Scientific American - February 2019

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ANTARCTIC COLLAPSE? MEET THE GLACIER THAT MIGHT SINK

THE WORLD’S COASTAL CITIES
PAGE
40
HOW
THE
BRAIN
READS
FACES
C ki the
Cracking h
neural code
S
PLU
GHOST FLOWERS
Resurrecting the genes of extinct plants PAGE 30
EXOPLANET NEXT DOOR

Venus can help in the hunt for extraterrestrial life PAGE 56
UNCONTACTED TRIBES FEBRUARY 2019

Can they be protected? PAGE 46
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FE B R UA RY 2 0 1 9
VO LU M E 3 2 0 , N U M B E R 2
NEUROSCIENCE A N T H R O P O LO G Y
22 Face Values 46 Guardians of
Researchers have isolated the Tiger People
the brain regions that process As anthropologists debate how best
faces and cracked the code to protect uncontacted tribes, indig-
for recognizing them. enous groups in Colombia are work-
By Doris Y. Tsao ing to shield their isolated neigh-
B I O LO G Y bors from the march of modernity.
30 Ghost Flowers By Adam Piore
The genes of Hawaiian plants, P L A N E TA RY S C I E N C E
extinct for more than a century, 56 The Exoplanet Next Door
have been brought back from What Venus can teach us about
the dead. Today we can smell planets far beyond our own solar
their scents. system. By M. Darby Dyar,
By Rowan Jacobsen Suzanne E. Smrekar and
Stephen R. Kane ON THE COVE R
ENVIRONMENT
Scientists have taken major steps toward
40 Is Antarctica E C O LO G Y understanding how the brain recognizes faces—
Collapsing? 64 Re-engineering one of the great challenges of neuroscience.
Rapid glacier retreat could put the Colorado River Not only have they found sections of the cerebral
cortex that perform this function, they have
coastlines underwater sooner Can dam releases that mimic natu-
also decoded the computations that enable
than anticipated. ral flows restore the Grand Canyon the brain to distinguish any given face.
By Richard B. Alley ecosystem? By Heather Hansman Illustration by Maciej Frolow.
Photograph by Juan Arredondo February 2019, ScientificAmerican.com 1
© 2019 Scientific American

3 From the Editor

4 Letters
6 Science Agenda
Embrace midwifery for better maternity care and
birth outcomes in the U.S. By the Editors
7 Forum
Better biomarkers could help speed the diagnosis and
treatment of Alzheimer’s. By Howard M. Fillit
8 Advances
Whales and chimpanzees have similar personality traits.
Fooling urine tests. A camera inspired by shrimp.
The science of bird jumping. Cosmic origin of sand.
8
18 The Science of Health
Virtual reality promises to transform patient care.
By Claudia Wallis
19 Ventures
Venture capital isn’t needed for a thriving
local economy. By Wade Roush
71 Recommended
Legendary man-eating tiger of Champawat. How the
world went digital. Is exercise recovery wishful thinking?
Lessons of the Little Ice Age. By Andrea Gawrylewski
72 The Intersection
Is the Internet of Things our friend? By Zeynep Tufekci
19 75 Anti Gravity
Producing, harvesting, identifying and recycling feces.
By Steve Mirsky
76 50, 100 & 150 Years Ago
78 Graphic Science
The hazards of space junk. By Mark Fischetti and
Jan Willem Tulp
SPECIAL REPORT
S1 Nature Outlook: Gene Therapy

A number of health issues that have proved difficult or
impossible to remedy—sickle cell anemia, epilepsy, certain
skin conditions—might be excellent targets for gene therapy.
This report, from Nature, highlights the latest research.
71
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2 Scientific American, February 2019

FROM
Mariette DiChristina is editor in chief of IY_[dj_ÒY7c[h_YWd$ THE EDITOR
Follow her on Twitter @mdichristina
What’s in Parsing these complex neural interactions begins on page 22.

Using our visual systems, we’re also seeing—and welcoming—
some new faces to Scientific American, as part of
a Face? our ongoing refinement of editorial
content. First of all, we’ve added some
new advisers to our board below; their
It’s remarkable how often seemingly pedestri- insights are invaluable to our science
an things ultimately spark a sense of wonder coverage. In addition, in recent months
when considered through the evidence-based we’ve been joined by Claudia Wallis
view of research. Take the question of how as the “Science of Health” columnist,
we see faces, a ho-hum everyday occur- as well as by climate scientist Kate
rence that we easily do without con- Marvel, who writes “Hot Planet” on
scious effort. Yet it is a feat full of ScientificAmerican.com.
puzzling intricacies that investi- In this issue, technosociologist Zey-
gators are attempting to parse. nep Tufekci shares her expertise. Her
How do the networks in the brain put monthly column, “The Intersection,” on
various features into recognizable faces page 72, promises to cover critical is-
and, eventually, assemble a sensible pic- sues that occur “where science and so-
ture of the world? ciety meet.” Her first essay, “Zombie
In this issue’s cover story, “Face Val- Baby Monitors Attack,” sheds light on
ues,” neuroscientist and MacArthur Fel- “blatantly negligent security practices”
low Doris Y. Tsao describes her journey that could undermine the Internet of
into this field of study. It began in her Things. Also penning his first monthly
high school calculus course using dif- installment is technology journalist
ferential equations to describe curves and continued Wade Roush. He will be writing “Ven-
in undergraduate studies—where she learned early exper- tures,” covering “the business of innovation.” In “Getting Out
iments in how the primary visual cortex extracts edges from of Silicon Valley’s Shadow,” he discusses whether local econo-
images—and graduate school. “I was captivated by the challenge mies need an economic injection from a so-called innovation dis-
of understanding vision and embarked on a quest,” Tsao writes. trict or technology cluster. The future awaits on page 19.
BOARD OF ADVISERS
Leslie C. Aiello Edward W. Felten Lene Vestergaard Hau Satyajit Mayor Daniela Rus
President, Wenner-Gren Foundation Director, Center for Information Mallinckrodt Professor Senior Professor, National Center Director, Computer Science and
for Anthropological Research Technology Policy, Princeton University of Physics and of Applied Physics, for Biological Sciences, Tata Institute ÍÜZD§Ürr§Zr"DO«ÍDÜ«Íëd$»»5»
Robin E. Bell Jonathan Foley Harvard University of Fundamental Research Eugenie C. Scott
Research Professor, Lamont-Doherty Executive Director and William R. Hopi E. Hoekstra John P. Moore Chair, Advisory Council,
Earth Observatory, Columbia University and Gretchen B. Kimball Chair, Alexander Agassiz Professor Professor of Microbiology and National Center for Science Education
California Academy of Sciences of Zoology, Harvard University Immunology, Weill Medical Terry Sejnowski
Emery N. Brown
Jennifer Francis Ayana Elizabeth Johnson College of Cornell University Professor and Laboratory
Edward Hood Taplin Professor of
Medical Engineering and of Senior Scientist, Woods Hole Founder and CEO, Donna J. Nelson Head of Computational
Computational Neuroscience, M.I.T., Research Center Ocean Collective Professor of Chemistry, Neurobiology Laboratory,
and Warren M. Zapol Professor Kaigham J. Gabriel Christof Koch University of Oklahoma Salk Institute for Biological Studies
of Anesthesia, Harvard Medical School 0ÍrÒfr§ÜD§fr{êrZæÜèr'}ZrÍd President and CSO, Robert E. Palazzo Meg Urry
Charles Stark Draper Laboratory Allen Institute for Brain Science Dean, University of Alabama Israel Munson Professor of Physics
Vinton G. Cerf
Harold “Skip” Garner Morten L. Kringelbach at Birmingham College and Astronomy, Yale University
Chief Internet Evangelist, Google
Executive Director and Professor, Associate Professor and Senior of Arts and Sciences Michael E. Webber
George M. Church
Primary Care Research Network Research Fellow, The Queen’s College, Rosalind Picard Co-director, Clean Energy Incubator,
Director, Center for Computational
and Center for Bioinformatics University of Oxford 0Í«{rÒÒ«ÍD§fÍrZÜ«Íd|rZÜèr and Associate Professor,
Genetics, Harvard Medical School and Genetics, Edward Via College Computing, M.I.T. Media Lab Department of Mechanical Engineering,
Robert S. Langer
Rita Colwell of Osteopathic Medicine David H. Koch Institute Professor, Carolyn Porco University of Texas at Austin
Distinguished University Professor, Michael S. Gazzaniga Department of Chemical Leader, Cassini Imaging Science George M. Whitesides
University of Maryland College Park Director, Sage Center for the Study Engineering, M.I.T. Team, and Director, CICLOPS, Professor of Chemistry and
and Johns Hopkins Bloomberg School of Mind, University of California, Space Science Institute Chemical Biology, Harvard University
Meg Lowman
of Public Health Santa Barbara Senior Scientist and Lindsay Chair Lisa Randall Amie Wilkinson
Drew Endy Carlos Gershenson of Botany, California Academy of Professor of Physics, Professor of Mathematics,
Professor of Bioengineering, Research Professor, National Sciences, and Rachel Carson Center Harvard University University of Chicago
Stanford University Autonomous University of Mexico for Environment and Society, Ludwig Martin Rees Anton Zeilinger
Nita A. Farahany Alison Gopnik Maximilian University Munich Astronomer Royal and Professor Professor of Quantum Optics,
Professor of Law and Philosophy, Professor of Psychology and John Maeda of Cosmology and Astrophysics, Quantum Nanophysics,
Director, Duke Initiative for }DÜr0Í«{rÒÒ«Í«{0«Ò«µëd Global Head, Computational Institute of Astronomy, Quantum Information,
Science & Society, Duke University University of California, Berkeley Design + Inclusion, Automattic, Inc. University of Cambridge University of Vienna
Illustration by Nick Higgins February 2019, ScientificAmerican.com 3

LETTERS
editors@sciam.com
“We must explicitly found in a comparatively smaller one” is

perhaps her most important observation.
acknowledge, fund What struck me was the high-handed
way that some of these journals don’t
and motivate stand by their product. That cheapens the
worth of the publication. If you publish a
reproduction of paper, the reputation of the publication is
study results.” behind that study from a marketing POV.
JOSE M. SOLER If the paper is later refuted by, or can’t be
AUTONOMOUS UNIVERSITY OF MADRID replicated in, another study, you have a
duty to publish the latter paper as well.
This could be encouraged by an indepen-
IOANNIDIS REPLIES: Lurquin points out dent organization that simply records the
the problem of large overheads, which number of times a counter paper was
have grown. Eliminating them is not easy, published in a different journal because
because one needs to find other sources the original publication refused it.
for sustaining the infrastructure of re- NEIL ROBERTSON El Cerrito, Calif.
search institutions. Unnecessary bureau-
October 2018 cracy could be trimmed, of course. LIMITED DECISIONS
East advocates the support of imprecise It was fascinating to learn in “The Unsolv-
exploratory methods when they fuel new, able Problem,” by Toby S. Cubitt, David
SHAPING UP SCIENCE exciting ideas. Such research is justifiable Pérez-García and Michael Wolf, that cer-
As a professor emeritus of genetics who and necessary when we have no other bet- tain important questions in theoretical
spent many long hours writing grant pro- ter tools for initial discovery. But it needs physics are undecidable by computation.
posals, I agree with “Rethink Funding,” by to be recognized explicitly as being explor- In discussing the primary example of
John P. A. Ioannidis [State of the World’s atory and thus often likely to be wrong such a question, the authors assert that de-
Science 2018]. The system is biased in fa- and in need of careful subsequent valida- termining the existence, or not, of an ener-
vor of “politically savvy managers.” tion with better methods. gy gap between the lowest energy state of
Yet Ioannidis does not address the over- a material and the next state up would de-
head funds that line the coffers of univer- REPLICATION TROUBLE pend on the material extending to infinity.
sities. With state funding constantly dwin- As an academic researcher, I was not too Yet in that case, presumably the material
dling, they rely on overhead more than surprised to learn that a large fraction of itself will be forever unable to decide
ever. This is why academia favors big results in even the best journals cannot whether it is gapped or gapless because
grant getters over innovative research. Re- be reproduced in “Make Research Repro- any causal influence between distant re-
ducing bloated academic administrations ducible,” by Shannon Palus [State of the gions can travel only at the speed of light.
would be one modest way to solve the co- World’s Science 2018]. As reported in both TONY DURHAM Brighton, England
nundrum, but who is going to do that? Palus’s and Ioannidis’s articles, research-
PAUL F. LURQUIN ers have many institutional pressures and THE AUTHORS REPLY: Strictly speaking,
Washington State University personal motivations to publish flashy re- any undecidable problem must have an
sults and none to replicate those of others. infinity somewhere. If you impose any
There is a danger that new ideas will be We must explicitly acknowledge, fund limit, even the lifetime of the universe,
held back if attention is directed too nar- and motivate reproduction. It would help then it is decidable, although in practice,
rowly on the precision of scientific meth- if journals had a section or associated pub- that is not much better than if it were not.
ods. Such ideas often arise from the use of lication accepting studies by independent In the case of the spectral gap problem,
imprecise approaches. For example, single authors seeking to reproduce works previ- for any reasonably large, finite lattice size,
case studies in medicine, surveys showing ously published by those journals. Their the systems we construct will either be
correlations in my own field of consumer referees would not judge originality or in- gapped or have an energy spectrum that
behavior, and odd observations in astrono- terest but would value methodological rig- is so dense, it becomes indistinguishable
my can all lead to major advances because or, clarity and, possibly, improvement or from gapless. In principle, if you limit
they pick up serendipitous findings that extension of the results. how large the lattice can get (say, it needs
are hard to anticipate. The new ideas that JOSE M. SOLER to fit in your lab!), then the problem is de-
are generated are usually tested by experi- Autonomous University of Madrid cidable. But the undecidability of an ide-
ments, but such tests often provide limited alized infinite lattice implies there is no
stimulus for new thinking. I think Palus’s note that the original work better way to figure it out than taking a
ROBERT EAST Emeritus professor, discussed “appeared in a topflight jour- sample of material the size of your lab;
Kingston University London nal,” whereas “the replication effort can be a smaller sample will tell you nothing

E35
"3®s
EDITOR IN CHIEF AND SENIOR VICE PRESIDENT

Mariette DiChristina
Curtis Brainard Maria-Christina Keller Michael Mrak
about the lab-sized one. Worse still, even MANAGING EDITOR COPY DIRECTOR CREATIVE DIRECTOR
if you determine whether the lab-sized EDITORIAL

CHIEF FEATURES EDITOR Seth Fletcher CHIEF NEWS EDITOR Dean Visser CHIEF OPINION EDITOR Michael D. Lemonick
sample is gapped or gapless, this could FEATURES
change just by adding a single extra atom. SENIOR EDITOR, SUSTAINABILITY Mark Fischetti SENIOR EDITOR, SCIENCE AND SOCIETY Madhusree Mukerjee
SENIOR EDITOR, CHEMISTRY / POLICY / BIOLOGY Josh Fischman SENIOR EDITOR, TECHNOLOGY / MIND Jen Schwartz
It’s important to emphasize that no SENIOR EDITOR, SPACE / PHYSICS Clara Moskowitz SENIOR EDITOR, EVOLUTION / ECOLOGY Kate Wong
materials anyone has encountered in real- NEWS

SENIOR EDITOR, MIND / BRAIN Gary Stix ASSOCIATE EDITOR, SUSTAINABILITY Andrea Thompson
ity display this perverse behavior. But we ASSOCIATE EDITOR, SPACE / PHYSICS Lee Billings ASSISTANT EDITOR, NEWS Tanya Lewis
can look for simpler systems that exhibit DIGITAL CONTENT

MANAGING MULTIMEDIA EDITOR Eliene Augenbraun ENGAGEMENT EDITOR Sunya Bhutta
similar physics, and we have made some SENIOR EDITOR, MULTIMEDIA Steve Mirsky COLLECTIONS EDITOR Andrea Gawrylewski
progress on doing so in a follow-up paper. ART
Durham’s scenario is somewhat similar ART DIRECTOR Jason Mischka SENIOR GRAPHICS EDITOR Jen Christiansen
PHOTOGRAPHY EDITOR Monica Bradley ART DIRECTOR, ONLINE Ryan Reid
to what we describe: In principle, given in- ASSOCIATE GRAPHICS EDITOR Amanda Montañez ASSISTANT PHOTO EDITOR Liz Tormes
finite time, the speed of light is no obstacle. COPY AND PRODUC TION
A time limit would be qualitatively similar SENIOR COPY EDITORS $`Dy¨
DïïD¨DjDý¨Î3`ÿ´¹COPY EDITOR Aaron Shattuck
MANAGING PRODUCTION EDITOR Richard Hunt PREPRESS AND QUALITY MANAGER Silvia De Santis
to imposing a finite size limit, equal to time
D I G I TA L
multiplied by the speed of light. TECHNICAL LEAD Nicholas Sollecito PRODUCT MANAGER Ian Kelly WEB PRODUCER Jessica Ramirez
CONTRIBUTOR S
DOWN UNDER DEVELOPMENT EDITORIAL David Biello, Lydia Denworth, W. Wayt Gibbs, Ferris Jabr, Anna Kuchment,
Robin Lloyd, Melinda Wenner Moyer, George Musser,
In “Body Balance” [Advances], Maya Mill- Christie Nicholson, John Rennie, Ricki L. Rusting
ART Edward Bell, Bryan Christie, Lawrence R. Gendron, Nick Higgins
er reports that developmental biologist
Alberto Roselló-Díez and his colleagues EDITORIAL ADMINISTRATOR Ericka Skirpan SENIOR SECRETARY Maya Harty
found that when they suppressed growth
of a limb in a mouse fetus, the surround-
ing cells communicated with the placenta, PRESIDENT
which slowed down the growth of the oth- Dean Sanderson

EXECUTIVE VICE PRESIDENT Michael Florek VICE PRESIDENT, COMMERCIAL Andrew Douglas
er three limbs to keep them symmetrical. PUBLISHER AND VICE PRESIDENT Jeremy A. Abbate
This mechanism for maintaining sym- MARKE TING AND BUSINE SS DE VELOPMENT
metry in development would, however, work HEAD, MARKETING AND PRODUCT MANAGEMENT Richard Zinken
MARKETING DIRECTOR, INSTITUTIONAL PARTNERSHIPS AND CUSTOMER DEVELOPMENT Jessica Cole
only with placental mammals. How would ONLINE MARKETING PRODUCT MANAGER Zoya Lysak
marsupials manage this coordination? I N T E G R AT E D M E D I A S A L E S

DAVID WEINTRAUB Edison, N.J. DIRECTOR, INTEGRATED MEDIA Jay Berfas
DIRECTOR, INTEGRATED MEDIA Matt Bondlow
SENIOR ADMINISTRATOR, EXECUTIVE SERVICES May Jung
ROSELLÓ-DÍEZ REPLIES: It is worth not- CONSUMER MARKETING

E-MAIL MARKETING MANAGER Chris Monello
ing that even though they lack a true pla- MARKETING AND CUSTOMER SERVICE COORDINATOR Christine Kaelin
centa, marsupials do form a yolk-sac-de- ANCILL ARY PRODUC TS
rived placentalike structure. And whereas ASSOCIATE VICE PRESIDENT, BUSINESS DEVELOPMENT Diane McGarvey
CUSTOM PUBLISHING EDITOR Lisa Pallatroni
the most obvious mechanism we found in- RIGHTS AND PERMISSIONS MANAGER Felicia Ruocco
volves the placenta, this does not mean it is C O R P O R AT E

Rachel Scheer
the only one. It is possible that other organs HEAD, COMMUNICATIONS, USA
PRINT PRODUCTION
with a key role in body growth, such as the ADVERTISING PRODUCTION CONTROLLER Carl Cherebin PRODUCTION CONTROLLER Madelyn Keyes-Milch
liver, also participate in the systemic re-
sponse triggered by a local injury. They
could do so either in parallel to the placen-
ta or at subsequent (postnatal) stages once LE T TER S TO THE EDITOR
3Zr§ÜZ¡rÍZD§d®%ré?«Í0DîDd3æÜr×ððd%ré?«Íd%?®ððð®×ä«ÍrfÜ«ÍÒNÒZD¡»Z«¡
the placenta is no longer present. "rÜÜrÍÒ¡DëOrrfÜrf{«Ír§ÜD§fZDÍÜë»=rÍrÍrÜÜDÜérZD§§«ÜD§ÒérÍrDZ«§r»
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ERRATUM H O W T O C O N TA C T U S
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February 2019, ScientificAmerican.com 5

SCIENCE AGENDA
O PI NI O N A N D A N A LYS I S FR OM
SC IENTIFIC A MERIC AN ’ S B OA R D O F E D I TO R S
Call the
Midwife ...
If You Can
For better birth outcomes, the U.S.
should rethink maternity care
By the Editors
Despite the astronomical sums that the U.S. spends on mater-

nity care, mortality rates for women and infants are significantly
higher in America than in other wealthy countries. And because
of a shortage of hospitals and ob-gyns, especially in rural areas,
many women struggle to access proper care during pregnancy.
Moreover, the rate of cesarean sections is exceedingly high at
32 percent—the World Health Organization considers the ideal
rate to be around 10 percent—and 13 percent of women report highest rates of adverse birth outcomes, such as deaths of new-
feeling pressured by their providers to have the procedure. borns. If midwives were allowed to work alongside other provid-
Widespread adoption of midwife-directed care could allevi- ers, patients would get the care advantages, and if difficulties
ate all these problems. In many other developed countries, such arose, a woman whose home birth suddenly became complicat-
as the U.K., France and Australia, midwifery is at least as com- ed could be seamlessly transferred to a hospital.
mon as care by obstetricians. In the U.S., certified midwives and Even when state laws are favorable, women who wish to work
nurse-midwives must hold a graduate degree from an institution with midwives often face financial obstacles. Medicaid will cover
accredited by the American College of Nurse-Midwives, and cer- all midwifery services, according to the Affordable Care Act, but
tified professional midwives must undergo at least two years of the requirement does not extend to private insurers, many of
intensive training. This is designed to make midwives experts in whom lack in-network midwives or refuse to cover midwifery care
normal physiological pregnancy and birth. Thus, for women with at all. Half of planned nonhospital births are currently paid for by
low-risk pregnancies who wish to deliver vaginally, it often makes patients themselves, compared with just 3.4 percent of hospital
sense to employ a midwife rather than a more costly surgeon. Yet births. Thus, a less expensive birth at home may paradoxically be
only about 8 percent of U.S. births are attended by midwives. out of reach for women who cannot afford to pay out of pocket.
The roots of America’s aversion to midwifery go back to the U.S. hospitals charge more than $13,000, on average, for an un-
late 1800s, when the advent of germ theory and anesthesia re- complicated vaginal birth, whereas a similar midwife-attended
duced much of the danger and discomfort associated with child- birth outside of the hospital reduces that figure by at least half.
birth. The benefits of these technologies brought doctors to the Insurers would save money by embracing midwife-attended, non-
forefront of maternity care and pushed midwives aside. Obste- hospital birth as a safe and inexpensive alternative.
tricians helped to bar midwives from practicing in hospitals, A national shortage of birth centers further limits women’s
which were now considered the safest birth settings. By the ear- choices. These homelike settings are designed to support natural-
ly 1960s midwifery was virtually obsolete. ly laboring women with amenities such as warm baths and spa-
It has made a comeback since then, with practitioners just as cious beds and are consistently rated highly in surveys of patient
well trained as doctors to supervise uncomplicated deliveries. satisfaction. Yet there are only around 350 existing freestanding
Studies show that midwife-attended births are as safe as physi- birth centers in the entire nation, and nine states lack regulations
cian-attended ones, and they are associated with lower rates of for licensing such facilities. More government support for birth
C-sections and other interventions that can be costly, risky and centers would help midwives meet a growing demand, which has
disruptive to the labor process. But midwifery still remains on already fueled an increase of 82 percent in centers since 2010.
the margins of maternity care in the U.S. Policy makers, providers and insurers all have good reasons
To bring it back into the mainstream, midwives must be fully to encourage a shift toward midwifery. The result will be more
integrated into the medical system. Some states currently refuse choices and better outcomes for mothers and babies.
to recognize them as legitimate practitioners, and some severe-
JOIN T HE CONVERSAT ION ONLINE
ly limit what midwives are allowed to do, despite evidence that Visit 2_w²í_Ĉ¬wÞ_C² on Facebook and Twitter
states with the most restrictive policies also have some of the or send a letter to the editor: editors@sciam.com
6 Scientific American, February 2019 Illustration by Ramona Ring

FORUM
Howard M. Fillit is founding executive director and chief C OMM E N TA RY O N S C IE N C E IN
ÒZr§Zr«}ZrÍDÜÜrîr¡rÍÊÒÍæÒZ«èrÍë«æ§fDÜ«§ T H E N E W S FR OM T H E E X P E R T S
§%ré?«ÍÜë»
New Strategy Despite the existing tests for diagnostic and prognostic bio-
markers, few patients in the U.S. have been tested with these con-
firmatory tests because of cost and access restrictions. And payers,
for Alzheimer’s including Medicare, will not cover amyloid PET scans, based on
the perception that a definitive diagnosis has little clinical value.
We need better molecular biomarkers But recent studies on the value of PET beta-amyloid brain
scans, supported by the Centers for Medicare & Medicaid Servic-
to create targeted drugs es, have shown that practicing “dementia expert” doctors mis-
By Howard M. Fillit diagnose Alzheimer’s in about 50 percent of cases and change
their management and treatment of patients nearly 70 percent of
Alzheimer’s disease is the sixth leading cause of death in the the time when this test is used. An inexpensive blood test, covered
U.S., and unlike with cancer and heart disease, we lack the tools by insurance, which can be performed in any clinical setting,
to effectively diagnose and treat it. In sharp contrast to other ill- would have a big impact on patients and their caregivers.
nesses and despite many efforts, huge expense and hundreds of Recently the FDA issued guidelines recognizing the important
clinical trials, no new treatments have been approved in the past role of biomarkers in demonstrating efficacy in clinical trials for
16 years. The emphasis has been on drugs targeting beta-amy- Alzheimer’s (especially early-stage ones). These new guidelines
loid proteins, which clump into plaques in the brains of afflicted are a major step forward for fast-tracking drugs for the disease.
people. Unfortunately, these approaches have not
yet yielded the results we hoped for.
So now it is time to target novel pathways to tack-
le this incredibly complex disease. This has been a
challenge because of the absence of affordable and
noninvasive tests based on biomarkers that doctors
can easily use in their offices. The alternatives have
been expensive and invasive spinal taps or neuro-
imaging tests that can be performed only in a hospi-
tal or freestanding radiology office. New biomarkers
are needed for specific molecular targets that can be
used to subtype patients; for predicting the likeli-
hood that they will acquire Alzheimer’s; and possibly
for providing a diagnosis even before symptoms are
noticeable, enabling prevention. That is, they could
do what currently available amyloid positron-emis-
sion tomography (PET) scans and cerebrospinal flu-
id tests do. Biomarkers can also be used to enroll pa-
tients in clinical trials directed to a specific target,
such as beta-amyloid, and to measure how the body
responds to a treatment—as was done most recently
by Biogen with its anti-beta-amyloid monoclonal an-
tibody. Ultimately biomarkers can determine which therapies We need comparable tests—preferably blood tests—to help
would be most effective for an individual. diagnose Alzheimer’s and evaluate treatments. This will aid us in
Such tools are already available for other diseases, including making clinical trials more rigorous, affordable and efficient,
diabetes, hypertension, hyperlipidemia and cancer. In heart dis- will accelerate drug development and will improve clinical care
ease, for instance, serum cholesterol levels, which are measured by providing access to accurate diagnoses. A new initiative called
after simply drawing blood with a needle stick, have long been the Diagnostics Accelerator, under the auspices of the Alzhei-
used as a biomarker to identify patients at risk. The test is afford- mer’s Drug Discovery Foundation, aims to develop novel bio-
able and generally covered by employers or health insurance pro- markers from blood and accessible fluids and tissue. Such mark-
viders, including Medicare. If blood levels are high, drugs such as ers, specifically tied to Alzheimer’s or other forms of dementia,
statins can be prescribed to lower cholesterol and with it the risk will allow us to predict more accurately which treatment and pre-
for heart disease. Doctors can also use cholesterol levels to see if vention strategies will work in at-risk populations, as we can now
a prescribed drug is working or needs an adjustment. LDL cho- do in cancer, heart disease and other diseases of aging.
lesterol is also recognized as a biomarker for heart disease risk by
JOIN T HE CONVERSAT ION ONLINE
the Food and Drug Administration, so clinical trials can show Visit 2_w²í_Ĉ¬wÞ_C² on Facebook and Twitter
that a drug lowers cholesterol and get approval for it. or send a letter to the editor: editors@sciam.com
Illustration by Benjamin Currie February 2019, ScientificAmerican.com 7

ADVANCES
Orcas can be rated on traits such

as extraversion or dominance.
8 Scientific American, February 2019

D I S PATC H E S FR OM T H E FR O N TIE R S O F S C IE N C E , T E C H N O LO GY A N D M E D I C IN E IN S ID E
• A camera inspired by a sharp-eyed shrimp

• An algorithm that knows when someone
is lying to the police
_ä`D³ßx`¸³ąxøD³D`xä³Çß¸§x
_3D³läDlx¸xĀÇ§¸l³äîDßäîø
ANIMAL COGNITION
Killer
Personality
Despite evolving separately,
orcas and chimpanzees
have strikingly similar
personality traits
Anybody who has taken an undergradu-

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conscientiousness, extraversion, agree-
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stable by adulthood, and the idea that it
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J O I N T H E C O N V E R S AT I O N O N L I N E Visit 2_w²í_Ĉ¬wÞ_C²on Facebook and Twitter

ADVANCES
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538 individual chimpanzees through a sta- îxä³3ÇD³D³lîx7Í3Íî¸
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10 Scientific American, February 2019 Illustrations by Thomas Fuchs

D§îāD³l§xäÇD³jD³l§îä`ø§¸ø³lDä§Dß New Version!

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most important personality dimension related
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the most lackadaisical chimps are given a good
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äxäDāäÍ0xD`xD§ä¸ÿDß³äîDîD¦xøß³x Over 75 New Features & Apps in Origin 2019!
makers could easily add substances such as For a FREE 60-day
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February 2019, ScientificAmerican.com 11

A A S
B I O M I M I C RY
How the Camera Mimics the Shrimp Eye
Crustacean Multidirectional A
Camera light waves Sunlight contains waves that vibrate in every

direction. Polarized light waves vibrate in just
one. The human eye perceives polarized light
e device mimics mantis Då¨DàyjD´ùåD´`yày®¹ÿymUĂ¨ïyàåÎ
shrimp’s astounding vision
Unidirectional
anti rim hold the title or the 0¹¨DàĆ´¨ïyà light waves
astest punch in the animal kingdom—
po er ul enough to break seashells and Compound eye A SS
a uarium glass. hey also boast some Each “pixel” in a mantis shrimp’s compound
o the orld’s most complex, extra- eye has a rodlike structure (rhabdom) made
ordinary eyes. Human eyes have three of light receptors with threadlike structures
(microvilli) that are alternately stacked at right
kinds o light receptor cells, but these
angles. Cells in the two hemispheres of the
shrimp have a dozen, allo ing them eye are tilted at 45° to each other. So the eyes
to sense properties o light invisible to ýy`ï`¹ÿyà¹ùàÈ¹¨DàĆDï¹´mày`ï¹´åÎ
other animals.
ngineers at the niversity o llinois Dorsal Ventral
at rbana-Champaign have no made hemisphere hemisphere
45° 0°
a camera that closely copies the crusta-
cean’s impressive visual system. he
device, described last October in Optica,
is a one-inch cube, and researchers say
it could be made in bulk or apiece.
hey believe it could ultimately be used
to help cars detect hazards, to let mili- 135° 90°
îDßālß¸³xääxx`D¸øDxl¸ßäDl-
o ed targets, and to enable surgeons
to per orm more accurately.
antis shrimp have t o visual Microvilli Rhabdoms
superpo ers. For one, they can sense
“polarized light, in hich all the aves
Polarization 0° 45° S A A
undulate in the same plane (unpolarized
imager The new pixel sensor is an array of silicon-
light vibrates in every direction . ight Pixel based detectors covered with aluminum
U¸ø³`³¸¸U¥x`îäD§ÿDāä`¸³îD³äD ´D´¹Āàyå¹åyïUĂpï¹y®ù¨Dïyïy
Nanowire
polarized component, and this property È¹¨DàĆDï¹´¨ïyà´®`à¹ÿ¨¨´åà®ÈyĂyåÎ
¸§î`D³ßxþxD§¸U¥x`îäîDî¸îxßÿäx 135° 90° Each silicon detector exponentially converts
blend into the background mantis light to electric current, enabling the camera
to sense a large range of light intensities.
äßÇøäxîî¸³lÇßxā³îxßU§øx
288 ls
tinged ocean environs. hey can also pixe pixe
ls 384
detect an extensive span o light intensi- SOURCE: “BIOINSPIRED POLARIZATION IMAGER WITH HIGH DYNAMIC RANGE,”
ties kno n as dynamic range, hich BY MISSAEL GARCIA ET AL., IN OPTICA, VOL. 5, NO. 10; OCTOBER 20, 2018
lets them see very bright and dark areas

at once. cameras. he researchers also covered the he mantis shrimp is the only creature
he ne camera emulates both abili- detectors ith microscopic aluminum that can sense a ull spectrum o colors
ties. lectrical and computer engineer ires to imitate microvilli, the tubular and polarization, says homas Cronin,
iktor ruev and his colleagues made an äîßø`îøßxä³äßÇxāxäîDî§îxßD³l a pro essor o biological sciences at
array o tiny, silicon-based light detectors sense polarized light. the niversity o aryland, Baltimore
similar to those ound in commercial polar- For a real- orld test, the team drove County, ho as not involved in the study.
ization cameras. But hereas conventional around in a car mounted ith their ne his characteristic makes it ideal or a
detectors produce an electric current that camera and a standard one. Pictures camera to emulate, he says “You ould
increases linearly ith light intensity, the rom the shrimp-eye camera had much xî`§xDßDxä¸¸U¥x`îä³D`¸Ç§
ne detectors respond exponentially. higher contrast, especially in oggy and `DîxlUD`¦ß¸ø³lîDîDßxl`ø§îî¸
his yields a dynamic range about , rainy conditions and in scenes ith a lot pick out ith other techni ues.
times higher than today’s commercial o light and shado s, ruev says. —Prachi Patel
12 Scientific American, February 2019 Illustration by Brown Bird Design

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A A S
DATA S C I E N C E
database of publications by these hires.
Idea ßäîîxā§¸¸¦xlDî¸ÿþxUlxDä³
computer science spread to new institu-
Epidemic tions. They found that hiring a new faculty

member accounted for this movement a
An infectious disease little more than a third of the time—and in
81 percent of those cases, transmissions
model shows how science
took place from higher- to lower-prestige
knowledge spreads universities. Then the team simulated the
dissemination of ideas using an infectious
Like infectious diseases, ideas in the aca- disease model and found that the size of an
demic world are contagious. But why some idea “epidemic” (as measured by the num-
travel far and wide while equally good ones author Aaron Clauset, also at Boulder. ber of institutions that published studies on
remain in relative obscurity has been a mys- Not only is this unfair—“it reveals a big an idea after it originated) depended on
tery. Now a team of computer scientists has weakness in how we’re doing science,” says the prestige of the originating institution.
used an epidemiological model to simulate Simon DeDeo, a professor of social and 5x³l³äÿxßxÇøU§äxl¸³§³x§Däî
how ideas move from one academic institu- decision sciences at Carnegie Mellon Uni- October in EPJ Data Science.
tion to another. The model showed that versity, who was not involved in the study. The researchers’ model suggests that
ideas originating at prestigious institutions There are many highly trained people with there “may be a number of quite good
caused bigger “epidemics” than equally good ideas who do not end up at top-tier ideas that originate in the middle of the
good ideas from less prominent places, institutions. “They are producing good pack, in terms of universities,” Clauset
explains Allison Morgan, a computer scien- ideas, and we know those ideas are getting says. DeDeo agrees. There is a lot of good
tist at the University of Colorado Boulder lost,” DeDeo says. “Our science, our schol- work coming out of less famous places, he
and lead author of the new study. arship, is not as good because of this.” says: “You can learn a huge amount from
“This implies that where an idea is born The Colorado researchers analyzed an it, and you can learn things that other peo-
shapes how far it spreads, holding the existing data set of computer science fac- ple don’t know because they’re not even
quality of the idea constant,” says senior ulty hires in North America, as well as a paying attention.” —Viviane Callier
GREENLAND EGYPT
3`y´ïåïååÈ¹ïïymDÀµ®ÿĀmy`àDïyàmmyÚy¨¹Ā An excavation near Cairo yielded dozens
IN THE NEWS
DĀDïD¨D`yà´´¹àïĀyåïàyy´¨D´mÎ5yĂUyÿÿy ¹®ù®®ym`DïåÎà`Dy¹¨¹åïåD¨å¹
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Join the Polygraph machines also attempt to spot lies.
Community.
Discover
world-changing
science.
M AC H I N E L E A R N I N G
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Scientific American is a registered trademark of
Springer Nature America, Inc.
14B Scientific American, February 2019

