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Science Biology

Unlocking the Hidden

History of DNA
Course Guidebook

Unlocking the Hidden

Sam Kean

History of DNA
Science Writer

Sam Kean
Science Writer
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Sam Kean
Science Writer

i
 Professor Biography

Sam Kean is the New York Times best-selling author of The Bastard
Brigade: The True Story of the Renegade Scientists and Spies Who
Sabotaged the Nazi Atomic Bomb; Caesar’s Last Breath: Decoding the
Secrets of the Air around Us; The Disappearing Spoon: And Other True
Tales of Madness, Love, and the History of the World from the Periodic
Table of the Elements; The Tale of the Dueling Neurosurgeons: The History
of the Human Brain as Revealed by True Stories of Trauma, Madness, and
Recovery; and The Violinist’s Thumb: And Other Lost Tales of Love, War,
and Genius, as Written by Our Genetic Code.

The Bastard Brigade was on NPR Science Friday’s list of Best Science
Books of 2019, while Caesar’s Last Breath was The Guardian’s science
book of the year in 2017 and a runner-up for the 2018 Best Book Award
from the National Academies of Sciences, Engineering, and Medicine.
In addition, The Disappearing Spoon was short-listed for the Royal
Society Winton Prize for Science Books in 2011, and The Violinist’s
Thumb and The Tale of the Dueling Neurosurgeons were nominated
for the PEN/E. O. Wilson Literary Science Writing Award in 2013
and 2015, respectively, as well as the AAAS/Subaru SB&F Prize for
Excellence in Science Books.

Mr. Kean edited the 2018 edition of The Best American Science and
Nature Writing, and his work has appeared in The New Yorker, The
Atlantic, The New York Times Magazine, Psychology Today, and Slate,
among other publications. He also has been featured on such programs
as NPR’s Radiolab, All Things Considered, and Fresh Air.

Mr. Kean’s books have been translated into 24 languages around

the world, and he hosts a podcast called Disappearing Spoon. He
received BA degrees with honors in Physics and English Literature
from the University of Minnesota Twin Cities as well as a master’s
degree in Library Science from the Catholic University of America in
Washington DC.

ii
 Table of Contents
INTRODUCTION
Professor Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i
Course Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

LECTURES
1 Genes versus DNA . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2 The Quest for DNA’s Structure . . . . . . . . . . . . . . . . . 15
3 The Double Helix Revealed . . . . . . . . . . . . . . . . . . . 25
4 From Genetic Codes to DNA Fingerprints . . . . . . . . . . 35
5 The War over the Human Genome . . . . . . . . . . . . . . . 44
6 How DNA Controls Itself and Shapes Our Culture . . . . . 54
7 Microbes Manipulate Us, Viruses Are Us . . . . . . . . . . . 64
8 How Epigenetics Turns Genes On and Off . . . . . . . . . . 74
9 Apes, Humans, and Neanderthals . . . . . . . . . . . . . . . 85
10 How DNA Reveals History . . . . . . . . . . . . . . . . . . . . 96
11 CRISPR’s Rise, Promise, and Peril . . . . . . . . . . . . . . . . 107
12 How DNA Redefines Medicine and Our Future . . . . . . . 117

SUPPLEMENTARY MATERIAL
Multiple-Choice Quiz . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Quiz Answer Key . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

iii
iv
 Unlocking the Hidden
History of DNA
For more than 3 billion years, DNA has been copying down a history
of every species on Earth—including human beings. And thanks to
recent advances in technology, we’re finally able to read these stories
for the first time and uncover that hidden history.

But whatever we know, or think we know, about DNA, our knowledge

is often intimately connected to how we made our discoveries. And
while there are many heroic stories involving the men and women who
illuminated this molecule, there have been rivalries and controversies
and villains as well. DNA has a dark side, too.

This course—a follow-up to the New York Times best-selling book The
Violinist’s Thumb—pulls back the curtain on DNA and reveals the
secrets of this remarkable molecule. It covers not only how DNA works
biologically, but how DNA knowledge has changed our perspective on
human life and history, and even what it means to be a human being.

The course starts with the basics—what genes and DNA are.
Surprisingly, although genes and DNA were discovered almost
simultaneously in the 1860s, scientists didn’t link them for nearly a
century. But once scientists realized that DNA did in fact carry genetic
information, there was a furious race to determine its structure: the
famous double helix. Indeed, the discovery of the double helix remains
one of the most controversial episodes in science history, one that’s still
causing acrimony today.

From the double helix, scientists expanded their horizons. DNA is a

vital blueprint for life, but how do cells actually use DNA to build
and run our bodies? The answer involves using DNA to build RNA
and proteins. And once they understood the genetic code for turning
DNA into proteins, scientists could expand that work to practical
applications like DNA fingerprinting, which helps fight crime.

1
 Course Scope

The biggest recent advance in DNA research was the Human Genome
Project, an effort to sequence all 3 billion base pairs of human DNA.
And given the stakes of the project, it’s no surprise that fierce scientific
rivalries and hatreds arose behind the scenes. But some amazing—and
surprising—science emerged from the project as well. For example, it
revealed that at least 8% of human DNA, and possibly up to 50%,
comes from old, broken-down virus DNA. In fact, thanks to the
project, we can now see the huge role that viruses have played in our
evolution. Even one of the hallmark traits of mammals, the placenta,
probably came from DNA that we stole from viruses.

Another surprising fact to emerge from the Human Genome Project

was that human beings have far fewer genes than expected—only
about 20,000, fewer than some species of onions have! How do so
few genes give rise to creatures as complicated as we are? The answers
involve DNA regulation: the turning on and off of genes or the ability
to turn their activity up or down. Only 2% of our DNA codes for
proteins, while perhaps 10 times as much of the human genome helps
regulate genes. And the exciting new field of DNA epigenetics explores
how our environment affects our genes.

With the basic DNA blueprint of human beings in hand, scientists

soon expanded their horizons to explore how they could use DNA in
fields outside biology, especially archaeology and history. Genetics has
uncovered fascinating new insights into our close hominin cousins,
such as Neanderthals. This includes the fact that in the not-so-distant
past, human beings interbred with Neanderthals, and most people
alive today carry a few percent’s worth of Neanderthal DNA inside
them. Historians have used DNA to investigate and illuminate the
lives and times of people as different as King Tut, Genghis Khan, and
Thomas Jefferson.

The more we understood DNA, the more natural it became to want

to tweak it—to improve crops and even our own bodies. Genetic
engineering has long been a dream of scientists, and new tools like
CRISPR-Cas9 have greatly simplified the process. But the ability to
edit and reprogram embryos evokes fears of a new, modern eugenics

2
 Course Scope

movement, even as those tools also offer the hope of personalized

medicine and possible solutions to complicated genetic diseases like
cancer.

The history of DNA ultimately reveals a trove of previously hidden

stories about our past, which in turn offer new windows on our
present. The old, standard narratives of history are being expanded and
revised, and DNA discoveries are presenting us with new challenges
and choices as we move into our future.

3
Genes versus DNA
LECTURE 1

T oday, DNA is practically synonymous with genes. But genes were

actually discovered independently of DNA. In fact, the person
who discovered genes and the person who discovered DNA made
their discoveries almost simultaneously, in the 1860s, but scientists
had no idea that genes and DNA had anything to do with each other
for nearly a century. Eventually, though, the connection between
them was discovered—that genes really are DNA.

Return
to TOC

MENDEL AND GENES

At a monastery in what’s now the
Czech Republic, a monk named
Gregor Mendel was trying to solve
the ancient problem of inheritance.
Red hair, baldness, diseases, even
extra toes—everyone knew that
traits like these could be traced
up and down a genealogical tree.
But how exactly did those traits
get passed down? That’s what
Mendel wanted to know.
around. But they also had advantages
for his research, because pea plants
tended to have binary traits.
In other words, pea plants had either
tall stalks or short stalks—nothing
in between. Or they had green
pods or yellow pods. So he started
breeding different combinations of
plants with each other and seeing
what their offspring looked like.

In the mid-1850s, Mendel began Mendel’s first important

some deceptively simple experiments
on pea plants. He chose peas partly
because he liked to have them for
dinner and wanted plenty of them
conclusion was that some traits
“dominated” others. For example,
crossing purebred tall plants with
purebred short plants produced
only tall offspring in the first
generation. Tall dominated.

4
 Lecture 1 Genes versus DNA

But the short trait hadn’t quite
disappeared. When Mendel mated
those second-generation tall plants
with each other, a few furtive
short peas popped up: one latent,
“recessive” short plant for every
3 dominant tall plants. That 3:1
ratio held for other traits as well.
Equally important, Mendel
concluded that having one trait
dominant or recessive didn’t
affect whether another, separate
trait was dominant or recessive.
Each trait was independent.
For example, even though tall
dominated short, a recessive-
short plant could still have
dominant-yellow peas. Or a tall
plant could have recessive-green
peas. In fact, every one of the 7
traits he studied was inherited
independently of the others.
This focus on separate, independent
traits allowed Mendel to succeed
where other scientists1 failed.
Looking at one trait at a time was
how he realized that each trait
must be controlled by a separate
factor. The separate factors that
Mendel called cell elements are the
discrete, inheritable units we now
call genes—the basis of genetics.
Mendel presented a paper on his
research at a conference in 1865
and published his work in 1866,
but all he got was silence. He
even ordered 40 reprints of his
paper and sent copies to famous
scientists. No one cared.
After his greenhouse was destroyed
by a storm in 1870, his plant research
virtually came to an end. He died in
1884, and it seemed the world would
never know what he’d discovered. 2

Inside each tiny cell of your body, there is an even

tinier closet, where DNA is packed. Yet the DNA from
just one cell, if stretched out, would be as tall as you
are. Combine the DNA from all your trillions of cells,
stretched out end to end, and that would be roughly
the distance from the Sun to Pluto—and back again!

