK REVIEWS by Philip Morrison
Monticello Redux too, was the craft of Mandan, Crow and in 1814 in Þres set by the British in-
Chippewa artisans, hardly to be seen vaders. After JeÝerson died in 1826,
THE WORLDS OF THOMAS JEFFERSON AT anywhere else east of the prairies. the family was compelled to sell oÝ the
MONTICELLO, by Susan R. Stein. Harry JeÝerson had in fact designed his high slaves, most of the farmland and the
N. Abrams, 1993 ($65). entrance hall at Monticello as a museum. contents of the house to a crowd of rel-
Once he built it, for years it was crowd- atives, neighbors and the public. Over-
I
n retirement Tom JeÝerson loved ed by a daily press of visitors, largely all, the Dispersal Sale, although it left
to show visitors to his mountaintop uninvited, who thronged from the wide Monticello a Òbare castle,Ó brought in
home the rough draft of the Decla- world, to sit in the Windsor armchairs hardly 50 cents for each creditorÕs dol-
ration of Independence he had penned ranked across that green-painted ßoor lar. A few years later a dashing oÛcer
during a visit to Philadelphia in 1776. and to gaze at the curiosities. But 40 of the U.S. Navy, Uriah Levy, bought
That year he had been a feisty, young, years of public service for the new na- empty Monticello; he and his heirs af-
red-headed, revolutionary legislator, tion, as minister to France, secretary of ter him proceeded in a slow, tangled res-
whose eloquence on paper was already state, vice president and then twice pres- toration of the great place, until in 1923
celebrated when he accepted the de- ident, had left collector, scholar and ex- the present owners, the Memorial Foun-
manding commission. Like his mind and hibitor JeÝerson heavily in debt. Con- dation, took over the task. They would
his life, his great neoclassical house gress bought his major library, all 10 reassemble what once had Þlled and an-
had since become fullÑbrimming with wagon loads of books, after their own imated both the spacious public rooms
paintings and sculptures; natural spec- book collection at the Capitol was lost and the intimate ones.
imens, from bison head to mammoth
tooth; maps (350 of them); handy house-
hold inventions; his own designs, cal-
culations and drawings, some done on
the prized sheets of coordinate paper
he once brought back from his embas-
sy to France.
The house was also Þlled with the
work of other admirable craftsmen, cab-
inetmakers, clockmakers and opticians
of London and Paris, as well as of the
products of the Monticello workshops
themselves. In the woodworking shop
John Hemings, at once slave and master
cabinetmaker, had learned to make and
repair Òevery thing of wood as well as
or perhaps better than any body there,Ó
as JeÝerson wrote. On proud display,
OBELISK CLOCK was designed by Thom-