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ALAMY
î¸îxßø§xä¸Çāä`äjîxāä¸ø§lîÇ¸þxß `Dîÿ§§UxDîD"DU¸ß³DU§¸¸îx Jason G. Goldman

Photo by Brent Nicastro

If the topic comes up,
acknowledge you’re
Supernova remnant G54.1+0.3
an atheist. No big deal.
A STROPHYSIC S Now let’s talk about
Sand from something interesting.”
— Daniel C. Dennett
Stardust Austin B. Fletcher Professor of
Silica may originate in exploding stars Philosophy, Tufts University,
FFRF Honorary Director
Astronomers have long argued that the phrase
“we are stardust” is more than poetic language.
Now new evidence adds another stanza to this Join the nation’s largest association of freethinkers,
great cosmic verse. working to keep religion out of government.
Dust from silica—a common component
of arth’s core, sandy beaches, concrete, glass For a free sample of FFRF’s newspaper, Freethought Today:
and even cell phones—has been detected with-
in the remnants of two supernovae in the Milky
Call 1-800-335-4021
ay galaxy. These observations, described last
October in Monthly Notices of the Royal Astro- ffrf.us/reason
nomical Society, Çß¸þlxîxßäîxþlx³`xîDî FFRF is a 501(c)(3) educational charity. Deductible for income tax purposes.
silica originated within exploding stars.
“This is a rich result in that something so
FFRF.org Freedom From Religion Foundation
common on arth has now been found to be
created in the most violent explosions in the
universe,” says study co-author aley omez,
D³Däîß¸³¸xßDîDßl7³þxßäîā³=D§xäÍ
“ t’s an origin story.”
Astronomers have long pondered how
cosmic dust—whether it is composed of, say,
silica, carbon or iron—is created. nitially they
thought it formed when sunlike stars reached
¸§lDxD³lîßxÿ¸îāÿ³läjÿ¸äx
gases were thought to condense into solid dust
ßD³ä¥øäîDää³¸ÿD¦xä¸ß³D`§§āDî¸-
sphere. But when observers detected dust in
galaxies so distant that they must have formed
soon after the big bang—well before sunlike
stars could have evolved—they knew there
must be another source.
They started to suspect that dust appeared
within supernovae explosions soon after the
universe formed, but astronomers have only
recently detected a handful of nearby super-
NASA, JPL-CALTECH, CXC, ESA/NRAO AND J. RHO SETI Institute
novae remnants sprinkled with dust. And Mika-

ko Matsuura, an astronomer who is also at Car-
lUøîÿDä³¸î³þ¸§þxl³îxäîølājäDāääx
is excited to see further evidence.
f the dust within these early-universe super-
nova remnants is also found to contain silica,
îxßäîÇ§D³xîäîDþx§¸¸¦xlä§Dßî¸
our own pale-blue dot. “ t’s really interesting to
know we can make planets like arth so soon” Scientific American is a registered trademark of Springer Nature America, Inc. Google Play and the Google Play logo are
trademarks of Google LLC. Apple, the Apple logo, iPhone, and iPad are trademarks of Apple Inc., registered in the U.S.
in the universe’s existence, omez says. “ t and other countries and regions. App Store is a service mark of Apple Inc.
doesn’t take 1 billion years.” —Shannon Hall

THE SCIENCE Claudia Wallis is an award-winning science journalist whose

OF HEALTH work has appeared in the New York Times, Time, Fortune and the
New Republic. She was science editor at Time and managing editor
of IY_[dj_ÒY7c[h_YWdC_dZ$
ing dressings. A 2011 study with 54 children in burn units found

an up to 44 percent reduction in pain during VR sessions—with
the bonus that these injured kids said they had “fun.”
Another success came in the wake of 9/11. Psychologist JoAnn
Difede of NewYork-Presbyterian/Weill Cornell Medical Center be-
gan using VR with World Trade Center survivors suffering from
post-traumatic stress disorder (PTSD) and later with soldiers re-
turning from Afghanistan and Iraq.
In Difede’s laboratory, I saw the original 9/11 VR program with
its scenes of lower Manhattan and the newer Bravemind system,
which depicts Iraqi and Afghan locales. Developed with Depart-
ment of Defense funding by Albert “Skip” Rizzo and Arno Har-
tholt, both at the University of Southern California, Bravemind is
used to treat PTSD at about 100 U.S. sites. The approach is based
on exposure therapy, in which patients mentally revisit the source
of their trauma guided by a therapist who helps them form a more
coherent, less intrusive memory. In VR, patients do not merely re-
imagine the scene, they are immersed in it.
Difede showed me how therapists can customize scenes in
Bravemind to match a patient’s experience. A keystroke can
change the weather, add the sound of gunfire or the call to prayers.
It can detonate a car bomb or ominously empty a marketplace. An
optional menu of odors enables the patient to sniff gunpowder or
The Promise of spices through a metal tube. “What you do with exposure therapy
is systematically go over the trauma,” Difede explains. “We’re
teaching the brain to process and organize the memory so that it
Virtual Reality can be filed away and no longer intrudes constantly in the
patient’s life.” The results, after nine to 12 gradually intensifying
sessions, can be dramatic. One 2010 study with 20 patients found
rom pain relief to mental health, that 16 no longer met the criteria for PTSD after VR treatment.
is poised to reshape patient care Until recently, large-scale studies of VR have been missing in
action. This is changing fast with the advent of cheaper, portable
By Claudia Wallis systems. Difede, Rizzo and three others just completed a random-
ized controlled trial with nearly 200 PTSD patients. Expected to be
f ou sti t ink of virtual reality as the province of dystopian sci- published this year, it may shed light on which patients do best
ence fiction and geeky gamers, you had better think again. Faster with this high-tech therapy and which do not. In a study with her
than you can say “Ready Player One,” VR is starting to transform colleague, burn surgeon Abraham Houng, Difede is aiming to
our world, and medicine may well be the first sector where the quantify the pain-distraction effects of a successor to SnowWorld
impact is profound. Behavioral neuroscientist Walter Greenleaf called Bear Blast, a charming VR game in which patients toss balls
of Stanford University has been watching this field develop since at giggly cartoon bears. They will measure whether burn patients
the days when VR headsets cost $75,000 and were so heavy, he need lower doses of intravenous painkillers while playing.
remembers counterbalancing them with a brick. Today some Greenleaf counts at least 20 clinical arenas, ranging from sur-
weigh about a pound and cost less than $200. Gaming and enter- gical training to stroke rehabilitation to substance abuse where
tainment are driving current sales, but Greenleaf predicts that VR is being applied. It can, for example, help recovering addicts
“the deepest and most significant market will be in clinical care avoid relapses by practicing “refusal skills”—turning down drinks
and in improving health and wellness.” at a virtual bar or heroin at a virtual party. Brain imaging suggests
Even in the early days, when the user entered a laughably low- that such scenes can evoke very real cravings, just as Bravemind
resolution world, VR showed great promise. By the mid-1990s re- can evoke the heart-racing panic of a PTSD episode. Researchers
search had shown it could distract patients from painful medical foresee a day when VR will help make mental health care cheap-
procedures and ease anxiety disorders. One initial success was er and more accessible, including in rural areas.
SnowWorld, which immersed burn patients in a cool, frozen land- In a compelling 2017 paper that reviews 25 years of work, Riz-
scape where they could lob snowballs at cartoon penguins and zo and co-author Sebastian Koenig ask whether clinical VR is
snowmen, temporarily blocking out the real world where nurses finally “ready for primetime.” If today’s larger studies bear out pre-
were scrubbing wounds, stretching scar tissue and gingerly chang- vious findings, the answer seems to be an obvious “yes.”
18 Scientific American, February 2019 Illustration by Celia Krampien

VENTURES
Wade Roush is host of Soonish, a podcast exploring H S SS A
how technology will shape the future.
Getting Out to build a tech cluster without at least one research university to
generate ideas and qualified employees.
And the ingredient list goes on. A base of older tech firms
of Silicon Valley’s gives future start-up founders a place to train. Federal invest-
ment, which helped to put Silicon Valley’s semiconductor indus-
Shadow try on the map, is a huge boost. Finally, you need local venture
capitalists willing to invest in high-risk enterprises.
Put it all together, and you get what I think of as the proximi-
You don’t need programmers or venture ty effect—a self-sustaining churn of people, inspiration, invest-
ment, intellectual property and profit. It’s no wonder that dozens
capitalists for a thriving local economy of U.S. cities, both large (San Diego, St. Louis) and medium-sized
By Wade Roush (Columbus, Chattanooga), are investing in innovation districts.
But there’s a problem: it can take decades of planning to assem-
Let s sa ou re t e ma or of idd e a e, a (fictional) medi- ble all the components of a cluster, and you can’t invest in just
um-sized city in Texas. The coal-fired electric power plant out- one element while ignoring the others.
side town just closed, and the steel mill in the next county over Floridians paid a lot to learn that lesson. Between 2003 and
has gone bankrupt. Now voters expect you to do something 2008 then governors Jeb Bush and Charlie Crist arranged hun-
about rising unemployment and the shrinking tax base. You dreds of millions of dollars in subsidies to bring biotech labora-
might look at America’s booming metropolitan areas, such as tories such as the Max Planck Florida Institute for Neuroscience
Boston, Seattle or Silicon Valley, and say what we need here is to the Palm Beach County area. The private-sector spin-offs
an “innovation district” or a “technology cluster.” Bush and Crist had promised never emerged, and between 2007
Sounds great! But it’s rarely the full answer. and 2012 the state’s spending spree had brought fewer than
1,000 new jobs to Florida. “We didn’t have the infrastruc-
ture that was needed to develop the industry at a rapid
pace,” the president of the Business Development Board
of Palm Beach County told reporters.
Fortunately, cities don’t need to follow the classic clus-
ter model. There’s new evidence that regions can develop
fast-growing business scenes even if some of the tradition-
al cluster ingredients are sparse or missing. The Detroit
area, for example, is home to only a handful of venture
firms. But it’s developing a distinctive mix of start-ups
focused on what Detroit does best: manufacturing, robot-
ics and next-generation transportation technologies, with
a dose of software. Ted Serbinski, managing director of
Detroit’s Techstars Mobility incubator, has called it “the
intersection of steel and bits.”
In fact, quite a few of the metro areas that show the
strongest start-up growth lately fall outside the tradition-
al cluster definition. In the Ewing Marion Kauffman
You certainly wouldn’t be the first public official to fall under Foundation’s 2017 rankings of start-up growth, the Columbus,
technology’s spell. After all, when high-growth companies flock Nashville and Atlanta metropolitan areas placed third, fourth
to a specific location, jobs and higher incomes do tend to follow. and fifth, respectively. All have strong universities. But none
Take the Kendall Square cluster, loosely defined as the area with- has a major tech-industry legacy or a substantial venture-
in a 10-minute walk of the subway station at the Massachusetts capital community.
Institute of Technology. It’s home to more than a dozen top bio- As mayor of Middlevale, you’re not going to build a research
tech firms. Google, Microsoft, Amazon and Facebook all have university from scratch or lure a flock of venture firms to town.
research outposts here. And some 750 start-ups incubate at the But you can focus on the skills your citizens already have and
Cambridge Innovation Center. It’s all helped to give Cambridge look for ways to match those with the more digital, distributed,
the lowest unemployment rate in Massachusetts and a family globalized economy of the 21st century. Admire the clusters—
income 59 percent above the national median. and then go your own way.
Of course, the city is also home to high-paying institutions
H SA L
like Harvard University and M.I.T. But that, too, is part of the isit 2_w²í_Ĉ¬wÞ_C² on acebook and Twitter
canonical definition of a cluster. Business scholars say it’s hard or send a letter to the editor: editors sciam com
Illustration by Zara Picken February 2019, ScientificAmerican.com 19


NEUROSCIENCE
FACE
VALUES
Brain regions that process faces reveal deep insights
into the neural mechanisms of vision
By Doris Y. Tsao
WHEN I WAS IN HIGH SCHOOL, I LEARNED ONE DAY ABOUT THE DENSITY OF CURVES
in an introductory course on calculus. A simple pair of differential equa-
tions, which model the interactions of predators and prey, can give rise
to an infinite number of closed curves—picture concentric circles, one
nested within another, like a bull’s-eye. What is more, the density of
these curves varies depending on their location.
This last fact seemed so strange to me. I could easily imagine a finite
set of curves coming close together or pulling apart. But how could an
infinity of curves be denser in one region and less dense in another?
I soon learned that there are different types of infinity, which have para-
doxical qualities, like Hilbert’s Hotel (where the rooms are always fully
booked but new guests can always be accommodated) and the
Banach-Tarski apple (which can be split into five pieces and rearranged
to make two apples of equal volume as the original). I spent hours poring
over these mathematical proofs. Ultimately they struck me as symbolic
magic of no real consequence, but the seed of interest had taken root.
Illustration by Brian Stauffer February 2019, ScientificAmerican.com 23

Later, as an undergraduate at the faces than to images of any other ob- a slightly larger number of neurons
California Institute of Technology, I ject when a person was inside a responsive to faces, like icebergs
learned about the experiments of functional magnetic resonance im- randomly clustered at sea.
David Hubel and Torsten Wiesel and aging (fMRI) brain scanner. The pa- Because I had done the imaging
their landmark discovery of how a per seemed bizarre. I was used to experiment in a monkey, I could di-
region in the brain called the prima- the brain being made of parts with rectly address this concern by in-
ry visual cortex extracts edges from names like basal ganglia and orbito- serting an electrode into an fMRI-
Doris Y. Tsao is a the images relayed from the eyes. I frontal cortex that had some vague identified face area and asking,
professor of biology
realized that what had actually mys- purpose one could only begin to What images drive single neurons in
at the California In-
stitute of Technology tified me back in high school was fathom. The concept of an area spe- this region most strongly? I per-
and an investigator the act of trying to imagine different cifically devoted to processing faces formed this experiment together
of the Howard Hughes densities of infinity. Unlike the seemed all too comprehensible and with Winrich Freiwald, then a post-
Medical Institute. She mathematical tricks I had studied in therefore impossible. Anyone could doctoral fellow in Margaret Living-
is also direc tor of the high school, the edges that Hubel make a reasonable conjecture about stone’s laboratory at Harvard, where
Tianqiao and Chrissy
and Wiesel described are processed the function of a face area—it should I was a graduate student. We pre-
Chen Center for
Systems Neuroscience by neurons, so they actually exist in probably represent all the different sented faces and other objects to a
at Caltech. In October the brain. I came to recognize that faces that we know and something monkey while amplifying the elec-
she was named a visual neuroscience was a way to un- about their expression and gender. trical activity of individual neurons
MacArthur Fellow. derstand how this neural activity As a graduate student, I had used recorded by the electrode. To moni-
gives rise to the conscious percep- fMRI on monkeys to identify areas tor responses in real time, the neu-
tion of a curve. activated by the perception of three- rons’ electrical signals were convert-
The sense of excitement this re- dimensionality in images. I decided ed to an audio signal that we could
alization triggered is hard to de- to show pictures of faces and other hear with a loudspeaker in the lab.
scribe. I believe at each stage in life objects to a monkey. When I com- This experiment revealed an as-
one has a duty. And the duty of a pared activation in the monkey’s tonishing result: almost every single
college student is to dream, to find brain to faces with activation to oth- cell in the area identified through
the thing that captures one’s heart er objects, I found several areas that fMRI was dedicated to processing
and seems worth devoting a whole lit up selectively to faces in the tem- faces. I can recall the excitement of
life to. Indeed, this is the single poral lobe (the area underneath the our first recording, hearing the “pop”
most important step in science—to temple)—specifically in a region of cell after cell responding strongly
IN BRIEF find the right problem. I was capti- called the inferotemporal (IT) cor- to faces and very little to other ob-
Understanding vated by the challenge of under- tex. Charles Gross, a pioneer in the jects. We sensed we were on to
vision remains one standing vision and embarked on a field of object vision, had discovered something important, a piece of cor-
of the grand chal- quest to learn how patterns of elec- face-selective neurons in the IT cortex that could reveal the brain’s
lenges that neurosci- trical activity in the brain are able tex of macaques in the early 1970s. high-level code for visual objects.
entists confront. to encode perceptions of visual ob- But he had reported that these cells Marge remarked on the face patch-
One key aspect of jects—not just lines and curves but were randomly scattered through- es: “You’ve found a golden egg.”
this problem relates even objects as hard to define as out the IT cortex. Our fMRI results I also remember feeling sur-
to the way the brain
faces. Accomplishing this objective provided the first indication that prised during that first experiment.
my´ïyåD`yåjïy
most important required pinpointing the specific face cells might be concentrated I had expected the face area would
social emblem. brain regions dedicated to facial into defined regions. contain cells that responded selec-
Neurons ´myým recognition and deciphering their tively to specific individuals, analo-
sections of the cere- underlying neural code—the means FACE PATCHES gous to orientation-selective cells in
UàD¨`¹àïyāj`D¨ÿm by which a pattern of electrical im- AFTER PUBLISHING MY WORK, I was in- the primary visual cortex that each
D`yÈDï`yåjDày pulses allows us to identify people vited to give a talk describing the respond to a specific edge orienta-
dedicated to recog- around us. fMRI study for a faculty position at tion. In fact, a number of well-publi-
nizing faces.
The journey of discovery began Caltech, but I was not offered the cized studies had suggested that
Uncovering the
organization of the in graduate school at Harvard Uni- job. Many people were skeptical of single neurons can be remarkably
face-patch system versity, where I studied stereopsis, the value of fMRI, which measures selective for the faces of familiar
served as a prelude the mechanism by which depth per- local blood flow, the brain’s plumb- people—responding, say, only to
to deducing the ception arises from differences being. They argued that showing in- Jennifer Aniston. Contrary to my ex-
underlying compu- tween the images in the two eyes. creased blood flow to a brain area pectation, each cell seemed to fire
tations that the One day I came across a paper by when a subject is looking at faces vigorously to almost any face.
brain makes to neuroscientist Nancy Kanwisher, falls far short of clarifying what I plugged madly away at Photo-
identify faces.
now at the Massachusetts Institute neurons in the area are actually en- shop during these early experi-
This neural code
may serve as a of Technology, and her colleagues, coding because the relation be- ments and found that the cells re-
Rosetta stone for reporting the discovery of an area in tween blood flow and electrical ac- sponded not just to faces of humans
representing other the human brain that responded tivity is unclear. Perhaps by chance and monkeys but even to highly
objects besides faces. much more strongly to pictures of these face patches simply contained simplified cartoon faces.

Observing this phenomenon, I

decided to create cartoon faces
with 19 different features that Where Are the Face Detectors?
seemed pertinent to defining the A set of six nodes in the inferotemporal (IT) cortex of both brain hemispheres specializes in
identity of a face, including inter- identifying faces. These “face patches” function as an assembly line: in the middle lateral and
eye distance, face aspect ratio and middle fundus patches, one neuron might become
mouth height, among other charac- active when faces look straight ahead; another
teristics. We then went on to alter might turn on for a face looking to the right.
these values—the inter-eye dis- At the end of the assembly line, in the ante-
tance, for instance, varied from be- rior medial patch, varying views are
ing almost cyclopean to just inside stitched together. Neurons in this patch
the face boundary. Individual cells are active in response to the face of a
responded to most faces but inter- äÇx``³lþløD§j³¸Dîîxßîxþxÿ
estingly did not always exhibit the is from the front or side. Responses Middle
exact same rate of firing to all faces. fundus
from a face patch of one monkey are
Instead there was a systematic vari- patch
generated for faces but not objects
ation in their response: when we
plotted the firing of cells for the dif-
(red areas in A ) and for the same in- ●
dividual, such as the dark-haired man, Middle
ferent cartoon features, we found a
pattern in which there was a mini-
from varying angles (red areas in B ). lateral ●
Inferotemporal cortex
Anterior
patch medial patch
mal response to one feature ex-
treme—the smallest inter-eye dis- Neuron activity level: Low High
tance, for instance—and a maximal Each column represents neuron activity for an image like the one shown above it
response to the opposite extreme— A
the largest eye separation—with in- Faces Not faces "yïÈà¹ÿ Front Back
termediate responses to feature val-
ues in the middle. The response as
D`à¹Ā¹mDïDàyÈàyåy´ïåDmyày´ï
cell within the anterior medial patch
a function of the value for each fea-

ture looked like a ramp, a line slant-
ed up or down.
Once again, I was invited to give
a job talk at Caltech. Returning, I
had more to offer than just fMRI im-
ages. With the addition of the new
results from single-cell recordings, it
was clear to everyone that these face
patches were real and likely played
FROM “FUNCTIONAL COMPARTMENTALIZATION AND VIEWPOINT GENERALIZATION WITHIN THE MACAQUE FACE-PROCESSING
3?35$jÛ
?=%2Î2="%'23?Î53'j%SCIENCE, <'"ÎññĈè%'<$
2j÷ĈÀĈÊdata grids and photo insets)
an important role in facial recogni-

tion. Furthermore, understanding
their underlying neural processes
seemed like an effective way to gain contrast relations can be used to that cells often had a significant
traction on the general problem of recognize a face: they should be the preference for a particular contrast
how the brain represents visual ob- ones that are immune to changes feature in an image.
jects. This time I was offered the job. in lighting. For example, left-eye- To our astonishment, almost all
darker-than-nose is a useful fea- the cells were wholly consistent in
CONTRAST IS KEY ture for detecting a face because it their contrast preferences—just a
AT CALTECH, my colleagues and I dug does not matter if a face is photo- single cell was found that preferred
deeper into the question of how graphed with lighting from above, the opposite polarity. Moreover, the
these cells detect faces. We took in- left, right or below: the left eye is preferred features were precisely
spiration from a paper by Pawan always darker than the nose (check those identified by Sinha as being
Sinha, a vision and computational for yourself ). invulnerable to lighting changes.
neuroscientist at M.I.T., that sug- From a theoretical standpoint, The experiment thus confirmed
gested faces could be discerned by this idea provides a simple, elegant that face cells use contrast relations
checking for specific contrast rela- computational mechanism for fa- to detect faces.
tions between different regions of cial recognition, and we wondered More broadly, the result con-
the face—whether the forehead re- whether face cells might be using it. firmed that these cells truly were
gion is brighter than the mouth re- When we measured the response of face cells. At talks, skeptics would
gion, for example. Sinha suggested cells to faces in which different re- ask, how do you know? You can’t
a clever way to determine which gions varied in brightness, we found test every possible stimulus. How
Illustration by Body Scientific (brain) February 2019, ScientificAmerican.com 25

can you be sure it’s a face cell and patches, moreover, are not random- tiny amounts of current—a tech-
not a pomegranate cell or a lawn ly scattered throughout the IT cor- nique called microstimulation—
mower cell? This result nailed it for tex. They are located in similar loca- while the monkey was inside an
me. The precise match between the tions across hemispheres in each fMRI scanner. The goal was to find
way cells reacted to changes in con- animal. Moreover, work by our out what other parts of the brain
trast between different parts of the group and others has found that a light up when a particular face
face and Sinha’s computational pre- similar pattern of multiple face patch is stimulated. We discovered
diction was uncanny. patches spanning the IT cortex ex- that whenever we stimulated one
Our initial experiments had re- ists in humans and other primates face patch, the other patches would
vealed two nearby cortical patches such as marmosets. light up but not the surrounding
that lit up to faces. But after further This observation of a stereotyped cortex, indicating that, indeed, the
scanning (with the help of a con- pattern suggested that the patches face patches are strongly intercon-
trast agent that increased several- might constitute a kind of assembly nected. Furthermore, we found that
fold the robustness of the signal), it line for processing faces. If so, one each patch performs a different
became clear that there are actually would expect the six patches to be function. We presented pictures of
six face patches in each of the connected to one another and each 25 people, each at eight different
brain’s two hemispheres (making a patch to serve a distinct function. head orientations, to monkeys and
dozen golden eggs total). They are To explore the neural connec- recorded responses from cells in
distributed along the entire length tions among patches, we electrically three regions: the middle lateral
of the temporal lobe. These six stimulated different patches with and middle fundus patches (ML/
MF), the anterior lateral patch (AL)
and the anterior medial patch (AM).
We found striking differences
Shape + Appearance = Face among these three regions. In ML/
MF, cells responded selectively to
Identifying the face patches ÿDä¸³§āDßäîäîxÇÍîîx³Ux`Dx³x`xääDßāî¸xĀÇ§¸ßxÿDîDÇ- specific views. For example, one cell
Çx³ä³îx³xøß¸³äÿî³xD`ÇDî`jäxîî³¸DäxDß`¸ßîxUßD³Üä`¸l³ä`xx¸ßD`- might prefer faces looking straight
es. To derive quantitative measures for faces, the Tsao laboratory came up with 25 features for ahead, whereas another might opt
shape and 25 for appearance that could be used by each neuron in a face patch—a 50-dimen- for faces looking to the left. In AL,
ä¸³D§D`xäÇD`xÍ5xäDÇxxDîøßxä`D³Uxî¸øî¸Däî¸äxlx³³îxä¦x§xî¸³¸ÿ cells were less view-specific. One
ÿlxîxxDlä¸ßîxläîD³`xUxîÿxx³îxxāxäÍ5xDÇÇxDßD³`xxDîøßxääÇx`āîxD`xÜä class of cells responded to faces
surface texture (complexion, eye or hair color, and so on). looking up, down and straight
ahead; another responded to faces
2'$Ú5''2"%55?%502$5

2%jÛ
?"%%'23?Î53'j%CELL, <'"ÎÀêµj%'Îêè 7%Àj÷ĈÀéÊf ace images)
Shape: Described by the position (x,y coordinates) of feature landmarks (yellow dots) looking to the left or right. In AM,
cells responded to specific individu-
x als regardless of whether the view of
the face was frontal or in profile.
Thus, at the end of the network in
AM, view-specific representations
were successfully stitched into a
y
view-invariant one.
Apparently face patches do act
as an assembly line to solve one of
āD®Èÿå¹ÿDàDU¨ïĂ ÿyàDyåDÈy
the big challenges of vision: how to
recognize things around us despite
changes in the way they look. A car
Appearance:<DàDï¹´å´¨ù®´¹åïĂ¹ïy®DyDïyààåïD¨´´ïï¹®Dï`D´DÿyàDyD`yåDÈy can have any make and color, ap-
pear at any viewing angle and dis-
Luminosity range tance, and be partially obscured by
closer objects such as trees or other
cars. Recognizing an object despite
these visual transformations is
called the invariance problem, and
it became clear to us that a major
function of the face-patch network
is to overcome this impediment.
āD®Èÿå¹ÿDàDU¨ïĂ Given the great sensitivity of
cells in face patches to changes in
facial identity, one might expect
26 Scientific American, February 2019 Graphics by Jen Christiansen

that altering these cells’ responses

should modify an animal’s percep-
tion of facial identity. Neuroscien-
The Face Code, at Last
tists Josef Parvizi and Kalanit Grill- Having 50 coordinates îDîlxä`ßUxäDÇxD³lDÇÇxDßD³`xD§§¸ÿä¸ßDlxä`ßÇî¸³¸³xøß¸³äÜ
Spector of Stanford University had ß³³ßxäÇ¸³äxî¸DÇDßî`ø§DßD`xDlxä`ßÇî¸³îDîø³`î¸³äDäD`¸lxîDî`D³UxþäøD§-
electrically stimulated a face-patch ized geometrically. In this code, each face cell receives inputs for a face in the form of the 50
area in human subjects who had `¸¸ßl³Dîxäj¸ßlx³ä¸³äÍ5x³xøß¸³îx³ßxäÿîDÇDßî`ø§Dß³îx³äîā³ßxäÇ¸³äxî¸D
electrodes implanted in their brains certain face (red outlines), along what is called the preferred axis. The intensity increases steadi-
for the purpose of identifying the ly (monotonically) along the preferred axis. Furthermore the response is the same for every
source of epileptic seizures and face on an axis at right angles to the preferred axis, even though those faces may look very dif-
found that stimulation distorted the xßx³îÍ5äDĀä¸lx§¸D`D§`¸l³lxßäß¸DÇßxþ¸øäxĀxÇ§Dß¸lx§îDîäøxäîä
subjects’ perception of a face. îDîxD`³xøß¸³ßxäÿîDĀø³îx³äîāî¸Dä³§x¸äîÇßxxßßxlD`xÍ
We wondered whether we would
find the same effect in monkeys Axis Exemplar
Orthogonal axis
when we stimulated their face model model
patches. Would doing so alter the Preferred axis (new) (old)
perception only of faces, or would it
affect that of other objects as well? Spike in
The boundary between a face and a nerve activity
nonface object is fluid—one can see
a face in a cloud or an electrical
outlet if prompted. We wanted to
use electrical microstimulation as a
tool to delineate precisely what
constitutes a face for a face patch.
We trained monkeys to report
whether two sequentially presented
faces were the same or different.
Consistent with the earlier results
in humans, we found that micro-
stimulation of face patches strongly
distorted perception so that the an-
imal would always signal two iden-
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tical faces as being different.

Interestingly, microstimulation
had no effect on the perception of
many nonface objects, but it did sig-
nificantly affect responses to a few
objects whose shape is consistent
with a face—apples, for one. But first began recording from face shape and another for appearance.
why does this stimulation influence patches was to achieve something Think of the shape features as those
the perception of an apple? more. I had intuited that these cells defined by the skeleton—how wide
One possibility is that the face would allow us to crack the neural the head is or the distance between
patches are typically used to repre- code for facial identity. That means the eyes. The appearance features
sent not just faces but also other understanding how individual neu- define the surface texture of the
round objects like apples. Another rons process faces at a level of detail face (complexion, eye or hair color,
hypothesis is that face patches are that would let us predict a cell’s re- and so on).
not normally used to represent sponse to any given face or decode To generate these shape and ap-
these objects, but stimulation in- the identity of an arbitrary face pearance descriptors for faces, we
duces an apple to appear facelike. based only on neural activity. started with a large database of face
It remains unclear whether face The central challenge was to fig- images. For each face, we placed a
patches are useful for detecting any ure out a way to describe faces set of markers on key features. The
nonface objects. quantitatively with high precision. spatial locations of these markers
Le Chang, then a postdoc in my lab, described the shape of the face.
CRACKING THE CODE had the brilliant insight to adopt a From these varied shapes, we calcu-
UNCOVERING the organization of the technique from the field of comput- lated an average face. We then
face-patch system and properties of er vision called the active appear- morphed each face image in the da-
the cells within was a major accom- ance model. In this approach, a face tabase so its key features exactly
plishment. But my dream when we has two sets of descriptors, one for matched that of the average face.

lets us predict the face being shown
Pictures Worth 205 Neurons from face cell responses:

50 face features = (1/weight
For a given face, we can predict how a cell will respond by taking a weighted sum of all 50 face matrix) × response of face cells
coordinates. To predict what face the monkey saw from neuronal activity, this entire process can
be reversed: By knowing the response of 205 face cells, it is possible to predict the 50 coordinates At first, this equation seemed
lx³³îxxĀD`îD`D§xDîøßxäD³lD¦xD§āD``øßDîxßx`¸³äîßø`î¸³¸Dþx³D`xÍ impossibly simple to us. To test it,
we used responses to all but one of
the 2,000 faces to learn the weight
matrix and then tried to predict
the 50 face features of the excluded
face. Astonishingly, the prediction
turned out to be almost indistin-
guishable from the actual face.
A WIN-WIN BET
AT A MEETING in Ascona, Switzer-
land, I presented our findings on
how we could reconstruct faces us-
ing neural activity. After my talk,
Rodrigo Quian Quiroga, who dis-
covered the famous Jennifer
Aniston cell in the human medial
temporal lobe in 2005 and is now
at the University of Leicester in
England, asked me how my cells
related to his concept that single
neurons react to the faces of specif-
ic people. The Jennifer Aniston
cell, also known as a grandmother
Corresponding Reconstructed Faces Based on Neuron Activity cell, is a putative type of neuron
that switches on in response to the
face of a recognizable person—a
celebrity or a close relative.
The resulting images constituted In our experiment, we randomly I told Rodrigo I thought our
the appearance of the faces inde- drew 2,000 faces and presented cells could be the building blocks
pendent of shape. them to a monkey while recording for his cells, without thinking very
We then performed principal cells from two face patches. We deeply about how this would work.
components analysis independent- found that almost every cell showed That night, sleepless from jet lag, I
ly on the shape and appearance degraded responses—resembling a recognized a major difference be-
scriptors across the entire set of ramp slanting up or down—to a tween our face cells and his. I had
faces. This is a mathematical tech- subset of the 50 features, consistent described in my talk how our face
nique that finds the dimensions with my earlier experiments with cells computed their response to
that vary the most in a complex cartoon faces. But we had a new in- weighted sums of different face fea-
data set. sight about why this is important. If tures. In the middle of the night, I
By taking the top 25 principal a face cell has ramp-shaped tuning realized this computation is the
components for shape and the top to different features, its response same as a mathematical operation
25 for appearance, we created a can be roughly approximated by a known as the dot product, whose
50-dimensional face space. This simple weighted sum of the facial geometric representation is the
space is similar to our familiar 3-D features, with weights determined projection of a vector onto an axis
space, but each point represents by the slopes of the ramp-shaped (like the sun projecting the shadow
a face rather than a spatial location, tuning functions. In other words: of a flagpole onto the ground).
and it comprises much more than Remembering my high school
DORIS Y. TSAO Êf ace images)
just three dimensions. For 3-D response of face cells = weight linear algebra, I realized this im-
space, any point can be described matrix × 50 face features plied that we should be able to con-
by three coordinates (x,y,z). For a struct a large “null space” of faces
50-D face space, any point can be We can then simply invert this for each cell—a series of faces of
described by 50 coordinates. equation to convert it to a form that varying identity that lie on an axis

perpendicular to the axis of projec- to the amount of red in any color. cause philologists knew Ancient
tion. Moreover, all these faces Such a cell would fire at the same Greek, they could use the Rosetta
would cause the cell to fire in exact- intensity for a brown or yellow col- stone to help decipher Egyptian hi-
ly the same way. or containing the same amount of eroglyphics and Demotic. Similarly,
And this, in turn, would suggest red mixed in with other colors. Face faces, face patches and the IT cor-
cells in face patches are fundamen- cells use the same scheme, but in- tex form a neural Rosetta stone—
tally different from grandmother stead of just three axes, there are one that is still being deciphered.
cells. It would demolish the vague 50. And instead of each axis coding By showing pictures of faces to
intuition everyone shared about the amount of red, green or blue, monkeys, we discovered face patch-
face cells—that they should be each axis codes the amount of devi- es and learned how cells within
tuned to specific faces. ation of the shape or appearance of these patches detect and identify
I was the first person in the any given face from an average face. faces. In turn, understanding cod-
meeting’s breakfast hall at 5 A.M. It would seem then that the ing principles in the face-patch net-
the next morning and hoped to Jennifer Aniston cells do not exist, work may one day lead to insight
find Rodrigo so I could tell him at least not in the IT cortex. But into the organization of the entire
about this counterintuitive predic- single neurons responding selec- IT cortex, revealing the secret to
tion. Amazingly, when he finally tively to specific familiar individu- how object identity more generally
showed up, he told me he had the als may still be at work in a part of is encoded. Perhaps the IT cortex
exact same idea. So we made a bet, the brain that processes the output contains additional networks spe-
and Rodrigo allowed the terms to of face cells. Memory storage re- cialized for processing other types
be framed in a way that would be gions—the hippocampus and sur- of objects—a whirring factory with
win-win for me. If each cell really rounding areas—may contain cells multiple assembly lines.
turned out to have the same re- that help a person recognize some- I also hope that knowing the
sponse to different faces, then I one from past experience, akin to code for facial identity can help ful-
would send Rodrigo an expensive the famed grandmother cells. fill my college dream of discovering
bottle of wine. If on the other hand, Facial recognition in the IT cor- how we imagine curves. Now that
the prediction did not pan out, he tex thus rests on a set of about 50 we understand face patches, we can
would send me solace wine. numbers in total that represent the begin to train animals to imagine
In search of an answer back in measurement of a face along a set faces and explore how neural activ-
our lab at Caltech, Le Chang first of axes. And the discovery of this ity is shaped by the purely internal
mapped the preferred axis for a giv- extremely simple code for face act of imagination. Lots of new
en cell using responses to the 2,000 identity has major implications for questions arise. Does imagination
faces. Then he generated, while still our understanding of visual object reactivate the code for the imag-
recording from the same cell, a representation. It is possible that ined face in the face patches? Does
range of faces that could all be all of the IT cortex might be orga- it bring back even earlier represen-
placed on an axis perpendicular to nized along the same principles tations of contours and shading
the cell’s preferred axis. Remark- governing the face-patch system, that provide inputs to the face-
ably, all these faces elicited exactly with clusters of neurons encoding patch system? We now have the
the same response in the cell. The different sets of axes to represent tools to probe these questions and
next week Rodrigo received an ex- an object. We are now conducting better understand how the brain
quisite bottle of Cabernet. experiments to test this idea. sees objects, imagined or real.
The finding proved that face Because almost all the brain’s
cells are not encoding the identities NEURAL ROSETTA STONE core behaviors—consciousness, vi-
of specific individuals in the IT cor- IF YOU EVER GO to the British Muse- sual memory, decision-making, lan-
tex. Instead they are performing an um, you will see an amazing arti- guage—require object interactions,
axis projection, a much more ab- fact, the Rosetta stone, on which a deep understanding of object
stract computation. the same decree of Memphis is perception will help us gain insight
An analogy can be made to col- engraved in three different lan- into the entire brain, not just the
or. Colors can be coded by specific guages: Egyptian hieroglyphics, visual cortex. We are only starting
names, such as periwinkle, celan- Demotic and Ancient Greek. Be- to solve the enigma of the face.
dine and azure. Alternatively, one
can code colors by particular com-
binations of three simple numbers MORE TO EXPLORE
that represent the amount of red, The Code for Facial Identity in the Primate Brain. Le Chang and Doris Y. Tsao in Cell, <¹¨ÎÀêµj%¹ÎêjÈDyåÀĈÀñÀĈ÷~è ùýÀj÷ĈÀéÎ
green and blue that make up that How Do We Recognize a Face? Rodrigo Quian Quiroga in Cell, <¹¨ÎÀêµj%¹ÎêjÈDyåµéµééè ùýÀj÷ĈÀéÎ
color. In the latter scheme, a color FROM OUR ARCHIVES
cell performing a projection onto The Face as Entryway to the Self. àåï¹!¹`è¹´å`¹ùåýåå2ymùājIY_[dj_ÒY7c[h_YWdC_dZ" D´ùDàĂëyUàùDàĂ÷ĈÀÎ
the red axis would fire electrical
cientificamerican c m ma a ine a
impulses, or spikes, proportional

| GHO ST | FLOWER S |
The genes of Hawaiian plants, extinct

for more than a century, have been
brought back from the dead.
Today we can smell their scents
By Rowan Jacobsen
Photographs by Floto + Warner

BACK FROM THE BRINK: The Wynberg conebush (left)

went extinct in 1806, and Maui’s mountain hibiscus
(right) followed in 1912. But their DNA has been recov-
ered, and some rejuvenated scent genes are once again
Çß¸lø`³ßDßD³`xäÍ5xUä`øäjä³xlUāÇx¸Ç§x
¸ßîxßäîîx³¸ßxîD³D`x³îøßājxþ¸¦xäUDß¦
and juniper, with hints of citrus and thyme.