1 Charles Darwin, who also experimented with pea plants, failed to understand
their heredity partly because he didn’t look separately at each individual trait.
2 Because Mendel brought negative attention to the monastery, his successor
burned all his personal papers—including his work on genes—when he died.
And his published work had been ignored.

5

MIESCHER AND NUCLEIN
Mendel’s idea of genes was abstract.
He didn’t know what genes were
made of, or really even care. He
simply used genes as an accounting
tool, a way to keep track of traits
from generation to generation.
But if Mendel’s genes were abstract,
DNA is not. DNA is a substance,
a chemical: deoxyribonucleic acid.
It appears inside our cells. And it
was first discovered by a biochemist
named Friedrich Miescher.
Miescher3 initially worked at a
scientific institute in Germany. In
the late 1860s, his boss assigned
him the task of studying white
blood cells. Miescher chose to focus
on the nucleus of the white blood
cells at a time when the function
of a cell nucleus was unknown.
To get white blood cells, Miescher
had to visit a local hospital each
day. There, he picked up their used,
pus-soaked bandages, since pus is
swimming with white blood cells.
To see what chemicals were in the
nucleus of the white blood cells,
Miescher ran some chemical tests.
3 Miescher was completely dedicated to science. In later years, friends had to
drag him away from his lab bench one afternoon to attend his own wedding.
6
Lecture 1 Genes versus DNA
One test involved washing the pus
in warm alcohol and then rinsing it
in acid from a pig’s stomach. This
dissolved the cell membranes and
allowed him to isolate a gray paste.
Miescher assumed the paste was a
protein, so he ran tests to identify
it. But the paste didn’t behave like
a protein. It wouldn’t dissolve in
salt water, or in boiling vinegar, or
even in dilute hydrochloric acid. His
paste also contained phosphorus,
an element that proteins lack.
Convinced he’d found something
new and unique in the nucleus of
those cells, Miescher named the
substance nuclein—and his discovery
contained what we now call DNA.
Miescher eagerly showed his boss
what he’d discovered. But his boss
didn’t quite believe Miescher. Was
it possible that a no-name assistant
had really discovered an entirely
new substance in cells? And even if
he had, what did this nuclein stuff
do? Another researcher was put to
work to confirm Miescher’s results.

Miescher finally convinced his
boss that he really had discovered
something unique. But when
Miescher published a paper with
his results in 1871, the boss tried
to downplay it. In a condescending
editorial that ran alongside the
paper, the boss said the work
was important mostly because it
enhanced our understanding of
pus. Anyway, Miescher still had no
idea what this nuclein stuff did.
Miescher was a stubborn fellow,
however, and he kept studying.
He soon moved from Germany
7
Lecture 1 Genes versus DNA
to his own lab in Switzerland
on the Rhine River, which is a
spawning route for salmon.
Salmon were good for studying what
we call DNA because, frankly, male
salmon are sperm-making machines.
During spawning season, their testes
swell like tumors, reaching weights
of up to 1 pound. Sperm is rich in
DNA, so Miescher would catch the
salmon, remove the testes, squeeze
them through cheesecloth to isolate
the sperm, and then extract DNA
using acids and other chemicals.
 Lecture 1 Genes versus DNA

Unfortunately, salmon sperm did a number on his health, and he

deteriorates at anything close to
room temperatures. Refrigerators
didn’t exist then, so Miescher had
to prop open the windows in his
lab, during the Swiss winter, and
let the temperature inside drop to
around 35° while he worked. He did
this year after year, suffering chills
and exposure while he dissected
thousands of salmon. Eventually, this
ended up contracting tuberculosis.4
His health sank quickly in 1895,
and he died soon afterward.
Miescher never figured out what
DNA did. There were some
hints that he suspected it was
important in heredity, but at
other times he doubted himself
and seemed to reject the idea.

Amino acids are the building blocks of

proteins, just like A, B, C, D, and so on
are the building blocks of words.

KOSSEL AND BASES

Seven years after Miescher’s paper,
another lab assistant was tasked by
Miescher’s old boss with figuring
out the chemical building blocks of
nuclein. This was Albrecht Kossel,
who published an entire book in
1881 showing that nuclein had both
a protein side and a nonprotein side.
The nonprotein side was later
called nucleic acid, and it turned
out to have several building blocks.
There is a 5-carbon sugar. There
are acidic molecules, where oxygen
atoms surround phosphorus, the
element that had gotten Miescher
excited. But most important turned
out to be what we call the bases.
Beginning in 1885, Kossel and
a partner identified 2 of the 4
bases we now know make up
DNA. For this work, they went
to a nearby slaughterhouse and
harvested hundreds of pounds
of raw pancreases, which they
boiled in a strong acid.

4 Because of his institute’s stingy budget, Miescher often ran out of glassware
and had to raid his wife’s china cabinet to finish experiments.

8

The first base they isolated was
guanine, which was already known
from bird droppings (a.k.a. guano).
They soon discovered a second base
they called adenine, named for the
Greek word meaning “gland.”
Another decade went by, until a
researcher under Kossel isolated 2
smaller bases, thymine and cytosine,
in 1894. They were still using
calves from the slaughterhouse, but
they switched from the pancreas
to a tiny gland called the thymus,
which gave us the name thymine.
As for cytosine, that was like
the word cytoplasm, taken from
a Greek word meaning “cell.”
9
Lecture 1 Genes versus DNA
While Kossel’s team was figuring
out the biochemical building blocks
of nucleic acids, biologists elsewhere
were using better microscopes to
look at the nucleus. Even before
the biochemistry was worked out,
biologists could see little noodle-
shaped structures they called
chromosomes living in the nucleus.
By watching sperm and egg cells
under a microscope, scientists
realized that these chromosomes
got passed down, whole and
intact, from parents to children.
And it just so happened that
chromosomes contain loads of
DNA. Could it be, then, that DNA
was the hereditary material?

Most scientists actually thought
that it was not, because in
addition to DNA, chromosomes
contained proteins.
This actually made a lot of sense
then. Think about inheritance as
a way to pass information, such
as eye color or height, from one
generation to the next. And just
like we humans store information
in words and letters, scientists
deduced that Mother Nature must
use an alphabet of her own—a
chemical alphabet. So was it a DNA
alphabet or a protein alphabet?
Proteins are long chains made up
of smaller bits called amino acids.
During Miescher’s lifetime, 10
amino acids had gradually been
discovered, and in the 8 years after
he died, 8 more amino acids were
identified. So by 1903, scientists
had discovered 18 of the 20 protein-
building amino acids that are
universal to all life. Clearly, the
protein alphabet had a lot of letters.
But DNA seemed to be a small
molecule—smaller than many
protein molecules. And it had only
10
Lecture 1 Genes versus DNA
a small alphabet of just 4 letters to
work with: A (adenine), C (cytosine),
G (guanine), and T (thymine).
If you’re trying to write an
instruction book for all of life—a
book with enough power to create
ants and redwoods and duck-billed
platypuses—then writing in a big
book, using an alphabet with 20
letters, seems far more powerful
than writing in a small book, with
an alphabet of just 4 letters.
So scientists concluded that proteins
were the genetic material. DNA was
probably just scaffolding for amino
acids, or perhaps a way to store
phosphorus for other processes.
It was a logical, commonsense theory.
And it was completely wrong.
But no one knew that in the late
1800s. As a result, Miescher’s
discovery of DNA started to
look less and less important.

LEVENE AND NUCLEOTIDES
A generation later, in 1929, the
idea that DNA was a pretty small
molecule actually hardened.
A former student of Kossel named
Phoebus Levene put the building
blocks together to realize that
DNA consists of little packages
he called nucleotides. Each
nucleotide has 3 components: one
of the 4 bases (A, G, C, or T); a
phosphorus atom surrounded by
oxygens (a.k.a. a phosphate); and
a 5-carbon sugar called ribose
that lacked an oxygen atom at a
key spot (hence de-oxyribose).
MORGAN AND CHROMOSOMES
While Miescher’s reputation
continued to decline after 1900,
the reputation of that other
genetics pioneer, Gregor Mendel,
was suddenly taking off.
In one of those odd quirks of
history, 3 separate scientists all
rediscovered Mendel’s paper on
pea plants in 1900. Each one
11
Lecture 1 Genes versus DNA
This idea that DNA is made of neat
little nucleotide packages turns out
to be correct. This was one step
forward. But since everyone was still
thinking that DNA was a pretty
small molecule, Levene then took
2 steps back. His proposal was that
the structure of DNA might be what
he called a tetranucleotide; that is,
DNA could be nothing more than
one A, one G, one C, and one T—a
grand total of just 4 nucleotides.
But if DNA were merely 4
nucleotides with 4 bases, that
would mean it could never be
the book of life. It would never
be more than a 4-letter word.
recognized how important it
was, and the monk’s name was
suddenly on the lips of every
hereditary biologist in the world.
A new field called genetics quickly
arose. Just a year later, in 1901,
an English medical researcher
used Mendel’s ideas to interpret
family histories for a disorder