as JeÝerson, who included the sketch be-
low in a 1790 letter about its construc-
tion. His preoccupation with the obelisk
never ßagged, and in his later years he
chose the ancient Egyptian form as the
marker for his grave .
JeÝerson was born in April 1743. This blades. It came from SheÛeld before
year of his 250th anniversary is marked 1816, quite independent of the Swiss
by a special eÝort. Hundreds of descen- Army. Any who admire such modest and
dants, collectors and museums have purposeful intricacies will be at home
been persuaded to send back for a while at Monticello. (No such visitor ought to
whatever they hold from JeÝersonÕs miss JeÝersonÕs architectural triumph
Monticello, to stay there on public dis- set across the Lawn of the University of
play until the Þnal day of 1993. This Virginia, just down the hill.)
large, attractive volume is in fact a col- JeÝerson retired from the presidency
orful, tightly annotated, illustrated cat- in 1809 to the Òtranquil pursuits of sci-
alogue of JeÝersonÕs possessions, 280 ence.Ó Almost 70, he could write that
authentic items in nearly 20 categories, he had been Òfor some time rubbing up
from formal portraits to pocket pieces, my Mathematics from the rust contract-
all at last reunited. ed by 50 years pursuits of a diÝerent
The book opens with Curator SteinÕs kind, and thanks to the good foun-
substantial, authoritative and warm es- dation laid at College . . . I am doing it
say on the man and his home. For the with a delight and success beyond my
visitor with an eye to science and tech- expectation.Ó
nology, this is a good new harvest, even The Marquis de Chastellux, a man of
though many prized items had already the Enlightenment, fought for the Amer-
been gathered at Monticello. A small list ican side during the Revolution. He
may entice visitors. First comes a silhou- sought out Monticello at the end of the
ette of Baron Alexander von Humboldt, war, before JeÝerson had left for Paris,
as delicate of feature as he was hardy in to appraise his unique host for all time:
adventure, who sought a meeting with Òthe Þrst American who has consulted
President JeÝerson that set oÝ a life- the Fine Arts to know how he should
long correspondence. The baronÕs im- shelter himself from the weather . . . and
age (one of many that include a dozen without ever having quitted his own
ÒChiefs of the Osages, Missouris, Kan- country, is Musician, Draftsman, Survey-
zas . . .Ó) was made by a mechanical de- or, Astronomer, Natural Philosopher,
vice that allowed the sitter to trace his Jurist, and Statesman.Ó
own proÞle at full size. Reduced by a Happy birthday, Tom.
pantograph, four copies in miniature
were made all at once by deftly scissor-
cutting the twice-folded stiÝ paper. Next Travels in Central America
is a portable orrery made in London
about 1792; it is represented only by its INCIDENTS OF TRAVEL IN CENTRAL AMER-
photograph. The object itself was stolen ICA, CHIAPAS, AND YUCATAN, by John
from the Franklin Institute in 1961 and Lloyd Stephens. New Edition by Karl
is still Òunlocated.Ó Ackerman. Smithsonian Institution Press,
An elegant image micrometer, made 1993 ($33; paperbound, $11.95).
by the AbbŽ Rochon, depends on ray-
T
doubling in a carefully cut and polished he narrative of a year-long adven-
block of Iceland crystal. An achromatic ture through the Mayan lowlands
telescope was made by the Dollonds of was a runaway best-seller when
London around 1790 but was not good it came out in 1840 in two volumes.
enough to note the eclipses of JupiterÕs One of its strongest notices read: ÒPer-
satellites, then a major means of longi- haps the most interesting book of trav-
tude measurement on land. A better el ever published.Ó The enthusiastic re-
equatorial telescope, Òa noble instru- viewer was Edgar Allan Poe, who knew
mentÓ by Ramsden, is also missing, al- a rattling good story when he read one.
though the Þne Ramsden theodolite is The text is as vivid today as it was for
back, once used by JeÝerson to measure Poe. Indeed, StephensÕs clear and level
the height of the Peaks of Otter along vision and the drawings of his compan-
the Blue Ridge Mountains. ion, Frederick Catherwood, known as
Here, too, is the famous obelisk clock ÒMr. C.,Ó a talented London artist and
whose form he designed in black mar- architect, suit our current taste more
ble and whose mechanical capabilities than some celebrated romances of the
he speciÞed. We see the crude sketch time.
he sent oÝ to the Paris clockmaker. That Here is a brand-new abridgment of
clock would become an intimate. In the old chronicle, done into one very
Daniel WebsterÕs words, ÒMr. J. rises in handsome volume. It includes some of
the morning as soon as he can see the Mr. C.Õs delightful drawings of glyphs
hands of his clock (which is directly op- and ruins, augmented now by plenty of
posite his bed).Ó evocative photographs, old and new,
The array ends with his wooden-han- even a couple of stereo pairs. You see
dled pocketknife Þtted with 12 toolsÑ long Þles of soldiers, happy drummers,
saw, Þle, drill, corkscrew and knife village folk, mountain scenes, tree-
wrapped sculptures and museum tro- were thought to compose all matter.
phies. Karl Ackerman is the kind of gift- How would an audacious new particle
ed editor who can bring genuine add- help? Why, a penetrating, light, neutral
ed value by cutting out two thirds of particle can simply sneak oÝ unnoticed
the old text. His version crisply focus- along with the conspicuous electron, if
es on the archaeological wonders in both are emitted at once in the decay
their deep-green context, not neglecting event. The energy of the little neutral
the continuum of encounters with land- particle is of course still there, but it is
poor grandees and with unshod infan- oÝ the books. The electrons take oÝ ran-
trymen and their touchy commanders. dom shares of the available energy, so
A decade of civil war burned and smol- that they are seen to be distributed over
dered around the resilient and obser- a band of energies, instead of clustered
vant travelers. into one single sharp energy peak. That
The pair visited many ruins then is the surprising signature of all elec-
scarcely known, including Cop‡n, Pal- tron-emitting radioactivity (called beta-
enque and Uxmal. Stephens, already cel- rays in the old jargon). But if you could