Journalist Rowan Jacobsen is author of several books,

such as Shadows on the Gulf (Bloomsbury, 2011) and The
Essential Oyster (Bloomsbury, 2016), and many magazine
articles. He was a 2017–18 Knight Science Journalism
Fellow at the Massachusetts Institute of Technology.
N 1912, ON THE ANCIENT LAVA FIELDS OF HALEAKAL A– ON THE HAWAIIAN ISLAND OF MAUI, A SINGLE
I tree stood near death. Fifteen feet tall, its bark encrusted with lichens, it was down
to its last flower.
The Hawaiians called this tree hau kuahiwi, the mountain hibiscus. Unlike the more
familiar Hawaiian hibiscus, which grows in moist valleys and opens wide in a welcom-
ing aloha, the mountain hibiscus grew only on the dry, well-drained lava fields of
Hawaii’s volcanoes. The plant unfolded only two of its five hibiscuslike petals, keeping
the rest closed in a demure, curved tube designed for Maui’s honeycreepers—nectar-eating
songbirds with curved bills that were its favored pollinators.
But this tree had not reproduced in years. Most

honeycreepers had disappeared as the 19th century
gave way to the 20th. The lava fields of Haleakalā had
yeast—and human noses smelled something that had
vanished from the planet more than a century ago.
Like Odysseus raising the dead in Hades and plying
been turned into cattle ranches. Cows rubbed its trunk them for information, some kind of communication
raw. Rats ate its seeds. took place between the living and the deceased. There
Up the slope came a botanist, dressed in Rough were no flowers, no petals, but these were the actual
Rider cavalry hat and khakis, a collector’s bag over his DNA sequences of the plant telling cells to churn out
shoulder. His name was Gerrit Wilder, and he was on molecules as they used to do on Maui, and those mole-
the original expedition that identified this tree in 1910. cules were grabbed in people’s noses, sending signals
Because of that, the tree was named for him, Hibisca- to their brains. It was the most tangible sign yet that
delphus wilderianus. It was the only member of its the hard membrane of extinction is beginning to soft-
species ever found. Its sickly state was why Wilder had en. This newfound porosity forces a strange question:
returned. He plucked the last flower, along with some Can we reboot enough genes to say that something
twigs and leaves, and nestled them into his bag. Then isn’t quite dead anymore?
he turned and made his way slowly down the slope.
IN BRIEF Not long after that, the tree succumbed to the cattle SCENT OF LIFE
Dead is dead, went and the rats and dropped its final leaves. H. wilderia- THE RESURRECTION PROJECT BEGAN, oddly enough, at the
the dogma of extinc- nus was extinct. And that should have been that. Ex- 2014 annual convention of the International Federa-
tion, for when the tinction is supposed to be forever. tion of Essential Oils and Aroma Trades in Rome,
last of a species van- Recent breakthroughs in DNA sequencing, howev- where Jason Kelly, Ginkgo’s CEO, was looking to drum
ishes, it is gone from er, have made it increasingly easy to read the genes of up business. Kelly and his Ginkgo co-founders graduat-
the world forever.
long-dead organisms and “reboot” those DNA stretched in 2008 from the Massachusetts Institute of Tech-
But genes of the
dead can be resur-
es. Serious efforts are underway to use such tech to re-
rected, a group of vive the passenger pigeon and the woolly mammoth.
scientists has shown, Both projects depend on bioengineering advances that RECOVERED GENES: Researchers found fragmented
by recovering DNA are still years away. Yet in 2018, in an eighth-floor lab- DNA in extinct plant specimens at the Harvard
and making it oratory built above the burgeoning Seaport District in Herbaria. They spliced the DNA together into scent
function again. Boston, a crucial part of this long-dead mountain hi- genes for the Wynberg conebush (Leucadendron
Scent genes biscus came back to life. ßC³l¸ßøSalisb.) (1); the mountain hibiscus
from long-gone
A collection of gene engineers, working for a com- (Hibiscadelphus wilderianus2¸`¦ÊÉ2); and the Falls-
¹ĀyàåDÿyUyy´
recovered in this pany called Ginkgo Bioworks, was able to re-create the of-the-Ohio scurfpea (&ßTxĀ§ø äîÇø§Cîø [Torr. &
way, and research- scent genes from the flower. They rebuilt the genetic A. Gray] Rydb.) (3). These three produced fragrant
ers have smelled material that had produced the flowers’ distinctive compounds. A myrtle, Myrcia skeldingii Proctor (4),
their products. odor, got it working again in another life-form—a āx§lxlDx³xîDîll³¸îD¦xD ä`x³î¸§x`ø§xÍ

1 2
SPECIMENS PHOTOGRAPHED AT HERBARIUM OF ARNOLD ARBORETUM AND GRAY HERBARIUM OF HARVARD UNIVERSITY

nology with some of the first Ph.D.s in synthetic biology awarded bacteria to produce hydrogen fuel and created art based on the
for that specialization. His firm is also highly specialized: if an- shapes of antibodies. Warm and witty, she was drawn to research
other company needs a new microbe to produce some valuable that probed the borderlands between natural and unnatural and
molecule—for fuel, fiber, fragrance, pharmaceutical, whatever— opened up interesting conversations about genetically modified
Ginkgo will design and test hundreds of prototypes in its bio- organisms. A perfume of extinct florals that people could smell
foundries and hand over the top performers. while meditating on these lost species was right up her alley. She
Many of Ginkgo’s best clients are in the flavors and fragranc- dubbed the venture “Project Cretaceous,” after the period when
es industry, where raw ingredients can be astronomically ex- flowers first came into existence. She began by contacting ex-
pensive. All those fragrance molecules are produced by enzymes perts in Ice Age excavations, who told her it was impossible to se-
in the plant cells, and the blueprint for those enzymes is coded quence a full genome out of the gunky specks of plant that
in DNA by a gene. Like software, this code can run on any com- emerge from the permafrost. The Ice Age was a dead end.
patible platform, and life is surprisingly platform-agnostic. All Before giving up, Agapakis did what any good Millennial
living things use the same four-letter language of DNA—compo- would do: she googled “extinct plant DNA sequencing.” Far down
nents labeled A, T, C and G—and yeast and plants run many of the list of results, she found an obscure paper from the Biological
the same genes. By inserting fragrance genes into specially engi- Journal of the Linnean Society on museomics, a new technique
neered strains of brewer’s yeast, Gink- for extracting DNA from museum-pre-
go brews scent molecules in a flask, served plants and animals. So she did
just like making beer. “The planet has not need permafrost after all. She just
At the trade show, Kelly met a con- needed an herbarium.
sultant for Givaudan, the Swiss per- spent hundreds of The realization made the Harvard
fume giant, who told Kelly about Gi-
vaudan’s Scent Trek program, which
millions of years grad smile. She knew just where to
find one of those.
dispatched explorers into the world’s evolving DNA. And
rain forests to capture the air around THE DNA SEARCH
rare flowers so the scents could be we just have to let it THE HARVARD HERBARIA, which date
identified. Kelly was intrigued. If Gink- go away? For a back to 1842, anchor one brick-lined
go could get samples of these plants, end of a street named Divinity Avenue,
the company could sequence the biological designer, and their numerous floors are filled
genes and synthesize the enzymes
that made the smells. But as the two
it’s frustrating.” with formaldehyde-scented cabinets
holding more than five million sam-
brainstormed, Kelly had a much cra- —Jason Kelly, ples. They do not embrace change en-
zier idea. What if he was able to go be- Ginkgo Bioworks thusiastically, so when Agapakis
yond obscure plants and bring back pitched her plan in 2016, the curator
the scent of flowers that no longer was skeptical. Do what with their
even existed? plants? The herbaria were not in the business of giving away
This would be the first step, he thought, in reversing a tre- their collection to for-profit entities. Besides, they had no search-
mendous biological waste. “The planet has spent three billion able database for their holdings, so they had no idea if they had
years trying out different DNA sequences through this process any extinct plants or not.
we call evolution,” Kelly says, “and that’s what we have today. But It took Agapakis months of negotiations to reach an agree-
along the way, a lot got lost for some random reason—a meteor or ment. The deal was sealed when she offered to provide genomes
whatever—and some of that stuff was incredible. The planet of any extinct plants she found to the research community. Even
spent hundreds of millions of years evolving DNA. And we just so, she had to find the plants on her own, with no help from
have to let it go away? For a biological designer, it’s frustrating to herbaria staff, and if she did find what she was looking for
imagine losing all that great code.” she could not take more than a pinky-nail-sized fragment of ex-
Kelly’s original plan riffed on Jurassic Park: Recover an Ice traneous material.
Age flower from the Arctic permafrost, sequence its genes and Agapakis and Dawn Thompson, Ginkgo’s head of Next Gener-
synthesize the ones responsible for fragrance, then put them in ation Sequencing, printed out the IUCN Red List of 116 modern
yeast cells. When the genes instructed the cells to make the fra- plant extinctions and began their quest. The collection was ar-
grant molecules, Kelly could brew up a little Extinction N° 5. ranged by plant family first and geography second, so the only
It was a long shot. Although a handful of ancient genes had way to find a sample was to go to the corresponding floor of the
been reconstructed in labs, most simply sat there, never being herbaria, find the aisle for the right family and then search in all
asked to produce a protein and thus rejoin our world. Even if the folders for the particular country or area. The aisles were end-
Ginkgo was able to rebuild old genes, those genes might not less, the cabinets seemingly filled with everything but the plants
function in new yeast. Kelly also worried about tying up precious they were looking for. Then, in the Hawaii room, Agapakis
resources. Everyone at his company was already overworked. cranked a big wheel to roll the creaking cabinets apart, opened
The last thing they needed was to get sucked into a Jurassic lark. the doors, paged through the folders, opened one, and gazed down
But the project found a champion in Christina Agapakis, at three long twigs holding an array of broad, beautiful leaves and
Ginkgo’s creative director. Agapakis earned her Ph.D. in synthet- a single pressed flower bud. “Flora of the Hawaiian Islands” read
ic biology at Harvard University, and she worked on optimizing the attached card. “Hibiscadelphus wilderianus.” Agapakis felt an

Road to Resurrection

ß³³x³xäUD`¦ß¸îxlxDlä³¸îäÇ§āDDîîxß¸³l³
D³`x³î%Í5xx³xî`DîxßD§Däî¸UxßxDä¸³xl³î¸
Dÿ¸ß¦³x³xîDî`D³³äîßø`îD`x§§î¸D¦x¸§x`ø§xäÍ
Dried 5xx³x³îä`Däxß¸D³xĀî³`îDÿDD³Ç§D³î`D§§xl
Hibiscadelphus
D¸ø³îD³Uä`øäîx³Däî¸UxÇ§D`xl³î¸D³xÿj§þ³
wilderianus specimen
¸äîÍ3ā³îxîÙ¸§¸äîäDî³¦¸
¸ÿ¸ß¦ä³äxßîxlîxx³x
³î¸āxDäîjÿxßxîD`îøD§§āDlxßDßD³î`¸Ç¸ø³läÍ
1 From dried plant samples,
researchers extract tiny
DNA fragments.
A A A T C G G G G C T A G
G A T
2 The fragments are analyzed C A C G A T T
in a sequencer machine, A G G C C A
which reads the order of their T A G T
DNA fragments Sequencer
component nucleotides
(dubbed A, T, C and G).
Template SQS gene drawn from related organism
A C G T A A G G T G T T T A A A G T T A G A G G C C A A G T A G G G G C T A G T C A C G A T T C C T G A T G
The gene that researchers Mismatch

want to re-create is for A A A T C G G G G C T A G
sesquiterpene synthase (SQS),
the enzyme that assembles Template sequence helps C A C G A T T G A T
®¹åï¹àD¨å`y´ï®¹ÿ`ùÿåÎ to determine which DNA
Scientists take the ancient fragments go next to one Missing sections
A G G C C A
åyÕùy´`yåD´m´må¹®y another and if some nucleo- between fragments
that match parts of an SQS tides are mismatched. Dày¨ÿmĀï
sequence based on a gene in sequences from
a current organism. The living Reconstructed mountain T A G T the template.
sequence becomes a template hibiscus SQS gene
to determine the position of G A G G C C A A A T C G G G G C T A G T C A C G A T T C C T G A T G
each fragment.
The reconstructed sequence

is turned into real DNA with
a DNA printer, which builds out
the molecule one component DNA printer
at a time. The end product is
an SQS gene.
Nucleus
Yeast cell
The gene is inserted into

a yeast “host” engineered Gene
to accept it, and the yeast transferred
colonies grow in small wells. to yeast
The instructions coded into Scent molecule
the SQS gene tell the yeast Printed SQS gene
to make a scent molecule,
just as they once instructed
the ancient hibiscus.
Illustration by Rebecca Konte February 2019, ScientificAmerican.com 35

DE-EXTINCTION ROOM: î³¦¸

¸ÿ¸ß¦ä³
¸äî¸³j
a laboratory (1) is set up to engineer yeast to produce nonyeast
molecules—such as scent compounds of extinct plants. An
engineer there ( 2) prepares cells so their genetic code can be
D³D§āąxlÍ³D§§ājßäî³DDÇD¦äjÿ¸lßx`îxlîxßxäî¸ßDî¸³
project (3Êjä³äĀîøßxä¸lxßx³î`¸Ç¸ø³läîDî¸ß³Dîxl
from the recovered DNA of the extinct mountain hibiscus.

electric thrill. It was Wilder’s extinct tree, right in front of her. ing at Ginkgo, was tasked with this book-reassembly problem.
In the end, the scientists found 20 of the plants on their list He realized those modern SQSs could serve as the template. It
in the herbaria, 14 of which had enough material to spare. Under was like trying to reconstruct a lost version of the Bible using the
the baleful eye of the curator, they snapped off the least impor- King James and New International versions as guides. The
tant bits and placed them in plastic baggies. wording would not exactly match, but they would be a decent
Then it was time for the hard part. DNA degrades after an or- guide to what went where.
ganism dies. Ginkgo was going to have to find needles of DNA in Bit by bit, Wang built his genes on the scaffolding modern
haystacks of cellulose. And the team had only enough material relatives provided, relying on sequence overlaps for placement.
for a few attempts. The researchers decided to practice on an He filled in any missing letters of DNA from the modern tem-
oak leaf scavenged from the streets of Boston. Even that did not plates. If his fragmented Bible read “In th_ beg_ _ning was the
go well. Despite their state-of-the-art sequencing equipment, W_ _ d,” he could look to the King James and be pretty confident
they struggled to extract DNA from the samples. The ancient which letters were missing.
samples did not produce anything. Ultimately Wang was able to reconstruct 2,738 versions of genes
With pressure mounting to yield the sequencing machine to from the extinct flowers. Undoubtedly these strings of biological
paying projects, Agapakis and Thompson had a sobering con- letters had a few typos. Would that ruin their functions? Occasion-
versation. If they kept trying, they were going to run out of plant ally a single wrong letter of DNA will break a gene catastrophically,
material, and there was no way they were getting more. They de- as in sickle cell anemia. But often minor changes do not affect the
cided to put Project Cretaceous on hold until they found a more end product. In fact, sometimes genes with significantly different
effective way of doing it. forms will function similarly. In Biblical terms, “In the begin-
Months later, at a conference, Kelly met Beth Shapiro, co-di- ning was the Word” (King James) and “The Word was first” (The
rector of the Paleogenomics Lab at the University of California, Message) do not match letter by letter, but both get the job done.
Santa Cruz. This is the place you go if you want to de-extinct a Wang thought most of his letter strings would be too glitchy. He
mammoth or a passenger pigeon. Every year it gets better and just hoped a few would work as instructions for a real cell.
better at extracting tiny amounts of DNA from iffy old material. For that to happen, these genes, which existed solely in
In 2016 the lab was able to identify 0.01 to 0.05 percent mam- Wang’s computer, had to be converted into physical DNA. That
moth DNA—a mere whiff of pachyderm—in 5,650-year-old lake is a fairly straightforward job, done with a DNA printer that re-
sediments from an island in the Bering Strait. Send us your sembles a 3-D printer but shoots out As, Cs, Gs and Ts, which
flowers, Shapiro said. bind together chemically into a classic double helix. Although
Thompson overnighted her plastic baggies of leaf matter to this is often called synthetic DNA, it is just as real as any other
Josh Kapp, a grad student in the Paleogenomics Lab. Kapp did DNA. Molecules are molecules.
not like what he saw. He pulverized each sample into powder to Then it was up to the yeast, each of the 2,000-odd genes go-
maximize the surface area, but the plants did not powder as ing into a colony bred to accept new DNA and make molecules
nicely as the bone he was used to. But after many filtration steps according to its instructions. For several days the colonies
and some creative applications of chemicals that bind to DNA frothed like beer brewing in their tiny containers. Scott Marr, a
fragments, Kapp ended up with 14 microtubes holding the se- molecular microbiologist at Ginkgo, watched, wondering what
crets of lost plants, which he packed in dry ice and sent back to they had made. When the fermentation subsided, Marr ran a
Ginkgo. When Thompson ran the samples through her sequenc- sample of each colony through a mass spectrometer, a kind of
ing machine in Boston, she was thrilled to see numerous short artificial nose that was capable of detecting and identifying the
reads come through: millions of fragments of genetic code, each minuscule amount of molecules being produced in each strain.
just 40 or 50 letters long. Each mass shows up as a differently sized peak on a graph. It
was Marr’s job to read the pattern of peaks like a fingerprint.
RECONSTRUCTION IN ACTION He wrote programs to eliminate all the regular products of
BUT DID ANY OF THOSE fragments belong to a scent gene, and could yeast metabolism in the machine’s readout, so only nonyeast
they be put back together? Ginkgo was looking for genes, typi- SQS products—scent-making sesquiterpenes—would show up.
cally about 1,700 letters long, that made enzymes called sesqui- Mindful of the long odds and the likelihood of typos in the Gink-
terpene synthases (SQSs); these are the enzymes that stitch to- go translations, Marr crossed his fingers and ran the samples.
gether most good floral scent molecules. A typical flower might The readouts showed nothing. Then more nothing. It looked like
have several of these genes. With all the tiny fragments they had the scientists had pieced together book passages with too many
recovered, it was as if the Ginkgo researchers had a book for letter mistakes, paragraphs that no cell could read.
each plant—the extinct plant genome—all chopped up into ran- And then there it was: a peak. After a while, there was anoth-
dom 50-letter chunks and mixed together, and they needed to er and another. Marr let out a pent-up breath and began to
reassemble a few 1,700-letter passages in just the right way. match the molecular fingerprints to his database of terpenes.
If the scientists had copies of the original books to use as a Then he broke the good news to the Project Cretaceous team:
template or even a few chapters, they could figure out where the dozens of the flower-yeast chimeras were alive.
fragments went. Here evolution came to the rescue. It never in- Agapakis sat at a table, listening to Marr’s report and taking
vents anything from scratch. New species evolve from older spe- it all in. It had been three years since the initial crazy idea. Many
cies, tweaking or repurposing the original genes. So most SQS times she and her colleagues had nearly abandoned it. And now
genes in modern plants share a lot of DNA code with closely re- they had molecules. Real molecules! Made by genes that had not
lated ancestors. Jue Wang, a computational biologist then work- existed in a century!

1 2
PROJECT CRETACEOUS: ³îx³¦¸

x¸ßîjÿ`îxßxäxDß`xßäÿä`D§§ā
named for the Cretaceous period, they
re-created genes for scent molecules
from 14 extinct (or nearly so) plants.
These eight yielded promising DNA
sequences but did not churn out scent
compounds when placed in designer
yeast: ß_C ÇāßClC§ä Sol. (1), Crassula
subulata var. subulata L. (2), Nesiota
elliptica É2¸ĀUÍÊ¸¸¦ÍÍÉ3), Pradosia
glaziovii (Pierre) T. D. Penn. (4),
Macrostylis villosa (Thunb.) Sond. (5),
Shorea cuspidata P. S. Ashton (6),
2îx³¸_CßÇøä løTxx³ää Guillaumin (7)
and 4C³xC lxÇßxääC Oliv. (8).

BACK IN THE REAL WORLD Lurking in the background of several samples was a smoky
GINKGO’S YEAST was able to get genes from three different extinct hint of sulfurous dirt. Kelly’s eyes twinkled as he held one under
plants to produce sesquiterpenes. Although the microscopic his nose. “This is pretty magical, to be honest,” he said. “I hope it
amounts were far too small to smell directly, the scientists had captures people’s imagination and gets them to think about
some inklings of what the eventual floral nature might be, based what we’ve lost.”
on the smells of modern counterparts. One of the plants, the The scent—and the thoughts it inspires—is an important
Falls-of-the-Ohio scurfpea—a legume that made the fatal mis- milestone, says Stanford University bioengineer Megan Palmer,
take of growing only on a few rocky islets in the Ohio River that a board member of Revive & Restore, a nonprofit that is sup-
were drowned by dams in the 1920s—produced a handful of ses- porting the passenger pigeon and woolly mammoth resurrec-
quiterpenes that, if some 21st-century relatives were any guide, tion projects. “We can’t know exactly what these flowers smelled
would have woody, peppery, balsamic scents. like,” she says, “but we can get molecular hints that we interpret
The Wynberg conebush—a five-foot-tall flower with white pet- through what we know about the species we see in the world to-
als and a yellow head that grew in the granite hills above Cape day.” As scientific advances, she adds, “these techniques can
Town until 1806, when it disappeared forever underneath South help us make smarter guesses at how extinct species functioned.
Africa’s expanding vineyards—produced an astonishing 21 ses- They may even allow more ambitious projects to restore those
quiterpenes, many of which are associated with tantalizing functions and the species that gave rise to them.”
scents: jasmine, lemongrass, cannabis, chamomile, turmeric, Because of this work, we are a tiny bit closer to coaxing sa-
ginger, hops. That awkward mix ber-toothed tiger musk or Neandertal
sounded like a good match for a flower hemoglobin out of cells. And as more
that had been noted for its “strong and Because of this work of these freelance genes return to
disagreeable smell.” function in new forms, they make us
Eleven sesquiterpenes came from with ancient flowers, begin to question our old emphasis
H. wilderianus, the mountain hibis-
cus, which had last released its es-
we are a tiny bit on species. The traditional genetic
container may not limit the life of its
sence to the world in 1912, as Gerrit closer to coaxing contents. Sitting in that Boston con-
Wilder picked that final flower and
descended Haleakalā, never expect-
saber-toothed tiger ference room, it seemed clear that
one of the most opportune moments
ing that anyone would smell the hau musk or Neandertal in DNA’s four-billion-year career had
kuahiwi again. From there, the genes’ begun. This novel environment of
unlikely journey along Resurrection hemoglobin out bioengineering labs and digital data-
Road had taken them to the College of
Hawaii’s herbarium, where the plant
of cells. bases and DNA printers was giving
genes a newfound freedom to flow,
was dried and pressed and eventually new ways to replicate, new habitats to
shared with the Harvard Herbaria. There it waited for decades populate, new organisms to seduce. The original form may go
for Agapakis to open its manila folder and break off a piece of extinct, but many functions can return, and at some point—no-
the corpse. The genes were liquefied in Santa Cruz, digitized in body really knows what that is—that resurrection may get an or-
Boston, then reanimated in the tender embrace of an organism ganism to the point of “no longer dead.”
completely unlike the one that hosted their last appearance on As the essential oils saturated the air, the room became an un-
planet Earth. The genes had crossed time and space and out- likely tropical oasis, a hint of smoke in the distance, and it was
ward form, but their information held. easy to imagine the sun-baked lava fields of Haleakalā in the an-
And then it was time to smell them. The Project Cretaceous cient past, a forest of mountain hibiscus all around, bright red
team picked the Hibiscadelphus to go first because its allure was honeycreepers flitting from blossom to blossom. That world will
captivating, much as it had been for many a honeycreeper for mil- never come again, but some of the countless genes from primor-
lennia. On a bright August day in a crisp white conference room, dial Hawaii and other lost landscapes may do just that. They are
the group gathered to sample a variety of formulations—created pressing against the membrane of extinction at this very moment,
for the company by Berlin-based scent artist Sissel Tolaas—that probing, hungry for any chance to get back in the action.
blended the Hawaiian molecules in different combinations and
concentrations. One of the molecules, juniper camphor, was a pric-
ey ingredient in fragrant oils. Hibiscadelphus had expensive tastes. MORE TO EXPLORE
They dipped paper fragrance test strips into 11 elfin bottles, Timing and Causes of Mid-Holocene Mammoth Extinction on St. Paul Island, Alaska.
held them a few inches from their noses and sniffed gently. Team Russell W. Graham et al. in Proceedings of the National Academy of Sciences USA, Vol. 113,
No. 22, pages 9310–9314; August 16, 2016.
members grinned at one another as if they could not quite believe Natural Selection Shaped the Rise and Fall of Passenger Pigeon Genomic Diversity.
they were here. “First resurrected fragrance!” Kelly announced. Gemma G. R. Murray et al. in Science, Vol. 358, pages 951–954; November 17, 2017.
Agapakis’s reaction was more visceral. “I feel overwhelmed,” she IUCN Red List of Threatened Species on Hibiscadelphus wilderianus: www.iucnredlist.org/
said. “I couldn’t imagine what this was going to smell like.” species/30397/9536660
Some samples had flashes of citrus or thyme. All had a woody FROM OUR ARCHIVES
core of bark and juniper that must have been the essence of hau Ancient DNA. Svante Pääbo; November 1993.
kuahiwi. “I like the lightness,” Agapakis said, eyes closed as she
inhaled. “It feels ethereal.”

ENVIRONMENT
Rapid
glacier
retreat
could put
coastlines
underwater
sooner
than
anticipated
Is Antarctica
Collapsing?
By Richard B. Alley
Illustration By Peter Horvath


LACIERS ARE MELTING. SEAS ARE
G rising. We already know ocean

water will move inland along the
Eastern Seaboard, the Gulf of
Mexico and coastlines around the
world. What scientists are urgent-
ly trying to figure out is whether
the inundation will be much worse than anticipated—
many feet instead of a few. The big question is: Are
we entering an era of even faster ice melt? If so, how
much and how fast? The answer depends greatly on
how the gigantic Thwaites Glacier in West Antarctica
responds to human decisions. It will determine wheth-
Richard B. Alley is a professor of geosciences
at Pennsylvania State University. He has spent
more than 40 years studying ice sheets and
has advised the U.S. government on a variety
of climate issues.
speed toward the shore. Today Jakobshavn is retreating

and thinning extensively and is one of the largest single
contributors to global sea-level rise. Geologic records in
rocks there show that comparable events have occurred
in the past. Our current observations reveal similar ac-
tions transforming other Greenland glaciers.
If Thwaites, far larger, unzips the way Jakobshavn
did, it and adjacent ice could crumble, perhaps in as lit-
er the stingrays cruising seaside streets are sports cars tle as a few decades, raising sea level 11 feet. So are we
or stealthy creatures with long, ominous tails. risking catastrophic sea-level rise in the near future? Or
is the risk overhyped? How will we know how Thwaites
Global warming is melting glaciers up in mountain- will behave? Data are coming in right now.
ous areas and expanding ocean water, while shrinking
ice at both poles. Averaged over the planet’s oceans for WAFFLES ON THE COAST
the past 25 years, sea level has risen just over a tenth of CALCULATING THWAITES’S THREAT is complex. To make
an inch per year, or about a foot per century. Melting sense of it, let’s begin with breakfast. If you pour batter
the rest of the globe’s mountain glaciers would raise the on a waffle iron, your mound will spread across the
sea a little more than another foot. But the enormous iron’s crosshatched grid. Physically, the weight of the
ice sheets on land in the Arctic and Antarctic hold more batter pushes the mound outward against the friction
than 200 feet of sea-level rise; a small change to them on the grid below it. This spreading slows as cooking
can create big changes to our coasts. Ice cliffs many stiffens the batter—or if you hold the batter back with
miles long and thousands of feet high could steadily your spatula.
break off and disappear, raising seas significantly. Glacial ice sheets are like big waffles, up to two miles
Well-reasoned projections for additional sea-level thick and a continent wide. Snow falls on top and is
rise this century have remained modest—maybe two squeezed into ice under the weight of subsequent snow-
IN BRIEF
feet for moderate warming and less than four feet even falls. These huge ice mounds are strong—I have landed
Big glaciers on with strong warming. Scientists have solid evidence on them in heavy ski-equipped military transport
Greenland, such as that long-term, sustained heating will add a lot to that planes—but they still spread. Their temperature is often
Jakobshavn, are over ensuing centuries. But the world might be entering within a few degrees of the melting point, making the
¹Ā´Õù`§¨Ă´ï¹
an era of even more rapid ice melt if the front edges of ice soft enough to slowly flow from the high, central re-
ïy¹`yD´jàDå´
åyDÿÿy¨å¨ï¨ĂÎ the ice sheets retreat. gion toward the edges, where it more readily melts and
The much larger To learn whether this could happen, we look for breaks off. Thicker or steeper mounds such as those on
Thwaites Glacier ´ clues from changes underway today, aided by insights Greenland and Antarctica spread faster.
=yåï´ïDà`ï`DDå gained about Earth’s past and from the physics of ice. Left to itself, an ice sheet grows until it is thick and
Uyù´¹Ā´Dåï- Many of the clues have come from dramatic changes steep enough for the spreading, melting and breaking
yàjï¹¹Î5y§yĂD`- that started about two decades ago on Jakobshavn Gla- to balance the ongoing, additional snowfall. The mound
ï¹àmyïyà®´´ïå cier, an important piece of the Greenland Ice Sheet. Gla- can stay at one size for a long time. But that is not the
DïyåĀyïyàïĀ¨¨
ciers spread under their own weight toward the sea, case on our warming planet. The moisture in the snow
àyïàyDï´ï¹ïyàyDï
y´ïÿĂ3ùU¨D`D¨ where the front edges melt or fall off, to be replaced by that falls on Greenland and Antarctica each year, which
PRECEDING PAGE: GETTY IMAGES (hand, water, buildings)
5ày´Ùy´mïÎ ice flowing from behind. When the loss is faster than the almost entirely comes from the sea, is equal to a layer of
If it does retreat, flow from behind, the leading edge retreats backward, water evaporated from all oceans, just over a quarter of
ïDïĀ¹ù¨m`àyDïy shrinking the ice sheet on land and raising sea level. an inch deep. The ice sheets are now returning about
ÿyàĂ`y`¨å During the 1980s Jakobshavn was among the fastest- 15 percent more than this amount to the oceans, by
ïDïĀ¹ù¨mUàyD§¹ moving glaciers known, racing toward Baffin Bay, even meltwater runoff or icebergs that “calve” off, raising sea
´ï¹ïy¹`yD´Î though it was being held back by an ice shelf—an exten- level a little. If melting remains greater than snowfall
5ĀDïyååïDàïåï¹
sion of the ice floating on top of the sea. In the 1990s for long enough, an ice sheet can disappear. But that
`àù®Uÿjï`¹ù¨m
àDåyåyDÿÿyÜĂDå ocean warming of about 1.8 degrees Fahrenheit (one de- could take almost 100,000 years at recent rates. If
®ù`DåÀÀyyï´ gree Celsius) dismantled the ice shelf, and the glacier on warming rises, however, the melting quickens. That is
¦ùåïDyĀmy`DmyåÎ land behind it responded by more than doubling its the case we are facing globally.