called alkaptonuria. This became
the first instance of a recessive
inheritance identified in humans.
And in 1905, geneticists confirmed
that the chromosomes biologists
could see in their microscopes
were the carriers of genes. That
was the year the pioneering
biologist Nettie Stevens discovered
the sex chromosomes, X and
Y, which determine whether
babies are male or female.
But many of the biggest advances in
our understanding of chromosomes
came from a most unlikely
place: a cramped, squalid, fly-
infested laboratory at Columbia
University in New York.
The lab was run by Thomas Hunt
Morgan, who wanted to study
heredity in animals. He began
studying mice, guinea pigs, and
pigeons, but they bred too slowly
for his purposes. So he consulted
Stevens, who suggested working
with fruit flies, which produce a new
generation about every 12 days.
In 1907, Morgan cut up some
bananas, left them on a windowsill
to attract some fruit flies, and
captured them in a milk bottle to
let them breed. Morgan’s team kept
the flies in bottles, but with all the
12
Lecture 1 Genes versus DNA
rotten fruit lying around to feed
the fruit flies, the place reeked,
and the squalor attracted pests.
Along with his talented assistant
Hermann Muller, Morgan managed
to make some amazing discoveries in
the second and third decades of the
20th century. Their basic process was
this: They would first look for flies
with unusual traits—for example,
stubby wings or white eyes instead
of the normal red eyes. Then, they’d
breed these flies with normal flies
and see how often the novel trait
appeared in future generations.
They confirmed that many of the
novel traits were recessive, not
dominant. They also found that the
traits appeared in later generations
in a 3:1 ratio. This proved that
Mendel’s work on genes applied
to both plants and animals.
Even more importantly,
Morgan’s crew determined
what chromosomes were.
Again, biologists knew that
chromosomes were involved in
heredity somehow, since they
got passed down from parents
to children. Some biologists
had therefore proposed that

chromosomes must be genes
and that every hereditary trait
had its own chromosome.
Yet fruit flies had just 8
chromosomes and hundreds
of inheritable traits. So a 1:1
pairing didn’t make sense.
But at the same time, some careful
statistical work revealed that certain
traits almost always appeared
together in the same individual.
If one fly had green bristles and a
sawtooth-shaped wing, then another
one with green bristles almost
always had a sawtooth wing as well.
Those traits clustered together.
13
Lecture 1 Genes versus DNA
And the number of different clusters
of traits ended up being exactly
equal to the number of chromosomes
that fruit flies had. In other words,
chromosomes weren’t single
genes—they were clusters of genes.
So scientists now knew that
chromosomes were bunches of genes
and that genes controlled inheritable
traits. But they still didn’t know
what genes were made of. What
was their chemical composition?
By the 1930s, scientists knew that
chromosomes were made of proteins
and DNA. But because proteins
had 20 main amino acids—20
 Lecture 1 Genes versus DNA

Morgan’s team compared chromosomes to pearl necklaces.

Each chromosome was like a necklace, while each pearl
was like a single gene for a specific trait. And because fruit
flies passed whole chromosome-necklaces to their children,
bunches of traits got inherited together in clusters.

letters—compared to the 4 letters as boiling in acid, and apparently

of DNA, proteins still seemed more that had also been breaking DNA
likely to be the genetic material. into unnaturally small pieces.

In the 1940s, scientists started Suddenly, after almost a century,

testing this assumption. And they
began to realize that everyone from
Miescher and Kossel onward had
been extracting DNA in a very rough
and potentially damaging way, such
it was looking like the DNA
molecule’s book of information
could be much bigger than a
protein. In fact, maybe DNA was
big enough to be the book of life.

Readings
Carlson, Mendel’s Legacy.
Endersby, A Guinea Pig’s History of Biology.
Henig, The Monk in the Garden.
Lagerkvist, DNA Pioneers and Their Legacy.

14
The Quest for DNA’s
Structure
LECTURE 2

B y the mid-20th century, scientists were realizing that DNA, not

proteins, had to be the molecule of life. This realization would
set off a series of discoveries, capped off by a furious competition to
determine the structure of DNA.
Return
to TOC

HERSHEY AND CHASE’S BLENDER

EXPERIMENT

By 1947, Erwin Chargaff at Hershey and Martha Chase ran

Columbia University had confirmed
that DNA was a very long
molecule—at minimum, hundreds
of times longer than it was wide. He
also showed that different organisms
had different amounts of each of
the 4 DNA bases. This suggested,
for the first time, that the DNA
“alphabet” was saying something
distinct for each kind of organism.
a startling experiment involving
viruses and a kitchen blender.
The now-famous blender experiment
took place at a lab on Long Island,
where Hershey and Chase worked
with a type of virus called a phage.
Just as animals catch viruses, so
can bacteria, and phages happen
to specialize in infecting bacteria.

And the mistaken dogma that Hershey and Chase’s experiments

proteins had to be responsible
for heredity finally died for good
in the early 1950s, when Alfred
involved unleashing phages into
2 petri dishes full of bacteria. The
viruses locked onto the outside
of the bacteria and injected
something into them—genetic

15
 Lecture 2
material, which hijacks the
bacteria’s internal machinery
and forces it to manufacture
more copies of the virus.
Hershey and Chase’s purpose was
to prove once and for all that the
genetic material being injected
wasn’t DNA, but proteins. To this
end, they designed a clever test.
They started with 2 flasks that
contained a simple virus called
T2, which consists of just DNA
and proteins. The flasks also
contained a broth full of minerals
and nutrients that viruses need,
including sulfur and phosphorus.
But in one flask, the broth contained
radioactive sulfur. In the other flask,
the broth contained radioactive
16
The Quest for DNA’s Structure
phosphorus. The key point is that
DNA contains phosphorus but no
sulfur. Proteins, in contrast, can
contain sulfur, but never phosphorus.
As a result, the T2 viruses
swimming around in one broth
had radioactive DNA, because
the phosphorus in the DNA was
radioactive. Meanwhile, the viruses
in the other broth had radioactive
proteins, because the sulfur was
radioactive. Hershey and Chase
could therefore track the movement
of DNA or proteins by following
2 different trails of radioactivity.
The experiment started when
they withdrew a few drops of T2
virus from one flask and squirted
it into a petri dish with bacteria.
 Lecture 2
Then, they squirted a drop of
virus from the other flask into a
second petri dish with bacteria.
The scientists let perhaps an hour
pass, giving the viruses time to lock
on the bacteria and inject genetic
material. Then, they used a kitchen
blender to agitate the bacteria and
knock the empty virus husks off.
They used a centrifuge after that to
separate the bacteria for examination.
Next, Hershey and Chase waved a
Geiger counter over the bacteria that
had been infected with radioactive
sulfur in the proteins. If proteins
were the genetic material, the Geiger
counter would have made a clicking
sound. Instead, it remained silent.
PAULING: THE WIZARD OF CALTECH
Linus Pauling, known as the wizard
of Caltech, was considered the
best chemist in the world at the
time. His signature achievement,
dating back to the 1930s, was
reimagining the chemical bond.
17
The Quest for DNA’s Structure
Then, they examined the other
bacteria, which had been injected
with radioactive phosphorus
and DNA. To their shock, the
Geiger counter began to click.
It could mean only one thing:
The virus had injected DNA.
Against all expectations, then,
here was the genetic material.
Genes weren’t made of proteins.
They were made of DNA.
After this blender experiment,
DNA became the hottest molecule
in the world—the chemical basis
for all biological heredity.
But if the blender experiment
answered one question—that genes
do depend on DNA—it raised
many others, starting with, What
is the structure of this DNA stuff?
Chemistry involves atoms forming
bonds with each other. In H2O,
for instance, the hydrogens (H)
bond with the oxygen (O). As for
what bonds were, chemists had
 Lecture 2
always talked vaguely of atoms
sharing electrons, but nobody
really knew what that meant.
Pauling used the new field of
quantum mechanics to explain
how electrons behave and how they
get shuffled around and shared
between atoms. And since chemistry
basically is the study of atoms
swapping electrons and shuffling
them around, Pauling single-
handedly revolutionized the field.
In the early 1950s, Pauling
decided he wanted to determine
the structure of DNA: what shape
As one colleague said, after Pauling,
“chemistry could be understood rather
than being memorized.”
THE CHEMICAL NATURE OF DNA
Structurally, each of the DNA
bases—adenine (A), cytosine (C),
guanine (G), and thymine (T)—is
made up of rings of carbon and
nitrogen. C and T are smaller, more
compact, with only one ring. A
and G are bulkier, with 2 rings.
As Pauling showed, atoms form
bonds by sharing electrons. These
bonds are called covalent bonds,
and hydrogen atoms form them
18
The Quest for DNA’s Structure
the DNA molecule was. However,
he was distracted with several
other projects and didn’t give
DNA his full attention at first.
This created an opportunity for
others, including a graduate student
and a young postdoc in England
named, respectively, Francis Crick
and James Watson. Unfortunately,
they would nearly blow this
opportunity—because of both their
haste and their ignorance about
the chemical nature of DNA.
readily. Overall, the hydrogen atom
is simple: It’s just a single negatively
charged electron circling a single
positively charged proton. It forms
bonds by sharing its lone electron
with oxygen or carbon or nitrogen.
But when hydrogens share that
negative electron with an atom on
one side, that also leaves its positive
 Lecture 2 The Quest for DNA’s Structure