ebrated as Òthe American TravellerÓ for catch both particles from each decay
other best-sellers, recounts reading the and add up their energies, the total en-
news of Congress in Washington by the ergy release would be constant from
light of brightly luminous beetles as he event to event, as quantum theory de-
sat within the ruined palace of Palen- mands. ÒDear radioactive ones, examine
que. He was among the Þrst who viewed and judge.Ó
the grand relics of Mayan culture with Thus Christine Sutton opens the main
understanding. These works of art, he text. She is an experimental particle
concluded, Òwere constructed by the physicist at the University of Oxford,
races who occupied the country at the already well known for popular exposi-
time of the invasion by the Spaniards, tion of physics. This book is a brief,
or of some not very distant progeni- richly illustrated, informed and up-to-
tors.Ó They are there to this day to be date overview of the entire physics of
pondered and admired. Read some of neutrinos. Her style is easy, the lan-
Stephens before you go, as this review- guage lively and familiarÑwitness the
er did, or at least now that you are perhaps too sprightly titleÑwhile the
back. (The unwieldy books with all of mathematics, if not the careful argu-
Mr. C.Õs drawings are still to be found ment, is minimal (a few lines even try
in print, too.) to explain exponential notation). Begin-
ners and physics-wise readers can prof-
it alike. Certain editing puzzles, more
A Desperate Solution often in the Þgures and captions, sug-
gest some hastiness, but her timely
SPACESHIP NEUTRINO, by Christine Sut- choice of topic in all its breadth is hard
ton. Cambridge University Press, 1992 to match.
($44.95; paperbound, $24.95). Rather more than half the text treats
the laboratory neutrino from its prehis-
A
famous letter posted in 1930 tory before World War I through its
from a young Zurich physicist growth in Cambridge, Berlin and Rome,
to a meeting gathered in TŸbin- to the time of nuclear power reactors
gen begins: ÒDear radioactive ladies and kilometer-size accelerators. In just
and gentlemen: I have come upon a three years Enrico Fermi, in a classic pa-
desperate way out.Ó The wonderful the- per, turned PauliÕs intuitive proposal
orist Wolfgang Pauli, then 30 years into a coherent quantitative theory. As
old, sent the letter to a small group of diplomatic in public as he was bold at
physicists musing over a stubborn para- heart, Fermi called his compelling pa-
dox. The paradox was a set of convinc- per only a ÒtentativoÓ in Italian, an Òat-
ing discrepancies in the analysis of nat- tempt,Ó if we translate his German title.
ural radioactive decay, among which (The English version was not printed;
the most intolerable was the apparent the prim editors of Nature rejected it as
failure of energy conservation in cer- too speculative.) His theory bore fruit
tain decays. That result became over 15 from the start: the varying beta-decay
years so well documented a challenge rates as they depend on the nucleus
to youthful nuclear physics that for a and its energy levels, and the detailed
while Niels Bohr himself abandoned the form of electron energy distributions.
indestructibility of mass-energy. The By the 1950s only Þrm skeptics doubt-
way out was PauliÕs initial proposal of ed FermiÕs invisible ßying neutrinos.
the neutrino, not yet named. It took, the theory implied, a layer of
Postulation of a wholly new particle lead 100 light-years thick to absorb most
seemed a desperate act in that time of of the ordinary neutrinos that enter it.
illusory simplicity, when two particles Yet energy that disappears must in
onlyÑthe electron and the protonÑ principle be recapturable if the conser-
vation law is to be more than words. The
experimenters were not forever daunt-
ed: Fred Reines and Clyde Cowan count-
ed the uncountable neutrinos handily
enough in 1956. You can win any lot-
tery by buying enough tickets; you can
see a few neutrinos stop, however im-
probable their interaction, if you send
in Òneutrinos galoreÓ and patrol many
nuclei for the right change. The Savan-
nah River nuclear reactor matched the
neutrino output of a couple of hundred
tons of radium; the pioneers had prized
a single gram of radium as a premier
laboratory source. That gained some
eight powers of 10. Ingenious new wa-
ter-Þlled detectors by the ton augment-
ed by another millionfold the response
of the old-style simple gas counter.
Gotcha! Reines and Cowan cabled Pauli
about their catch as soon as they were
sure.
By that time the list of particles was
almost rococo. The mu meson (muon)
was only one entry among a longish list.
FermiÕs theory, plainly not made for
high energy, was good enough to estab-
lish a clear connection between observed
meson decay and beta decay. And it
showed that the decay of energetic
muons (themselves in turn among the
decay products of pi mesons) would
emit neutrinos so energetic that their
interactions became a million times
more probable than for any individual
neutrino at Savannah River. That factor
of a million meant that the accelerators
could rival the power reactors at pro-
ducing neutrino interactions; although
their beams of secondary neutrinos were
far less copious, each neutrino was
much more likely to interact.
Since 1960, as Sutton recounts, the
properties of neutrino beams have been
worked out in detail. The Þndings
helped to bridge the old physics with
its laundry lists of particles to the new
physics of ordered uniÞcation that ex-
plains quark and gluon structures un-
der strong, weak and electromagnetic
interactions. The well-supported Stan-
dard Model now includes three pairs of
particles (each pair a distinct kind of
ÒelectronÓ and its corresponding neu-
trino) and three matching pairs of
quarks. The neutrinos are built into the
foundations of the unifying theory. With
the demonstration in the 1990s of the
massive Z and W bosons that carry and
at last rationalize FermiÕs weak interac-
tion, the photons that mediate the elec-
tromagnetic interaction were given the
counterparts the electroweak theory
calls for.
The rest of the text treats of neutri-
nos from afar, dubbed Òspaceship neu-
trinos.Ó Neutrinos are now partners of
the photons in bringing us news of the