Raising
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Small glaciers drain parts of West
Antarctica and can raise sea level a lit-
tle if they melt. But the truly vast gla-
ciers such as Pine Island and Thwaites
pose a much larger threat (main map).
5ÿDîxäääîDßî³î¸î³ç`x¸ÿä³î¸îx
sea as the leading edge recedes inland (illustra-
tions). The broad Bentley Subglacial Trench onne ce el
r
behind Thwaites could allow the glacier to
ns
retreat as far as the Transantarctic Mountains,
which would raise sea level by 11 feet.
nt
ine sl nd
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How to Unzip an Ice Sheet

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ce s eet now r ir elts ice `y¹ĀåÈyymåùÈ $y¨ïĀDïyàÈ¹ùàå l cier retre ts until

m¹Ā´`àyÿDååyåj ïïåà¹ù´m
ce s el slows r w ter elts ice ce s eet t ins ¨ùUà`DïÚ¹ïï¹®
`yåyyï¹ĀË
`y¹Ā `yåy¨`àù®Uÿå
ce n
uture se le el
e le el
Grounding point Basin
Jumping the Bump à¹ù´m´È¹´ï

ày`ym´`yåyyï`D´`Dï`¹´DåyD¹¹ààåyj¹àUù®Èj`àyDï´ ce
à`ï¹´D´mU¨¹`§´ĀDà®ĀDïyàà¹®®y¨ï´ïyù´myàåmyÎïy
àyïàyDï`ÿDàåïyUù®Èjà`ï¹´mà¹ÈåjD´mïyĀDïyàDå¹Èy´D``yååÎ
3yD¹¹ààåy
Map by Mapping Specialists, Illustration by Ben Gililand February 2019, ScientificAmerican.com 43

TERRIBLE BEAUTY and extends about nine times that much below the water. As
AN ICE SHEET’S FLOW depends on how strong the mound is, how these icebergs roll over, they make splashes 50 stories high and
well lubricated it is underneath on land, and whether or not it is earthquakes that can be monitored from the U.S.
held back by a spatula—an attached, floating ice shelf. General at- So far ice-shelf loss and ice-cliff calving are contributing mod-
mospheric warming can soften ice and thaw the places where the erately to sea-level rise. But at Thwaites, this process could make
ice bottom is frozen to the rock below, allowing the ice to slide the rise much more dramatic because a geologic accident has
faster toward the sea. But the heat takes a long time to be con- placed the glacier near a “tipping point” into the great Bentley
ducted through two-mile piles. The big ice sheets have not fin- Subglacial Trench.
ished warming from the rising air temperatures that ended the
most recent ice age more than 10,000 years ago! JUMP THE BUMP
A speedier way to warm the ice and its bed is for water melting ON AN AUTUMN MORNING in 1956, Charles Bentley (who years later
on top to pour down into crevasses. In some places on the flanks would be my Ph.D. adviser) defended his thesis at Columbia Uni-
of Greenland’s ice, meltwater in summer collects in large hollows versity. The next day he hopped a train to Panama, then caught a
on the surface, forming big, beautiful blue lakes. The water, being ship heading south, to be part of the International Geophysical
denser than ice, tends to wedge open crevasses that can reach the Year research project that would analyze planet Earth. He spent
bed at the bottom and drain the lake. An two years in West Antarctica before re-
expanding lake can break through half turning to find that he had not graduat-
a mile of ice or more, creating a flow of ed yet, because his thesis fee had not
water greater than Niagara Falls. In an been paid. In the meantime, he and his
hour, that can warm the bed as much as team traversed more than 3,000 miles
would have occurred over 10,000 years. of ice, to and from the Byrd Station re-
This process is important, and we are search base and across vast reaches of
studying it eagerly. But it is not the great- West Antarctica. (Bentley died at age 87
est worry for people on Earth’s coasts, in 2017.)
because the bumpy bed can also keep the Of the many measurements and dis-
ice from speeding toward the sea. coveries they made, the most important
The same mechanism presents a for our story involved the ice thickness.
stronger threat if it happens on an ice They set off small explosions on the sur-
shelf. In very cold places, the ice flowing face and used seismometers to listen to
into the ocean remains attached but sound traveling through the ice sheet
floating. These ice shelves almost always and bouncing back off the bed. These
occur in protected bays or fjords. The data showed that West Antarctica was
motion of ice shelves is slowed by friction not a thin drape of ice overlying a high
along the shorelines around them and continent, as some had expected. Instead
perhaps with upward protrusions from Bentley and his team found very thick ice,
MELTWATER pours into the Greenland
the seafloor, where the ice locally runs and they discovered the Bentley Subgla-
ice sheet, hastening its slump toward the
aground. The shelf slows the flow of the cial Trench. There the bed plunges more
sea—a sign of things to come in Antarctica.
nonfloating ice on land toward the sea. than a mile and a half below sea level—
Warming air can create lakes on top Earth’s deepest place not under an ocean.
of the ice shelves. When the lakes break through crevasses, a shelf And the ice filling it extends more than a mile above sea level.
can fall apart. For example, the Larsen B Ice Shelf in the Antarctic Bentley and glaciologists who followed him had found a tip-
Peninsula, north of Thwaites, disintegrated almost completely in ping point. The great trench and adjacent basins underlie the vast
a mere five weeks in 2002, with icebergs breaking off and top- center of the West Antarctic Ice Sheet. If the front edge of
pling like dominoes. That did not immediately raise sea level—the Thwaites retreated from the coast back into the trench, it could
shelf was floating already—but the loss of the shelf allowed the ice make an ice face thousands of feet high, extending from far above
sheet on land behind it to flow faster into the ocean—like pulling the trench to deep down into it. Such a cliff—much bigger than at
a spatula away, allowing the batter to run. The ice flowed as much Jakobshavn or anywhere else on Earth—could break fast, making
as six to eight times quicker than it had been moving earlier. For- incredibly tall icebergs that would roll over and float away
tunately, there was not a lot of ice behind the Larsen B Ice Shelf in through the trench outlet to the ocean, raising sea level a lot.
KONRAD STEFFEN, CIRES AND UNIVERSITY OF COLORADO
the narrow Antarctic Peninsula, so it has raised sea level only a lit- Decades of additional research have established just how im-
tle. But the event put society on notice that ice shelves can disinte- portant this mechanism is. John Anderson, who recently retired
grate quickly, releasing the glaciers they had been holding back. after 43 years at Rice University, and many of his graduate stu-
Ice shelves can also be melted from below by warming seawater, dents tirelessly mapped the continental shelf under the ocean
as happened to Jakobshavn. around Antarctica, using side-scan sonar and other tools. During
When shelves are lost, icebergs calve directly from ice-sheet ice ages, Antarctic ice spread many miles farther in all directions
cliffs that face the sea. Although this delights passengers on cruise and withdrew as ice ages ended. The seafloor around Antarctica
ships in Alaska and elsewhere, it speeds up the ice sheet’s demise. today was the bed under the ice sheet in the past. Telltale imprints
At Jakobshavn today, the icebergs calve from a cliff that towers left in seafloor sediments give us accurate stories about ice sheets.
more than 300 feet above the ocean’s edge—a 30-story building— One story is that as expanding ice sheets push forward into the

sea, they drag sediment with them. The ice stabilizes when it a few decades even under fast warming before the collapse of
reaches a local high in the seafloor and then builds the seafloor Thwaites is triggered by loss of its shelf and meltwater widening
higher there by piling the sediment into raised moraine shoals— crevasses. Thwaites then would take a century or so to collapse
long, stony walls that grow where the ice ends. Ice can sit in such completely. They did not know how fast the ice could break,
a position for hundreds or thousands of years, rebuffing weak ef- though, so they set a top rate equal to what Jakobshavn had done
forts to dislodge it. But if enough warming occurs, the ice retreats in Greenland. (It has already exceeded that rate briefly.) And be-
back down the sloping bed into the valley behind the shoal. The cause Thwaites is thicker, it could make much higher cliffs than
ice rarely stabilizes again until it reaches the next high ridge, often Jakobshavn. Higher cliffs tend to break faster (one reason high-
far behind it. Meanwhile icebergs float over the abandoned mo- way engineers leave slopes rather than cliffs). So we could be un-
raine shoal, which is still below sea level, and out into the ocean. derestimating the worst-case scenario, but we really do not know.
This is now happening in many places around Antarctica and This is a good model, but it surely is not the last word from
Greenland. Jakobshavn Glacier has “jumped the bump” of a for- Pollard and DeConto or others. Some hope remains that Thwaites
mer moraine shoal and is retreating back through its valley- could stabilize on a deeper ridge on the downslope of the trench,
shaped fjord, “unzipping” a path into the greater ice sheet. When behind its current position, before retreating still more, for ex-
the first European explorers visited the area that is now Glacier ample. Or icebergs could break off and pile up for a while behind
Bay in Alaska, it was filled with a vast glacier ending on a large the current ridge where the ice now starts to float, helping to re-
moraine shoal. Since then, the ice has retreated from that ridge, or form a shelf that could lessen the ice loss.
bump, more than 60 miles inland to get to the next high ground, To address these and other questions, the National Science
which today is the current shoreline of the beautiful bay. Foundation and the British Antarctic Survey, together with other
Fortunately, most such retreats have only a limited effect on international collaborators, have launched a major effort to learn
global sea level. Even a big Glacier Bay–sized glacier is small com- even more about Thwaites’s history, how the glacier is flowing,
pared with the world ocean. Jakobshavn is just one of dozens of and what the seafloor surface is that it is flowing over, which will
major drainages around Greenland’s ice sheet, but they do not help all of us involved to better predict its future. The data are al-
quickly destabilize their neighbors in adjacent fjords, and they most guaranteed to reduce uncertainties and to be fascinating.
end not too far inland where the bed rises again. Similarly, Ant- Some questions may remain difficult to answer. Think of all
arctica is drained by a great number of glaciers flowing down into the ceramic coffee cups you have seen dropped on a hard floor.
their own waffle-iron valleys. With enough warming, many of Some bounce, some crack, some chip, some break into a million
them might retreat in unison, but each by itself is not a huge influ- pieces. The physical processes of these fractures are well known
ence on the global sea. and readily calculated, and the behavior averaged across many
The Bentley trench in West Antarctica and a few other deep re- dropped cups is predictable. But you would not want to bet your
gions in East Antarctica, including the Wilkes and Aurora basins, career, or anything else important, predicting the fate of the next
present a different story. Retreat through one of these to the next cup that hits the floor.
high ground would have global importance. Models point to The future of Thwaites depends a lot on fractures. Will the ice
Thwaites Glacier as the most likely path into the Bentley trench shelf fracture from the ice that now feeds it, causing the ice sheet
and connecting basins. If it started unzipping into the interior as to jump the bump and retreat into the deep basins? Will huge ice-
Jakobshavn has, the melting could potentially raise sea level 11 bergs break off rapidly if ice-shelf loss produces a cliff along the
feet before it stabilizes on high ground on the other side of the sheet’s face that is higher than any now on Earth, driving retreat
trench. The East Antarctic basins by themselves could raise sea faster than any we have seen? Meltwater is important, but how
level more than Thwaites would, but they require more warming much of the water will run off in rivers to the sea, and how much
to cause those glaciers to jump their bumps. will percolate into snow and refreeze? How fast will the air warm?
Note that there is nothing bizarre about this scenario. With I suspect that coffee cups are easy to predict in comparison.
sufficient warming, ice retreats, usually to the next high ground. If the world can muster the effort, slowing and stopping warm-
This has been observed over and over in the past and present. If ing from greenhouse gas emissions will slow sea-level rise, easing
Thwaites becomes warm enough to start acting like ice in Green- the mounting costs of coastal damage. But if Thwaites is poised to
land and Alaska, then it should retreat. retreat briskly, preventing warming by limiting the damage in-
curred by human activity could be vastly more valuable.
A FRACTURED FUTURE?
HOW FAST COULD THWAITES GO? How much warming can we cause
before it goes there? MORE TO EXPLORE
My colleagues David Pollard of Pennsylvania State University Oceanic Forcing of Ice-Sheet Retreat: West Antarctica and More. 2`Dàm
Î¨ÿĂ
and Robert M. DeConto of the University of Massachusetts Am- yïD¨ÎÁnnual Review of Earth and Planetary Sciences, <¹¨ÎñjÈDyå÷Ĉé÷ñÀè$DĂ÷ĈÀÎ
Contribution of Antarctica to Past and Future Sea-Level Rise. 2¹Uyàï$Îy¹´ï¹D´m
herst programmed an ice-flow model that uses the relevant phys- Dÿm0¹¨¨DàmŃature, <¹¨ÎñÀjÈDyåµÀµéè$Dà`ñÀj÷ĈÀêÎ
ics and can be run fast enough on advanced computers to study How Much, How Fast?: A Science Review and Outlook for Research on the
big changes in ice sheets over long times. I helped them a little Instability of Antarctica’s Thwaites Glacier in the 21st Century. 5ÎÎ3`D®U¹åyïD¨Î
with the physics of calving from high cliffs after ice shelves break ´Global and Planetary Change, <¹¨ÎÀñjÈDyåÀêñè ùý÷ĈÀéÎ
off, especially if surface meltwater wedges open crevasses. FROM OUR ARCHIVES
Pollard and DeConto optimized this model to match data from Witness to an Antarctic Meltdown. ¹ù¨Då¹āè ù¨Ă÷ĈÀ÷Î
the geologic past and to assess the impacts of different amounts of
human-caused warming. They determined that we probably have

CECILIA GUIDO patrols a stretch of the

Caquetá River in Colombia with her son,
Luis Eduardo Marin, and granddaughter,
Nayda Guido, as part of their community’s
x¸ßîäî¸Çß¸îx`îîxøßDßx"¸ä³§xäxä
Indigenous Reserve and the uncontacted
people who live there.

GUARDIANS
of the
TIGER
PEOPLE As anthropologists debate how best to
protect uncontacted tribes, indigenous
groups in Colombia are working
to shield their isolated neighbors
from the march of modernity
By Adam Piore
Photographs by Juan Arredondo

J
JHONATTAN ANDRES PEREA SQUINTS THROUGH Adam Piore is a freelance journalist. His last article
for I Y_[dj_ÒY7c[h_YWd examined the movement to
the blinding Amazonian sunlight into a wall bring evolution back to the classroom.
of jungle. He steers the tiny motor powering
his wood longboat through a tributary of
Colombia’s mighty Caquetá River and putters
up to a muddy bank. Hopping onto a barely 1
discernible path, the twentysomething
member of the Carijona tribe beckons five
others, including me, to follow. Then he
disappears into the green, amid a cacophony
of unseen birds, monkeys and insects. The
vegetation is so dense and the dark, musty path
so twisting that for a few moments, it seems
to those of us behind Perea that the jungle has
swallowed our young guide whole. Until we
emerge from the trees a few minutes later to
find him standing before a shimmering salt
lake. Perea is gazing intently into the distance.
“This is as far as we are allowed to go,” he says.
“There’s a swampland beyond this. According
to legend, that swampland divides us physically
and spiritually.” Then he points solemnly across
the lake. “That way,” he says. Somewhere out
modern Western world reached this remote area. The legends
there. “That is where they are.” tell of a clan of fierce warriors who painted stripes on their bod-
ies, pierced their noses and ate their enemies before fleeing
“They” are the mysterious tribespeople who reside as close as down a Caquetá tributary called the Bernardo River into the wil-
six miles from the invisible boundary that marks the beginning derness around the 19th century to escape the white man. The
of their territory here in the Curare–Los Ingleses Indigenous Carijona and the 14 other tribes that inhabit the lands that bor-
Reserve in southeastern Colombia. Unlike the Carijona and the der the territory of the uncontacted group regard their isolated
other tribes that live on the periphery of this territory, which neighbors with a mixture of awe and fear; they envy the purity of
extends into the neighboring Río Puré National Natural Park the tribe’s culture and believe its shamans to be so close to
and other areas, this enigmatic group has had virtually no expo- nature that they can control the elements.
sure to modern civilization. Indeed, it has actively sought to Nobody knows how many of these secluded people now re-
avoid any contact with the outside world. Its members survive side in this jungle sanctuary—estimates range from 50 to 500.
much as they have for millennia, naked in the jungle, hunting But encroachment by outsiders would threaten their way of life—
with poison-tipped arrows and blow darts, using stone axes to in fact, their very existence. Perea and his peers are working to
fell trees and bamboo knives to cut their food. prevent intrusion. I have come to Curare to see how they are
Some of Perea’s tribe call these men and women “our broth- helping their uncontacted neighbors maintain their solitude in
ers living in a natural state.” Other locals call them the “Tiger an increasingly connected world.
People.” (There are no tigers in South America, but the word Anthropologists, activists and government officials have long
tigre is sometimes used to refer to local jaguars.) It is a nick- debated how best to protect such uncontacted tribes in the
name passed down through the generations from a time before Amazon and elsewhere. Because they have been living in isola-
the missionaries, the rubber barons and all the trappings of the tion, they have little or no immunity to diseases common among
IN BRIEF
An estimated 100 tribes around the world live in Scholars and policy makers have long debated how Their work could pave the way for safeguarding
isolation. Contact with outsiders can be disastrous, to protect these uncontacted groups. In Colombia, perhaps as many as 17 other uncontacted tribes that
often exposing them to deadly pathogens. indigenous people are defending their neighbors. are thought to live in the Colombian Amazon.

LONGHOUSE, or maloca, in Curare serves as a gathering

Ç§D`x¸ßîx§¸`D§`¸ø³îxäî¸lä`øääx¸ßîäî¸Çß¸îx`î Living in Solitude
their isolated neighbors ( 2ÊÍ5¸äxx¸ßîä³`§ølxD³³³
several control posts strategically located along the border Deep in the Colombian Amazon, tribespeople have been found
of the protected lands (1). living in isolation from the outside world. Their territory encom-
passes part of the Curare–Los Ingleses Indigenous Reserve and
neighboring areas, including a large portion of the Río Puré
National Natural Park. Other tribes are working to
denizens of the industrial world. Encounters with outsiders—
protect the uncontacted group.
all of whom carry potentially deadly pathogens—could thus
wipe out these communities. Many experts contend that
keeping visitors away is the only way to safeguard them from Bogotá COLOMBIA
disease. Perhaps more important, many of these tribes are
aware of a larger world and have chosen to remain isolated.
“No contact,” in this view, is thus a matter of human rights.
Others counter that contact is inevitable and that preparing
the tribes for that eventuality is the most prudent course of COLOMBIA
action. The march of modernity stops for no one. And with-
out regular contact, it is impossible to protect the tribes from Ca
qu
armed, evil actors who covet virgin timber, gold and other áR Curare-Los Ingleses
et
iver
natural resources often hidden in their lands. Indigenous Reserve
In 2012 Perea’s tribe and the other communities of Curare,
ECUADOR
along with groups in other nearby areas, launched an aggres-
sive effort to patrol the borders and protect the lands of their Río Puré National
ona Natural Park Puerto Franco
uncontacted counterparts from incursions of loggers, hunters,
gold miners, missionaries, smugglers, drug dealers and com-
munist insurgents. Recently their mission has taken on added PERU BRAZIL
urgency. For decades Colombia’s civil war stalled development
in the Amazon, and the presence of insurgent camps, right-
Map by Mapping Specialists February 2019, ScientificAmerican.com 49

wing paramilitaries and drug labs hidden 1

within its jungles rendered them too dan-
gerous to many of the forces most likely to
try and exploit them. In November 2016,
however, the government and the insur-
gents signed a peace accord. Stability
could bring economic boom times—and,
many fear, the kinds of development pres-
sures that have jeopardized efforts to pro-
tect isolated tribes in neighboring coun-
tries. The peace accords have also spawned
an array of more immediate perils in the
form of new splinter groups and hard-line
rebel holdovers that are looking to set up
novel routes through the vast unexplored
interior and fund their efforts with clan-
destine drug facilities and illegal mining.
Now the race is on to implement a na-
tionwide policy hammered out among
nongovernmental organizations (NGOs),
Colombia’s indigenous leaders and its
Ministry of Interior and signed by the na-
tion’s outgoing president Juan Manuel
Santos and his cabinet ministers last
summer. The new protocols guarantee the rights of isolated tion that would later be visited on other native peoples across
peoples to self-determination and spell out the procedures for the rest of the Amazon. Lacking immunity to many modern dis-
defending these rights for new groups identified across the eases, many villages have lost 50 to 90 percent of their popula-
country. Although the Tiger People are the only uncontacted tions in the wake of contact. The survivors have often ended up
tribe whose presence has so far been confirmed, evidence sug- in squalid jungle settlements or on the streets, alienated from
gests that as many as 17 other tribes may be living in isolation traditions and community, living as alcoholics or prostitutes and
elsewhere in the Colombian Amazon. losing any semblance of self-sufficiency.
As international NGOs gather the proof they need to demon- In the early 1960s a pair of famed sertanistas, the brothers
strate the presence of new tribes deserving of federal protec- Cláudio and Orlando Villas-Bôas, succeeded in leading efforts to
tion, the efforts of Perea and others in Curare are serving as an create a vast reserve, known as the Xingu National Park, the first
important model that is showing doubters that such security is in a mosaic of closed sanctuaries where indigenous peoples
even possible. could, in theory, live unmolested. Xingu would become a model
for other such indigenous reserves across the Amazon, includ-
THE NGO SURVIVAL INTERNATIONAL estimates there are more than ing Curare. Even so, in the years that followed, first contacts
100 uncontacted tribes around the world, groups it defines as often continued to prove calamitous, with disease devastating
“tribal peoples who have no peaceful contact with anyone in the tribes even before relocation could be considered. Colombia saw
mainstream or dominant society.” In Colombia, as in the rest of its own share of tragic tales, perhaps most famously that of the
the Amazon, most live in isolation by choice. Many originally Nukak-Maku, a hunter-gatherer tribe that was ravaged by dis-
fled the colonists of the 18th to early 20th centuries, rubber bar- ease after official contact was established in 1988 and is fighting
ons who brutalized and enslaved indigenous workers and mis- extinction today.
sionaries who attempted to “civilize” and convert natives by for- In Brazil, by the 1980s, the ill effects of contact had come to
bidding the practice of long-held traditions. seem so inevitable that some sertanistas, led by a dynamic Vil-
More recent “first contacts” have proved catastrophic in oth- las-Bôas protégé named Sydney Possuelo, had begun to equate
er ways. The most common contacts in recent decades have oc- contact with genocide and to advocate for a radical strategy. In
curred across Colombia’s border in Brazil, home to the largest 1988 Possuelo won support for a new “no contact” approach:
tracts of virgin rain forest. Throughout the 20th century, the mapping indigenous lands and keeping out loggers, miners and
Brazilian government sought to open up the region, sending a other interlopers—and thus, many believe, saving countless
core of explorers into the wilderness to establish small airstrip lives. Brazil’s no-contact policy has since remained the standard
outposts in the jungle and later cutting new roads, allowing civ- for how to approach indigenous rights in nations across the
ilization to creep ever deeper into the interior. To contact the region, favored by indigenous groups and NGOs alike. It was
tribes living there, first the nation’s Indian Protection Service used as a model by Peru and officially incorporated into its
and later the National Indian Foundation (FUNAI) sent scouts national policy in 2006.
known as sertanistas ahead of the explorers, with the mission of Even so, ever since, the hands-off approach has been under
luring natives out and assimilating them into society. virtually constant attack from would-be colonists and powerful
Those initial encounters provided a catalog of the devasta- mining, ranching and timber interests, who have long sought

SHAMANS Moises Nilmore Yakuna (red

2
shirt) and Alfonso Matapí (blue striped shirt)
join the annual meeting of the Curare
communities to review their protection
plans for the uncontacted tribespeople (1).
Daniel Aristizabal of the Amazon Conser-
vation Team (center) and members of the
Río Puré National Natural Park team work
on the meeting minutes ( 2).
al, the organization that has been perhaps

the most vocal critic of Hill’s and Walker’s
argument. “When you look at cases where
tribes have been contacted recently, it’s
not making their life any better. In fact,
you could argue it’s making it worse. Now
they are surrounded; their lands are be-
ing invaded; they’re much more exposed
to disease.”
Many of Hill’s colleagues, meanwhile, re-
main torn. Stephen Beckerman, a cultural
anthropologist at Pennsylvania State Uni-
versity, notes that “everyone can agree that
access to protected lands—sometimes with success. In 2006 Pos- the most important thing is to keep them alive.” But he says no ex-
suelo was fired from his post after criticizing the head of FUNAI isting approach is ideal. “Every cell in my body emotionally
for stating publicly that native peoples had too much land. screams, ‘Leave them the hell alone!’ ” says Beckerman, whose
More recently, some anthropologists have begun to suggest fieldwork focuses on the Barí tribe of Venezuela and Colombia and
that the no-contact policy is ill conceived in the face of ruthless the Waorani of Ecuador. “And every day of experience I have had in
groups that operate outside of the law in the jungle. In a contro- the tropical forest working there, reading about it, talking to other
versial editorial published in 2015 in Science, Robert S. Walker of people who have worked there, says, ‘That’s not going to happen.’ ”
the University of Missouri and Kim R. Hill of Arizona State Uni-
versity argued that miners, loggers and hunters routinely pene- FOR A FIRST-TIME VISITOR, the trip to Curare can seem like a journey
trate into protected territories, exposing the tribespeople there to the end of the earth. To get there, I caught a plane to Bogotá,
to deadly pathogens and committing atrocities with virtual where I met Daniel Aristizabal, a skinny thirtysomething Colom-
impunity. The safest, most humane approach to safeguarding bian with a dark ponytail, a worn, white T-shirt and faded cargo
isolated tribes, in their view, was “controlled contact.” pants. Aristizabal works for the Amazon Conservation Team
Hill says the essay was the culmination of decades of work in (ACT), an American NGO. Together we flew to Leticia in Colom-
the field and repeated encounters with tribes that spoke of star- bia’s extreme south, then boarded a beat-up World War II–
vation, brutality and an unsettled life on the run. He spoke out, era cargo plane bound for the remote frontier town of La Pedre-
he says, because these stories long ago burst his early idealism, ra, a dusty outpost deep in the Amazon built around an airstrip.
and he is convinced that the epidemiological challenges can be Cruising at 15,000 feet and surrounded by pallets of eggs,
managed with better planning. “All of the isolated tribes in the powdered milk and sacks of flour, I gazed through a small
world are pretty much under the control of pathetically inept window. Below, hundreds of miles of thick primary jungle un-
and corrupt Third World governments that are doing a piss- folded, broken only by the many long, powerful tributaries of
poor job of protecting them,” he explains. “So that protection is the Amazon River curling through the green in an endless suc-
really an illusion. By keeping the tribes away from transparent cession of brown curves. I did not see a single settlement the
information collecting, we have no idea what’s really happening entire 200-mile trip. In La Pedrera we stepped onto a rickety,
to them. And I think all kinds of horrific things are happening wood longboat and headed upriver. Five hours later—four full
and stay hidden, specifically because we can’t talk to them and days after setting out from New York City—I finally arrived at
ask them what’s going on.” my destination.
Despite Hill’s stated intentions, the Science editorial sparked The people here live in jungle settlements along the river
widespread outrage from indigenous-rights groups, NGOs and with no running water or electricity aside from a few rarely used
others, prompting angry letters—even death threats. (Walker generators. They obtain most of their food through hunting,
declined to comment for this article, saying he no longer speaks fishing and the cultivation of traditional crops. There are no
publicly about the issue.) roads, just jungle paths and dugout canoes. La Pedrera is the
“Even if you could [make] safe, controlled contact, which I nearest town, with a hotel and restaurant. The tribespeople like
don’t think you can, what then happens?” demands Fiona Wat- to say they are poor in money and material possessions but rich
son, director of advocacy and research for Survival Internation- in land and natural resources.

Yet as remote as Curare is, life here in the borderland is none- engine Cessna. On the first day they spotted a longhouse sur-
theless shot through with elements of modernity. Many of the rounded by fruit trees—and snapped photographs of an indige-
children attend a boarding school across the river from La Pedre- nous tribeswoman, her face and body painted, who could clear-
ra that was run by Catholic priests until last year, when the gov- ly be seen gazing up at the plane. The footage, along with the
ernment took it over. Tribespeople regularly travel to La Pedrera identification of four other malocas, was enough to get the gov-
for modern health care and to more distant cities such as Leticia ernment and the nation’s indigenous groups to agree to begin
and even Bogotá when they have a serious illness or a broken the process of hammering out protections for the nation’s isolat-
bone. Many wear modern clothing and use machetes, flashlights ed peoples.
and steel pots purchased in towns such as La Pedrera and have In 2014 Franco was flying home from another community
been exposed to television. It is a testament to the determination farther north when his aircraft went down, killing all 10 people
of the uncontacted tribespeople and their self-appointed guard- onboard—including Daniel Matapí, another ACT staff member.
ians that these influences have not reached the interior. It was a devastating blow for ACT and for Aristizabal, then a
The indigenous people in Curare and Río Puré have known young Ministry of Interior official, whose graduate thesis
for generations of the presence of their mysterious brethren in focused on preserving the privacy of isolated tribes. Aristizabal
the interior, believed by scholars to be members of two related had been closely collaborating with Franco to develop new laws
tribes called the Yuri and Passé. But it was the arrival of a Colom- to that end. After Franco’s untimely death, Aristizabal agreed to
bian environmentalist named Roberto Franco and ACT in the join ACT and continue his legacy.
early 2000s that would thrust them into the center of Colom-
bia’s dialogue over how to defend its most isolated peoples. A CENTRAL TENET of that legacy has been partnering with the
Franco, the author of numerous books on the history of the indigenous groups in Curare to support their protection efforts.
Amazon, was for years one of the leading Colombian proponents While I was in Curare, the communities were holding their an-
of the idea that the best way to protect the rain forests was to nual meeting to review those efforts and plan for the year ahead.
uphold the land rights of the nation’s indigenous tribes, whose Aristizabal and I made our way to an enormous maloca with a
cultures were based on living in harmony with their surround- 30-foot-high thatched-palm roof to join them.
ings. He had also worked as an anthropological consultant to Once inside, Aristizabal and I were greeted like old friends.
government agencies, had seen the ravages of first contact first- In the center of the structure, eight male community elders
hand and had come to believe that “self-isolation” was a human- dressed in soccer shirts and T-shirts were clustered together on
rights issue. Intent on finding a way to shield the nation’s most their ritual wood benches. As they chatted and laughed, they
vulnerable groups, Franco began collecting
scraps of information about isolated peoples
during his expeditions through the Amazon
in the 1980s. He scoured the historical litera-
e t n er in an rain
ture for clues, pored over maps and conduct-
ed interviews—even meeting with former
ere a me a e fr m t e i er
rebel commanders and drug traffickers who
had come across uncontacted tribespeople in
e e a in ea e a ne
their travels through the bush. —Alfonso Matapí, shaman
To win official government protection, how-
ever, Franco needed concrete proof of the ex-
istence of these tribes. In 2007 ACT agreed to support his efforts passed around tall, cylindrical Tupperware containers of mam-
to get it. By then Franco had already decided that Curare and be, a mixture of coca leaves and ash, copious amounts of which
Río Puré were the most promising places to start. In the late they shoveled into the space between their lips and gums with
1960s a rubber tapper and fur trader named Julian Gil came metal spoons. Around them, children chased one another, trip-
across a well-worn path deep in the jungle, far from any settle- ping and laughing, as their parents watched from long planks
ment, and followed it to a vast longhouse, or maloca, where he arrayed between the pillars holding up the structure. Others
discovered scores of tribesmen in the middle of a celebration. reclined in hammocks slung to the far walls.
They wore nothing but tiny pouches covering their privates and Over the next three nights, various tribal figures would step
sticks as thick as pencils through piercings in their ears and nos- across the hard-packed earth to the front of the maloca to deliv-
es. They had painted their bodies in stripes. But the tribe wanted er reports on a wide range of activities, conducted over the pre-
nothing to do with the visitors, and the meeting turned violent, vious year, aimed at securing the reserve and its inhabitants.
resulting in the disappearance of Gil and the deaths of a number The proceedings were unhurried and deliberate, offering ample
of tribesmen. The Colombian military took several tribe mem- opportunity to reflect on the challenges facing both the uncon-
bers prisoner, prompting a worldwide outcry. The military subse- tacted peoples and their guardians.
quently freed the prisoners and vowed to leave the tribe in peace. Some participants spoke about preserving the cultural tradi-
These people are believed to have been members of the Yuri tions of the tribes that do have contact with the world beyond.
and Passé tribes, groups that began fleeing white slavers hun- One young tribesman described his efforts to make story books
dreds of years ago, settled in the area and were thought to have for the smallest children detailing the traditional legends that
gone extinct. But in 2010 Franco and a small crew flew over the would help explain the importance of the protection of sacred
most likely habitation zones in Curare and Río Puré in a single- places and the reserve management plan. “As you know, the sto-

MEMBERS of the indigenous communities in and around the

øßDßxßxäxßþxUD§D³`xîxßÇß¸îx`î¸³x¸ßîäÿîîxîDä¦ä
¸xþxßālDā§xiîx³l³`¸¸¦³ßxäÉ1), making cassava meal ( 2)
and preparing mambe, a mixture of coca leaves and ash (3).
ries of the elders are very, very long. For example, the origins of From the east, illegal gold-mining barges, crossing in from
animals and the origin of crops,” he noted. “So we listened to all Brazil, are a constant concern. Drug traffickers and bandits,
the stories, and part of the challenge was to summarize them.” meanwhile, have made intermittent appearances in some areas
The report was followed by a chorus of low, deep-throated mm- of Curare itself—and some fear their presence might actually
hmms from the elders and the rest of the maloca, a traditional increase as the insurgent demobilization progresses. In 2016
way of showing their appreciation or support for a point. members of a dissident faction of the Revolutionary Armed
Other speakers raised the issue of sustainability of the re- Forces of Colombia (FARC), unhappy with the peace accords,
serve’s flora and fauna. When a tribal elder reported on the re- entered the reserve. Toting their weapons and slogans, they
sults of an investigation into the illegal killing of a pregnant convinced the teenage son of a Curare community elder to run
tapir in an area where the tribe had restricted hunting, an angry away with them.
debate broke out over how large a fine or how much volunteer To monitor these threats and help respond to them, ACT
work to impose on the guilty parties as a penalty. staffers supplement the tribal on-the-ground patrols with mod-
Eventually the topic turned to the battle to keep interlopers ern technology. From offices in Bogotá and Virginia, ACT staff-
out of the reserve. Even without development, the threats to the ers comb through reams of satellite imagery, searching for signs
location and the isolated tribespeople that live there are many. In of illegal barges and deforestation while looking for isolated
2015, before the peace accords, Colombian authorities intercept- tribal dwellings. (The images are provided free of charge by U.S.
ed two American evangelical missionaries south of Río Puré who commercial satellite provider DigitalGlobe, and the quality and
were attempting to contact and convert the isolated tribes to resolution improve by the year: it is now at 30 centimeters, clear
Christianity, seemingly indifferent to the danger that contact enough to examine a banana leaf from space.)
might pose to their targets—and to themselves. ACT staffers also confer regularly with partners in the Na-

tional Natural Parks of Colombia, take re-

ports from neighbors who border the in-
digenous lands and, when necessary, call
on allies in the Ministry of Interior and
Ministry of National Defense to act as
their muscle. It was the Ministry of Interi-
or that issued a formal warning to the
American missionaries, who were de-
terred the following year. Previously, the
Colombian military conducted flyovers at
the border to scare away would-be pros-
pectors in Brazil. And in 2017 the military
bombed a pair of illegal mining barges to
the north, after ACT notified them of the
presence upriver.
But the heart of protection plans re-
mains the efforts of the indigenous com-
munities themselves to police their lands,
provide eyes on the ground and, when
possible, shield their vulnerable neighbors
from outsiders. In 2012 the communities
incorporated the untouchable zone into a
detailed reserve management plan and es-
tablished two ACT-funded “control posts”—
three others are run by the National Natu-
ral Parks of Colombia and are placed at
strategically located bends in the river on
the border of the protected territories. The
locals and the park rangers are not armed
during these patrols. Instead they rely on
human connection, politely explaining the
protected zone, refusing bribes and then
retreating if they sense any danger. Often
this simple approach is enough. For now,
there are plenty of other places to mine
and fish. But the danger of violence is al-
ways a concern.
The recent missionary incursion is
an indication of a key liability. With lim-
ited funding, the guards are stretched
thin, leaving parts of the borderland vul-
nerable to penetration by stealthy inter- CHILDREN from the indigenous community of Borikada in Curare play on jungle vines.
lopers. At the meeting tribesmen com-
plained that the loss of support from
another NGO had forced them to reduce the number of guards ses Nilmore Yakuna, age 55, removed a small pouch from around
at the post. his neck. He shook out a fine, black powder into his palm and
Perhaps the most vulnerable control post is in on the south- explained how he uses the powerful snuff, made from tobacco
ern end of the isolated peoples’ territories, just across the border and other ingredients from the jungle, to “open up” his mind
from Brazil, where illegal gold-mining barges proliferate. The and reach the tribespeople using his thoughts. By performing
post, known as Puerto Franco, is so remote, the situation so dan- traditional rituals, including dances, he and the other tribal sha-
gerous, that guards are required to make radio contact several mans have built a protective wall with the spirits to keep miners,
times a day and are taught to use code words to convey if they loggers and drug traffickers out of the forbidden territories.
are in trouble. In case of an attack from gold miners, ACT has “Through our spiritual work with our thoughts, we give them
built an emergency shelter with supplies and a spare radio in a space, so they can live in peace,” he told me.
secret location nearby. It is a job that is so important the locals have brought in out-
For the tribespeople themselves, an essential element is the side help. They did so in 2016, a few months after Franco’s death,
involvement of their shamans, their spiritual guides and the when a guard at one of the control posts mysteriously fell ill and
keepers of traditional tribal knowledge. Sitting on a bench in died. That incident, along with a series of unexplained thunder-
the longhouse one afternoon during my visit, local shaman Moi- storms on otherwise sunny days, prompted the elders to send

for a shaman from a community three days upriver in a neigh- the land rights and protections conferred on isolated tribes as con-
boring national park. firmation of their existence moves from suspected to confirmed.
The shaman, Alfonso Matapí, age 78, says that when he arrived, The document also requires contingency planning in case of first
he quickly realized that the locals were out of sync with the nat- contact and creates a national committee for coordination that
ural elements of the jungle and had angered the far more power- would include indigenous leaders and representatives from the
ful medicine men of the Tiger People. Franco’s plane, he opines, national land agency treasury, ministries of environment, health
“came down not because of a malfunction but because the tribes and interior, and armed services, among others.
didn’t want the flights. There were many flights. And they made For his part, Aristizabal is under no illusions as to the size of
his plane crash.” (The others onboard were innocent victims.) the challenges that he faces. If anyone needed a reminder, cer-
The guard perished because he entered forbidden lands near the tain events of late have provided plenty. Recently a dissident
sacred salt lake; the animals that rely on the lake fought back. FARC faction was back in the area. One group found the wife of
“The thunder, wind and rain were [a message from the Tiger a prominent local leader and village elder whom I met during
People] saying, ‘Leave us alone,’ ” Matapí explains. “So I try to my visit and threatened to kill him and his family if he did not
send them thoughts saying, ‘Don’t worry, we’re going to leave stop speaking out about indigenous land rights. Yet Aristizabal
you alone. Don’t worry, we’re not going to bother you.’ ” remains firm in his belief that shielding isolated tribes from con-
tact is the best thing to do. “Of course, it is very difficult to pro-
IT IS POSSIBLE, of course, that the isolated tribes will initiate con- tect someone from contact forever,” he says. “But that doesn’t
tact with their neighbors in the borderland. To help prepare mean that we shouldn’t respect their desire to avoid contact.
the residents of Curare for such an event, ACT and community Why should we make the decision for them?”
members have consulted with groups and individuals who In recent months ACT has continued to try to gather the proof
have experience with uncontacted tribes. Among them is Luis it needs to expand its efforts to other tribes. Not long ago it had a
potential breakthrough in the region up the
Caquetá where Franco perished. For five years
Ùîäþxßāl`ø§îî¸Çß¸îx`î
ACT members had been combing through
high-resolution photographs, searching for
evidence of the isolated, indigenous communi-
me ne fr m c ntact f re er ty believed to live in Chiribiquete National
t t at e n t mean t at e Park. One day in January 2017 Brian Hettler, a

staffer at ACT’s Virginia office, received some
n t re ect t eir e ire of the clearest photographs he had ever seen of

the area, which was often obscured by clouds.
t a i c ntact That day, the ubiquitous clouds had mirac-
ulously lifted, revealing tabletop mountains
—Daniel Aristizabal, studded with emerald green triple-canopy
Amazon Conservation Team jungle and rugged cliffs that are home to some
of the greatest concentrations of pre-Colum-
bian cave paintings in the world. It did not
Felipe Torres, an anthropologist, who led a Ministry of Culture take long for Hettler to spot a patch of white in the impenetrable
team in Peru from 2012 to 2017 that oversaw a high-profile case wall of green and, within it, what appeared to be the telltale faded-
of contact. brown color of a man-made dried-thatch roof.
In recent years different bands consisting of several mem- Hettler believes he has found evidence of another isolated set-
bers of the Mashco Piro tribe began to emerge with increasing tlement. ACT is already at work with the other indigenous tribes
frequency from the jungles in the Madre de Dios region of south- that live in the area to develop protection plans. Now that the
ern Peru and attempt to trade with the locals. Their contacts Colombian government has embraced the ACT vision, if the pres-
have continued intermittently ever since. Though mostly peace- ence of the tribe is further confirmed, perhaps it will be possible to
ful, misunderstandings have resulted in the deaths of at least help that tribe continue living in its present state. Perhaps there,
two villagers in 2011 and 2015—they were both shot with too, for a time the relentless tide of modernity can be held at bay.
arrows—which prompted the government to send in Torres and
his team to manage the situation.
MORE TO EXPLORE
Often, Torres notes, the emerging isolated peoples are eager
to exchange goods and food and may misinterpret the efforts of Colombian Government Approves Decree for the Protection of Isolated Indigenous
Groups. Amazon Conservation Team. Published online July 18, 2018. a a on
the locals to shield them from potentially contaminated items as tea org colo ian-govern ent-a roves-ground reaking-co unit -led-
a hostile gesture. That is likely what led to the two deaths in national- u lic- olic - or-t e- rotection-o -isolated-indigenous-grou s
Peru. Torres has helped Aristizabal arrange mutual visits be-
FROM OUR ARCHIVES
tween those living in Madre de Dios and the locals in Curare so
Prime Directive for the Last Americans. Claudio Angelo; Insights, May 2007.
that the Colombians can learn from their counterparts. The American Killed by Asian Islanders Hoped to Save Their Souls. Madhusree
Colombia’s new policy on isolated tribes assigns responsibili- $
ù§yà¦yyè'UåyàÿDï¹´åj3`y´ï`®yà`D´Î`¹®j%¹ÿy®Uyà÷êj÷ĈÀ~Î
ties to a wide array of government agencies once the presence of a
previously unknown isolated tribe is suspected. And it increases