proton exposed on the opposite side.
In other words, hydrogen now has
a negative side and a positive side.
And this residual charge—especially
the positive side—creates an
opportunity for a different type of
bonding. In contrast to hydrogen,
atoms like oxygen hoard electrons
and therefore have relatively negative
patches on their surfaces. With electric
charges, opposites attract. So the
positive side of the hydrogen attracts
the negative patches on the oxygen
or nitrogen. This type of attraction
is called hydrogen bonding.
Hydrogen bonding is weaker
than normal, covalent bonding.
But hydrogen bonds are crucial
to understanding DNA. In fact,
hydrogen bonds are what hold
DNA strands together: The
positive side of the hydrogen
atoms of one base attracts the
negative side of the oxygen or
nitrogen atoms of another base.
Mother Nature was quite clever
in using hydrogen bonds to hold
DNA together. For comparison, the
covalent bonds between the atoms
within the rings of DNA bases are
quite strong, like screws or bolts.
You can’t pull those atoms apart
without lots of effort. In contrast,
the hydrogen bonds between strands
are weaker. Instead of screws or
bolts, they’re more like magnets. A
little tug and they can come apart,
and coming apart is necessary to
copy DNA or build proteins.
Overall, these hydrogen bonds are
the perfect Goldilocks bond for
holding DNA bases and strands
together. These bonds are strong
enough to keep bases from separating
spontaneously but not so strong
to prevent cells from teasing apart
the bases when it’s time to copy
DNA or use it to build proteins.
Hydrogen bonds are just right.
But DNA consists of more than
just bases. It also has a backbone,
which consists of 2 additional
parts: phosphate molecules1
and sugar 2 molecules.

1 These phosphate molecules contain the phosphorus that was the key to the
blender experiment.
2 DNA merely includes sugar as part of a long string. Using chains of sugars
for structural support is actually common in nature. Plants do it all the time,
whenever they’re making carbs or fiber. This is the same idea that’s behind
the sugar backbone of DNA.

19
 Lecture 2
In 1953, scientists knew the rough
shape of the DNA strands. The
sugar-phosphate units are stacked
on top of each other like vertebrae
in your spine. The A-C-G-T bases
then stick out from this backbone,
kind of like the knobs on your spine.
What they did not know was the
overall shape of this DNA spine.
Is it straight or curved? Or did it
WATSON AND CRICK
Watson and Crick’s effort began
when Watson attended a lecture in
London, where Rosalind Franklin
was outlining some preliminary
work she’d done on DNA.
Franklin’s experiments involved
firing x-rays at a sample of DNA
and then capturing the reflected
rays on photographic film. From the
patterns that appeared on the film,
she then tried to guess the shape of
the DNA backbone and determine
how many strands there were.
When Watson returned to
Cambridge, he sought out Crick
to build a physical model of DNA
based on the data he’d heard from
20
The Quest for DNA’s Structure
have some other shape? They also
didn’t know for sure how many
strands of DNA were involved.
Was there a single backbone,
or were there multiple strands
coiled around each other?
These were questions that
Watson and Crick at Cambridge
thought they could answer.
Franklin’s lecture. That way, they
could sweep in and determine
the structure of DNA before
Pauling or anyone else did.
Watson and Crick were perfectly
within their rights to try this;
after all, Franklin had made her
results public during the lecture.
But this was pretty arrogant,
considering neither Watson nor
Crick was a DNA expert.
Watson soon convinced Crick to help
him start building the model. To do
so, they used what Watson described
as giant tinker toys. The DNA
backbone of sugars and phosphates
 Lecture 2
was made of metal rods and rings
fastened together in a 3-dimensional
spiral that was several feet tall.
There were certain things they knew
for sure about DNA, such as the
fact that it had a phosphate-sugar
backbone and that the A, C, G, and
T knobs were sticking out. The trick
was how those parts fit together.
Based on Watson’s half-remembered
data from Franklin’s lecture, they
decided on a 3-stranded DNA
molecule with the shape of a spiral
staircase—a triple helix. They now
had to decide what to do with the
21
The Quest for DNA’s Structure
knobs sticking out of the backbone.
In particular, did the knobs face
inward, toward the molecule’s
center? Or did they face outward?
Bases facing inward seemed unlikely
to them. The 4 knobs—the A, C, G,
and T bases—were different sizes. A
and G are bulky molecules because
they have 2 rings; C and T have a
single ring, so they’re skinny. And
when trying to fit all the differently
sized bases in the center, Watson and
Crick ended up with either unsightly
bulges or hollows and dents. The
whole thing just looked ugly and
unstable. So they decided the knobs
couldn’t possibly face inward.
But flipping the molecule around
and putting the knobs on the outside
presented its own troubles. That
arrangement put the phosphate
backbone in the molecule’s center.
The problem was that phosphate
molecules have negative charges.
Like the way opposite charges
attract, similar charges repel each
other. Phosphates are strongly
negative, so if you pack a bunch
of negative charges into the
molecule’s center, the whole thing
seemed likely to blow itself apart.
To solve this conundrum, Watson
and Crick got creative—that is, they
started making things up. They
 Lecture 2 The Quest for DNA’s Structure

theorized that cells might have element magnesium caught their

other, positively charged atoms, or
ions, floating around inside. And
maybe all those positive ions could
get vacuumed into the center of the
DNA molecule. These hypothetical
positive ions would neutralize the
negative charges on the phosphates
and make everything stable.
But as for what those positive ions
might be, they had no idea. So
they grabbed a chemistry textbook 3
and started paging through. The
eye: Magnesium gives up 2 electrons,
so it has a positive charge, and cells
have magnesium. Based on no real
evidence, then, they declared that
magnesium holds DNA together.
They still had to build their tinker-
toy model after that. It didn’t go
very smoothly; they had to cram to
make everything fit. But by the next
morning, they’d slapped together
a snappy-looking triple helix.

WILKINS AND FRANKLIN

It was time to get some feedback.
So Crick called Maurice Wilkins,
who was researching DNA at
King’s College in London. Wilkins
agreed to come to Cambridge
to see the model, accompanied
by Rosalind Franklin.
A year earlier, a Swiss biologist
named Rudolf Signer had developed
a recipe to isolate large, pure DNA
molecules from the thymus gland
of a cow. This DNA came out as
a goopy gel. He gave a talk about
his work in 1950 in London and
generously gave a sample to Wilkins.
Wilkins took this DNA goo back to
London and developed a way to draw
off very thin strands4 of DNA using
a glass rod. These DNA strands led
to Wilkins’s biggest contribution to
DNA research. While examining
the strands under a microscope,

3 In fact, this chemistry textbook was written by Linus Pauling.

4 In his poetic moments, Wilkins compared the strands to a spider web. In his
sophomoric moments, he said they looked like strings of snot.

22
 Lecture 2 The Quest for DNA’s Structure

he saw that they looked quite
uniform, with a regular, repetitive
shape—like a “pile of pennies.” So
he decided to investigate that shape
using an already-popular technique
called x-ray crystallography.
admitted he needed help and asked
his boss at King’s College to find
an expert on x-ray photography.
The boss found Rosalind
Franklin, a 30-year-old physical
chemist, who accepted the job.

This technique involved firing x-rays
at molecules and using photographic
film to capture the rays as they
bounced off. The rays would leave
spots on the film, and by studying
the patterns of those spots, scientists
could work backward and determine
what the shape of the molecule was.
Wilkins was correct to investigate
DNA’s regular, repeating shape,
and x-ray photography would
eventually crack the secret of
DNA’s structure. But it wasn’t
Wilkins himself who would do so.
That’s because when Wilkins tried
to take some x-ray photographs, he
proved clumsy with the equipment.
His pictures turned out poorly—
too blurry to be useful. After
several months of frustration, he
The boss who hired Franklin
assured her that she’d be
directing her own research and
running her own projects. But
this promise contradicted what
Wilkins wanted: an assistant.
Eventually, the work environment
became hostile, and the boss
stepped in and brokered a truce—
one that favored Franklin. She
got access to Wilkins’s precious
supply of pure DNA and all the
best equipment and cameras.
As a result of all this, Franklin
and Wilkins were barely speaking
to each other when they arrived
in Cambridge to see Watson
and Crick’s DNA model.

Franklin’s advantage over Wilkins was that she could

produce much tighter beams of x-rays. As a result,
she got sharper photographs. The advantage Wilkins
had was a background in physics, and he’d been
talking with mathematicians about which shapes could
produce which sorts of photographic images.