cosmos. Patience, huge detectors and
prodigious cosmic sources are what
you need; usually the observatory goes
underground or underwater to shield
against most of the cosmic rays, for
only neutrinos penetrate solid matter
so well.
The eÝort is ambitious. The neutri-
nos from the hot center of the sun have
been under scrutiny for decades from
a gold mine in South Dakota, where each
day they make a few radioactive atoms
within a big tank of cleaning ßuid. The
ßux (lately conÞrmed elsewhere) is much
lower than expected from our views of
the solar interior, perhaps because of a
subtle interaction in ßight that switch-
es neutrinos from one kind to another.
A number of heroic experiments are
now under way to settle the question.
Still bigger dark pools of pure water
await deep within two mines, one in
Japan, one in Ohio. In them, multiple
light ßashes signal the capture of neu-
trinos. A supernova in 1987 tripped
both detectors at once a hemisphere
apart (no one would have believed a
single report, for sometimes even reli-
able computers deceive). The neutrino
ßash illuminated the earth more pow-
erfully in energy terms than the full op-
tical light of our neighbor sun, al-
though the supernova was more dis-
tant by a couple of diameters of the
Milky Way. Less than two dozen neutri-
nos were caught out of the myriads
that ßew through the earth, but they
are fully credible. The great explosion
was probed at its hottest second and
conÞrmed the theoristsÕ views. Such a
brilliant supernova is a puny source of
light compared with its prodigal radia-
tion of neutrinos, even though that im-
ploded star shone in optical light a bil-
lion times more brightly than the sun.
Other romantics plan astronomy in
this channel using mountain tunnels,
or within the clear waters of Lake Baikal,
or from a worldwide network in many
smaller lakes or with instruments sunk
a mile deep in the oceans oÝ Hawaii or
heat-drilled far into the icy cap at the
South Pole or one day even placed in
some lava cavern on the moon. If any
unseen neutrinos possess intrinsic rest
massÑwe have only crude limits on
what any neutrinos might weighÑthey
may yet compose a major portion of all
the mass there is, up to 100-fold more
than all the familiar starstuÝ put to-
gether, indeed a prize.
Within three decades the neutrino has
passed from a faintly embarrassing con-
struct to rival the electrons, neutrons
and protons, perhaps to outnumber and
even outweigh them all. The particle that
the builders could hardly accept may
yet become their cornerstone.
ESSAY by Barry R. Bloom
Immunology and Reciprocity ern Europe and Japan combined and is