A A S
THE EXOPLANET
What Venus can teach us about planets
far beyond our own solar system
By M. Darby Dyar, Suzanne E. Smrekar and Stephen R. Kane

NEXT DOOR
A A A A fr m t e a e an
acecraft a e t create t i
c m ter enerate ie f en
at na r na an ai a ma

M. Darby Dyar is a mineral spectroscopist who studies extraterrestrial

minerals and glasses from the moon, Mars, comets and asteroids.
She is a senior scientist at the Planetary Science Institute and Kennedy-
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Suzanne E. Smrekar ÒÜæfrÒÜrf|rÍr§Ürè«æÜ«§DÍëµDÜÒ

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of the InSight Mission at NASA’s Jet Propulsion Laboratory,
where the mountain biking is awesome.
Stephen R. Kane is a planetary astrophysicist who has

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N 1982 ALL ANYONE COULD TALK ABOUT IN THE PLANETARY SCIENCE DEPARTMENT AT THE
Massachusetts Institute of Technology was the cancellation of NASA’s latest flagship mis-
sion, the Venus Orbital Imaging Radar (VOIR). One of us (Dyar) was a graduate student
there at the time. (The other two were still in college and elementary school.) Graduate
students wept openly in the hallways, and veteran faculty shook their heads. The newly
elected Reagan administration had enacted sweeping cuts to space exploration, and VOIR
was one of the casualties.
Shortly afterward, though, scientists cobbled to- main the foundation of Venus geoscience to this day.
gether plans for a bargain-priced spacecraft ($680 But planetary scientists never give up, and we have
million) made of leftover hardware and, miraculously, made progress in uncovering the secrets of this world
saved the mission. In 1989 the Magellan orbiter launched nonetheless. Since Magellan, the European and Japa-
on a reconnaissance mission to Venus, and by 1990 it nese space agencies have sent successful missions to
was in orbit. Over the next five years the orbiter Venus, leading to breakthroughs in understanding its
returned near-global radar images, gravity data and a atmosphere. Meanwhile scientists have been busy
topographic map of the second planet from the sun. It rewriting the textbooks on our sister planet by per-
was the latest in a long line of Soviet and U.S. missions forming new analyses of Magellan data. We now think
to our neighboring planet, but when Magellan that volcanoes are rampant on Venus, and we have
plunged to Venus’s surface in 1994, NASA’s support for even found hints of the start of plate tectonics, which
Venus spacecraft died with it. Since then, scientists scientists think is critical for a planet’s habitability.
have submitted more than 25 proposals for return New theoretical models also suggest Venus may have
missions to Venus, and although some of those had liquid water on its surface until relatively late in
received high rankings from review boards, none were its history—meaning that it may have been hospitable
approved. Decades-old data gathered by Magellan re- to life much longer than we once thought.
PRECEDING PAGES: NASA AND JPL
IN BRIEF
Venus and Earth started out much the same, Venus’s surface, meanwhile, became inhospitable Learning why Venus evolved the way it did could illu-
but at some point, the planets diverged. Earth to life. Yet our neighboring planet still has active minate the possibilities for life on the many Venus-like
went on to host oceans and an atmosphere. volcanism and hints of nascent plate tectonics. exoplanets out there. A new mission to Venus is needed.

All of this coincides with another stunning devel- stars for telltale brightness fluctuations that occur as VENUS’S
opment in astronomy: the discovery of thousands of orbiting worlds pass in front of them. With this tech- ATMOSPHERE,
exoplanets in other solar systems, many of them nique, we can measure a distant planet’s size, but size as seen in
roughly the same size and distance from their stars as tells us only so much. After all, if an extraterrestrial this composite
Venus. Anything we learn about the planet next door observer were to look at our solar system using the image from
could teach us about these distant, inaccessible worlds. transit method, Venus and Earth would appear almost data taken by
In particular, if we can figure out whether and when identical. Yet Venus is forbidding to life, whereas Japan’s Akatsuki
Venus may have had the conditions to host life, we will Earth has been continually habitable for the past four spacecraft,
JAXA, ISAS, DARTS AND DAMIA BOUIC
know more about the likelihood of finding living billion years. contains thick
beings on the plethora of Venus-like bodies through- We can further differentiate between similarly sized clouds of
out the Milky Way. planets by measuring their distances from their stars. sulfuric acid.
The “habitable zone” is the region around a star where
A A A a rocky planet could have liquid water on its surface.
MOST OF THE EXOPLANETS discovered so far were found Earth, obviously, is in this zone. Venus, we think, used
using the transit method, in which astronomers watch to be in this zone—for quite a while, in fact. Yet the

boundaries of the habitable zone move outward with water by dissociating it into hydrogen and oxygen ions
time as the sun’s luminosity increases with age. Venus and carrying them off into space. Without surface
is now outside this range and occupies what we call water to dissolve the carbon dioxide and other gases
the “Venus zone,” where surface conditions are so hot constantly escaping from the interior, these chemicals
that a planet is likely to have a runaway greenhouse accumulated in the atmosphere. Because of the green-
atmosphere that would boil its oceans away. house effect of this atmosphere, surface temperatures
Venus and Earth formed under very similar condi- on Venus are nearly 800 degrees Fahrenheit higher
tions—including those that gave Earth its oceans. than on Earth—hot enough to make rocks glow.
Comet impacts probably brought ice to the surface of The only data we have from the surface of Venus
both planets. The solar wind (charged particles gush- were collected by the four Soviet Venera landers that
ing off the sun) most likely implanted a thin layer of touched down in the 1970s and 1980s. These probes
hydrogen ions on the surfaces of both. And when survived for only a few minutes on the planet’s brutal
Venus and Earth were protoplanets building up from surface, but in that brief time they gathered and sent
the primordial dust disk that circled the sun, both col- back rough measurements of the chemical composi-
lected hydrogen and other volatiles, chemicals that tion there. Beyond those readings, our knowledge of
the surface mineralogy rests solely on controversial
interpretations of radar measurements made by
We have never had Magellan and our limited knowledge of probable

chemical reactions between the planet’s rocks and
atmospheric gases under Venusian conditions.
better reasons to Recently, though, researchers found that it is pos-

sible to map the minerals on Venus from orbit by
send a new major looking through several “windows” in the electromag-

netic spectrum where visible light escapes absorption
by carbon dioxide in the atmosphere. Serendipitously,
mission to the oft- these windows coincide with critical regions for iden-
tifying the typical planetary minerals olivine and
ignored second pyroxene, offering hope that we could finally deter-

mine the basic ingredients of Venus. Europe’s Venus
Express spacecraft, which orbited Venus from 2006 to
planet from the sun. 2014, used one of these windows to produce the first
map of heat radiating from the planet’s surface over
much of the southern hemisphere. This map includes
spectral features—peaks and dips in light and heat—
can easily boil away. Simulations of early Venus show that can identify minerals on the ground.
that the planet’s surface may have had liquid water The map also identifies many hotspots—areas emit-
earlier than Earth and that water might have been ting so much heat that the most likely explanation is
there until about a billion years ago. recent volcanism. This is an exciting find because it
The fact remains, though, that Venus is now for- shows that unlike the moon, which has long been
biddingly inhospitable. What happened? Does Venus silent, and Mars, where modern volcanism has been
represent the end state for all habitable planets, or is isolated at best, Venus is still active—and that discov-
it merely one of many ways that planets of this size ery has implications for the planet’s suitability for life.
can turn out? These are some of the major questions
we want to go back to Venus to answer. A S
ON EARTH, volcanism is usually associated with plate
S S A tectonics—the shifting and sliding of large pieces of
OUR KNOWLEDGE OF VENUS is limited in part by the crust responsible for most of the geologic features on
immense difficulty of seeing through the planet’s our planet. Plate tectonics is also behind the long-
thick, noxious atmosphere. High up, clouds of sulfuric term climate cycles, occurring over periods of around
acid shroud the world. On the ground, the air pres- 100 million years, that enabled life to arise on Earth.
sure is comparable to the water pressure 3,000 feet Plate tectonics formed new crust at Earth’s mid-ocean
below the surface of Earth’s oceans. The atmosphere ridges and allowed layers of its crust to sink into the
there is so dense that its main constituent, carbon mantle—two processes that enabled our planet to lose
dioxide, acts as a supercritical fluid, with properties its internal heat and cool to a point where life could
midway between a gas and a liquid. arise. Tectonics also released volatile chemicals such
Scientists think this atmosphere was once Earth- as water, carbon dioxide and sulfur dioxide from deep
like. Unlike our world, though, Venus now lacks a within Earth out into the atmosphere and cycled vola-
magnetic field to repel the solar wind. We think that tiles back into the mantle when plates slipped under-
over the eons, the solar wind eliminated the planet’s neath other plates.

Planetary Comparisons
at ma e a anet a ita e This is one of the biggest plate tectonics and other conditions on Venus, scientists hope
questions in astronomy. Earth and Venus started out quite to understand why the planet evolved as it did and whether it
similar, but one is now a bastion of life and the other an inhos- can teach us about the prospects for life on the many Venus-
pitable wasteland. By studying the development of volcanism, like exoplanets throughout the Milky Way.
Mercur enus Eart Mars VOLCANIC/

Planet formation TECTONIC ACTIVITY
Volcanism and the related process of
Period of shifting planetary plates called plate
heavy cratering tectonics play a large role in the
habitability of Earth. They help sus-
4 billion years ago
tain our planet’s atmosphere and
Low levels of oceans and provide the continents
cratering continue needed to support life. Venus is the
only other inner planet with signs
of both phenomena today.
LIQUID SURFACE
WATER PRESENT
3 billion years ago
Water, the key ingredient for life,
was present inside the building
blocks of planets and was re-
leased to the surface via volcan-
ism, with lesser contributions
from cometary impacts. Aside
from Earth, Venus most likely
held onto its oceans the longest.
2 billion years ago
CONDITIONS
FAVORABLE TO
DNA-BASED LIFE
Scientists can only speculate on
when and how long each planet
had the necessary ingredients
1 billion years ago to host life. But researchers have
reason to believe Venus became
a habitable world before Earth and
spent more than a billion years
with the conditions needed for life.
Today
HABITABLE ZONE
This region is the area around a star
where planets could sustain liquid
water and thus potential life.
Because the sun has grown more
luminous over time, the boundaries
Sun of the habitable zone in the solar
system have shifted outward.
Habitable Zone
1 billion years ago
Sun and planets
not drawn to scale Astronomical units: 0.5 1.0 1.5 Today
Graphic by Tiffany Farrant-Gonzalez February 2019, ScientificAmerican.com 61

Without volcanism, there would be little surface

water and no place for the origins of life. This cycling
of volatiles helps to sustain Earth’s atmosphere, which
was crucial for the emergence of life. Similarly, conti-
nents, which provide a buoyant, stable platform above
sea level for marine life to evolve onto land, are a
product of plate tectonics. For these and many other
reasons, understanding whether Venus has plate tec-
tonics—and why or why not—is key.
On Earth, limited data suggest that plate tectonics
began as early as four billion years ago, leaving little
record. We do not really know how a planet transitions
from a basalt-covered world, possibly with oceans, to
an intricate system of moving plates with complex
features. One leading hypothesis is that blobs of mate-
rial from deep inside Earth called plumes burst onto
the surface, initiating subduction—the act of one
plate sliding under another. The hot plume weakens
the lithosphere (which includes the crust and upper
mantle) and pushes up, causing the surface to crack,
or “rift.” Pressure from the plume head can create vio-
lent volcanism, as observed on both Earth and Venus.
The load on the cracked lithosphere can cause this
layer to sink and prompt subduction, whereby one
layer of the lithosphere slides under another. If this
process happens often enough, the subducting plates
link up, and plate tectonics begins.
This may be happening on present-day Venus. The
lithosphere on Venus now is warm and thin—much
like Earth’s was back when plate tectonics started up.
And some data show compelling similarities between
features on Venus and terrestrial subduction zones.
One example is Artemis Corona, a circular formation
near the equator on Venus that is similar in scale and
shape to the Aleutian trench that lies under the ocean
along the coast of Alaska. Scientists have theorized
that such Venusian features represent spots where
plumes from the mantle are rising up to the surface
and pushing the crust apart.
Furthermore, recent laboratory experiments and
GLOBAL MAPS
computer simulations suggest that these plumes are
of Venus from
inducing subduction where they crack through the Magellan and
questions follow: Why did plate tectonics not develop
top layer of crust. In particular, the experiments Venera space- sooner, and what course will it take now? As Venus
explain why subduction seems to take place around craft data show cools more fully over time, the faults that are now
only part of the circle: as the brittle lithosphere rips diverse features, opening may endure, allowing the planet to undergo
apart in the center, it splits into segments, just as including the the same transition to plate tectonics experienced on
paper rips into different wedges when poked with a circular Artemis Earth. If we can watch the beginning of plate tectonics
pencil. As the lithosphere sinks, it continues to tear, Corona (box), unfold on Venus, then this process and its accompany-
forming segments. If these segments were to join, that could be ing atmospheric stabilization may be common on exo-
we would be seeing the initiation of plate tectonics indications of planets on the path to habitability themselves.
on Venus. plate tectonics.
Existing images of these features are too low in res- A
olution for us to know for sure what we are seeing. WE HAVE NEVER HAD BETTER REASONS to send a new major
But it appears that plate tectonics on Venus is in the mission to the oft-ignored second planet from the sun.
early stages of development. The Magellan observa- With high-resolution global imaging and spectra, we
NASA, JPL AND USGS
tions show no evidence of interconnected plates— can answer compelling questions about volcanism
rather we see isolated spots where subduction is and possible plate tectonics at Venus. Is the process
beginning, in each case around one of these circular truly occurring now? How do the surface activities
regions where plumes appear to be rising up. Two relate to what is happening in the planet’s interior?

How do the conditions on Venus, such as its tempera- the generation of scientists who launched Magellan is
ture, affect this tectonic activity? And are some sur- growing old and retiring. A mission to Venus now
face features we see, such as the crinkles scientists call would allow researchers to pass the torch to a new
tesserae, remnants of a past, wet epoch? generation who can bring us closer to understanding
In 2019 NASA will solicit proposals for the next why our planetary sister evolved so differently from
group of its smallest class of space probes, called Dis- Earth. Perhaps we may even discover what conditions
covery missions. Another of us (Smrekar) and Dyar are necessary for the emergence of life.
are leading one proposed mission called VERITAS
(Venus Emissivity, Radio Science, InSAR, Topography,
and Spectroscopy), which would map the surface in MORE TO EXPLORE
much greater detail than ever before. It would carry Was Venus the First Habitable World of Our Solar System? M. J. Way et al. in Geophysical Research
several instruments, including an imaging camera Letters, Vol. 43, No. 16, pages 8376–8383; August 28, 2016.
and spectrometer, to provide orders-of-magnitude- Experimental and Observational Evidence for Plume-Induced Subduction on Venus. A. Davaille
level improvements in topography resolution and the in Nature Geoscience, Vol. 10, pages 349–355; May 2017.
first-of-its-kind global composition map of the planet. FROM OUR ARCHIVES
Other Venus mission proposals are also in the works, Global Climate Change on Venus. Mark A. Bullock and David H. Grinspoon; March 1999.
and we should find out the final results in 2021.
Nearly 30 years after Magellan arrived at Venus,

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Can dam releases that mimic natural flows
restore the Grand Canyon ecosystem?
By Heather Hansman
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ON WEEKDAY EVENINGS, MILLIONS Heather Hansman is a freelance writer who lives

in Seattle. Downriver, her book about the Green
of workers return to their River, climate change and water in the West, comes
homes across the American out this spring from the University of Chicago Press.
Southwest and turn on their

air conditioners, microwaves
and televisions. From Tucson Bugs might seem like a lowly thing to focus on. But they form
to Burbank, power needs surge. the basis of a complex food web. When their numbers drop, that
reduction affects species, such as bats and endangered humpback
Meeting this demand begins chub, that feed on them. In a national park held up as an iconic
wild, Kennedy and his group are trying to figure out why, accord-
at 5 or 6 A.M. inside the ing to their research published in 2016 in BioScience, the Grand
Glen Canyon Dam, the chip Canyon section of the Colorado has one of the lowest insect diver-
sities in the country. “There are more bugs in the Detroit River,”
of concrete that plugs the says Jeff Muehlbauer, a biologist in Kennedy’s laboratory.
Colorado River just above Last summer the researchers were testing whether adjusting
dam releases so that the Colorado runs closer to its natural course
the Grand Canyon. At noon, might help insect populations recover. In those tests, they artifi-
cially created the kind of flow patterns that allowed life to flourish
an average peak of 14,000 before the dam went in—without removing the dam itself.
cubic feet of water per second Nearly 40 million people depend on the Colorado for the
necessities of daily life, including electricity, tap water and the
is churned through eight irrigation of 10 percent of land used for U.S. food production.
turbines, then released. Ever since Glen Canyon Dam opened in 1963, the river has been
engineered to accommodate these demands. Doing so changed
the ecosystem balance, which was dependent on ingredients
Artificial tides oscillate downstream where the canyon gorge such as sediment, snowmelt and seasonal flows. For more than
is steep and narrow for more than 200 miles, sloughing the sand- 30 years researchers have been trying to figure out how to help
stone banks and sluicing fish out of eddies. These flows are calcu- the ecosystem coexist with human needs, and they are finally
lated and controlled at all times by the U.S. Bureau of Reclama- beginning to test some solutions. By working out an experimen-
tion, sometimes doubling in volume as the water moves down- tal flow schedule that minimally impacted power generation, the
stream. Raft guides who lead trips down the Colorado know to 2018 bug tests marked one of the first times that dam operations
stake their boats high and leave lots of rope for them to float, so were adjusted for species health in the Grand Canyon.
that they do not get stranded in the morning as the levels go Meanwhile, though, the river is dwindling. The Colorado Riv-
down overnight. The river, they know, is constantly changing. er Basin has been in a drought for almost two decades; 2018 was
If you were boating or fishing on the Colorado in the summer the third-driest year ever recorded. Since 2000 ambient tempera-
of 2018, however, you might have noticed that days passed without tures in the basin have been 1.6 degrees Fahrenheit warmer than
any tides at all. In a rare opportunity for scientists who are trying 20th-century averages, and researchers predict they will reach up
to better understand the river ecosystem, the Bureau of Reclama- to 9.5 degrees F hotter still by 2100. The effects of climate change
tion was releasing steady flows of 8,000 cubic feet per second could decrease river flow by as much as half by the end of the cen-
through summer weekends. Aquatic ecologist Ted Kennedy and tury. With earlier snowmelt and more evaporation, the Bureau of
his team at the Grand Canyon Monitoring and Research Center Reclamation has predicted that it may have to cut the amount of
(GCMRC) wanted to see if holding the river at a consistent level water it sends downstream for the first time—as soon as 2020.
would aid the struggling native bug population, 85 percent of That will stress every part of the system, from hydropower and
which lay their eggs in the intertidal zone. Those eggs can get wet, city water supplies to native fish populations. It will also mean
but they cannot get dry; eggs laid at high tides desiccate within an less room for experimental flows, a tool the scientists think is crit-
hour of the water dropping. ical for understanding how to protect the canyon.
PRECEDING PAGES: MICHAEL HALL Getty Images
IN BRIEF
Nearly 40 million people rely on the Colorado In 2018 researchers tested consistent dam releases But as the result of climate change, decreased
2ÿyà¹àĀDïyàD´mÈ¹ĀyàjD´mïå¹Āåy´ that allowed the river to run more “naturally.” They snowfall and increased evaporation mean there is
neered to maximize those resources. But the ever DàyïàĂ´ï¹ù´myàåïD´m¹Āï¹UàÚD`§´Dïÿy ÿååĀDïyàDÿD¨DUÿ¹àyāÈyà®y´ïD¨¹ĀåÎåýĀ
`D´´àyÿDåyåà¹®ïyÿ´D´Ă¹´D® insect populations—and restore ecosystem àyåyDà`´¹à®å®D´Dy®y´ï¹ïy¹¨¹àDm¹2ÿyàj
have harmed the Grand Canyon ecosystem. yD¨ïĀï¹ùïmåàùÈïýýàĂÈà¹mù`ï¹´Î ïyĀyåïyà´7Î3ÎåÈàyÈDà´¹àĀDïyà`ùïUD`§åÎ
the Adaptive Management Program (AMP), it is made up of 25

Lake Powell
stakeholders who represent groups that have legal rights to the
len OMIN
Lees Ferr water or depend on the canyon economically. They include the
Can on
oR Hualapai Tribe, whose reservation runs 108 miles along the riv-
orad i Da
Col ve r er and the Grand Canyon; Western Area Power, which provides
rand Can on
National Park River power to customers in 15 states; and the tourism industry, which
ado
lo or brings $938 million to the local economy. Adaptive manage-
UA C COLORADO
ment, a term coined by fish biologists in Canada in the 1970s, is
U er Basin the practice of changing management decisions based on ongo-
NE ADA
ing research. In other words, it is learning by doing. The Glen
Area Canyon AMP was the first time that adaptive management had
enlarged been applied to a federal project with so many stakeholders.
CALIFORNIA Exactly how the dam, drought and other variables stress the
Colorado River ecosystem had long been poorly understood.
d o R i ve r
ARIZONA NE ME ICO Shifts in water temperature, flood timing, sediment suspension,

Lo er Basin chemical composition and species diversity all respond to one
Colora
another. “You can’t pull one string and not expect it to change,”
Kennedy says. So, in 1995, as part of the AMP, the U.S. Geological
Survey created the Grand Canyon Monitoring and Research Cen-
ter to investigate those impacts and serve as the sole science voice
ME ICO among its powerful group.
Under the aegis of the USGS, the geologists, hydrologists, biol-
ogists, ecologists and other scientists of the GCMRC monitor the
river and advise the AMP. During the past two decades the
The insect research is a meaningful step toward sustaining the researchers have built a longitudinal data set to establish a base-
river for habitat as well as for humans. It also runs straight into a line of life in the canyon. They devised experiments to explore
core conflict between science and Colorado River policy: scien- declining fish populations and disappearing sandbars—all, ide-
tists want the flexibility to experiment, whereas power and water ally, without cutting into the needs of the other stakeholders.
managers want stability. As the Colorado dries up, this conflict “Nobody had done ecosystem science and looked at the manage-
will intensify. And yet if Kennedy and others can show that chang- ment of a dam before,” says Dave Wegner, a former Bureau of
ing the flow can bring back insect populations, it could make eco- Reclamation ecologist who set up the GCMRC at its outset. “We
system health a bigger priority for those who manage the most were making it up as we went.”
used river in the West. It is easier to flexibly manage an ecosystem in the single-spe-
cies fisheries where adaptive management was first conceived. In
A a nonlinear system as complex as the Colorado River, this iterative
AS SOON AS THE PENSTOCKS CLOSED on the Glen Canyon Dam in 1966, strategy is also a tension point—especially when any tweaks re-
it became clear that the fragile, federally protected downstream quire consensus among 25 competing values. “We change some-
ecosystem of the Grand Canyon National Park was unexpectedly thing we can control, and then two things we can’t control very
altered. Inconsistent, sediment-depleted flows scoured sandbars, quickly change,” says geologist Ted Melis, deputy director of the
a significant habitat structure for native plants such as coyote Southwest Biological Science Center, which oversees the GCMRC.
willow and arrowweed. The clear, 48-degree water, released from For instance, the GCMRC is currently trying to unpack a 1,000 per-
the depths of Lake Powell, stressed endangered fish, which cent increase in populations of predatory, nonnative brown trout
were adapted to silty, 80-degree flows. Very little was known since 2012. The spike happened around the same time as experi-
about the interconnectedness of such elements before the dam mental high flows that were designed to build sandbars. But that
was constructed, so these changes came about without fore- is the point of adaptive management, Melis says: learning from
thought for the consequences. the ecosystem shifts and responding to them.
It was not until 1989, after scientific evidence from an initial
1982 assessment and under pressure from both the public and "''!5'5
73
agencies such as the National Park Service, that the secretary of IN NOVEMBER 2017, several months before the weekend bug flow
the interior asked for the first environmental impact statement experiment began in the Grand Canyon, I joined Muehlbauer and
on the dam. The results, finalized in 1995, confirmed that endan- David Goodenough, another researcher in Kennedy’s lab, to col-
gered species and valuable resources were being affected, but the lect monthly samples of insect populations on the shore and in
Department of the Interior did not have enough data to quantify the river. If the GCMRC scientists can understand what is trig-
how much things were changing. Information found during that gering the bug die-offs, they can explicitly show how factors such
investigation sparked the 1992 Grand Canyon Protection Act, as flow and food webs are related—and why they must be consid-
which required the Bureau of Reclamation to maintain both hy- ered in any management strategy for a rapidly changing future.
dropower and natural habitat while managing the dam. Kennedy has been studying Grand Canyon insects since 2002.
To uphold the act, in 1996 the Bureau of Reclamation formed He thinks that hydropeaking—that is, spiking flows up and down
a federal advisory committee to guide dam operations. Called for power needs—is part of why scientists see minimal numbers of
Map by Mapping Specialists February 2019, ScientificAmerican.com 67
midges and almost no mayflies, stone flies or caddis flies, all of made reservoir behind the Glen Canyon Dam—and divert it to
which are prevalent on other western rivers and were likely once two growing counties in southern Utah. The pipeline was first
abundant on the Colorado. His team modeled how insect egg-lay- proposed in 2006 by the Utah Division of Water Resources, and
ing cycles responded to hydropeaking, and in 2016 the researchers in September 2018 the Federal Energy Regulatory Commission
released a paper hypothesizing that limiting the artificial tides agreed to license the hydroelectric part of the project. As expand-
created by dam releases—for even just two days in a row—would ing communities try to claim every drop of water they are legally
give bugs enough time to reproduce. Now Kennedy and his team allotted, Kennedy is looking at how bugs are tied to the rest of
are racing to test whether adjusting the flow toward a more natu- the river system—and demonstrating how the AMP can manage
ral state will restore and protect the Grand Canyon ecosystem in for both in the face of less water coming downstream.
an increasingly drought-strapped, human-impacted river.
It is only recently that such an experiment could take place. In '552j227572
2016, because both science and statutory responsibilities (such as GIVING SCIENTISTS A VOICE in water management has led to new
additions to the endangered species list) had changed, the insights about how the Colorado River reservoirs are suffering
Bureau of Reclamation and the National Park Service revised the from climate change. Much of the news is alarming. A 2017 study,
original environmental impact statement to allow for a broader published in Water Resources Research, by climate scientists Brad
range of experimental flows. The 2018 bug flow is the first test the Udall of Colorado State University and Jonathan Overpeck, then at
GCMRC has tried within the new legal framework. It is timely the University of Arizona, found that average Colorado River flows
work in the context of a global problem: a 2017 paper in PLOS in the 21st century were 19 percent lower than in the 20th. They
ONE found that in Germany, flying insect populations have plum- predicted flows could drop by up to 55 percent by 2100 as a result
meted by 75 percent since 1990. The authors, led by Caspar A. of the effects of global warming. “If you’ve been paying attention,
Hallmann of Radboud University in the Neth-
erlands, warned this drop would have cascad-
ing impacts on pollination and nutrient cy-
cles across Europe—a scenario already play-
5xä`x³îäîäÿD³îî¸Çßxäx³î
ing out on the Colorado.
On a chilly November dawn, the research-
ßxDä¸³ä¸ßDx³l³¸ÿä³îx
ers and I left the GCMRC offices in Flagstaff, ³Dx¸³DîøßxUx¸ßxîäî¸¸
§Dîxî¸Dþ¸lx`¸äāäîx`¸§§DÇäxÍ
Ariz., and drove down to the Lees Ferry boat
ramp, which is 16 miles below the Glen Can-
yon Dam. In a jet boat named Quicksilver,
we zipped up the black glass of the river
toward the dam, then turned downstream into the throat of the especially in the past two or three years, you should be frightened
Grand Canyon. Muehlbauer and Goodenough set four sticky right now,” Udall says, referring to how soon there might not be
traps—back-to-back petri dishes lined with adhesive and glued enough water to meet legal and environmental needs. In the
to aluminum stakes—at monitoring points approximately every Bureau of Reclamation’s yearly water tally, which ends in Septem-
mile to catch adult invertebrates. We passed through 21 miles of ber, the amount of water that flowed into the Colorado River
the canyon, taking drag samples of what is suspended in the Basin in 2018 was only 43 percent of the historical average.
water column to see how bug density and species diversity There is also problematic math at Lake Powell. Because the
changed the farther we got from the dam. Colorado’s water is allocated down to virtually the last drop, the
There were almost no bugs on the river. None in our teeth or lake level is crucial to a 1922 legal compact that guarantees 8.23
our eyes as we motored downstream. Nothing biting when we million acre-feet of water will flow past Lees Ferry every year.
pulled up in tamarisk bushes to collect the sticky traps. When The Bureau of Reclamation built reservoirs—including Powell—
Muehlbauer pulled a sample stake and looked inside the petri starting in the 1950s. But these storage systems only work if they
dish, he was underwhelmed. “Oh, my God, David,” he said, roll- are replenished. Lake Powell is considered “full” at 3,700 feet
ing his eyes at Goodenough. “We caught . . . midges!” above sea level; the last time that happened was 1986. In 2002,
Later, they sorted through the samples in the lab, pulling out the driest year on record, only 3.8 million acre-feet flowed into
chironomine bodies with tweezers and tallying the different spe- Powell from upstream on the Colorado. Because Lake Powell’s
cies, painstakingly adding to a 22-year record of the individual entire purpose is to keep the downstream water supply consis-
bug totals along the river. Kennedy hopes the data from the content even when it does not rain or snow, the legally obligated 8.23
trolled flows during the summer of 2018 will reveal how the million acre-feet still went out.
physical processes of dam releases impact the bugs. The research- This logic, however, is fundamentally flawed. The compact
ers are worried that climate change, among other factors, is water was allocated based on calculations done by the Bureau of
altering conditions faster than they can study them. But if the Reclamation in the early 1900s, the wettest recorded period in
GCMRC can show that engineering the river to run more natu- measured history, which concluded that 18 million acre-feet of
rally makes the entire ecosystem more sustainable, it will empha- water flowed through the river basin every year. Data collected
size the riskiness of new projects that threaten to divert even from USGS river gauges installed at Lees Ferry in 1922 have
more water from the Colorado. showed that average yearly flows are actually 14.8 million.
Take the Lake Powell Pipeline, for example. It would remove Because the compact is federal law, the 8.23 million acre-feet of
86,249 acre-feet of water every year from Lake Powell—the man- downstream obligations still stand. Water managers call this a
too late to avoid ecosystem collapse. In