23
 Lecture 2
Watson and Crick started their
presentation with enthusiasm.
But things quickly unraveled. As
theorists, not experimentalists,
the duo had very little practical
knowledge about DNA—the
kind of knowledge Franklin
had. And she proceeded to
tear their model to shreds.
For instance, Franklin pointed
out their ignorance of how DNA
interacts with water. DNA is a
thirsty molecule, able to soak up
vast amounts of water. Under
other conditions, DNA loses
water just as easily. This implied
something crucial about the
structure of DNA—something
Franklin would figure out that
Watson and Crick had not.
Water has 3 atoms: 2 Hs and an O.
But the electrical charges on the
atoms are not equally distributed.
Chargaff, Essays on Nucleic Acids.
Watson, The Annotated and Illustrated Double Helix.
24
The Quest for DNA’s Structure
The 2 hydrogens have less hold
over the shared electrons. So the
hydrogen side of the water molecules
ends up being more positive.
Meanwhile, the oxygen hoards
more of the shared electrons, giving
the oxygen side of the molecule a
more negative charge. And it’s the
positive side of each water molecule
that’s attracted to the negative
charges in the DNA phosphate
backbones. The phosphates are
what actually suck up the water.
And for DNA to absorb or lose water
so readily, the phosphate backbones
cannot be facing the inside of
the molecule. The phosphate
backbones had to be accessible—on
the outside. That’s the only way
the water could come and go so
easily. In other words, Franklin
told Watson and Crick that their
tinker-toy model was inside out.
Readings
Hager, Force of Nature.
The Double Helix
Revealed
LECTURE 3

I t was almost 1952, and the Cambridge researchers James Watson

and Francis Crick had just built an inside-out, triple-helix model of
DNA. The errors and ignorance of this model were then torn apart by
their rivals at King’s College in London, especially Rosalind Franklin.
As a result, Watson and Crick’s graduate advisor had banned them
from working on DNA—a demand they secretly did not intend to
honor.

Return
to TOC

PAULING’S TRIPLE HELIX

Linus Pauling, the best chemist in

the world, was also looking into the
structure of DNA. At this point,
however, he was effectively being
accused of treason. The problem was
his speeches and articles opposing
atomic weapons. He also spoke out
against loyalty oaths, which were
designed to root out Communist
agents within the government,
and people started thinking he
might be a Communist himself.

In early 1952, when Pauling applied

for a passport to travel to England for
an important biochemical conference

25

on May 1, the US State Department
refused to renew his passport. As a
result, he missed the conference.
Franklin did attend the conference,
and she talked to one of Pauling’s
assistants there. She even showed
the assistant some top-notch x-ray
photographs she’d recently taken of
DNA. But Pauling himself never saw
the pictures. After the conference,
Wilkins and Franklin had decided
to stop sharing the pictures with
anyone. As a result, Pauling was at
a major disadvantage in the race to
determine the structure of DNA.
Given all his other scientific projects,
and his political activities, Pauling
didn’t work on the structure of
DNA until the fall of 1952. And
because he hadn’t seen Franklin’s
pictures, he relied on a few low-
quality photographs taken by
another colleague. Unfortunately,
the DNA in these pictures had
not been prepared very well and
ended up dehydrated. That’s a
big problem, because dehydrated
DNA shrivels up and changes
shape somewhat. It would be like
Linus Pauling had a son, Peter, who happened to be in
graduate school in 1952 at Cambridge University. In fact,
he worked in the same department as—and even shared
an office with—Watson and Crick.
26
Lecture 3 The Double Helix Revealed
trying to reconstruct what a flower
looks like based on a poorly lit
picture of a dried-up bouquet.
But Pauling didn’t know that when
he started working. The shriveled
DNA seemed tightly packed to him.
So, after running some numbers on
his trusty slide rule, he calculated
that there must be 3 strands.
And given the tight packing, he
decided that the knobs on the DNA
backbone couldn’t possibly fit into
the molecule’s center. He decided
to flip the knobs outward instead.
In other words, Pauling came up
with an inside-out triple helix—the
exact same structure that Watson and
Crick had proposed a year before.
Like everyone else, Pauling knew
that whoever cracked the mystery
of DNA’s structure first would be
showered in glory, so he rushed a
paper into print, submitting it to
a journal in December 1952.

WATSON AND CRICK’S DOUBLE HELIX
Before Pauling’s paper made it to
print, Watson and Crick got ahold
of it and noticed that Pauling
had reproduced the naïve errors
they’d made a year earlier—those
that Franklin had corrected them
on. So Pauling hadn’t beaten
Watson and Crick. They were
still very much alive in the race.
But there was still the awkward
matter that their advisor had
banned them from working on
DNA. So they took Pauling’s paper
to their advisor and confessed
that they’d been working on
DNA in secret this whole time.
To their surprise, their advisor, who
was Lawrence Bragg,1 didn’t chew
them out. That’s because Bragg was
widely considered Pauling’s top rival
in the world of experimental science,
except Pauling kept beating Bragg to
major discoveries. Bragg saw a chance
for his lab to humiliate Pauling—to
finally beat the wizard of Caltech.
Bragg ordered Watson and Crick
to resume working on DNA
immediately. But to win the race for
DNA, they’d need better clues and
1 Bragg had won a Nobel Prize for x-ray crystallography in 1915, at the
age of 25.
27
Lecture 3 The Double Helix Revealed
data. And the most likely source to
try was Franklin. So Watson took a
train to London and barged into her
lab. Franklin and Watson quarreled
about whether DNA was a helix.
Then, Wilkins showed up and
unburdened himself to Watson about
his own frustrations with Franklin.
And then—without Franklin’s
permission—Wilkins showed
Watson the crucial photograph
Franklin had taken, Photograph 51.
The photo confirmed Watson’s
hunch that DNA had to be a helix.
He raced back to Cambridge to
tell Crick. And as they worked
over the next few days, other
clues began to fall into place.
Franklin had torn apart their
model of DNA a year earlier for
having the bases—adenine (A),
cytosine (C), guanine (G), and
thymine (T)—on the outside,
among other reasons. Somehow
the bases had to fit into a very
tightly packed space on the inside.

So instead of a triple helix, they
started thinking about a double
helix: 2 strands of DNA coiled
together. With a double helix, the
packing problem became easier,
since they had to fit only 2 bases
into the limited space, not 3.
CHARGAFF’S CONTRIBUTION
The data came from Columbia
chemist Erwin Chargaff, who had
discovered that A and T always
appeared in equal amounts in DNA,
even though the total amount
of A and T could vary from one
organism to another. For example,
if some stretch of DNA was 22%
28
Lecture 3 The Double Helix Revealed
Using a double helix also had
another benefit: It made sense of
some data that Watson knew about
but did not yet understand.
A, it was also 22% T. Likewise, the
percentage of C always matched the
percentage of G. In other words,
those bases always appeared in
pairs. And the existence of pairs
could be explained quite naturally
with 2 strands in a double helix.

Every time an A appeared on one
strand, you simply needed a T on
the other strand, and vice versa.
Similarly, every time a C appeared
on one strand, you needed G on the
other, and vice versa. It’s the simplest
way to get equal amounts of both.
And when Watson and Crick
looked at the shapes of A, C, G,
and T more closely, their hearts
began racing. Another objection to
having the bases face inward had
been their awkward shapes. A and
G were bulky bases, having 2 rings;
C and T were skinny bases, having
single rings. And pairing different
bases up would leave the DNA
molecule with dents or bulges.
WATSON AND CRICK’S DISCOVERY: THE
SECRET OF LIFE
Watson and Crick’s model finally
came together in February 1953.
Everything fit: It was a double helix
2 Chargaff had actually mentioned these results to Pauling years before on an
ocean cruise. But Chargaff could be a loudmouth, and Pauling was annoyed
with him for interrupting his vacation. So Pauling had blown off Chargaff—a
terrible mistake.
29
Lecture 3 The Double Helix Revealed
But it just so happened that each
of Chargaff’s pairs contained one
skinny base and one bulky base. So
when these bases paired up, there
weren’t any bulges or dents. In fact,
when Watson and Crick started
building a double helix model, they
saw that A fit with T and C fit with
G as snugly as puzzle pieces. Plus, the
extra hydrogens and oxygens lined
up to give ideal hydrogen bonding.
Along with Franklin’s photograph,
Chargaff’s rule 2 for matching
A with T and C with G was
the key to solving DNA.
with the bases turned toward the
center, in which A always paired
with T and C always paired with G.
 Lecture 3 The Double Helix Revealed

The discovery of DNA’s double helix would electrify biology

and give scientists a tool for deciphering the whole history
of life on Earth. On a more individual level, it would also
explain several age-old mysteries of heredity.

The duo was so excited that, during
lunchtime, Crick reportedly burst
into The Eagle pub in Cambridge
and started crowing about how
they’d just discovered the secret of
life. And it really was one of the
biggest discoveries in science history.
Watson and Crick spent the next few
weeks working out some last details
and then hurriedly mailed off a paper
to the scientific journal Nature.
Pauling even helped promote
Watson and Crick’s discovery over
the next few months, giving their
careers a boost and cementing the
double helix as one of the most
famous concepts in all of science.
The elegant structure of the helix
told Watson and Crick something
important about how DNA
worked—specifically, how DNA
copies, or replicates, itself.