our most rapid area of growth. In
recognition of both the needs and the
R
eciprocity, recognized from the and vaccines have proved to be one of opportunities, 71 heads of state, an un-
time of Confucius as a funda- the most cost-eÝective interventions to precedented number, met at the United
mental value in human relation- prevent death and disease. In our own Nations in 1990 for the World Summit
ships, has not usually been regarded as country, President Bill Clinton has pro- for Children. They pledged to put the
important to the scientiÞc endeavor. Yet posed a comprehensive childhood im- health and education of children at the
few areas of biomedical science have munization initiative. The program aims top of the international agenda. And
provided greater opportunities for re- to eliminate an impressive list of dis- immunology and vaccines have a spe-
ciprocal interaction between science and eases by the end of this decade: diph- cial role to play. By the end of the de-
the real world than immunology. Basic theria, tetanus, poliomyelitis, measles, cade paralytic poliomyelitis can be erad-
knowledge of the immune system is rubella, mumps, whooping cough and icated, neonatal tetanus can be elimi-
clearly essential for informing new ef- bacterial meningitis. It would reduce nated and measles can be controlled.
forts to resist infections, to reject tu- pneumonia and inßuenza in adults old- Although parasites are the largest single
mors and to ameliorate allergies and er than 65 years. It will promote the de- source of infection, no vaccine against
autoimmune diseases. velopment of immunologic interven- a human parasite currently exists; clear-
In that sense, it is easy to Þt immu- tionsÑvaccines in the broadest senseÑ ly, the need is urgent for vaccines
nology into the classical paradigm of not only against infectious diseases, against malaria, leishmaniasis and oth-
the unidirectionality of science, proceed- such as AIDS, but against allergies, ar- er parasitic diseases.
ing from the basic to the applied. But it thritis, multiple sclerosis and cancer. The argument has often been heard
is crucial to appreciate that many of Beyond the borders of the U.S., more that keeping children alive in the Third
the most practical applications of im- than three million lives have been saved World merely increases suÝering from
munologyÑdiagnostic tests, vaccines by childhood immunizations. Since 1974 poverty and malnutrition. I would point
and therapeutic interventionsÑderive the eÝorts of UNICEF and the World out that in no country have birth rates
from fundamental research undertak- Health Organization have brought the declined prior to a decline in death
en with no obvious practical application number of the worldÕs children receiv- rates and that one of the most power-
in mind. To cite just one example, ba- ing immunizations by the age of one ful forces for reduction in fertility is
sic studies of communication between from 15 to 80 percent. It is shocking child survivalÑkeeping children alive
white cells led to identiÞcation of the that in the U.S. only about half of our so that parents know they will be taken
receptor on T cells for the AIDS virus. children receive their recommended im- care of in old age. In addition to con-
Many in the scientiÞc community are munizations by the age of two, and in tributing to child survival by prevent-
concerned because society seems to be such cities as Houston and Miami that ing infectious diseases, immunology
placing increasing emphasis on solving Þgure is less than 30 percent. At anoth- has a more direct impact, through im-
real-world problems without recogniz- er level for reciprocity, then, we have munization against unique antigens of
ing that useful applications cannot sim- much to learn from developing coun- sperm, eggs or hormones to develop
ply be legislated but depend on basic tries that protect their children. safe and reversible antifertility vaccines.
knowledge not yet acquired. And in This winding path leads inevitably to
I
modern times, that knowledge has de- n his book Preparing for the Twen- the paramount issue for the next cen-
rived from the imaginations of scien- ty-First Century, Paul Kennedy iden- tury: the environment. The single most
tists with the freedom to pursue original tiÞes the major issues to be addressed important action that can protect the
ideas independent of their perceived as we head into the next century as eq- future of our planet is the reduction of
immediate utility. If science appears al- uity, population and the environment. population pressure on the earthÕs nat-
ways to lag our needs, it still remains In a curious way, immunology may ural resources. This key point about
ahead of everything else. have something to contribute to each. the environment was virtually ignored
In another sense, however, understand- There are enormous disparities in qual- at last yearÕs Earth Summit in Rio de
ing in immunology has derived from a ity of life of people born in diÝerent Janeiro.
diÝerent paradigm, from a reciprocity parts of the world. The Third World In reßecting on some of the reciproc-
with clinical medicine and efforts to contains three fourths of the earthÕs ities between immunology and the real
master diseases. Studies of children who population. There 87 percent of all world, I am ineluctably drawn to the
have rare genetic deÞciency diseases births and 98 percent of all infant and conclusion that biomedical research, if
that make them highly susceptible to childhood deaths occur. One in 10 peo- allowed to ßourish, has incalculable po-
infection, for example, helped research- ple suÝers from a tropical disease; 190 tential for humane contributionsÑand
ers to decipher the crucial role of the million children are undernourished; to Oscar WildeÕs view that Òa map of
thymus and antibody-producing cells in and 10 million people die of acute res- the world without utopia on it is not
immunology. piratory and diarrheal infections each worth glancing at.Ó
Through this reciprocity has come year.
the ultimate application of immunolo- At the same time, the U.S. acquires BARRY R. BLOOM is an Investigator
gy to improving the human conditionÑ many of its raw materials from the at the Howard Hughes Medical Institute
vaccines. Economists know it costs much Third World. In fact, our trade with de- of Albert Einstein College of Medicine in
less to prevent disease than to cure it, veloping nations exceeds that with West- Bronx, N.Y.