Kennedy’s “encouraging” preliminary re-
sults from the bug flows, he says his team
saw more than twice as much larval emer-
gence in May 2018 as it has in any month it
has monitored over the past seven years.
On these “bug flow weekends,” the re-
searchers found millions of rinds of spa-
ghettilike midge egg casings on the banks.
The Arizona Game and Fish Department’s
creel survey reported that fishing catch
rates were up, and anecdotally, river run-
ners and fly-fishing guides complained
that it was buggier than usual. “These find-
ings are a powerful reminder that flows
really do matter,” Kennedy says.
This success represents a promising
step toward increased experimentation
and variable flows on the Colorado River.
Kennedy hopes it convinces the AMP to
CLIMATE CHANGEäD``x§xßDî³D³xDß§āöćāxDßlß¸øîDî"D¦x0¸ÿx§§çîxßäî green-light another year or two of bug
ever cutbacks to downstream water allotments could occur as soon as 2020. flows. But it could have wider implications,
too. The AMP is starting to become a glob-
al model for managing dam operations
structural deficit, and it means that if every state claims its entire while balancing the competing demands of ecosystems, energy
share—a near-future scenario thanks to projects like the Lake and irrigation. Over the past 20 years, Melis says, hydrologists and
Powell Pipeline—there will not be enough to go around. engineers from planned dams in the Brazilian Amazon—as well as
The accelerating drought has become so threatening that in researchers from Japan, China, Canada and other Bureau of Rec-
2018, seven “basin states” drafted contingency plans. Each state lamation projects in the U.S.—have come to Arizona to learn from
outlined how much of its allocated compact water it would leave and share information with the AMP.
in reservoirs if Lake Powell’s level hit 3,525 feet above sea level— The collaborative, long-term thinking of adaptive manage-
just high enough to comfortably maintain power production at ment can seem idealistic. Melis refers to a “potpourri” of re-
the dam. (In November 2018 Powell was at 3,588 feet.) Although sources the scientists must consider as they try to find the con-
interim guidelines came out in 2007, this official step marked nections that will restore ecosystem health. But in the changed
the first time since the compact was signed nearly 100 years ago and changing Colorado River system, there is plenty that still
that the basin states made a legally enforceable plan for a drier feels wild, even if it will take precise management to keep it
future. Finally, policy is starting to reflect science. seemingly so.
This shrinking volume of water also makes experimentation When Muehlbauer, Goodenough and I came back to the boat
more difficult to pull off. “Everything we do within the Adaptive launch after a day of collecting bug samples, the late November
Management Program has to work within the annual volume of sun was casting shadows on the canyon walls. The temperature
release,” says Katrina Grantz, former Upper Colorado region was rapidly dropping. We were the only humans around as bats
chief of the AMP. The GCMRC researchers have considered any circled and clicked in the coming dark. But far down the grid,
reasonable options that would increase the supply. One long- people across the Southwest were coming home from work and
standing and controversial idea is to remove the Glen Canyon turning on their lights. The river had come up to meet them.
Dam altogether, then store the reservoir’s water in Lake Mead to
minimize evaporation. But so far neither science nor policy sup-
ports removal. A 2016 white paper by John C. Schmidt, a geomor- M O R E T O E X P L O R E
phologist at Utah State University and a former head of the Active Adaptive Management of the Colorado River Ecosystem below Glen Canyon Dam,
GCMRC, found that any water savings from consolidating reser- USA: Using Modeling and Experimental Design to Resolve Uncertainty in Large-River
voirs would be less than 1 percent of the average inflow. It is Management. Theodore S. Melis et al. Presented at the International Conference on
impossible to untangle the human uses of the river without 2yåyàÿ¹à'ÈyàDï¹´D´m2ÿyà$D´Dy®y´ïjùD´Ć¹ùj´Dj3yÈïy®UyàÀé÷ñj÷ĈĈÎ
Flow Management for Hydropower Extirpates Aquatic Insects, Undermining River Food
upending life in the Southwest, Schmidt explains. “Sometimes Webs. Theodore A. Kennedy et al. in BioScience, <¹¨Îêêj%¹ÎéjÈDyåêÀéè ù¨ĂÀj÷ĈÀêÎ
we are agreeing to compromise the environmental health of the More Than 75 Percent Decline over 27 Years in Total Flying Insect Biomass in Protected
ADRIA PHOTOGRAPHY Getty Images
rivers to provide utilitarian benefits,” he says. Areas. Caspar A. Hallmann et al. in PLOS ONE, <¹¨ÎÀ÷j%¹ÎÀĈjàï`ÿ%¹ÎyĈÀ~~Ĉµè
'`ï¹UyàÀ~j÷ĈÀéÎ
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AS AN IMPENDING WATER CRISIS DAWNS, the GCMRC scientists are try- Change of State. D´
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ing to experiment as much as possible. They want to present con-
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crete reasons for amending flows in the name of nature before it is
OUTLOOK
GENE
THERAPY
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OUTLOOK
GENE THERAPY
P
OUTLOOK 13 December 2018
Supplement to Nature
Research journals
harmaceuticals cannot always fix a malfunctioning
human body. Sometimes the only way to treat what ails CONTENTS
GENE
THERAPY
a person is to tinker with their genes: the blueprints
for how biological systems are built and how they operate. S4 NEONATOLOGY
Some researchers are using gene-editing techniques such The fix is in utero
as CRISPR to precisely alter DNA sequences. Others are Hereditary diseases healed prenatally
genetically modifying immune cells to imbue them with S7 PERSPECTIVE
Revolutionary
A genetically augmented future
Produced with support from:
repairs
the ability to fight cancer. And in the past couple of years,
Ellen Wright Clayton on medical ethics
Cover art: Sam Falconer there has been a rapid acceleration in the development of a
wide range of treatments in which disease-causing genes are S8 NEUROLOGY
replaced in their entirety. Repairs for a runaway brain
Editorial
A way to suppress epileptic seizures
Herb Brody, This Outlook therefore focuses on the rich assortment of
Richard Hodson, research in which new genes are introduced into a person, S10 BLOOD DISEASE
Elizabeth Batty, Medicine is in the blood
Lewis Packwood, usually by means of a viral vector (see page S16). Successful Fixing the gene in sickle-cell disease
Nick Haines animal experiments indicate that human genetic disorders
S12 DERMATOLOGY
Art & Design could one day be repaired in the womb, so that a baby might Under the skin
Mohamed Ashour, enter the world disease-free (S4). And a number of health
Wesley Fernandes,
Epidermal cells extracted and repaired
Kate Duncan issues that have proved difficult or impossible to remedy — S14 IMMUNOLOGY
Production such as sickle-cell disease (S10), epilepsy (S8) and certain A genetic shortcut
Nick Bruni, Karl intractable skin conditions (S12) — might be excellent targets How to make an antibody factory
Smart, Ian Pope for gene therapy. S16 THERAPEUTICS
Sponsorship But gene therapy need not be limited to diseases that Special delivery
David Bagshaw,
Jay Berfas,
originate from genetic abnormalities. It might be possible to Making viral vectors more efficient
Anushree Roy treat some viral infections with DNA, by using it to prompt S18 POLICY
Marketing the body into creating just the right monoclonal antibodies to Regulating a revolution
Nicole Jackson ward off invading pathogens (S14). Health authorities tackle gene therapy
Project Manager Gene therapy remains an expensive medical path, however. S21 PERSPECTIVE
Rebecca Jones Moving it out of the laboratory and into the clinic will require Access and affordability for all
Creative Director innovative pricing schemes (S21) and regulatory policies Michael Sherman on value-based deals
Wojtek Urbanek
(S18). Along the way, clinicians, patients and policymakers
Publisher
Richard Hughes will grapple with tricky ethical questions (S7).
Editorial Director We are pleased to acknowledge the financial support of
Stephen Pincock Pfizer Inc. in producing this Outlook. As always, Nature has
Magazine Editor sole responsibility for all editorial content.
Helen Pearson
Editor-in-Chief Herb Brody
Magdalena Skipper Chief supplements editor
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S3
OUTLOOK GENE THERAPY
JOHN FEDELE/GETTY
NEONATOLOGY
The fix is in utero

Some genetic diseases cause damage even before a child is born.
The answer to these devastating conditions could lie in gene
therapy delivered while the baby is still in the womb.
Hereditary disorders that are

discovered during prenatal scans
could one day be cured before birth.
BY SARAH DEWEERDT born normally, and lived for at least 18 weeks evidence yet that the approach could be fea-
with little evidence of brain pathology. “You’re sible in humans. “The combination of those
I
n July, an international team of researchers talking about prolonging life significantly,” two aspects of the study made it very, very
reported that they had used gene therapy says Jerry Chan, a fetal-medicine specialist at exciting,” says Bill Peranteau, a fetal surgeon
to correct a fatal brain disorder in mice — Duke-NUS Medical School in Singapore and at the Children’s Hospital of Philadelphia in
before the mice were even born1. an author of the study. Pennsylvania.
The mice had a defect in a gene known as The researchers also administered the The technical challenges, safety concerns
GBA, which encodes an enzyme responsible gene therapy to healthy macaque fetuses, and and ethical issues of prenatal gene therapy are
for breaking down a fatty molecule called showed that it could transform brain tissue substantial. But this approach is more than just
glucocerebroside. Without the enzyme, glu- without serious side effects in an animal model hotshot medicine. It could be the best way to
cocerebroside builds up in the brain, causing that more closely approximates the body size treat a select group of devastating genetic dis-
irreversible brain damage. The mice typically and pregnancy physiology of humans. eases — and perhaps the only way to achieve
die within about 14 days of birth. “What we were trying to do is show the best a lasting cure.
The mice model a condition in humans possible experiments that would justify, if
called acute neuronopathic Gaucher’s disease. there ever was, a path to human clinical trans- EARLY ADVANTAGES
Children born with this genetic mutation lation,” says study leader Simon Waddington, a Acute neuronopathic Gaucher’s disease is one
rarely live past the age of two. gene-therapy researcher at University College of the best candidates for treatment with pre-
In the study, researchers injected a virus London. natal gene therapy. That’s because the build-up
bearing an intact copy of the GBA gene Other researchers in the small field of of glucocerebroside begins in the fetus. In the
into the brains of fetal mice about mid-way prenatal gene therapy see the research as a absence of any intervention, irreversible brain
through gestation. The treated mice were leap forward, and say it provides the strongest damage can occur even before birth. “The
S4
GENE THERAPY OUTLOOK
main advantage is preventing the damage from therapy is fairly straightforward. It involves Often, scientists have looked to the prenatal
occurring in the first place,” Waddington says. injecting the treatment into an umbilical window not just for the opportunity to treat
With other genetic diseases, the effects blood vessel, the amniotic fluid or occasionally diseases that begin before birth, but as a way
might not begin until sometime in infancy or directly into fetal tissue — often with the guid- around some of the difficulties of postnatal
early childhood. But even then, prenatal gene ance of an ultrasound probe. The techniques gene therapy. Charles Coutelle at Imperial
therapy might be more effective or efficient are similar to well-established methods used College London, says that what prompted him
than waiting until after birth. “You are trying in amniocentesis, chorionic-villus sampling or to enter the field in the mid-1990s was, “to be
to take advantage of the normal developmental umbilical-vein blood transfusion. quite frank, frustration with the efficiency of
properties of the fetus to increase the efficiency “The procedures themselves are relatively gene therapy at the time”.
and the likelihood of success of the treatment,” safe,” says David. Still, they do come with a Coutelle had been involved in one of the first
says Peranteau, who is working on animal small risk of infection, preterm labour and human trials of gene therapy for cystic fibro-
studies of prenatal gene therapy for metabolic loss of the pregnancy. All in all, she says, “it’s sis, a genetic disorder that affects the lung and
diseases affecting the liver. going to be a lot safer, probably, to treat it after other organ systems. It was difficult to deliver
Before birth, the blood–brain barrier that the baby is born when you’ve got the baby and gene therapy to the lungs of people with cystic
prevents many molecules from crossing from you’re not risking the mother”. fibrosis because even in young children, the
the bloodstream into brain tissue is imma- Then there are the usual risks involved in airways were full of viscous mucus and scar
ture, a situation that eases delivery of genes to gene therapy, such as the potential for the tissue; immune-system
the central nervous system. In a 2011 paper2, vector to provoke an immune reaction in “You are dysfunction also pre-
Waddington and his colleagues showed that the patient, or incorporate into the genome trying to take sented a hurdle. Coutelle
a gene-therapy vector called AAV2/9 reaches in a location where it could trigger cancer. advantage of thought it might be
nerve cells in the brain much more reliably in Some of these risks are magnified in the pre- the normal easier to correct cystic
fetal mice than in those already born. natal setting. For example, if the gene therapy developmental fibrosis in utero, when
Another advantage of prenatal intervention gets into the mother’s bloodstream, it could properties of amniotic fluid moves
is that the immune system is still immature. cause a dangerous immune reaction in her the fetus.” freely in and out of the
Therefore, the packaging used to deliver gene body or even be incorporated into her cells. lungs.
therapy — whether a virus or another type of In the fetus, especially if given early in Coutelle and his team spent several years
vector — might be less likely to cause an adverse development, the gene therapy could alter perfecting fetal transfer techniques in mouse
reaction. Also, the body develops immune germ cells that will eventually develop into models, as well as working out which vectors
tolerance to the vector, so if a gene therapy eggs and sperm, causing changes that could would be best to use prenatally against cystic
‘booster shot’ needs to be administered later in be passed down to eventual offspring — a pos- fibrosis or other serious diseases. The first big
life, it is more likely to succeed. The immune sibility that many scientists consider ethically success — and an achievement that remains
system will also accept the normal protein problematic. The therapy might also disrupt significant today — came in 2004. That year,
encoded by the gene therapy, rather than normal body-system development by trigger- a group including Coutelle and Waddington
destroying it — as has sometimes been seen ing the expression of genes in an inappropriate corrected the bleeding disorder haemophilia B
with postnatal gene therapy and protein- place or at an inappropriate time. That could in prenatal mice by injecting them with a virus
replacement therapies. potentially cause lasting effects, such as organ bearing an intact copy of factor IX, a protein
In addition, rapid fetal growth and malformation. involved in blood clotting4.
development means more bang for the gene- Parents facing an in utero diagnosis of a But the team soon had to switch gears. One
therapy buck. At any given time, a large serious genetic condition must often decide vector used in the haemophilia work yielded
proportion of cells in the fetus is actively whether to raise a child with a lifelong disabil- only a temporary cure; another produced
dividing. That yields a greater likelihood of ity or terminate the pregnancy. The appeal of more lasting results but led to an increased
the vector integrating into the genome. The prenatal gene therapy is that it offers a poten- risk of liver tumours. More importantly, the
population of corrected cells will continue to tial third path. But these treatments also raise development of postnatal gene therapy for
expand throughout gestation. Furthermore, the stakes: what if the gene therapy doesn’t haemophilia had taken a sudden leap forward.
to effect a cure, it is important to get replace- work, leaving parents with a seriously ill child “Once you have an established postnatal gene
ment genes into stem cells or progenitor they weren’t prepared for and would not have therapy there’s no point in doing it prenatally.
cells — and these long-lived cells are more chosen to raise? Similarly, a gene therapy that Or you have to have good reasons for doing it,”
abundant and more accessible before birth. is only partially effective could turn a dis- Coutelle says.
Finally, a 20-week fetus weighs roughly ease that previously would have been fatal in
300 grams, whereas a newborn tips the scales infancy into one that results in long-term dis- A SURFEIT OF TARGETS
at around 3.5 kilograms. That small size trans- ability — so it could actually increase suffering Waddington decided to look for a more
lates directly into a higher therapeutic effect for the patient and family. challenging target disease that causes more
from a given dose of treatment. That’s a big As a result of such concerns, researchers are severe effects earlier on, which led him to
advantage because gene-therapy products can cautious about the prospect of attempting pre- Gaucher’s disease. But that is just one of a fairly
be expensive and laborious to produce. natal gene therapy in humans. “If there is an broad array of metabolic disorders, including
adequate treatment for something after birth, Tay–Sachs disease, Niemann–Pick disease and
A RISKY BUSINESS that is the way to go,” Peranteau says. mucopolysaccharidosis, that cause in utero
But the fetal time period also poses unique damage and could therefore be good targets
challenges. Any prenatal intervention is com- ORIGIN STORY for prenatal gene therapy.
plex because it affects two people — the mother Even so, scientists have been thinking about Other researchers argue that haemophilia
and the fetus. “You’ve always got to take both prenatal gene therapy for nearly as long as they remains a good prenatal target. Researchers
into consideration, and you’ve also got to think have been working on postnatal gene therapy. led by Graça Almeida-Porada and Christopher
about the future children of the mother her- The first proof-of-concept studies3 in animal Porada at Wake Forest University in Winston-
self,” says Anna David, a fetal-medicine special- models, showing that a gene could be intro- Salem, North Carolina, are working with a
ist and gene-therapy researcher at University duced into an organism before birth, were sheep model of haemophilia A. This form of
College London. published in 1995 — just a couple of years after haemophilia accounts for about 80% of hae-
Generally, the delivery of prenatal gene the first human gene-therapy trial. mophilia cases in humans, but has proven
S5
much more difficult to address with postnatal going to reach clinical practice much faster,” Clinicians would need to be able not only
gene therapy than has haemophilia B. says Chan. The safety of stem-cell or bone- to detect a disease before birth, but also to
One major issue is that the protein involved marrow transplantation is better established confidently predict that its severity would be
in haemophilia A — factor VIII — is highly than that of gene therapy, he says. sufficient to warrant gene therapy. These are
immunogenic. Many people with a severe complex questions that aren’t fully resolved
form of haemophilia A develop antibodies A BOON FOR RESEARCH for all the prenatal target disorders. However,
against factor VIII, which makes replacement But even if prenatal gene therapy doesn’t reach if there is no prenatal treatment for a disease,
therapy more costly and complicated, says the clinic, it could still be useful as a research there might be little point in identifying it
Almeida-Porada. “The goal of going prior to tool. That’s already the case with cystic fibro- in utero.
birth is that you would induce tolerance to the sis, says Marianne Carlon, a gene-therapy Waddington’s attitude is simply to bypass
protein — these patients would never develop researcher at the Catholic University of Leuven this catch-22 situation. “We’ll develop the
an immune response,” she explains. The team in Belgium. cures, and then that justifies doing the diag-
aims to cure haemophilia A in fetal sheep by noses,” he says.
collecting stem cells from the amniotic fluid, On the flip side, the first prenatal gene
ADELE RICCIARDI/DAVID STITELMAN LAB/YALE

correcting the factor VIII gene and infusing therapy to reach human trials might be one
the cells back into the fetus. targeting a condition that is exclusively
Studies of prenatal gene therapy in diagnosed in utero because it only affects
animal models are a dance between fetuses before birth. Intrauterine
practicality and possibility. They growth restriction (IUGR) affects
depend on the availability of animal about 3% of all pregnancies and
models for a given disease, and are results in babies with dangerously
shaped by the pace of advances low birth weight.
in postnatal therapy or other Unlike other prenatal gene
experimental treatments, such therapy targets, IUGR is not a
as in utero stem-cell therapy or single-gene disorder. It occurs
bone-marrow transplantation. when, for unknown reasons,
In June, researchers at Yale the normal remodelling of
University in New Haven, uterine arteries during preg-
Connecticut, reported that they nancy does not occur. That
had corrected the inherited leaves the placenta and devel-
blood disorder β-thalassaemia oping fetus starved of blood
in fetal mice5. The disease is and nutrients.
caused by mutations in the David has shown that IUGR
β-globin gene, which encodes a can be alleviated — at least in
subunit of haemoglobin, the oxygen- sheep — by delivering a gene encod-
carrying protein found in red blood ing VEGF, a protein that stimulates
cells. In β-thalassaemia, haemoglobin is the development of blood vessels, to the
less able to carry oxygen, leading to fatigue, maternal side of the placenta6. “We’re giving
growth stunting and damage to organs. gene therapy to the mum, to treat a condition
In the study, researchers used gene-therapy in the mum that causes a problem in the fetus,”
delivery vehicles called peptide nucleic acids Fluorescent nanoparticles reveal a mouse fetus, David says.
(PNAs). PNAs are particles consisting of a umbilical cord and placenta. VEGF is expressed for only about a week,
biocompatible polymer surrounding an intact but that’s long enough to trigger expansion of
copy of the β-globin gene. “In utero injection Carlon and her colleagues have found that the placental vasculature. A similar approach
of these molecules with a single injection was gene-therapy vectors can distribute more has been used to stimulate the growth of
effective to achieve a phenotypic correction in evenly through the lungs of fetal pigs than blood vessels in the heart and neck, so the
the mice after birth,” says study author Peter through the lungs of newborn pigs. The therapy, known as therapeutic angiogenesis,
Glazer, a radiation oncologist and geneticist question is whether such even distribution is is well established postnatally. David has
at Yale. necessary or whether just reaching the large- applied for regulatory and ethical approval
The PNAs make use of a cell’s own DNA- and medium-sized airways is sufficient to to conduct a trial of the therapy in pregnant
repair mechanisms to incorporate the correct prevent the lung damage in cystic fibrosis. women.
copy of the β-globin gene into the genome, In utero studies in animal models could also “It’s a major cause of cardiovascular disease
potentially sidestepping some of the safety help to resolve questions about which cell types and diabetes later in life,” David says, referring
issues associated with gene-therapy delivery by in the airways need to be targeted for gene to IUGR. “There’s no treatment. And women
viruses. And, crucially, the approach might be therapy to be effective in cystic fibrosis. want it, when you ask them. They’re desperate
more effective prenatally than it is after birth. “We would rather start in a neonatal setting” to have a treatment.” ■
“In the developing fetus, the cells are more for attempting gene therapy on cystic fibrosis,
amenable to gene editing,” Glazer says. “The Carlon says. Then, she adds, it would make Sarah DeWeerdt is a science journalist in
DNA-repair capacity of the cells is revved up” sense to “move towards a fetal setting if you Seattle, Washington.
because cells are dividing so rapidly, his team’s really see that you have difficulties targeting 1. Massaro, G. et al. Nature Med. 24, 1317–1323
data suggest. the right cell”. (2018).
Glazer envisions PNA-based gene therapy One reason that prenatal gene therapy for 2. Rahim, A. A. et al. FASEB J. 25, 3505–3518 (2011).
3. Coutelle, C., Douar, A.-M., Colledge, W. H. &
for thalassaemia or sickle-cell disease (another cystic fibrosis is not likely to be practical is that Froster, U. Nature Med. 1, 864–866 (1995).
inherited blood disorder) being tried first in in utero screening for the disease is not wide- 4. Waddington, S. N. et al. Blood 104, 2714–2721
children, then infants and finally in utero. But spread. As a result, the diagnosis is rarely made (2004).
5. Ricciardi, A. S. et al. Nature Commun. 9, 2481
how quickly this might happen is not clear. “For until after birth. “Without a prenatal diagnosis (2018).
thalassaemia, a stem-cell approach is probably there is no prenatal gene therapy,” Coutelle says. 6. Carr, D. J. et al. Biol. Reprod. 94, 142 (2016).
S6
PERSPECTIVE
A genetically augmented future
Gene therapy could one day be used for bodily enhancement, creating
an ethical minefield for physicians, says Ellen Wright Clayton.
T
he year is 2030. Gene therapy to insert the DNA sequence for The request might reflect issues with self-image. The desire to be
dystrophin has been approved by regulators and is commonly stronger could reveal a psychological problem that needs to be resolved.
used in children with Duchenne muscular dystrophy (DMD), Or a physician could conclude that Alex is suffering, thereby making
a disorder linked to the X chromosome. Evidence shows that the inter- the case for gene therapy more compelling. For example, medical and
vention increases muscle mass in anyone who receives it. The treatment surgical interventions are sometimes prescribed to prevent or relieve
is widely available, but very expensive. psychological distress in children or young people who are abnormally
Alex, a slender adolescent, walks into a physician’s office, short3 or who have potentially stigmatizing physical features4. It is
accompanied by well-to-do parents. Alex does not have DMD, but important to ensure that Alex understands and agrees to the therapy,
wants to be stronger. Exercise is not providing enough benefits, and but in the end, it can be hard to ascertain the source of a person’s desire
anabolic steroids have too many side effects. Alex is adamant about for a given treatment — especially if the person is an adolescent.
wanting dystrophin gene therapy and accurately cites its risks and Are Alex’s parents wrong to support their child’s desire? Perhaps they
benefits. Alex’s parents are willing to pay for the treatment. are putting undue pressure on Alex. Perhaps they want to alleviate Alex’s
The cure for DMD described previously represents a cherished goal distress. Perhaps they are just indulgent. Society’s default position is that
for gene therapy, and there is a lot of public support for fixing such herit- parents should have the last say in such matters because they are assumed
able disorders in this way1. Yet Alex’s request raises a host of questions. to care more for their children than does anyone else. Parents have a
We do not know why Alex wants to be stronger. responsibility for shaping their children’s future,
Alex could have a milder form of muscular creating opportunities and drilling into them all
dystrophy or, if female, could be a carrier who sorts of values. Parents are largely free to pursue
experiences milder symptoms of DMD2. Alex
might have some other cause of muscle weak-
CONCERNS their vision for their children’s lives, unless those
actions are illegal or constitute abuse or neglect.
ness — or might want to be stronger for the sake of ABOUT EQUITY So what is the physician to do? Assuming that
appearance, or to be more competitive in athletics.
As is the case for many medical interventions, the
SHOULD LEAD gene therapy for enhancement has not been out-
lawed, he or she can and should turn to medical
potential uses of this therapy go beyond the spe- SOCIETY TO DEVELOP ethics and the goals of medicine5 for guidance.
cific disease for which it was developed. Possible
applications range from treating milder disease to GUIDELINES Respect for persons — a fundamental principle
of medical ethics — would direct the physician
improving human characteristics — a continuum
that could lack clear boundaries. FOR GENE THERAPY to attempt to discover more about what is driv-
ing the patient and their parents’ wishes, and to
Let’s assume that Alex does not have a TO AVOID A ensure that they understand what is at stake and
diagnosed physical problem and wants the ther-
apy simply to become stronger. The main debate NIGHTMARE that their expectations are realistic6. If the deci-
sion to proceed was made to relieve suffering,
FUTURE.
about using medical interventions for such bodily and with the adolescent’s informed assent and the
enhancements focuses on the extent to which they parents’ permission, pursuing the goals of medi-
give individuals an advantage over other people. cine would lead the physician to use the therapy
A 2017 report by the US National Academies on to confer only traits within the normal range of
gene editing in humans captures the debate well1. human characteristics.
The authors summarize surveys that show that most people disapprove Ultimately, the ethics of enhancement are intertwined with views of
of using gene therapy to improve a person’s physical and intellectual fairness. Concerns about equity should lead society to develop guide-
characteristics. The public tends to honour narratives of success based lines for gene therapy to avoid a nightmare future in which a group of
on personal diligence, or even accident of birth, over traits that can be privileged people becomes stronger, smarter and more beautiful than
purchased. This preference touches on a larger issue: the extent to which the rest. But because drawing lines between treatment and enhance-
uses of gene therapy would exacerbate social inequality. If there is a ment is difficult, the more likely and more unsettling scenario is that
widespread perception that this would be the result, society might try physicians will be left to rely on their own ethical commitments to
to limit its use to the few people who genuinely need it to treat their decide when to use gene therapy. ■
disease. Or there might be an effort to make such therapies available to
all who want them. Ellen Wright Clayton studies medical ethics and health policy at
Back to Alex in the world of 2030. Assuming that the US Food and Vanderbilt University Medical Center in Nashville, Tennessee.
Drug Administration’s regulations are still the same, physicians would e-mail: ellen.clayton@vanderbilt.edu
be free to use the approved DMD intervention for any purpose. After 1. US National Academies of Sciences, Engineering and Medicine. Human
all, many medicines are legally prescribed for reasons that have noth- Genome Editing: Science, Ethics, and Governance (National Academies, 2017).
ing to do with their original indication. So what should happen? How 2. Papa, R. et al. Pediatr. Neurol. 55, 58–63 (2016).
hard should a physician try to understand the source of Alex’s desire 3. Grimberg, A. et al. Horm. Res. Paediatr. 86, 361–397 (2016).
4. Rohrich, R. J. & Cho, M.-J. Plast. Reconstr. Surg. 142, 293e–302e (2018).
to be stronger? 5. Allert, G. et al. Hastings Cent. Rep. 26, S1–S27 (1996).
Alex’s wish might be a product of the social and cultural environment. 6. Grady, C. N. Engl. J. Med. 372, 2172 (2015).
S7
Excitatory neurons release neurotransmitters
DAVID BISHOP/UCL HEALTH CREATIVES

that electrically stimulate neighbouring cells,
whereas inhibitory neurons release neurotrans-
mitters that suppress electrical activity. A seizure
is a period of runaway electrical activity during
which the normal balance between excitation
and inhibition is lost. Current anti-seizure drugs
either dampen excitatory mechanisms or boost
inhibitory ones. But they do so indiscriminately,
producing wide-ranging side effects by affecting
neural circuits throughout the nervous system.
Current gene-therapy strategies, by contrast,
use harmless viruses to introduce one or two
therapeutic genes into the defined volume of
tissue from which focal epilepsy emanates. “It
is more personal, more targeted, and prob-
ably has fewer side effects because we treat
the tissue that needs to be treated, instead of
treating the whole body,” says Merab Kokaia,
a neuroscientist working on this approach at
Lund University in Sweden. The strategies in
development target focal epilepsy, but treating
generalized epilepsy is a longer-term possibility.
Elizabeth Nicholson and Dimitri Kullmann at University College London. RESTORING BALANCE
The brains of people with epilepsy contain
N E UROLOGY increased amounts of neuropeptide Y (NPY), a
chemical that certain neurons release when they
Repairs for a are especially active. NPY acts on five receptors,

Y1 to Y5, some of which are excitatory and some
inhibitory. The levels of some of these receptors
are also altered in epilepsy: notably, levels of
runaway brain Y2, which strongly inhibits neurotransmitter

release, are higher. Overall, the accumulation of
NPY and the altered levels of its receptors seem
to represent an adaptive response — an intrinsic
bid to hold back runaway brain activity.
Gene therapy could damp down epilepsy seizures in people In 2004, investigators used a viral vector to
for whom current drugs are ineffective. deliver the NPY gene into the brains of rats
that had been manipulated to display a form of
epileptic activity1. The resulting overexpres-
BY LIAM DREW people with epilepsy, each one selected to quell sion of NPY caused a reduction in seizure
the rampage of electrical activity that causes frequency. Other animal experiments also
T
he seizures of around one-third of epileptic seizures. The most advanced projects showed that overexpressing the neuropeptide
people with epilepsy are resistant to avail- are now being readied for clinical trials. galanin likewise suppressed seizures.
able medicines — a statistic that haunts Kokaia, who was already working on NPY
neurology. It has been this way for decades. The EXCITATION AND INHIBITION and epilepsy at the time, became interested
medicines have got better by becoming safer Epilepsy comes in many forms. It is defined in the therapeutic potential of this approach
and causing fewer side effects. But still there by the repeated occurrence of seizures — but and started experimenting with introduc-
are people for whom the drugs simply don’t these seizures can vary in their nature, inten- ing genes for neuropeptides, their receptors
work — and for them, epilepsy can be ruinous. sity and frequency. And the disorder can arise or both. He found that overexpressing NPY
“There’s stigma; they can’t drive; they have from numerous causes, progress in different alone decreased seizure frequency, but simul-
difficulty holding down jobs; they have diffi- ways and affect distinct parts of the brain. taneously overexpressing it with the inhibi-
culty maintaining relationships,” says Dimitri Crucially, epilepsy can either be focal, with tory Y2 receptor dramatically heightened the
Kullmann, a neurologist and neuroscientist at seizures beginning in a specific brain region, anti-seizure effect2. “What we are trying to do
University College London (UCL). or generalized, with seizures developing across is boost the natural response of the brain by
Currently, the main hope for people with wide spans of the brain. Focal epilepsy is more gene therapy,” says Kokaia.
severe drug-resistant epilepsy is surgery. Some- common, and it can be further subcategorized In 2015, Kokaia co-founded CombiGene in
one whose seizures arise from a well-defined according to whether the seizures remain focal Lund, Sweden, to commercially develop this
region of the brain might be offered an opera- or spread to become generalized. There is also technique. In the past two years, CombiGene
tion to remove that region. This is a drastic pro- variation in the size of the seizure-generating has confirmed the anti-seizure effects of the
cedure, but not especially rare; it is carried out focus and whether it is discrete, and therefore NPY–Y2 combination therapy, now called
about 500 times every year in the United States. potentially removable, or enmeshed with vital CG01, in further rodent models of epilepsy.
Kullmann is hoping that gene therapy can brain tissue, and thus inoperable. And the company has successfully introduced
make such surgery unnecessary. His group and Brains essentially work by relaying electri- the NPY and Y2 genes into brain tissue that was
others are investigating the potential benefits cal signals from neuron to neuron through surgically removed from people with epilepsy.
of introducing different genes into the brains of the release of chemical neurotransmitters. Experiments using such tissue also ended
S8
interest in the second neuropeptide, galanin. tool — DREADDs (designer receptors exclu-

ESTHER KROOK-MAGNUSON
Whereas NPY suppressed neurotransmis- sively activated by designer drugs) — into a

sion in human tissue, galanin did nothing — therapy. DREADDs are genetically engineered
human neurons lack functional receptors for it. receptors that, like opsins, sit silently in neurons
Kullmann’s move into the epilepsy field was unless they are activated by a stimulus, but in
serendipitous. His group was investigating the this case, the stimulus is a drug rather than light.
voltage-gated potassium channel Kv1.1 — a Both Kullmann and Kokaia have found that
type of ion channel that electrically quiets neu- inhibitory DREADDs can suppress seizures
rons — as part of work on an entirely different when the genes encoding them are inserted
neurological condition, episodic ataxia. The into the seizure foci of epileptic animals using
group made a virus that transferred the Kv1.1 viral vectors. If the therapy were translated to
gene into neurons. Because a neighbouring humans, people might take the activating drug
laboratory was routinely using rodent models regularly in a similar way to current epilepsy
of epilepsy, Kullmann and colleagues thought it medicines — but with the advantage that the
might be worth testing Kv1.1 in these animals. DREADDs would not inhibit brain tissue out-
The effect, published in 2012, was a dramatic side the region where the DREADD is situated. Brain cells could be manipulated using light.
reduction in seizure frequency3. After see- Alternatively, people might receive the drug
ing this effect in three separate animal mod- automatically through an implanted, seizure- awkwardly located foci make them ineligible for
els, Kullmann and UCL colleague Stephanie activated drug-delivery system, or simply take surgery, says CombiGene chief executive Jan
Schorge developed a viral vector that intro- the drug when they feel the first indications of Nilsson. And, more speculatively, if it is success-
duces a modified Kv1.1 gene specifically into a seizure. ful, gene therapy could potentially be adopted
excitatory neurons, and does not integrate the Kullmann is also exploring an ion channel by some people instead of conventional drugs.
gene into the cell’s genome. that was originally identified in nematode But for the time being, CombiGene and
In principle, CG01 or Kv1.1 could provide worms. In nematodes, the glutamate-gated Kullmann’s team are
long-term suppression of epileptic seizures chloride (GluCl) channel is inhibitory and is “What we are planning safety and
following a single injection, with the genes activated by the neurotransmitter glutamate. trying to do tolerability trials that
continually generating products that calm the But in mammals, glutamate is the main excita- is boost the will involve only peo-
neurons in which they are expressed. tory neurotransmitter that is responsible for natural response ple with drug-resist-
driving excess activity during seizures, and ant epilepsy who are
of the brain by
TRIGGERED ACTIVATION none of its receptors is inhibitory. awaiting surgery. This
Several alternative approaches are mainly Kullmann and his colleague Andreas Lieb
gene therapy” is not because people
based on converting widely used basic- were interested in using an engineered version in this group are the
research technologies into clinical tools. These of the GluCl channel that is activated by a drug, sole intended recipients of gene therapy —
approaches are more complicated, but hold but then they learnt that mutations in GluCl rather, they present a unique opportunity.
potential advantages over CG01 or Kv1.1. can change its glutamate sensitivity. If they The virus is likely to be given during presur-
Opsins, for example, are membrane picked a mutated channel that was insensitive gical investigations of the seizure locus, then
proteins that are activated by light, and the to normal levels of glutamate, but activated by allowed to enter neurons and deposit its genetic
genes encoding them have been isolated from the high levels of glutamate that occur during cargo while the patient spends weeks to months
microorganisms. When illuminated, some seizures, they might have an appealing gene- awaiting surgery. In phase I trials, surgeons will
types excite neurons, whereas others inhibit therapy agent: an inhibitory ion channel that then almost certainly remove the focus. This
them. The big appeal of opsins is that they is ordinarily inactive but called into action procedure will allow researchers to carefully
could remain inert in neurons when brain during seizures. Early findings are encourag- examine whether the gene delivery worked,
function is normal and only be called into ing: in two rat models, GluCl decreases seizure and will also provide a fail-safe mechanism for
action when needed. frequency5. excising genetically modified tissue should any
Esther Krook-Magnuson, a neuroscientist at safety issues arise.
the University of Minnesota in Minneapolis, has PRIMED FOR CLINICAL TRIALS The alternative is that people could opt out
shown that opsins can control seizures in rats4. In January, CombiGene partnered with the of surgery. If gene therapy is to be approved
Her team introduced inhibitory opsins into London-based incubator Cell and Gene for epilepsy, numerous larger, more strin-
the rats’ epileptic foci, then implanted seizure- Therapy Catapult to develop manufacturing gently controlled trials specifically designed
detecting electrodes into their brains, along with processes for CG01 in preparation for clinical to look at anti-seizure effects will be needed.
fibre optics that light up to activate the opsins. trials. And in April, Kullmann and Schorge But Kullmann allows himself to imagine a
An algorithm switched on the light when it received nearly £2 million (US$2.5 million) best-case scenario with the first exploratory
detected the first signs of epileptic activity, from the UK Medical Research Council to move trial. Someone who has stopped having sei-
quashing seizures early. Krook-Magnuson notes the modified Kv1.1 virus towards the clinic. zures after the gene transfer, he says, might
that implanting electrodes and light sources into Several technical hurdles remain, including simply elect not to have surgery — entering a
humans would be less invasive than the current scaling up the drug-delivery system: a human realm where their seizures are quelled not by
option of removing an area of brain. brain is around 700 times larger than the rat conventional medication, but by DNA. ■
However, this system requires a reliable brains in which the viral vectors have been
seizure-detection method, an effective light- tested. But a major advantage of using NPY, Y2 Liam Drew is a freelance science writer in
delivery technique and a way to get the right and Kv1.1 is that they are derived from human London.
amount of virus into the right neurons. All three genes — and therefore unlikely to evoke an
components will have to be optimized before immune response. By contrast, microbial 1. Richichi, C. et al. J. Neurosci. 24, 3051–3059
(2004).
the system has a chance of reaching the clinic. opsins and GluCl from nematodes carry the 2. Ledri, L. N. et al. Neurobiol. Dis. 86, 52–61 (2016).
The need to develop more than one risk of rejection by the immune system. 3. Wykes, R. C. et al. Sci. Transl. Med. 4, 161ra152
technology can put off potential investors, says The hope is that gene-therapy treatments (2012).
4. Krook-Magnuson, E., Armstrong, C., Oijala, M. &
Kullmann. He has first-hand experience of will be applicable to all drug-resistant focal Soltesz, I. Nature Commun. 4, 1376 (2013).
this from trying to transform another research epilepsies, including in people whose larger or 5. Lieb, A. et al. Nature Med. 24, 1324–1329 (2018).
S9
be a challenge: it involves such hefty upfront
STEVE BABULJAK/UCSF
costs that insurers might not be able to cover
the treatment, even if it saves them money
in the long term.
The only current cure for sickle-cell disease
is a bone-marrow transplant from a matched
healthy donor. The stem cells that serve as
blood-cell factories — haematopoetic stem cells
— are removed from the donor’s bone marrow
or blood, then infused into the recipient. If the
transplant works, the donor’s stem cells churn
out non-sickle-shaped red blood cells, curing
the disease. Donors can be a sibling or some-
one unrelated with the same bone-marrow type,
but less than one-third of people with sickle-cell
disease can find a matched donor.
Gene therapy could provide a cure for many
more people because it doesn’t rely on a donor:
instead, stem cells are harvested from the
patient’s own bone marrow. As a further benefit,
gene therapy avoids conflict between the donor’s
and recipient’s cells. After a bone-marrow trans-
plant, doctors have to suppress the recipient’s
immune system to prevent it from attacking the
transplant, which leaves the patient vulnerable
to infection. Even then, the donor cells might
attack the recipient’s cells, resulting in graft-
versus-host disease — the leading cause of death
after a bone-marrow transplant. Gene therapy
Six-year-old twins Tylee and Taleeke both have sickle-cell disease. eliminates this concern.
BLOOD DISEASE GENE THERAPY ON TRIAL

Mark Walters, a paediatrician at UCSF
Medicine is in Benioff, is working on two gene-therapy clini-

cal trials. One by Bluebird Bio in Cambridge,
Massachusetts, is in phase I/II, and one by
Bioverativ in Waltham, Massachusetts, will
the blood start soon.