But before the paper appeared
in print, Pauling caught wind of
it. He had serious doubts that 2
greenhorn scientists had beaten him.
He happened to be traveling to a
conference in Belgium around that
time, so he scheduled a side trip to
Cambridge to meet with the men.
Watson and Crick showed Pauling
their tinker-toy model and watched
as he cast a critical eye over it.
But to Pauling’s credit, he quickly
conceded that they’d beaten him.
The double helix is so elegant and
makes sense of so much data that
he realized it had to be correct.
Picture the DNA double helix
as a zipper, with the 2 strands
enmeshed. The first step in
copying DNA is unzipping it. A
cell breaks the hydrogen bonds
holding the 2 strands together
and teases each one apart.
Then, the actual copying starts. A
special piece of cellular machinery
zooms along each strand, kind of
like the pull tab on a zipper. The
machinery reads each DNA base
along the strand one by one. And
each time it does so, it adds a base
to the new strand being built.
Specifically, whenever it reads an A
on the original strand, it adds a T
to the one being built. Whenever

30

it reads a C on the original strand,
it adds a G to the new one—
and vice versa, in both cases.
In other words, each strand
acts as a template for building a
new one. And when the process
finishes, you have 2 exact copies.
Cells copy DNA like this right before
they divide. And because the copies
are exactly the same, each of the
daughter cells inherits a complete
library of the original DNA. In fact,
THE SCIENTISTS WHO WERE LEFT
BEHIND
But however celebrated, that
first paper on the double helix by
Watson and Crick has always been
controversial because of Watson and
Crick’s relationship to Franklin.
Contrary to popular belief, the paper
did credit Wilkins and Franklin,
however tepidly: “We have also been
stimulated by a knowledge of the
general nature of the unpublished
experimental results and ideas of
Dr. M.H.F. Wilkins, Dr. R.E.
Franklin and their coworkers….”
31
Lecture 3 The Double Helix Revealed
all the DNA in your body started
off as a single copy in an embryo
9 months before your birth date.
Several trillion cell divisions later,
here you are. And each of your
cells still has the same essential
DNA as that first embryo, thanks
to this clever copying process.
That’s why Watson and Crick are
so famous. It wasn’t just that they
discovered the double helix. They
also realized that the shape of the
helix revealed how DNA worked.
Moreover, Franklin and Wilkins
each published their own papers
on DNA—right next to Watson
and Crick’s paper in the same
issue of the same journal.
But for various reasons, Franklin
and Wilkins have faded somewhat
from history. It was probably a
combination of Wilkins’s quiet
personality, Franklin’s gender,
and Watson and Crick’s discovery
of how DNA copies itself.

As a result, most of the glory fell on
Watson and Crick alone. Franklin
especially has become a scientific
martyr—a cause célèbre about
gender discrimination in science.
In 1968, Watson published a
book called The Double Helix: A
Personal Account of the Discovery of
the Structure of DNA. As he later
admitted, it paints a one-sided,
misleading portrait of Franklin.
Even Crick got upset with parts
of it. Years later, Watson admitted
that he didn’t know Franklin very
well. If he could write the book
over, he said, “I would write more
sympathetically about the plight
of both Wilkins and Franklin.”
Despite this, the anger over
Franklin’s treatment has not
died down in the nearly 70 years
since the double helix race. In
2003, on the 50th anniversary of
Crick bursting into The Eagle to
announce the “secret of life,” the
pub posted a plaque outside its door
to celebrate Crick and Watson. No
other scientists rated a mention.
So in October 2017, someone
either defaced or corrected the
plaque, depending on your
point of view, by writing “+
Franklin” across the bottom.
32
Lecture 3 The Double Helix Revealed
Beyond the way Franklin got
treated, another perplexing issue
is why she didn’t solve the double
helix first, especially since she
had Photograph 51 and other
evidence right in front of her.
Like Pauling, Franklin had been
working with dehydrated DNA.
In fact, it was she, not Watson
and Crick, who discovered that
DNA has both a hydrated form
and a dehydrated form. And in
her lab work, part of the time
she photographed fully hydrated
DNA, but part of the time she
photographed dehydrated DNA.
For technical reasons, photographs
of dehydrated DNA showed
up better on film; that is, the
pictures were sharper, with more
structures visible. And to someone

like Franklin, trained to interpret
such photographs, having clearer
pictures meant better data to study.
So even though she had good
pictures of hydrated DNA, too,
Franklin put those pictures
aside. She concentrated on the
dehydrated form instead. And at
least at first, the dehydrated form
didn’t look like a helix to her.3
Unfortunately, Franklin was wrong
here. Inside the body, DNA is
surrounded by water and doesn’t
get dehydrated and shriveled. This
meant that Franklin was studying an
obscure, misshapen form of DNA,
not the kind surrounded by water
that cells normally use. As a result,
any conclusions she drew about
dehydrated DNA missed the point.
The real question was DNA’s
shape when it was fully hydrated.
Photograph 51 did show fully
hydrated DNA. And after Wilkins
sneaked the photograph to Watson,
Watson became convinced that the
DNA in cells was helical, too.
3 Franklin sent Wilkins a fake obituary in mid-1952 mocking the death of
the DNA helix. This shows Franklin’s dry sense of humor, something most
historical accounts ignore.
33
Lecture 3 The Double Helix Revealed
Overall, you could argue that
Franklin missed out on the double
helix in part because she was
too good of a scientist. She was
a perfectionist and wanted to
nail down every last detail of the
dehydrated form before moving on
to the other one. She also refused
to make any speculative leaps until
she’d collected all her data and
checked everything several times.
Watson and Crick were the opposite
of Franklin. They made no original
discoveries themselves. They
simply swept in and interpreted
other people’s findings.
But they were also willing to
gamble and speculate and even
suffer public humiliation in pursuit
of a big prize. Franklin was more
cautious. Her attitude is normally
the ideal in science; we don’t want
people spouting off theories half-
cocked. But in the race for the
double helix, it cost her dearly.
There’s another, sadder reason
Franklin has faded somewhat from
science history. After years of taking
x-ray photographs in her lab, she
developed ovarian cancer in the

late 1950s and ultimately died of
it in 1958. As a result, her work on
DNA was ineligible for the Nobel
Prize 4 years later, since only living
scientists can win the prize.
Had she lived a few more years, the
Nobel committee would have had an
excruciating decision to make, since
only 3 scientists can share a Nobel
Prize for a given discovery, and
Watson, Crick, Franklin, Wilkins,
and even Chargaff all had claims.
As it was, the committee awarded the
prize to the 3 living scientists closest
to the final result—Watson, Crick,
Watson, Genes, Girls, and Gamow.
34
Lecture 3 The Double Helix Revealed
and Wilkins—who split the prize in
1962. Wilkins’s Nobel Prize speech
did say that Franklin “made very
valuable contributions to the X-ray
analysis.” But neither Watson’s nor
Crick’s speech mentioned her at all.
But if Franklin was missing from
the Nobel stage in 1962, there
was a surprise Nobel laureate
that year: Pauling won the Nobel
Peace Prize for his work on nuclear
disarmament. The same activities,
then, that had blocked his passport
and cost him a shot at solving
DNA ended up paying off.
Readings
Maddox, Rosalind Franklin.
Wilkins, Maurice Wilkins.
From Genetic Codes to
DNA Fingerprints
LECTURE 4

T he famous and controversial discovery of the double helix of

DNA in 1953 was, in many ways, just the beginning. DNA stores
information. It’s a biological blueprint. But blueprints aren’t the final
product. Our cells have to build things with the DNA blueprint.

Return
to TOC

GAMOW’S GENETIC CODE

So if DNA is a blueprint, what does
our body build with it? Primarily,
proteins, which are vital in every
biochemical process. But our
bodies don’t make proteins directly
from DNA. Instead, we use an
intermediary, which is a chemical
cousin of DNA called ribonucleic
acid (RNA). Overall, DNA makes
RNA, and RNA makes proteins.
Scientists in the early 1950s already
knew RNA was important, because
they could see the concentration of
RNA spike inside cells whenever
the cells started making protein.
By the end of the 1950s, Francis
Crick had summarized the existing
knowledge about DNA and RNA
and amino acids into what he called
the central dogma of molecular
biology, which says that DNA
produces RNA and RNA produces
proteins—in that order. You
can’t skip a step, and you can’t go
backward. It was the new foundation
for understanding heredity.
RNA differs from DNA in a few
ways. Both have backbones made
of phosphate and sugar, but RNA
is single-stranded, not double-
stranded. Also, the RNA sugars are
ribose, which are more chemically
reactive than the deoxyribose
sugars of DNA. And while the 4
DNA bases are A, C, G, and T,
RNA makes one substitution: In
place of T, it uses U (for uracil).