September

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SEPTEMBER 1993

THE IMMUNE SYSTEM

Copyright 1993 Scientific American, Inc.

52 Life, Death and the Immune System

64 How the Immune System Develops

Just nine weeks after conception, a handful of precursor cells begins to

72 How the Immune System Recognizes Invaders

80 How the Immune System Recognizes the Body

The cells of the immune system must be capable of launching an assault in

90 Infectious Diseases and the Immune System

Bacteria, parasites and viruses have evolved elaborate ways of concealing

Copyright 1993 Scientific American, Inc.

98 AIDS and the Immune System

106 Autoimmune Disease

Misguided assaults by the immune system cause a surprising number of

116 Allergy and the Immune System

126 The Immune System as a Therapeutic Agent

Knowledge of the immune system has given clinicians a potent instrument:

136 Will We Survive?

Copyright 1993 Scientific American, Inc.

Page Source Page Source

8 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

12 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

ÒFor very fast de luxe air passenger

16 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

WAXAHACHIE TUNNELS: construction

20 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

24 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

Jovian Jolt approach, Shoemaker-Levy whizzed a actual moment of contact. Yeomans

26 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

DENISE APPLEWHITE Princeton University

30 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

34 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

CUSTOM MEDICAL STOCK

38 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

Copyright 1993 Scientific American, Inc. SCIENTIFIC AMERICAN September 1993 39

42 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

44 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

The All-Star of Buckyball conductor and even a superconductor

semble Òas a bunch of guys snapping

46 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

48 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

Copyright 1993 Scientific American, Inc. SCIENTIFIC AMERICAN September 1993 53

54 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

How the Immune System Defends the Body

T he body is protected by a diverse army of cells and molecules that work in

55 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

B ecause infectious agents can enter the body at any

PEYER’S PATCH ON SMALL INTESTINE

Copyright 1993 Scientific American, Inc. SCIENTIFIC AMERICAN September 1993 56

CLONAL SELECTION enables the immune system to react to a myriad of possible

Copyright 1993 Scientific American, Inc. SCIENTIFIC AMERICAN September 1993 57

58 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

antibodies on the bodyÕs innumerable B of surgery, preempting a lymphocyte

Copyright 1993 Scientific American, Inc. SCIENTIFIC AMERICAN September 1993 59

60 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

62 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

by Irving L . Weissman and Max D. Cooper

Copyright 1993 Scientific American, Inc. SCIENTIFIC AMERICAN September 1993 65

66 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.

Copyright 1993 Scientific American, Inc. SCIENTIFIC AMERICAN September 1993 67

CD4 CD8 T CELL RECEPTOR DEAD CELL

68 SCIENTIFIC AMERICAN September 1993 Copyright 1993 Scientific American, Inc.