For the Bluebird Bio trial, Walters has
enrolled two people so far, and plans to enrol
four or five in all at his institution — a total of
50 people will be recruited across the United
Sickle-cell disease is an ideal target for gene therapy, but States. The trial is using the gene-therapy drug
economic and social barriers to treatment are rife. LentiGlobin BB305 to insert a healthy version of
the β-globin gene into people’s blood stem cells.
With the gene, the stem cells will make normal
BY ANNA NOWOGRODZKI “If they were tracked before,” says Vichinsky, red blood cells instead of sickle-shaped ones.
“they would not be dead.” Stem cells are harvested from each person in
E
lliott Vichinsky estimates that at least Gene therapy might offer a cure for sickle- the trial, and they receive blood transfusions
30% of his adult patients with sickle- cell disease, and clinical trials are already every 3–4 weeks to reduce the percentage of
cell disease die from preventable under way. “In the long run I think it will be sickle cells in their blood, says Walters. “We
causes. Red blood cells are supposed to be able to cure the disease,” says Vichinsky, a hae- don’t want patients having complications in the
shaped like concave discs, but in people with matologist and oncologist at the University of middle of the trial or leading up to it.”
sickle-cell disease, a mutation in a single gene California, San Francisco (UCSF) Benioff It takes about a month for the new gene to
collapses them into a crescent shape. The Children’s Hospital in Oakland. The approach be inserted into the patients’ stem cells. After
pointy sickles catch on each other and clog is promising because just a single gene needs being collected up, the cells are shipped over-
blood vessels. They cut off oxygen to limbs. correcting: the one for the β-globin subunit night by plane to a central manufacturing
They cause kidney failure, hypertension, lung of haemoglobin, the body’s oxygen ferry. location, where they spend several days just
problems and strokes — along with bouts of But Vichinsky is concerned that the same multiplying. Then scientists put the β-globin
excruciating pain. problems that make current care ineffective gene into the stem cells using LentiGlobin
Thes e are common and treatable will also plague this gene-therapy treatment. BB305, a vector made from a virus. After qual-
complications, so why the high death rate? As his patients attest, sickle-cell care is often ity-control testing, the improved stem cells are
Vichinsky attributes it to a lack of infrastruc- inadequate for reasons that have little to do frozen and shipped back to UCSF Benioff.
ture, such as care centres, to properly monitor with scientific advancement and lots to do with In the meantime, the patients receive four
adults with sickle-cell disease. This is partly economics and racism. days of intensive chemotherapy to wipe out any
because the disease mainly affects low-income For people with sickle-cell disease in the remaining stem cells with the old, problematic
minorities and people in developing countries. United States, paying for the treatment could version of the gene. The improved stem cells
S10
are then reinfused into the person around a

EYE OF SCIENCE/SPL
day later, and their immune system regains its

strength slowly. “It takes about three months to
completely recover,” says Walters.
A COSTLY ENDEAVOUR
The clinical trials will demonstrate whether
gene therapy is effective at curing sickle-cell
disease. But even if it is, the cost of treatment
is likely to be very high. For example, voreti-
gene neparvovec (Luxturna), a gene therapy
for degenerative blindness, costs US$425,000
per eye. “We’re looking upwards of $500,000 to
$700,000” for sickle-cell gene therapy, spread
over multiple years, says Stephanie Farnia,
director of health policy and strategic relations
at the American Society for Blood and Marrow
Transplantation in Chicago, Illinois. And this is
a disease for which more than 50% of patients
in the United States rely on government health
insurance such as Medicare and Medicaid.
In the long term, an expensive cure for
sickle-cell disease would probably be cheaper
than — and much more preferable to — dealing Normal red blood cells (red) compared with the elongated blood cells in sickle-cell disease (pink).
with 30–40 years of the disease’s chronic, long-
term effects. But even if the pharmaceutical one-third who have a suitable bone-marrow just because there’s no basic care available,” he
company spreads the cost to insurers over donor, it doesn’t open it up to everyone. “It’s says. The US Centers for Disease Control and
5–7 years, Farnia says, insurers, particularly still an intensive procedure,” says Walters, Prevention list 175 providers of paediatric
government-funded ones, will probably not particularly the high dose of chemotherapy care for sickle-cell disease in the United States,
have sufficient capital to pay for everyone who that people receive before the stem cells are but only 44 providers of adult care. Vichinsky
wants the treatment. “The really tough part is returned to their bodies. “Not everybody is started his own adult programme because he
these budgets do not have a lot of room in them well enough to go through it.” had nowhere else to transfer his young patients
for additional costs,” Farnia says. It’s like trying Recruiting for clinical trials might also be a when they became adults. “It has to do I think
to pay for an entire 30-year mortgage in just problem. Current trials involve small numbers with money and ethnicity,” he says.
five years, she says. “You’re going to save a lot of people with sickle-cell Basic care for sickle-cell disease should be
more money down the road, but can you come disease, but if the treat- “Sickle-cell modelled on current programmes for cystic
up with the money to do that?” ments work, future trials fibrosis or childhood cancer, says Vichinsky.
disease
For a possible preview, Farnia suggests will require many more He advocates that sickle-cell-disease medical
looking to chimeric antigen receptor T-cell participants. In the United
represents centres should include multidisciplinary teams
(CAR-T) therapy — a type of immunotherapy States, sickle-cell disease
the best and to monitor people for the degenerative effects
that has shown promising results in treating is more common among worst of of sickle cells across many different organ sys-
certain types of cancer. US medical centres black and Hispanic popu- health care tems, such as the lungs, heart, kidneys, spleen
and hospitals are paying for CAR-T therapy lations, and there is an ugly in the United and brain. That way, doctors could detect early
up front to treat their patients, before know- history of non-consensual States.” warning signs of problems such as renal failure
ing whether insurers will reimburse them medical research on black and hypertension.
for it. “And they have to hope they can figure people, causing some to be wary of participat- He is optimistic, however, that sickle-cell gene
out with payers that they get reimbursed for ing in clinical trials. And racial bias also gets in therapy might act “as a kind of door opener to
enough of that,” Farnia says. the way of treating the disease. “The hallmark the field of gene therapy”. There are a handful of
of sickle-cell disease is pain, and it’s excruciat- gene-therapy drugs on the market, but sickle-
CHALLENGES AHEAD ing pain. It’s like putting a tourniquet on and cell disease’s role as an early gene-therapy target,
There are other concerns with gene therapy depriving a limb of oxygen,” says Walters. And and the promise of that therapy, might attract
as well. For one, more long-term monitoring unfortunately, doctors have been shown by interest in how best to care for people with this
is needed. The added gene slips in at random multiple studies to be less likely to believe black disease, and propel standards of care forward.
places in each stem cell’s genome, so it has people’s claims to be in pain than white people’s “Sickle-cell disease represents the best and
thousands of opportunities to land in the (see, for example, K. M. Hoffman et al. Proc. worst of health care in the United States,”
middle of another important gene. It could Natl Acad. Sci. USA 113, 4296–4301; 2016). Vichinsky says. Technologically advanced
theoretically wind up in a gene that suppresses Sickle-cell disease is a chronic condition. gene therapy is a hot research area, but not
cancer. No one has yet observed a leukaemia Management of chronic diseases isn’t typically yet proven to work. Mundane chronic illness
caused by delivering treatments with the fam- groundbreaking, and even among chronic dis- care is neglected, but it would save lives. “Most
ily of viral vectors that LentiGlobin BB305 eases, sickle cell is typically neglected. “It’s not adults don’t have access to multidisciplinary
belongs to, Walters says, but a stem cell is received the attention or the national funding services,” says Vichinsky. “I believe to some
long-lived. “If you treat a child, it’s going to be that it maybe should have received, because it’s extent that gene therapy will actually stimulate
a source of blood for the next 50–60 years.” No not as politically connected,” says Walters. the medical and scientific community to bring
patients have been monitored for anywhere Vichinsky argues that gene therapy should that to sickle cell.” ■
near that long after gene therapy. be part of a multidisciplinary programme that
Although gene therapy opens up bone- includes basic care, not a substitute for basic Anna Nowogrodzki is a science writer based
marrow transplants to more people than the care. “We shouldn’t push them into gene therapy in Boston, Massachusetts.
S11
DE RMATOLOGY
Under
the skin
The largest organ in the
body is a prime target for
gene therapy.
B Y K AT A R N E Y
I
t’s not often that a figure in a scientific
paper can make you wince with pain.
But it’s impossible to look at figure 1a in
Michele De Luca’s 2017 Nature paper and
not feel a sympathetic twinge at the sight of a
young boy, Hassan, covered from head to toe
with red-raw wounds1.
The son of Syrian refugees who fled to
Germany, Hassan was born with junctional clinical experience, so it was obvious to try and version of LAMB3. The next challenge was
CMR UNIMORE
epidermolysis bullosa (JEB) — a condition genetically modify these cells for treating rare growing enough 12-centimetre-square sheets
caused by a genetic fault in one of three genes skin diseases like JEB,” De Luca says. of modified cells for Ruhr University plastic
(LAMA3, LAMB3 and LAMC2) encoding sub- The idea of growing genetically modified skin surgeon Tobias Hirsch to wrap around the
units of the laminin-332 protein, which binds for therapeutic use was first proposed in 1994 by child’s fragile body.
the surface of the skin to the underlying layers. dermatologist Gerald Krueger at the University After two major operations to replace the
Affected children rapidly develop large, pain- of Utah in Salt Lake City2, and De Luca and skin on Hassan’s limbs and torso, followed by
ful blisters over their skin and internal mucous his team reported the results3 from an initial some smaller procedures, around 80% of the
membranes, which can easily become infected. small clinical trial of genetically modified skin entire epidermis had been replaced, making
By 2015, when Hassan was seven, his skin grafting back in 2006. it the largest genetically modified graft per-
was almost entirely destroyed and he was The recipient was a 36-year-old man with formed to date. By the time the results were
suffering from severe bacterial infections. JEB caused by a LAMB3 mutation. He was published in 2017, Hassan was like a different
Doctors at Ruhr University in Bochum, treated with nine small patches of skin that child, his raw blisters replaced with smooth,
Germany, could offer only palliative care were grown from his own epidermal cells perfectly functional skin.
to relieve his suffering. But Hassan’s father and modified with a viral vector expressing
enquired about experimental treatments, and the missing gene. The grafts remained stable
XIAOYANG WU/CYNTHIA LI
the doctors got in touch with De Luca at the and healthy for more than a year, proving that
University of Modena and Reggio Emilia, Italy, the technique had the potential to provide
who was working on a radical skin therapy. long-term correction of the condition.
De Luca’s research builds on the life-saving
work of cell biologist Howard Green at the UNSCHEDULED INTERRUPTION
Massachusetts Institute of Technology in Despite this early success, De Luca’s clinical
Cambridge. Green was the first to discover that work ground to a halt for nearly a decade owing
sheets of skin cells could be grown in the labo- to European Union legislation governing cell
ratory, creating personalized skin grafts that and gene therapies. “The regulations regarded
avoid the problems of immune rejection. De our grafts as medical products, so they had to
Luca worked with Green at Harvard Medical go through the same regulatory process,” he
School in Boston, Massachusetts, in the sighs. “We had to stop all our activities, build up
1980s, and he later decided to develop Green’s a compliant manufacturing facility and register
approach for treating genetic skin conditions the therapy — it was only in 2015 that we were
by genetically modifying the skin cells to fix finally able to start our trials again.”
the disease-causing mutation. Luckily, this was just in time for Hassan.
“We’ve been using epidermal skin-cell De Luca’s team took a tiny unblistered skin
cultures for many years to treat hundreds sample from the child’s groin, then carefully
of patients, carrying out a lot of work on cultured the epidermal stem cells and modified
basic stem-cell biology as well as gaining them with a viral vector carrying a functional A skin graft with fluorescent staining.
S12
They then grew the cells into small skin grafts epidermolysis bullosa, which can be caused by a
and transplanted them onto the backs of mice. fault in any one of at least 18 different genes and
The researchers found that the engineered affects around 1 in every 20,000 children born
skin grafts could successfully secrete GLP1 in the United States. And it’s by focusing on the
into the animals’ blood in response to the drug, youngest patients, who have the most to gain
slowing weight gain and preventing diabetes in from early intervention, that De Luca hopes to
mice kept on a high-fat diet. make the biggest difference.
Wu’s team has now used this technique to “If we treat these children as soon as we can,
create similar patches of CRISPR-modified we will prevent the formation of skin lesions
skin cells that produce a tweaked version of rather than having to cure them — and, obvi-
an enzyme called BChE, which breaks down ously, we need to grow less skin to cover them,”
cocaine5. Wu’s version metabolizes the drug he says. “If you asked me 30 years ago if it was
more than 4,000 times faster than the natu- realistic to replace
rally occurring form, rapidly clearing it from “After three the whole skin with
the body and quickly killing the ‘high’. years, his skin transgenic epidermis,
When tested in mice, the skin patch stopped is stable with I would have said no,
the animals from becoming addicted to cocaine no blistering, but we have done it.
and prevented them from overdosing, pointing and it should The final aim of my
towards a potentially promising treatment for last a lifetime.” career is to make this
people with drug addictions. Wu and his team gene therapy a real
are also working on skin patches that could treatment for children — not a clinical trial
serve as long-term living biosensors — for or a demonstration of what we might do, but
example, engineering cells that change colour something that is used to treat everyone who
or fluoresce in response to blood glucose levels. needs it.”
“Many researchers are focusing on gene Three years on from his record-breaking
A sheet of therapy for internal organs like the liver, but skin replacement, Hassan is living testament
genetically the skin is much easier — we can culture the to this possibility, regularly visiting the team
modified cells indefinitely and do the editing outside the in Modena for check-ups.
skin cells. body,” Wu explains. “We can also very care- “When he was in hospital he weighed just
fully choose the correct clones to grow up into 17 kilos and was dying, but now he is growing
patches, with no off-target effects or rogue up,” De Luca says proudly. “I last saw him two
As well as detailing Hassan’s progress, the genetic changes.” weeks ago and he is like a mascot for the insti-
paper1 reveals why the treatment was a success. But human trials are likely to be some years tute — there is a big celebration every time we
The skin is made up of many different types off. “Right now we are still at the proof-of- see him, and everyone who was involved in his
of cells, some that are short-lived and others concept stage,” Wu says. “Once the technology treatment wants to give him a hug.” ■
that are much more persistent. The research- is more established and we are confident in the
ers showed that long-term grafting was only procedure, we can think about moving into Kat Arney is a science writer and broadcaster
possible if the genetically modified cells were clinical trials to treat diseases.” living near London.
holoclones — a relatively rare type of immortal Although De Luca finds this idea intriguing,
cell that can self-renew indefinitely. By adjust- he is more focused on making genetically modi- 1. Hirsch, T. et al. Nature 551, 327–332 (2017).
2. Krueger, G. G. et al. J. Invest. Dermatol. 103,
ing the culture conditions, De Luca and his fied skin replacement a viable treatment for the 76S–84S (1994).
team were able to encourage the growth of thousands of children born every year with 3. Mavilio, F. et al. Nature Med. 12, 1397–1402 (2006).
holoclones, greatly increasing the chance that genetic skin disorders. He is currently running 4. Yue, J., Gou, X., Li, Y., Wicksteed, B. & Wu, X. Cell
Stem Cell 21, 256–263.e4 (2017).
the resulting grafts would work. two clinical trials for people with different forms 5. Li, Y. et al. Nature Biomed. Eng. https://doi.
“After three years, his skin is stable with no of JEB, but is keen to expand into other forms of org/10.1038/s41551-018-0293-z (2018).
blistering, and it should last a lifetime,” says
De Luca. “There are still some areas of blister-
RUHR-UNIVERSITY BOCHUM
ing that weren’t covered with the grafts, and

there are other tissues like the mouth mucosa
that we couldn’t treat, but although we didn’t
completely cure the disease, we still fixed 80%
of his skin.”
FROM GRAFTS TO PATCHES

Over at the University of Chicago in Illinois,
Xiaoyang Wu is generating genetically modi-
fied skin with a different purpose in mind. In
2017, he and his team showed that genetically
modified skin grafts could be used as living
‘drug patches’ in mice4, akin to plastic nicotine
or hormone patches.
Using the gene-editing technique CRISPR–
Cas9, the researchers modified epidermal
stem cells with a version of the gene encoding
GLP1 — a hormone that controls blood sugar
levels and suppresses appetite — which could
be switched on by the antibiotic doxycycline. Around 80% of Hassan’s skin was replaced with genetically modified skin grafts.
S13
Taking notes from the fields of DNA vaccines
SAM FALCONER
and gene therapy, researchers are working to
bring treatments based on antibody gene trans-
fer into clinical trials, using infectious diseases
as a proving ground. The approach also holds
promise for tackling non-infectious conditions
such as cancer. “Wherever antibodies work, we
believe this technology can work in the same
way,” Padte says.
Antibody gene transfer has to overcome
the same hurdles relating to safety and deliv-
ery as does any other gene therapy, as well as
more-specific challenges such as getting cells
that don’t normally make antibodies to pro-
duce them in large quantities. “We know it
works [in mouse models]. You can do it for
another thousand disease indications and it
will work every time,” says Kevin Hollevoet, an
immunologist at the University of Leuven in
Belgium. The big question, he says, is whether
the approach can be applied to people.
PICK-YOUR-OWN ANTIBODIES
David Weiner, director of the Vaccine and
Immunotherapy Center at the Wistar Institute
in Philadelphia, Pennsylvania, has devoted
almost three decades to developing and refin-
ing DNA-vaccine technology. But about eight
years ago, Weiner realized that his work could
make an impact in a very different field. His
then-teenage daughter was diagnosed with
severe Crohn’s disease, and the only treatment
that worked for her was a monoclonal-
antibody drug that had to be injected several
times a month. Weiner took notice of the fast
IMMUNOLOGY growth of therapies based on monoclonal
antibodies, which include anti-inflammatory
A genetic shortcut drugs such as adalimumab (Humira) and

checkpoint inhibitors such as pembrolizumab
(Keytruda). “It’s one of the most important
fields in biotech,” Weiner says.
The drugs that the field produces are also
Gene therapies that turn the body into a designer antibody among the most expensive. Costing up to
factory could bypass drawbacks of expensive treatments. US$100,000 per year of treatment, monoclonal-
antibody therapies are out of reach for most of
the world’s population. Weiner thinks that gene
BY AMANDA KEENER it takes to grow the cells that produce such anti- therapy could make such drugs more acces-
bodies and to purify and test the resulting pro- sible. It costs much less to make DNA in the
O
utbreaks of infectious disease are teins. “There’s a short window of opportunity lab than to produce monoclonal antibodies.
becoming more common in many one has to halt an emerging infectious-disease The approach would also require fewer doses
parts of the world. Between 1980 breakout, and making antibodies takes time,” because lab-made DNA can last for weeks to
and 2010, the number of outbreaks reported says Neal Padte, chief operating officer at bio- months in the cell nucleus, while continuously
worldwide more than tripled every five years. technology company Renbio in New York City. instructing the cell to churn out antibodies.
Unexpected outbreaks caused by viruses such Padte belongs to a growing group of Since 2013, Inovio Pharmaceuticals in
as Ebola and Zika have led researchers to seek researchers who want to skip those steps by Plymouth Meeting, Pennsylvania, a company
faster and cheaper strategies for addressing simply giving the body the genetic information co-founded by Weiner, together with Weiner
pathogenic agents they know little about. These it needs to make the antibodies. This can be and his team at Wistar, has been develop-
strategies include using laboratory-made, achieved by delivering the DNA that encodes ing a number of DNA-encoded monoclonal
monoclonal antibodies that can immediately those antibodies to the cell nucleus — a process antibodies. It started by creating antibodies
bind to and neutralize specific viruses or bac- called antibody gene transfer. It’s similar to the to tackle viral infectious diseases such as
teria in a person who has been infected, but also idea behind DNA vaccines, which deliver DNA chikungunya and dengue fever and has now
protect, for a time, anyone who is likely to be that encodes vaccine components to cells. broadened its scope to develop such antibodies
exposed to a particular pathogenic species. The approaches differ in that DNA vaccines against antibiotic-resistant pneumonia and two
But monoclonal antibodies are expensive to are designed to trigger the immune system to proteins found at elevated levels in tumours of
produce, must be stored in the cold and often make its own antibodies, whereas antibody the prostate gland. They are now working on
require repeated administration by injection to gene transfer aims to introduce antibodies DNA-encoded monoclonal antibodies that
work. That’s not to mention the one to two years without inciting such an immune response. mimic antibodies against the Ebola virus from
S14
the blood of people who survived infection.

CAROLINE SINNO PHOTOGRAPHY
Inovio is not alone. Several groups of

researchers have produced monoclonal anti-
bodies in mice that can protect the animals from
infection and attack tumours. For example,
Padte and his collaborators in the United States
and China delivered genes that encode the three
antibodies that comprise the anti-Ebola-virus
vaccine ZMapp, as well as three anti-influenza
antibodies, into mice1. The antibodies protected
the animals from both Ebola and influenza.
This ability to pick and choose the most
effective antibodies for a disease is especially
attractive to researchers who study a special
class of antibody that can neutralize multiple
strains of HIV. Up to one-third of people with
the virus make these antibodies. That could be
down to genetic differences between individuals;
it might also relate to the strain of HIV encoun-
tered. “What you can do with antibody gene
transfer is just take the successful antibodies that
came out of these unusual pairings of people and
viruses and give them to a broad audience,” says
Alejandro Balazs, who studies immunity against
HIV at the Ragon Institute of MGH, MIT and Neal Padte (left) is building DNA constructs that could enable the body to produce tailored antibodies.
Harvard in Cambridge, Massachusetts. That
way, he says, “You are taking the black box of the an immune response. And because the virus THE HUMAN PROBLEM
immune response out of the equation.” is grown inside cells, production can be time- As antibody gene transfer enters clinical
The US National Institute of Allergy and consuming and costly. Approaches that leave out testing for infectious diseases and cancer,
Infectious Diseases in Bethesda, Maryland, is viruses, such as Weiner’s DNA-encoded mono- some researchers are starting to consider how
testing the delivery of a gene that encodes one clonal antibodies, avoid those limitations. But to make it work for chronic conditions such
such neutralizing antibody, on which Balazs without a virus to transfer the DNA, cells have to as arthritis. This is more challenging because
has worked for more than ten years. The trial be coaxed into accepting foreign genes, usually people with such disorders often have to switch
will evaluate the therapy’s safety in people with by a process called electroporation, in which an between monoclonal antibodies to find the one
HIV. If it goes well, Balazs says, there might electric current is used to create tiny, temporary that works best. A therapy that enables the
be opportunities to check whether the partici- holes in cells through which DNA can pass. body to produce antibodies for up to years at
pants’ bodies are converting the gene into the Scancell, a cancer-immunotherapy company a time, as can be the case with AAV-delivered
desired antibody. A separate trial, run by the in Oxford, UK, has used electroporation genes, would remove that option. “There is the
International AIDS Vaccine Initiative in New to transfer a gene encoding a lab-designed risk that you can’t shut it off,” says Crystal.
York City, is testing the safety of another gene antibody that primes immune cells called Balazs and other researchers are working
encoding an HIV-neutralizing antibody in a T cells to target tumours in people with mela- on ‘off switches’ in the form of complementary
cohort of healthy men. The outcomes of both noma. In 2017, the company reported that the gene therapies or drugs. But for now, Balazs
HIV trials will signpost how well antibody treatment safely induced an immune response says, it is still unclear whether approaches
gene transfer works in humans. “A lot of people against the cancer. that have been successful in mice will work in
are looking at this very closely,” Balazs says. For an even simpler approach to delivering humans. “We’re asking this one site of muscle
antibody genes, others are turning to messenger to pump out enough antibodies to distribute to
IT’S ALL IN THE DELIVERY RNA — the molecule that conveys information the entire body,” says Hollevoet, who is study-
There are many ways of delivering genes to stored in DNA to the cellular machinery that ing sheep to get a better sense of how much
cells. Few have been tested in people, however, makes proteins. For reasons not fully under- antibody the human body might produce.
and none has been assessed for inducing anti- stood, mRNA can make its way into muscle For the antibodies that have been tested only
body production. The HIV trials use a virus cells without the need for electroporation. in animals, it’s impossible to know the concen-
called adeno-associated virus (AAV) to carry In 2017, Drew Weissman at the University tration in blood that will be needed to treat a
genes encoding HIV-targeting antibodies of Pennsylvania in Philadelphia and his col- given disease. “That’s why these first clinical
into the muscle cells of participants. AAV has laborators injected an mRNA sequence for trials are going to be so important,” says Balazs.
a knack for getting foreign DNA into human an HIV-neutralizing antibody into mice, Then researchers can deal with next-level
cells, says Ronald Crystal, who works on gene protecting the animals from infection with features such as off switches. The mission is
therapy at Weill Cornell Medicine in New York HIV 3. The biopharmaceutical company straightforward, he says: “Let’s just see if we
City. “That’s what they live for.” CureVac in Tübingen, Germany, and its can make the thing turn on.” ■
AAV is also well suited to inserting antibody collaborators reported success with mRNA-
genes into hard-to-reach organs such as the encoded antibodies against viral proteins Amanda Keener is a freelance science writer
brain. Crystal and his collaborators used the involved in influenza and rabies, as well as in Littleton, Colorado.
AAV approach to deliver an antibody that the mRNA-encoded monoclonal-antibody
1. Andrews, C. D. et al. Mol. Ther. Methods Clin. Dev. 7,
reduced levels of tau, a protein implicated in drug rituximab, which is used to treat non- 74–82 (2017).
Alzheimer’s disease, into the brains of mice Hodgkin’s lymphoma4. And BioNTech in 2. Liu, W. et al. J. Neurosci. 36, 12425–12435 (2016).
with another type of dementia2. Mainz, Germany, is experimenting with mRNA 3. Pardi, N. et al. Nature Commun. 8, 14630 (2017).
4. Thran, M. et al. EMBO Mol. Med. 9, 1434–1447
But AAV, as well as other viruses used in anti- as a means of introducing T-cell activating (2017).
body gene transfer, has downsides. It can incite antibodies for cancer immunotherapy5. 5. Stadler, C. R. et al. Nature Med. 23, 815–817 (2017).
S15
THE RA PEUTICS
Special
delivery
By tweaking a virus’s shell,
Luk Vandenberghe thinks he
can transport genes into cells
much more efficiently and
cost-effectively.
B Y N E I L S AVA G E
L
uk Vandenberghe walks over to a shelf
in his office and picks up two fist-sized
objects. One is a more complicated
version of a Rubik’s Cube, with 20 individu-
ally coloured sides instead of the standard 6.
The other is an off-white glob of hard plastic
produced by a 3D printer. It’s studded with
bumps, dimples and repeating triads of vaguely
pyramid-like shapes, 20 in all.
Both are models of an adeno-associated virus
(AAV), a favourite vector among clinicians
for delivering genes to cells. Vandenberghe, a Luk Vandenberghe at Massachusetts
bioengineer who directs the Grousbeck Gene Eye and Ear in Boston holds a model
Therapy Center at Massachusetts Eye and Ear of an adeno-associated virus.
in Boston, is trying to work out what effect all
those tiny structures have on the behaviour
of the virus. His aim is to manipulate them to with which they penetrate tissue. The goal of Rubik’s Cube dilemma,” says Vandenberghe.
ARAM BOGHOSIAN/MASSACHUSETTS EYE AND EAR