35
 Lecture 4
The question that scientists
could not yet answer was how
our cells turned strings of the 4
RNA letters into amino acids.
Physicist George Gamow had gotten
things off to a good start. Our bodies
use 20 amino acids. And Gamow
noticed that a combination of 2 bases
would have given only 4 × 4, or 16,
possibilities—fewer than 20. So he
suggested a genetic code with 3 bases,
since 4 × 4 × 4 = 64, which was more
than enough. In other words, the
DNA code probably involved triplets.
NIRENBERG’S RNA TRIPLETS
In 1961, Marshall Nirenberg of the
National Institutes of Health (NIH)
ran a clever experiment. He started
with a long chain of one RNA base
uracil; the chain was just U-U-U-U,
on and on. He then mixed this
long U string with different amino
acids, plus the protein-making
apparatus from a bacterium.
36
From Genetic Codes to DNA Fingerprints
And in 1961, Crick led an
experiment that proved the code
must use triplets. Crick’s group
knocked out single bases and then
knocked out pairs of bases, and
the resulting proteins were totally
different. But when they knocked
out 3 bases in a row, the protein
was essentially the same, but
with just one amino acid missing.
Everything else stayed in place.
So the biggest question in genetics
became figuring out the relationship
between those 2 numbers: Why did
64 triplets code for 20 amino acids?
And why not 19 amino acids, or 21?
The protein-making apparatus
read the RNA string and then
produced a protein. And this protein
consisted of just one amino acid,
phenylalanine, over and over.
This was his big clue. Again, the
RNA here was a long string of
Us. And because the genetic code
works with triplets, he therefore
knew that the triplet U-U-U must
 Lecture 4
code for phenylalanine. Similar
experiments linked other RNA
triplets to other amino acids.
In August 1961, Nirenberg—who
was a complete outsider to DNA/
RNA research1 —presented his
findings on the uracil triplets at
a conference in Moscow. Only
a few dozen people attended,
and the room seemed dead.
But one of those attendees mattered.
Nirenberg had gotten lucky and
met James Watson the day before
his presentation. When Nirenberg
explained his results, Watson
FROM DNA TO RNA TO PROTEIN
Once Nirenberg revealed the
genetic code for translating RNA to
proteins, scientists quickly pieced
together how the rest of the DNA-
to-RNA-to-protein process worked.
When cells copy DNA, they unzip
the weak hydrogen bonds of the
double helix. Wherever cells detect
1 A later biography of Nirenberg was titled The Least Likely Man.
37
From Genetic Codes to DNA Fingerprints
thought he was full of baloney. But
just in case, Watson dispatched
a colleague to attend the talk.
The colleague was blown away. He
told Watson that Nirenberg was
the real deal. And to his credit,
Watson overcame his skepticism
and had Crick organize a much
bigger talk for Nirenberg. As
Nirenberg later said, “The reaction
was incredible. It was a standing
ovation…. For the next five years I
became like a scientific rock star.”
Over 5 years, Nirenberg built a
large team at NIH that cracked
all 64 triplets. And just 2 years
later, he won a Nobel Prize.
an A on one strand, they add a T
to the strand being made, and vice
versa. Whenever cells detect a C
on one strand, they add a G to the
other strand, and vice versa. This is
called complementary base-pairing.
 Lecture 4
When building proteins, cells use
the same general process as copying
DNA. It starts with transcription,
which involves using DNA as a
template to make a string of RNA.
Consider this strand of DNA: C-A-
C-G-A-T. When cells turn that into
RNA, it becomes G-U-G-C-U-A, 2
because RNA uses U instead of T.
Once this RNA string is complete,
it leaves the cell nucleus, where
DNA is stored. Because this
RNA carries information from
one place to another, it’s called
messenger RNA (mRNA).
This mRNA ends up at special
cellular equipment called ribosomes.
Ribosomes grab the mRNA and
examine the first 3 letters—each
triplet is also called a codon. In the
example, G-U-G is the first triplet.
At this point, a second type of RNA
gets involved: transfer RNA (tRNA).
Each tRNA consists of 2 parts: an
RNA triplet and an amino acid that’s
being transferred, or towed behind.
2 In reality, this RNA string could be thousands of letters long.
38
From Genetic Codes to DNA Fingerprints
The tRNA triplet is complementary
to the mRNA triplet. In the
example, the mRNA was G-U-G,
so the tRNA will be C-A-C.
At this point, the tRNA docks with
the mRNA. The ribosome then grabs
the amino acid trailing the tRNA.
This becomes the first amino acid in
the protein—the first building block.
Then, the process repeats. The
ribosome shifts down 3 letters and
reads the next mRNA triplet. A
complementary tRNA approaches,
towing another amino acid. That
second amino acid gets added to
the first—a second building block.
This process continues. A third
amino acid gets added, then a fourth
and a fifth, up to several thousand.
The key point is that cells turn
DNA into RNA and then use
triplets of RNA to string amino
acids together into a protein.
That’s how information encoded in
DNA gets turned into proteins.
 Lecture 4
GENES AND MUTATIONS
With this understanding in place,
scientists in the 1960s could now
redefine some important ideas in
genetics, such as what a gene is.
A gene is a stretch of DNA that
stores the instructions for making
a protein. It has a starting point
and a stopping point, and the
triplets in between tell you what
amino acids made up the protein.
Scientists could also now use DNA
to define what a mutation is. There
are different types of mutations,
but the most common mutations
involve a copying mistake.
Cells are amazingly accurate when
copying DNA; they rarely make
mistakes. But given that we have
trillions of cells, each with billions
of DNA bases to copy, mistakes do
happen. Maybe the cell wanted a T
in one spot but put a G instead.
Sometimes these mistakes don’t make
a difference. It’s like British versus
American spelling—for example, grey
versus gray, respectively. Similarly,
the triplets G-T-T and G-T-C and
G-T-A all code for the same amino
acid. So a mutation from one triplet
to the other makes no difference.
39
From Genetic Codes to DNA Fingerprints
Other mutations do make a
difference, though. In those cases,
changing one letter to another
leads to a different amino acid,
with different properties. This can
change the shape of the protein or
disable it completely, sometimes with
terrible consequences for the body.
There are other types of mutations
as well. One is called a frameshift
mutation. In this case, the mistake
involves deleting a letter entirely.
This was the type of mutation that
Crick’s team caused in 1961 by
knocking out a letter or 2. Frameshift
mutations can also involve inserting
a letter, shifting the whole sequence
down by one. That cascade makes
frameshift mutations pretty deadly.
In a normal mutation, if you just
swap one letter for another and
get a different amino acid, the
resulting proteins can often still
function, since other amino acids
remain the same. But a frameshift
mutation messes things up not
only at the point of insertion
but everywhere down the line.
Because cells read RNA in
consecutive groups of 3, a frameshift
mutation can affect dozens, if
not hundreds, of amino acids.
 Lecture 4
Overall, this insight into different
types of mutations allowed scientists
to understand genetic disorders
at a root level, revolutionizing
our knowledge of cystic fibrosis,
hemophilia, Huntington’s
disease, and other ailments.
THE LEICESTERSHIRE MURDERS
In Leicestershire, a county in
England, in November 1983, a
15-year-old girl named Lynda
Mann was found beaten, raped,
and strangled to death. There was
semen inside her, and forensic
tests determined that the murderer
had blood type A. Other tests on
the sperm found that the killer’s
proteins were somewhat unique.
The police could rule out 90%
of the male population. But that
still left thousands of suspects in
the county. And with zero other
leads, the investigation stalled.
Sadly, history repeated itself 3
years later, in July 1986. In another
town in Leicestershire, 15-year-old
Dawn Ashworth was also found
beaten, raped, and strangled to
40
From Genetic Codes to DNA Fingerprints
But it turns out that there is one
type of mutation that takes place in
every human being at conception,
one that makes no medical difference
at all. Even more surprising, these
seemingly irrelevant mutations
offered a new way to fight crime.
death. Forensic tests once again
found blood type A and the
same sperm proteins as before.
This time, however, the police did
track down a suspect: a 17-year-
old named Richard who matched
the blood type and protein profile.
And after some harsh interrogation,
Richard confessed to the crime. But
Richard denied committing the first
murder, when he would have been
just 14. Also, Richard was somewhat
mentally handicapped, and his
confession might have been coerced.
So at this point, the police
turned to a new tool called
DNA fingerprinting.
DNA comes packaged in
chromosomes, which Thomas
Hunt Morgan’s team at Columbia
 Lecture 4
University had likened to a pearl
necklace, with each gene on
the chromosome being a single
pearl. The assumption in their
necklace metaphor was that genes
were tightly packed together.
Chromosomes do contain genes, but
the pearls are not tightly packed.
The genes are strung far, far apart.
So what’s in between genes? Those
in-between stretches are still made of
DNA, but this so-called noncoding
DNA doesn’t make proteins.
In stretches of noncoding DNA,
mutations can accumulate more
easily than inside coding stretches
that get turned into proteins. That’s
because if a mistake pops up inside a
JEFFREYS’S DNA FINGERPRINTING
The Leicestershire murders took
place just a few miles from the
University of Leicester, where a
geneticist named Alec Jeffreys was
working. He studied paternity. He
wanted to see whether he could
tell who someone’s parents were
based solely on their DNA.
41
From Genetic Codes to DNA Fingerprints
gene, the protein might be misshapen
or broken, and the person could
die. But if a mutation pops up in a
noncoding stretch, so what? The cell
isn’t doing anything with that DNA.
As a result, these mutations often get
passed down from parent to child.
That’s especially true of one type
of mutation. For unknown reasons,
our cells sometimes copy and paste
the same few DNA bases over
and over, such as C-A-G, C-A-G,
C-A-G. Sometimes it’s 5 or 6 times;
sometimes it’s 5 or 6 dozen times.
These repeated sections are called
satellites—either minisatellites
or microsatellites, depending on
how many bases get repeated.
Jeffreys was focused on satellites
in the paternity tests he created.
Like all our DNA, we inherit
some satellites from our mothers
and some from our fathers.
So in 1984, he asked a technician in
his lab for some blood and got some
blood from the technician’s mother
and father as well. He then examined
 Lecture 4
the DNA for all 3. The results were
a mess. Some of the repeats linked
the technician to her mom, while
some repeats linked to her dad.
But she also had other repeats that
were unique to her. How was he
supposed to sort through all this?
Eventually, he realized that he
could see both her parental DNA
and her own, unique DNA. But
if her DNA pattern was unique,
then it could distinguish her from
every other person in the world.
She had a unique DNA identifier.
Furthermore, there was nothing
special about his technician. Jeffreys
realized that all of us must have
unique DNA identifiers inside us. He
could therefore determine whether
someone had been at a crime scene
by extracting DNA from any cells
or bodily fluid collected there.
Before long, someone on the
Leicestershire police force suggested
using DNA fingerprinting on the
murders. Scientists first tested
17-year-old Richard, and his DNA
ruled him out—in both cases. This
Genetics came a long way in the first 3 decades after
the discovery of the double helix. Scientists cracked
the genetic code in the 1960s, and this opened the way
for DNA fingerprinting in the 1980s.
42
From Genetic Codes to DNA Fingerprints
was a relief for Richard, but it left
the police in a bind: Who, then,
had killed Lynda and Dawn?
The police decided to take a brute-
force approach to solving the case.
In early 1987, they solicited blood
or saliva from thousands of men
in Leicestershire who had no alibis
for the nights of the murders. They
spent the next 6 months trying
to find a match to the killer’s
DNA. Accounts vary, but after
examining at least 4000 cases,
they still had no DNA match.
And there the case might have
remained—unsolved—if not for
criminal stupidity. In September
1987, a woman at a pub in
Leicestershire overhead a man named
Ian Kelly bragging that his friend
Colin had paid him 200 pounds to
submit a DNA sample in place of his
friend. Colin supposedly didn’t want
the police harassing him about some
burglary charges from his youth. The
woman reported the conversation
to the police, who quickly arrested
the friend, Colin Pitchfork.
 Lecture 4 From Genetic Codes to DNA Fingerprints