improve the vector’s ability to deliver genes AAV research over the past two decades has “That’s not trivial on a cube, and it is certainly
without, in essence, messing up the colour pat- been treatments that use lower doses and do not trivial on an icosahedron.”
tern on the Rubik’s Cube — or in this case, the not affect off-target tissues.
icosahedron. Researchers are also trying to solve another LEARNING FROM HISTORY
Vandenberghe completed his doctorate problem. Because the viruses circulate in the To learn more about how structure affects
on the structural basis of AAVs in 2007 at the wild, many people have been exposed to them function, Vandenberghe and his team decided
Catholic University of Leuven in Belgium, and and have developed immunity. That puts thera- to reconstruct the evolutionary history of
later went on to become an associate professor pies that rely on AAVs out of reach for many AAVs. In 2015, he and his colleagues fed the
at Harvard University in Cambridge, Massachu- patients. Estimates for the number of people protein sequences of 75 AAV variants isolated
setts. Through a mix of computational model- with immunity vary widely, Vandenberghe says, from human and non-human primate tissues
ling and DNA synthesis, he has been trying to from 20–90%. Some of that variation is due to into an evolutionary computer simulation
solve the problems that arise from using natural geography; the viruses are more prevalent in and reconstructed the sequences of nine pos-
AAVs for gene therapy, and has founded three Africa, for instance, than in the United States. sible ancestors of modern AAVs2, the oldest
companies to bring his technologies to market. Bioengineers think they can achieve large of which they named Anc80. Vandenberghe
One of them is using an unusual non-profit changes in the function of AAVs by altering is not claiming these are the actual forms of
approach to tackle the economics of developing the capsid — the protein shell of the virus. For previous generations of viruses, but that isn’t
gene therapy for extremely rare diseases. instance, capsid differences are the reason why the point, he says. “We didn’t quite care. What
Naturally occurring AAVs have become a one naturally occurring AAV targets liver cells we really wanted to do was find inroads into
workhorse of gene therapy. They infect human with up to 100 times the efficiency of another. this structural problem that we had.”
cells without causing illness, and different vari- “Unfortunately, we still don’t know exactly what On the basis of the sequences, the researchers
ations of the virus target different cell types it is that makes one virus go to the liver 100-fold synthesized the ancestral viruses and examined
— so selecting the right virus is essential for better than the other,” Vandenberghe says. Sci- their characteristics — and Anc80 proved to be
getting replacement genes to cells where they entists also don’t fully understand how a change especially interesting. When injected into mice,
are needed. Vandenberghe and his colleagues in one part of the virus might affect the struc- the virus was able to penetrate all of the hair
have so far identified more than 140 natural ture in another part, in much the same way that cells in the inner ear and most of the hair cells in
variations of the virus1. moving a red square on a Rubik’s Cube might the outer ear, something no previous virus had
But scientists would like to fine-tune AAVs put a green square on another face out of place. accomplished. In 2017, Vandenberghe and his
to improve their specificity and the efficiency “What we’re trying to do is exactly solve that colleagues used Anc80 in mice to treat a genetic
S16
of the other 19 amino acids in existence in turn the retina is a relatively small organ, and some
to see what changes. Then he moves on to the retinal diseases are so rare that it’s possible
next amino acid in the sequence and repeats that a single batch of the drug could treat the
the process. “With this approach, we know entire patient population in the United States,
what the effect is for every possible individual Vandenberghe says.
change,” he says. Using machine learning, he
predicts what will happen when single-amino- A WIDER CONCERN
acid changes are combined, then synthesizes The question of how to develop gene therapies
promising sequences and tests the AAVs in for rare diseases is of great concern to the US
mice or non-human primates. National Institutes of Health, says P. J. Brooks,
Kelsic and Church have founded a company, program director at the institute’s Office of
Dyno Therapeutics in Cambridge, Massachu- Rare Diseases Research in Bethesda, Maryland.
setts, to create vectors this way. Kelsic predicts “When people discuss business models around
that even for tissues such as the brain that can treatments for rare diseases, the basic assump-
already be targeted with AAVs, more-efficient tion is that there is a business model,” he says.
viruses will lead to improved therapies. The “But for some of these diseases where there’s a
greater achievement, however, will be the ability very small patient population, there may not be
to target organs that are currently hard to treat, one.” Brooks says Odylia is the first company
such as the lung and kidney. “As we improve he has heard of to try this non-profit approach.
delivery further it will enable new therapies The idea, Vandenberghe says, is to find
which just aren’t possible today,” he says. economies of scale by sharing resources and
scientific and commercial expertise across the
A DIFFERENT BUSINESS MODEL development of a range of drugs that are simi-
The companies that these researchers have lar to one another. If the same group of people
founded follow the standard for-profit model develops the drugs, designs the clinical trials
used by most biotechnology start-ups. But and produces the materials, there should be
Vandenberghe is taking a different approach less duplication of effort, he notes. Vanden-
with Odylia Therapeutics, a not-for-profit berghe also hopes that after creating two or
company he founded in February. Odylia aims three successful treatments, the company will
to develop therapies for what Vandenberghe be able to provide data to convince the FDA
calls “ultra-rare” genetic causes of blindness, that there are enough similarities between the
which he defines as those that affect 3,000 or drugs to enable them to use experience with
fewer people in the United States. The firm is one drug to help establish the safety and effi-
supported financially by Massachusetts Eye cacy of another. It is also possible that Odylia
and Ear and the Usher 2020 Foundation in will take development of a drug far enough
Atlanta, Georgia, a charity focused on curing in this model that a for-profit company will
the sight loss caused by Usher syndrome. One decide to buy it and complete the work, pro-
of the charity’s founders, Scott Dorfman, who viding funding for Odylia while reducing the
disorder called Usher syndrome that causes has two children with Usher syndrome, is chief pharmaceutical company’s costs and risks.
deafness and visual impairment3. Excited by the executive of Odylia. If Odylia does bring a drug to market, it will
potential of such a vector, Vandenberghe and So far there is only one available gene therapy probably be sold at cost, Vandenberghe says.
his colleagues founded a company, Akouos, in for blindness. In late 2017, the US Food and That could still be expensive, but possibly less
Boston to develop treatments for hearing loss. Drug Administration (FDA) approved voreti- so than if it had been developed the usual way.
In August, the start-up secured US$50 million gene neparvovec (Luxturna) for the treatment There is also a chance that if a drug candidate
in a first round of investment. of eye disease caused by a mutation in the RPE65 gets through phase I and II clinical trials, the
Vandenberghe’s team is also collaborating gene, which normally produces a protein in the FDA could allow it to be provided on a com-
with Selecta Biosciences in Watertown, thin layer of cells at passionate-use basis without a final clinical
Massachusetts, which wants to develop gene the back of the eye. “As we improve trial, or that most patients could be treated as
therapies using Anc80. Vivet Therapeutics in As a proof of concept, delivery further part of an open-ended trial.
Paris is licensing the vector for use in devel- the treatment shows it will enable If the model is successful, it could be
oping treatments for inherited liver disease. that gene therapy can new therapies extended to other rare, single-gene disorders
And Lonza in Basel, Switzerland, is licensing be used to cure eye which just aren’t and perhaps provide insights for developing
the technique for making the virus so it can disease. But muta- possible today.” gene therapies for more common condi-
manufacture the vector for drug-makers. Back tions in more than tions. “Maybe this is one of those areas where
in 2011, before the Anc80 work, Vandenberghe 200 genes have been linked to hereditary eye industry can acknowledge that this is indeed
also co-founded GenSight Biologics in Paris to diseases, and Vandenberghe says that there is non-competitive,” Vandenberghe says. Ideally,
develop treatments for rare inherited retinal little appetite in the pharmaceutical industry for he says, that would set up a happy scenario.
diseases; the company currently has two drugs developing individual therapies to correct many “We can all come together around some of
in clinical trials. of the other genes. these common goals, apply them to ultra-rare
Creating better vectors is the key to It can cost millions of dollars to develop a diseases, and then take those lessons to the
expanding gene therapy, says Eric Kelsic, a drug and take it through clinical trials, and if more commercial world afterwards.” ■
systems biologist in the laboratory of molec- a disease is rare, it may not make economic
ular engineer George Church at Harvard sense for companies to pursue a treatment for Neil Savage is a science and technology
University. Kelsic is taking a data-driven it. That is a particular issue in gene therapy, journalist in Lowell, Massachusetts.
approach to capsid engineering. He selects an in which people are often cured with a single
1. Gao, G. et al. J. Virol. 78, 6381–6388 (2004).
amino acid from the protein sequence of an dose rather than a life-long drug regimen. The 2. Zinn, E. et al. Cell Rep. 12, 1056–1068 (2015).
AAV and systematically switches it with each doses required for eye diseases are tiny because 3. Pan, B. et al. Nature Biotech. 35, 264–272 (2017).
S17
REGULATING
A REVOLUTION
Health authorities
wade into the flood
of gene therapies.
BY ERIC BENDER
SAM FALCONER
S18
F
or rare genetic diseases that trials have gathered plenty of evidence about could come out of the blue. But that doesn’t say
affect the young, such as a therapies such as Luxturna that are delivered that gene therapy shouldn’t be made available
neurodegenerative condition by adeno-associated viruses (AAV), especially to patients.”
called spinal muscular atrophy, for systemic administration or for commonly
gene therapies bring much- targeted tissues such as the eye. Such AAV BETTER BY DESIGN
needed hope — a chance for the therapies often create a short-term immune Given the novelty and the potential risks and
child to live a relatively normal response in the liver, but this problem can gen- rewards of gene therapies, their sponsors
life. But they also raise serious fears about their erally be treated by using steroids. “For other tend to start working with regulatory agen-
efficacy and the potential risks that accompany target tissues, or for doses that are higher than cies early in development — often, very early.
irreversible one-off treatments. people have used to date, you may need addi- “Ideally, you talk with the agencies when you
The responsibility for balancing these hopes tional information,” High says. “There actu- are designing your preclinical development,”
and fears lies with the European Medicines ally are a wealth of approaches to overcome says Anne-Virginie Eggimann, vice-president
Agency (EMA) and the US Food and Drug immune response, and it’s a matter of doing the for regulation at biotech company Bluebird Bio
Administration (FDA). Their credentials as clinical investigations and finding answers.” in Cambridge, Massachusetts. “You can have a
gatekeepers to the therapies will soon be tested Barry Byrne, director of the Powell Gene general discussion with them on designing that
by a flood of clinical trials. This year the FDA Therapy Center at the University of Florida in programme, as well as how you see your first-
expects to receive about 250 applications to Gainesville, says it is far too soon to declare in-human clinical trial.” In October, Bluebird
start clinical trials for novel cell and gene thera- today’s gene therapies safe. “There’s very lim- Bio submitted a marketing application to the
pies, says FDA commissioner Scott Gottlieb. ited experience,” he cautions, “and there’s much EMA for its LentiGlobin gene therapy, which
Faced with rapid advances in biological more work to be done to understand how these is designed to treat a rare blood disease called
understanding and therapeutic delivery might be used in a variety of conditions.” transfusion-dependent β-thalassaemia.
technologies, the two regulatory agencies are There are many unanswered questions, such Like LentiGlobin, about 70% of the
establishing new guidelines for clinical trials as what happens if a patient who receives a investigational new drug (IND) applications
and are preparing to make tough decisions gene therapy delivered by AAV has previously for gene therapy submitted to the FDA are for
about which drugs to approve for marketing. been exposed to some form of the virus, or if rare diseases. Most of these conditions first
But drawing on their experience with hundreds proteins created by gene therapies provoke appear in childhood, and most of those have
of earlier studies, the agencies are confident that a reaction because the immune system has devastating results. But running a normal
they can assess gene therapies as effectively as not been trained to recognize them as ‘self ’, clinical trial, which includes large numbers of
they do any other novel therapeutics. Byrne adds. But he believes that strategies are subjects and a control arm, is often impossible.
emerging to avoid or control such immune “We know that in these situations you have
STANDARDIZING SAFETY problems. to exercise some flexibility, and that is exactly
Gene therapy has long been haunted by a very what we usually discuss with the companies
small number of deaths, originally in a 1999 when they come early,” says Eichler. “We nego-
US clinical trial and then in a European study
a few years later. However, a series of successful “YOU CANNOT tiate and see how can we get the best that is
doable in the circumstances.”
clinical trials over the past decade has created
sufficient confidence to move forward with
these treatments.
HAVE TWO Given the devastating nature of many rare
inherited diseases that strike children, parents
often press for accelerated clinical tests. But
One milestone, in December 2017, was the
first FDA approval of an in vivo gene-therapy STANDARDS developers emphasize that lowering safety
standards is not an option. “I really understand
product, for Luxturna from Spark Therapeu-
tics, based in Philadelphia, Pennsylvania.
Luxturna treats a rare, inherited eye condition
FOR SAFETY.” the urgency of parents whose child has a seri-
ous illness,” says High. “On the other hand, this
is a field where you cannot have two standards
caused by mutations to a gene called RPE65 for safety.”
that can cause blindness. New forms of gene-therapy delivery and Trial sponsors and regulatory agencies
Another was the announcement in August mechanisms of action sometimes do not also worry about how candidate products are
2018 that gene therapies no longer need to perform as expected when they enter clini- manufactured, and how the products might
be reviewed before clinical studies can begin cal studies. In September 2018, Sangamo be affected by changes in the manufacturing
by a US National Institutes of Health (NIH) Therapeutics, based in Richmond, California, process over time. Making gene therapies is
advisory committee on recombinant DNA reported the initial results of the first trial of a highly complex process using biological
that was created at the dawn of genetic medi- gene editing inside the body, for a therapy to materials, and extremely high quality must
cine. “There is no longer sufficient evidence to treat a rare metabolic disease called Hunter be assured at every step. Most academic labs
claim that the risks of gene therapy are entirely syndrome. The disease, which primarily affects and biotech startups lack the expertise and
unique and unpredictable — or that the field males, causes a host of serious symptoms, and the equipment to pull off this feat well enough
still requires special oversight that falls outside treatment currently requires weekly injections to produce commercial-grade therapies at
our existing framework for ensuring safety,” of enzymes. But the initial Sangamo trials failed a commercial scale. Few biomanufacturing
wrote Gottlieb and NIH director Francis to demonstrate clinical benefit, and they are facilities currently provide such services, and
Collins in a paper published earlier this year now continuing with higher doses. these operations are overloaded by the num-
(F. S. Collins & S. Gottlieb N. Engl. J. Med. 379, The regulatory agencies are seeking to provide ber of therapies now heading towards clinical
1393–1395; 2018). more guidance on such emerging gene-editing trials. The difficulties are compounded by the
Even so, such a new class of medicines still therapies. The EMA and the FDA are working need, as trials progress, to improve the manu-
poses serious risks. “It’s not that people say: together “to avoid digressions between the two facturing processes while keeping the product
‘Oh, it’s all safe, don’t worry’,” says Katherine of us”, says Hans-Georg Eichler, senior medical consistent enough to keep regulators happy.
High, a haematologist and president of Spark. officer at the EMA. “In gene therapy in general, “Manufacturing is something we will have
“It’s that now we really have some parameters we like to believe that we know what the major to think about differently, so we can get it right
inside which we can work.” risks are, but you can never know,” Eichler the first time,” says Peter Marks, director of
She points out, for example, that previous says. “Tomorrow, something totally new the FDA’s Center for Biologics Evaluation and
S19
ED SHIPMAN/MASSACHUSETTS EYE AND EAR

Surgeons use Luxturna, the first in vivo gene therapy to be approved by the US Food and Drug Administration, to treat a boy with a genetic eye condition.
Research in Silver Spring, Maryland, which committee members from various states meet find that reflected in the guidance documents
oversees gene therapies. to make decisions about marketing approval. that the FDA and the EMA provide.”
“Quite often people develop things on the At the FDA, reviewers within the appropriate Gene-therapy developers worry that the
lab bench at a very small scale, and they need division follow the drug candidate throughout agencies lack enough experts to deal with the
to scale up and scale out their thinking,” says its entire life cycle. incoming wave of trials for cell and gene thera-
Jacqueline Barry, chief clinical officer for the But the two agencies take similar data-driven pies, which the FDA estimates will reach 1,000
Cell and Gene Therapy Catapult, a UK gov- approaches to assessing drug safety and effi- a year by 2021. “They don’t have enough peo-
ernment commercial incubator. “We try to cacy, often actively working together in the ple to handle that kind of workload,” says High.
work with them very early on about moving process. Several times a year, for example, they “For the FDA, the issue is always around the
to a good manufacturing process and gather- hold teleconferences on gene therapies. “We all budget, and being able to have the appropriate
ing data that will support the evolution of the know there are so many uncertainties in this technology and people to deliver on their com-
product between clinical-trial phases without field, and so many new developments that we mitments,” says Peter Saltonstall, president of
having to go back and redo studies.” want to keep each other abreast of,” says Eichler. the National Organization for Rare Disorders
Gene therapies also require follow-up for based in Danbury, Connecticut.
patients that extends for years after prod- It is still early days for gene therapies, but
uct approval because the long-term effects
of these one-time treatments are simply “I DON’T SEE so far, developers generally give both agen-
cies high marks as partners. “I don’t see the
THE AGENCIES
not known. “Clinicians must come to grips agencies as a barrier at all,” says Byrne. “They
with that idea,” says Eichler. “As we treat, we have so many mechanisms for interacting with
must ascertain that the patient experience — sponsors now, and they’ve always approached
good or bad — must somehow be fed back to
decision-makers and contribute to long-term AS A BARRIER sponsors as collaborators in bringing these
agents forward.”
knowledge generation.”
SEEKING APPROVAL
AT ALL.” Eggimann agrees. “The regulators have been
very supportive of innovation and gene therapy
in general, and they are very eager to learn,” she
Europe and the United States have very different says. “Our challenge comes from the novelty of
legal and regulatory regimes for approving Both agencies released major updates to their the science, not so much from the regulatory
gene therapies. The main difference is that gene-therapy guidelines in 2018. The FDA, for aspects.”
the FDA oversees clinical trials, whereas the example, offered its first draft recommenda- Meanwhile, the therapies keep moving
EMA does not. To run a clinical trial in any tions by class of illness, starting with haemo- forward. Among them is AVXS-101, a gene
of the 28 members of the European Union, philia, retinal disorders and rare diseases. It therapy from AveXis based in Bannockburn,
“you have to get approval from a competent also added draft frameworks for certain man- Illinois. AVXS-101 has raised high hopes in
authority and from the ethics committee in ufacturing processes and requirements for early clinical trials for the treatment of spinal
that member state,” says Barry. You also have long-term patient follow-up. The EMA also muscular atrophy, that devastating neuro-
to get approval for using a genetically modified completely overhauled its frameworks for gene degenerative condition that affects children.
organism (GMO). However, “the clinical-trial therapies. For instance, it reworked its guidance In October 2018, AveXis applied to both the
directive and the GMO directive are trans- on the design, manufacture, characterization FDA and the EMA for marketing approval —
lated slightly differently in each country,” she and testing of delivery mechanisms. yet another bridge that gene therapy is crossing
points out. “As the field gains more and more on its journey from the lab to the clinic. ■
Moreover, participation in decisions is experience, the broad outlines of what needs
structured differently in Europe and the to be submitted to initiate clinical studies have Eric Bender is a science journalist based in
United States, says Eggimann. At the EMA, come more clearly into focus,” says High. “You Newton, Massachusetts.
S20
PERSPECTIVE
Access and affordability for all
The hope of gene therapy could be crushed by its financial burden unless
there are more rational ways of paying for it, says Michael Sherman.
G
ene therapy offers the possibility of a cure for previously extremely expensive treatments, is a good candidate for value-based
untreatable diseases. But although the science and technol- agreements. Take, for example, the high-cost biological drug eteplirsen,
ogy behind it are awe-inspiring, the costs can be daunting. which targets the gene responsible for Duchenne muscular dystrophy
Treatments are likely to have a price tag in the neighbourhood of (DMD). The FDA expedited approval of the drug in 2016 because
US$1 million or more — a cost that is ultimately borne by all individuals, DMD was a fatal, progressive disease with insufficient treatment
not just patients, through taxes and insurance premiums. options. Approval was granted despite the FDA’s advisory committee
In the United States, which lacks government-administered voting against it and despite slim evidence of efficacy — the pivotal trial,
provision of universal health care, there is a strong expectation that which enrolled just 12 boys, showed very small changes in the surrogate
health insurers will pay for therapies that have been approved by the measure used as an outcome.
US Food and Drug Administration (FDA), particularly if a treatment The agency’s decision sent shock waves through the US insurance
is the only effective one for a given malady. In cases in which the effi- industry and led to variability in coverage policies. Many companies
cacy data and value proposition are questionable, FDA approval can agreed to pay for the drug, which costs around $300,000 per year, but
create enormous pressure to provide coverage. others initially declined to do so.
Some stakeholders — including pharmaceutical companies and In this case, a value-based agreement could have set out a multi-
government policymakers — have been squeamish about introducing year payment model that would terminate if the effectiveness of the
measures of cost effectiveness into the decision- drug failed to persist over the long term. And
making process because of concerns that such because such a deal would enable broad access
an approach could lead to putting a price on life to the therapy, it would in turn generate robust
and, ultimately, the rationing of care. Unfortu-
nately, this has had an unintended consequence:
TREATMENTS real-world evidence of the treatment’s efficacy.
Such data could then be used to gain conven-
it has led to a system that has no mechanism for ARE LIKELY tional FDA approval. Sarepta Therapeutics in
imposing price ceilings. Many individuals in the
United States see substantial cost increases for
TO HAVE Cambridge, Massachusetts, the company that
developed eteplirsen, chose not to enter into
their medications year after year.
One possibility would be for the FDA to
A PRICE TAG value-based agreements for that drug, but it is
collaborating with a partner to develop a one-
consider a pathway in which it expedites approval IN THE time DMD gene therapy that is expected to be
for a treatment in the absence of sufficient high-
quality data, particularly for rare diseases that NEIGHBOURHOOD OF much more expensive. That therapy might pre-
sent an opportunity to enter into an innovative
have no effective treatment, in return for the
drug maker agreeing to a so-called value-based US$1 MILLION financing agreement to promote access.
Some pharmaceutical companies oppose
agreement that would tie reimbursement to the
success of the drug. When treatment works, the
manufacturer would receive full payment. When
OR MORE. value-based pricing, questioning whether the
approach maximizes shareholder value. It is fair
to acknowledge that any solution to improve
the patient shows a limited response to treat- access to health-care advances should provide a
ment, there would be a partial payment. And when the treatment fails reasonable return to the companies that develop such innovations. It is
altogether, no payment would be made. also appropriate to ask whether treatments for rare conditions should
I work for the health insurer Harvard Pilgrim Health Care in be priced higher to ensure that companies will pursue the development
Wellesley, Massachusetts, and in January my company entered into of drugs that will always have a limited market.
a value-based agreement with Spark Therapeutics in Philadelphia, Whether or not we choose to acknowledge it, there is a limit to the
Pennsylvania, for the gene therapy voretigene neparvovec portion of a country’s gross domestic product that can be spent on
(Luxturna), a treatment for a form of hereditary blindness. This agree- health care. To balance access and affordability over the long term and
ment is already driving considerable discussion between payers and ensure that our loved ones can receive the next generation of inno-
pharmaceutical companies that have upcoming gene therapies and vative therapies, payers, pharmaceutical companies and regulatory
other high-cost, innovative treatments. Other firms have forged simi- agencies need to collaborate in a way that benefits all stakeholders.
lar deals. For example, in 2016, the pharmaceutical company Novartis Value-based agreements from the past few years provide a model that
in Basel, Switzerland, signed a deal with several insurers, including could be applied to upcoming gene therapies and other high-cost,
Cigna in Bloomfield, Connecticut, and Harvard Pilgrim, for its com- innovative treatments. A spirit of collaboration among industry play-
bination drug sacubitril–valsartan, a treatment for heart failure. In ers could ensure that everyone who needs an innovative, expensive
the event that people receiving the drug fail to show a reduced rate of treatment can have access to it. ■
hospitalization for heart failure in clinical trials, the drug cost will be
reduced. Collaborative deals such as this give hope that stakeholders Michael Sherman is senior vice president and chief medical officer
will work together to ensure that all who might benefit have access to at Harvard Pilgrim Health Care in Wellesley, Massachusetts, and a
cutting-edge medical advances. faculty member at Harvard Medical School in Boston, Massachusetts.
Gene therapy, which offers the potential of extremely effective but e-mail: michael_sherman@harvardpilgrim.org
S21
www.nature.com/collections/gene-therapy-outlook
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it is hard to remember how Aschwanden went to relieve plored, Earth plunged into the
recently we lived without it. her sore legs with nitrogen gas. Little Ice Age from the late 16th
Computer scientist Steiglitz 3ïD´m´´D§ym´Dåïyy¨`D®- to the early 19th century. Across
examines the global transformation from analog ber and receiving a blast of frig- the Western world, failed har-
to digital and the ways it changed how we calcu- id air, she felt a rush of adrenaline. “I was ready to ÿyåïåÿmï¹D®ýD´må¹`D¨ù´àyåïÎ7å´àåïÈyà-
late, communicate and entertain ourselves. He §`§å¹®yDååÎ Î Î jÛåyĀàïyåÎÚĀDåå¹¨mÎÛ
ùïïy son accounts, history writer Blom shows how the
myå`àUyåïy´ùïåD´mU¹¨ïå¹ïD§´å¹®yï´ ïàùïjåy´må¹ùïjåïDï´¹å`y´ïåï`D´`¹´à® climatic upheaval helped to usher in economic and
analog, such as waves traveling through the air ïyUyýïå¹ïå§´m¹`àĂ¹ïyàDÈĂÎÿï®y å`y´ï``DýåÎ5y"ïïÿ`yyåÈùààymDà-
ïDï®D§yå¹ù´mjD´m`¹´ÿyàï´ïy®´ï¹ĈåD´m àD`yàD´m¹à®yà`à¹åå`¹ù´ïàĂå§yàjå`ĀD´my´ cultural innovations while causing considerable hu-
1s, all in witty and cogent language. In addition Èà¹ÿmyåD´D®ùå´D´myāDùåïÿyïD§ym¹Ā´ ®D´åùyà´D´mà¹Ā´ýÕùD¨ïĂÎ¹àyāD®Èÿj
to celebrating the gains of the digital revolution, ¹ïyày`¹ÿyàĂÈà¹mù`ïåD´mïày´måïDïïýåå displaced by new farming practices, landless peas-
3ïy¨ïĆÕùyåï¹´åĀDïĀy®DĂDÿy¨¹åïÎ%¹ï´ enthusiasts have transformed into a multibillion- D´ïåymï¹`ïĂå¨ù®åjĀyàymåyDåyåÈàyDmyDå¨ĂÎ
ANUP SHAH Getty Images
that the human brain uses both analog and digital dollar industry, from sweating at infrared saunas to 5yU¹¹§ÿyå`¹´ïyāïï¹ïy`ùàày´ïù®D´màÿ-
®y`D´å®åjyDå§åjÚåïyàyå¹®yÜ®D`ÝïDï Ăm àDï´ĀïåÈ¹àïåmà´§åÎyà´m´åmyUù´§ en climate crisis, which is catalyzing similar shifts
remains hidden in the analog world, beyond the many ideas about what does help the body recov- and underscores that our choices dictate how glob-
àyD`¹ïymïD¨`¹®ÈùïyàÖÛ Clara Moskowitz er—and what does not. —Emiliano Rodríguez Mega al warming impacts human life.—Andrea Thompson

THE INTERSECTION Zeynep Tufekci is an associate professor at the

S A S
University of North Carolina, whose research revolves
around how technology, science and society interact.
worldwide. To do their work, these devices run software and have

user profiles that can be logged into to configure them. Unfortu-
nately, a sizable number of manufacturers have chosen to allow
simple and already widely known passwords like “password,”
“pass,” “1234,” “admin,” “default” or “guest” to access the device.
In a simple but devastating attack, someone put together a list
of 61 such user name/password combinations and wrote a pro-
gram that scans the Internet for products that use them. Once in,
the software promptly installs itself and, in a devious twist, scans
the device for other well-known malware and erases it, so that it
can be the sole parasite. The malicious program, dubbed Mirai,
then chains millions of these vulnerable devices together into a
botnet—a network of infected computers. When giant hordes of
zombie baby monitors, printers and cameras simultaneously ping
their victim, the targeted site becomes overwhelmed and thus
inaccessible unless it employs expensive protections.
To make things worse, the authors of Mirai released the source
code shortly after their debut censorship attack on the Web site of
Brian Krebs, an Internet security investigative journalist. Now
even people with rudimentary levels of coding skill can assemble
their own giant zombie botnets. There are also “peeping Tom”
sites that randomly scan for, and easily find, cameras with these
simple, known passwords and stream their feed to the world.
What’s the fix? You might have noticed that phones or laptops
Zombie Baby occasionally need software updates. These introduce new features,
but they also often patch bugs and fix software vulnerabilities.
Alas, most devices vulnerable to Mirai were also shipped with no
Monitors Attack feasible or easy way to update or fix them.

I babysat various computer networks to pay for college, and the
passwords that Mirai uses would be the same combinations I’d try
It’s a malware-eat-malware world when faced with a device with an unknown login. That this is still
By Zeynep Tufekci true so many years later points to the actual problem: nobody is
minding the store. Indeed, why bother? For manufacturers of chips
a a man e ice come with chips and are connected to or devices, there is often little to no downside to shoddy security.
the Internet—the so-called Internet of Things. The smart fridge There is no authority with teeth and no clear law outlining lia-
that alerts you when milk is low or adds it to the shopping list— bility from harm caused by such blatantly negligent security prac-
maybe even orders it from the grocery app! The air conditioner tices. The original authors of Mirai appear to be U.S. college stu-
that anticipates when you want the house cooler for a run on the dents who eventually pled guilty after being caught, but that’s
treadmill but turns itself down when you’re out at the movies. A mostly irrelevant. As long as there are large numbers of devices
baby monitor that tells you when it’s time to stock up on teething with the “admin/admin” username/password combination, some-
gel: the little one has been tossing and turning a little too much. one would have done this eventually. The bad news is that there
It sounds useful and wondrous. It’s quite possible, however, is no real solution to Mirai except waiting for existing vulnerable
that your Internet-connected baby monitor instead spent last devices to degrade. The good news is that if a few device makers
night teaming up with millions of other devices—cameras, print- who shipped “admin/admin” gadgets were forced to pay hefty
ers, routers, speakers, air conditioners, DVRs, and more—to cen- fines or if parents of a hacked baby monitor could sue manufac-
sor journalists; take down music, social media, or movie sites such turers or sellers, security would probably improve rapidly.
as Twitter or Netflix; sabotage open-source software projects; The Internet of Things promised us great wonders, but I’d
knock almost a million German houses off-line; or bring down like them to be less exciting. It’s time to make baby monitors bor-
cell-phone communications in Liberia. With all this extra stealth ing again—and go back to worrying about the little one’s teeth-
activity, it’s also running up your electricity bill. ing rather than his or her security camera joining a zombie bot-
Wait ... what? The problem is painfully simple and terribly net and wreaking havoc across the globe.
thorny, and it is as much about globalization, law and liability as
SA
it is about technology. Most of our gizmos rely on generic hard- Visit 2_w²í_Ĉ¬wÞ_C² on Facebook and Twitter
ware, much of it produced in China, used in consumer products or send a letter to the editor: e it r ciam c m
72 Scientific American, February 2019 Illustration by Jay Bendt

ANTI GRAVITY
Steve Mirsky has been writing the Anti Gravity column since S A
a typical tectonic plate was about 36 inches from its current location. A A A S
He also hosts the IY_[dj_ÒY7c[h_YWdpodcast Science Talk.
What
the Deuce
A number of studies
about number two
By Steve Mirsky
ere een a t f cra in the news lately, and for a

change I mean that literally. Let’s start with the study
presented last November 18 at the annual meeting of the
American Physical Society’s Division of Fluid Dynamics
entitled “How Do Wombats Make Cubed Poo?” Yes,
wombats produce dicelike discharges. The marsupial’s
unique ability attracted the attention of researchers who
looked at the innards recovered from two wombats lost
in the everyday carnage of roadways around the world.
“In the final 8 percent of the intestine,” the dung
detectives wrote, “feces changed from a liquid-like
state into a solid state composed of separated cubes of
length 2 cm. This shape change was due to the azi-
muthally varying elastic properties of the intestinal
wall.” After that inspection, they emptied the intes-
tines and inflated them, presumably not by mouth.
“We found,” they wrote, “that the local strain varies
from 20 percent at the cube’s corners to 75 percent at its edges. In the same month the news site Crosscut ran a piece about
Thus, the intestine stretches preferentially at the walls to facili- the University of Washington’s Conservation Canines program.
tate cube formation. This study addresses the long-standing Reporter Hannah Weinberger wrote that “a rotating cast of 17
mystery of cubic scat formation and provides insight into new lucky dogs ... [are] taught to approach scent detection as a game,
manufacturing techniques for non-axisymmetric structures where they are rewarded for learning how to track the scents of
using soft tissues.” At long last, 3M meets BM. dozens of species’ feces.”
Back in March 2018, Israeli researchers published a study in The samples that the dogs then locate in the field give re-
the journal Applied Energy stating that poultry expulsions could searchers valuable information about local animal populations—
be pressure-cooked into a burnable powder that might replace more data than could be generated by camera traps or hair
some coal in electricity production. Or even be pressed into bri- snares. So what’s it like to sniff out scat for a living? One dog
quettes for cooking. Just before Thanksgiving, NPR did a story allegedly described it as “rough.”
about this research and pointed out that someone could theoreti- Also in November the Journal of Paediatrics and Child Health
cally collect a turkey’s droppings over its lifetime, turn that mess ran a study entitled “Everything Is Awesome: Don’t Forget the
into fuel and then use it to cook the very same turkey. Perhaps Lego.” Six pediatric health care professionals swallowed a plas-
selective breeding could even get the hapless bird to go pluck itself. tic Lego minifigure head, representing the myriad small objects
In the December 20th edition of the Journal of Cleaner Pro- little kids swallow, and then pawed through their own stool to
duction, the same Israeli group published a similar study with see how long it took for the head to emerge. The time between
human excreta. To quote: “It is postulated that hydrothermal car- ingestion and elimination was dubbed the Found and Retrieved
bonization of human excreta could potentially serve as a sustain- Time (FART), which averaged 1.71 days.
able sanitation technology.” Perhaps your future energy-efficient The authors noted that “it is likely that objects would pass
home will be able to connect the toilet directly to the furnace. faster in a more immature gut.” Therefore, they “advocate that
Last November, Tech Insider dredged up and tweeted video no parent should be expected to search through their child’s fae-
related to a story first reported in 2015 about Antarctica’s Gen- ces to prove object retrieval.” In other words, trust the process—
too penguins getting together to relieve themselves en masse. these things have a way of working themselves out.
Their warm guano helps to melt the snow and ice. Having thus
SA
cleared the field, the birds can build nests on beaches or small Visit 2_w²í_Ĉ¬wÞ_C² on Facebook and Twitter
patches of vegetation. or send a letter to the editor: e it r ciam c m
Illustration by Matt Collins February 2019, ScientificAmerican.com 75

50, 100 & 150 YEARS AGO S A A

FIND ORIGINAL ARTICLES AND IMAGES IN
A A S AS SC IENTIFIC A MERIC AN THE SCIENTIFIC AMERICAN ARCHIVES AT
¸Ç§xlTā C³x§Í2_§x³¸ ä`x³î`Dxß`D³Í`¸êDDą³xêäD
F E B R UARY
Evolution Barbed-Wire Disease

1969 Wars
“At the end of his Descent of Man
sealing and lubrication; such
problems are characteristic of
virtually all the rotary engines.”
“We welcome a little pamphlet by
Dr. A. L. Vischer, of Basle, devoted
and Selection in Relation to Sex to the study of prisoners of war,
(1871), Charles Darwin wrote: ‘The
main conclusion arrived at in this
work, namely that man is descend-
1919 Molasses
Disaster
What is there in molasses that
and especially what was called the
‘barbed-wire disease.’ Four to five
million men have been kept in
ed from some lowly organized 19 9 would make it explode, particular- confinement in enemy countries,
form, will, I regret to think, be ly in winter time when the sticky and many of them will return with
highly distasteful to many.’ Half syrup is proverbially slow? Two impaired mentality to their homes.
a century later his prediction was weeks ago a large tank of molasses Dr. Vischer draws a picture of a
fully realized in the U.S., where exploded in Boston, killing a doz- mentality characteristic of prison-
many Americans waged what is en persons and injuring 50 more, ers of war, to which the majority
sometimes called the ‘monkey war.’ and no completely satisfactory fall victim within two or three
Fundamentalists-Christians of var- explanation of the disaster is ob- months and from which few es-
ious denominations who believed tainable. The tank was a huge cy- cape completely. The factors in its
that evolution contradicted the 1919 lindrical structure with a capacity causation he considers to be loss
Bible sought to check the spread of two million gallons. Without of liberty for an unknown period
of evolutionary thought by making an instant’s warning the top was in close company with many oth-
it a crime to teach it. Not until No- blown into the air and the sides ers. The result is a continual long-
vember 12 of last year [1968], when were burst apart. Wreckage was ing with entire inability to per-
the U.S. Supreme Court ruled that scattered in all directions while form. The factor of loneliness in
a law barring the teaching of evo- a deluge of molasses spread over the midst of company he illus-
lution in public schools and colleg- the ruins and into the street, suf- trates from writings emanating
es was unconstitutional, could it focating many of the injured.” from various camps.”
be said that the monkey war had 1 9 <wC¦ã·Æ÷T¦ãwkÈ·²¦²wÉC²CÞí_¦w
·²Ĉ÷÷ãí¾iõĆ¾ïiTĀwÞÞãCTÞhØ4w
come to an end. The best-known
battle in this ideological conflict
was fought in 1925, when John
2_w²_w·íwÞwCí#·¦Cããwã¦··kÌÙ 1869 AProcedure
Dangerous
“The Medical Record gives an ac-

Thomas Scopes was tried in Day- count of a successful operation for
ton, Tenn., for teaching evolution. the transfusion of blood recently
—L. Sprague de Camp” performed by Dr. Enrico Albanese
De Camp is now best known as at the hospital of Palermo, Sicily.
Cã_w²_w_í·²þÞíwÞÌ A youth aged seventeen, Giuseppe
Ginazzo, of Cinisi, was received
Wankel Rotary Engine with an extensive ulceration of
“The reciprocating-piston internal- the leg, which in the end rendered
combustion engine has been so amputation necessary. In this
successful that one is seldom emergency Dr. Albanese had re-
aware that a small army of inven- course to the transfusion of blood
tors is determined to see it re- as the only remedy that had not
placed by some kind of ‘rotary’ yet been tried. Two assistants of
engine. In the piston engine the the hospital offered to have their
conversion of linear reciprocating veins opened for the purpose, and
motion to rotary motion, by thus at two different intervals,
means of the connecting rod– 220 grams of blood were intro-
SCIENTIFIC AMERICAN, VOL. CXX, NO. 5; FEBRUARY 1, 1919
crankshaft arrangement, is inher- duced into the patient’s system.

ently wasteful of the energy sup- After the first time he recovered
plied by the combustion process. the faculty of speech, and stated
There are 30 to 40 such rotary that before he could neither see
engines, all ‘ideal’ to a greater or nor hear, but felt as if he were fly-
lesser extent (such as the one con- ing in the air. He is now in a fair
ceived by Felix Wankel in 1956). state of recovery.”
There still appear to be problems, 1919 'øß`¸þxßDx¸ßîxßäîääøx³xUßøDßā 4wĈ
&T¦··kíĀÆwãþwÞw²·í
however, of providing adequate ä¸ÿ`DäxäUÇ§D³ä¸ßÇ¸§DßxĀÇ§¸ßDî¸³UāDßÇ§D³xÍ kã_·ýwÞwk÷²í¦¾³ĆĆ¾³Ć¾Ì
Soviet
GRAPHIC SCIENCE Union puts
Text by Mark Fischetti | Graphic by Jan Willem Tulp ïyàåïåDïy¨¨ïy
´ï¹åÈD`yÎRocket
U
launches globally
oins Soviet
since then:
Satellites and Debris Orbiting Earth Union and U S as
5,400
ach dot represents an o ect larger than centimeters a satellite proprietor
Satellites launched
1957
worldwide since
then: 8,650 Some
13
craft fall ac
1959 toward arth over
80 Total o ects trac ed time Satellites still
1961 ewly added y year in space: 4,700;
630 Decayed y year still functioning:
1963 1,800
1,180
1965
2,901
1967
1969
3,195 Space Junk
1971
4,040
4,477
Piles Up
EUROPEAN SPACE AGENCY www.esa.int; SPACE DEBRIS: THE ESA APPROACH. ESA BR-336. EUROPEAN SPACE AGENCY,
1973
4,943
Relentless accumulation
1975 threatens satellites and Earth
6,293
SOURCES: “SPACE DEBRIS BY THE NUMBERS” (INFORMATION CORRECT AS OF JANUARY 2018),

1977 S ace i a t Yet Earth orbits are becoming in-
6,811 creasingly littered with debris (speckled graphic).
1979
A satellite could be demolished if struck by a
6,850
10-centimeter piece of junk, about the size of a
MARCH 2017; ESA SPACE DEBRIS OFFICE discosweb.esoc.esa.int ( raw data)

1981
7,757 softball. Even a one-centimeter tidbit could dis-
1983 able a spacecraft. And the more functioning, de-
8,246 funct or fragmented objects up there, the more
1985 that decay in the atmosphere (pink stripe). The
9,682 collision problem has become so serious that
1987 in 2016 the European Space Agency (ESA),
10,281
which tracks the objects, announced it might
1989
9,659
capture derelict satellites in low orbits, start-
1991 ing in 2023. Clutter is rising fast as more coun-
10,152 tries and companies launch electronics. In Feb-
1993 ruary 2017 India sent 101 shoebox-sized “cube-
10,497 sats” into a low orbit on a single rocket.
1995
11,434
1997
China
deli erately
11,552
shatters a satellite
1999
in a missile test, creating
11,855
, trac a le fragments
2001
Other breakups,
11,993
explosions or collisions
2003 creating debris: more
11,739 A Russian
than 500
2005 military and U S
12,615 communications
2007 satellite smash
16,505 Shards ejected: more
2009
than 2,000
18,579
2011
18,412 Small its in high
2013 or its are impossi le
18,354 to trac The SA s models
2015 estimate total o ects in all or its
18,494 29,000 larger than 10 cm
2017 750,000 from 1 to 10 cm
19,738
166 million from
1 mm to 1 cm


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РЕЛИЗ ПОДГОТОВИЛА ГРУППА "What's News" VK.

ANTARCTIC COLLAPSE? MEET THE GLACIER THAT MIGHT SINK

EXOPLANET NEXT DOOR

UNCONTACTED TRIBES FEBRUARY 2019

Photograph by Juan Arredondo February 2019, ScientificAmerican.com 1

© 2019 Scientific American

3 From the Editor

S1 Nature Outlook: Gene Therapy

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2 Scientiﬁc American, February 2019

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What’s in Parsing these complex neural interactions begins on page 22.

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“We must explicitly found in a comparatively smaller one” is

4 Scientiﬁc American, February 2019

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EDITOR IN CHIEF AND SENIOR VICE PRESIDENT

if you determine whether the lab-sized EDITORIAL

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can look for simpler systems that exhibit DIGITAL CONTENT

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February 2019, ScientiﬁcAmerican.com 5

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