Even after his arrest, Pitchfork about 400 US inmates falsely

denied the crimes. But when
police got a DNA sample from
him, his satellite repeats matched
the repeats in the killer’s DNA
perfectly. The Leicestershire
murderer had finally been caught.
Pitchfork was the first person
ever convicted using DNA
fingerprinting. Equally important,
Richard was the first person ever
exonerated using the technique.
Police have been using DNA
fingerprinting for both purposes
ever since, collaring criminals and
absolving the innocent. By 2020,
DNA fingerprinting had exonerated
convicted of felonies, including
more than 20 on death row.
And while the basic idea behind
DNA fingerprinting remains the
same, forensic scientists have also
expanded how they leverage DNA
fingerprinting to track down
criminals. In particular, police used
genealogy data 3 to hunt down
Joseph James DeAngelo, the so-
called Golden State Killer, who had
committed at least 50 rapes, 12
murders, and 120 burglaries around
Sacramento, California. His crime
spree started in the mid-1970s and
lasted roughly 10 years. Investigators
announced DeAngelo’s arrest on
April 25, 2018—National DNA Day.

Readings
Portugal, The Least Likely Man.
Wambaugh, The Blooding.

3 Starting in 2018, the police turned to DNA databases found on publicly

usable genealogy sites like GEDmatch. And while there were no exact hits
on the killer, the police did find the killer’s relatives. They determined the
identity of the relatives and then built a family tree from birth certificates
and other public records. From there, they looked for a male who had lived
in Sacramento in the 1970s and 1980s. They eventually zeroed in on a former
police officer named Joseph James DeAngelo. After acquiring DeAngelo’s
DNA, they compared it to DNA taken from the crime scenes. It was a
perfect match.

43
The War over the Human
Genome
LECTURE 5

T he Human Genome Project was a multidecade, multibillion-

dollar effort to sequence all 3 billion bases of human DNA. It’s
sometimes called the Manhattan Project of biology—partly for its
scope and scale, but also for the moral ambiguities involved. There
were complex characters and ethical quandaries, heroes and villains.
But along the way, some pretty amazing science got done that
revolutionized the entire field of genetics.

Return
to TOC

SANGER’S SEQUENCING

The Human Genome Project traces Cleverly, though, Sanger used

its pedigree to the 1970s, when a
British biologist and previous Nobel
Prize winner named Frederick Sanger
invented a method to sequence
DNA. In other words, he figured
out a way to record the order of
the As, Cs, Gs, and Ts in DNA.
Sanger’s sequencing method involved
3 basic steps: heating the DNA until
the 2 strands separated, breaking
each of the 2 strands into fragments,
and using individual A, C, G, and T
bases to build new strands that were
complementary to the fragments.
specially made bases with radioactive
atoms in them, so these radioactive
bases got incorporated into the
complementary strand. He could tell
whether A, C, G, or T was producing
the radioactivity at any point
along the complement. He could
therefore deduce which base resided
there and record the sequence.
Unfortunately, Sanger had to read
these bases one by one—a tedious
process. Nevertheless, the process
allowed him to sequence the full
genome of a virus: a single strand of
nearly 5400 bases grouped into 11

44
 Lecture 5
genes. This was the first full DNA
genome ever sequenced, and the
work won Sanger his second Nobel
Prize, in Chemistry, in 1980.
In 1986, a few biologists in
California automated Sanger’s
method to speed it up. And instead
of using radioactive bases, they
substituted fluorescent versions of
A, C, G, and T. Each one produced
a different color when struck by
a laser beam. This machine, run
by a computer, suddenly made
large-scale sequencing feasible.
WATSON’S LEADERSHIP
Watson helped the NIH wrestle
most of the Human Genome
Project away from the Department
of Energy. Watson and his allies
also made several big promises to
Congress to ensure funding. In
fact, critics later accused them of
overpromising. Some scientists
claimed that sequencing the
human genome would eliminate
most diseases; some went so far
as suggesting that we could end
hunger, poverty, and crime.
45
The War over the Human Genome
In April 1987, the US Department
of Energy started the world’s first
human genome project, a proposed
$1 billion effort. In September 1988,
the National Institutes of Health
(NIH) set up a rival institute to
sequence the genome in 15 years
and secured James Watson of double
helix fame as the project’s chief.
Meanwhile, in London, a research
charity called the Wellcome Trust
also got involved via the Sanger
Institute, which had been founded
in honor of Sanger in 1992.
But for all of Watson’s early
leadership on the Human Genome
Project, he didn’t last long as its
leader. In year 3 of the project,
Watson found out that the NIH
planned to patent some genes that
one of its scientists had discovered.
The idea of patenting genes
nauseated most biologists then.
They felt that patents interfered
with basic research and distorted
science by making it all about profit.
 Lecture 5
Watson lit into his boss at the
NIH and went behind her back
to tell reporters that the policy
was moronic and destructive.
A power struggle ensued.
Unfortunately for him, Watson’s
boss proved the better bureaucratic
warrior. And it turned out that
Watson privately owned stock in
some biotech companies, which
raised concerns about conflicts
of interest. So his boss raised a
VENTER VERSUS THE NIH
At the NIH, Venter was studying
the genes that brain cells use but
despaired over the tedium of finding
genes by hand. Then, he heard
46
The War over the Human Genome
stink behind the scenes, and she
created conditions, he alleged,
that forced him to resign.
But Watson couldn’t go quietly.
The NIH scientist who wanted to
patent the genes had discovered them
with an automated process that—
unlike Sanger’s patient approach
by hand—involved computers
and robots. Watson didn’t like
the process because it lacked style
and craft. So in a hearing before
Congress about the patents, Watson
dismissed the operation as something
that “could be run by monkeys.”
This didn’t exactly endear him
to the “monkey” in question,
NIH biochemist Craig Venter.
In fact, partly because of
Watson, Venter soon became a
scientific villain—perhaps the
only scientist alive who was even
more polarizing than Watson.
about a shortcut. A colleague had
developed a way to identify the
messenger RNA that cells use to
make proteins. Because messenger
 Lecture 5
RNA comes directly from DNA,
Venter could work backward
from that RNA and eventually
learn the full DNA sequence.
Before he fully sequenced any
genes, however, Venter focused on
simply finding and cataloguing
new genes. To do so, he sequenced
just a short segment of each—
enough to establish that it was
new. Then, he submitted patent
applications for each new gene,
without any idea what it did.
To move as fast as possible, he also
automated the RNA-detection
technique with tabletop robots
and computers. In doing so, he
cut down the price for detecting a
new gene from $50,000 to $20.
At its peak, Venter’s group was
patenting 1000 partial gene
sequences each month. And it
was Venter who announced the
patents at a Congressional hearing,
setting off the firestorm.
But, love him or hate him, Venter
got results. And after feeling
wounded by Watson’s “monkey”
comments, Venter quit the NIH
in 1992 and joined an unusual
hybrid organization that had a
nonprofit arm dedicated to pure
science but also a for-profit arm
47
The War over the Human Genome
dedicated to patenting genes. Venter
himself got tons of stock in the new
company, making him a very rich
man. This side of Venter seemed
ominous to many scientists.
Venter’s approach to sequencing
DNA resembled the NIH’s approach
in some ways. But in other ways,
it was radically different.
The NIH planned to spend its
first few years and its first billion
dollars constructing a map of each
chromosome and determining
where each gene started and
stopped. It’s similar to mapping
an unknown continent. You start
with the coasts and the outline
and then fill in the interior later.
With the map complete, NIH
scientists would divide each
chromosome into segments and send
each segment to different labs around
the country. Each lab would then
shotgun the DNA: They’d make
lots of copies of the chromosome
segments and then use intense
sound waves to blast this DNA
into tiny overlapping fragments.
Scientists would then sequence every
individual fragment and use the
overlaps to piece the small sequences
together into a larger sequence.
 Lecture 5
Imagine dividing a novel into
chapters and then dividing each
chapter into paragraphs. Scientists
would photocopy each paragraph
and then blast it into random
phrases, such as “Once upon a
midnight,” and “midnight dreary,
while I pondered,” and “pondered,
weak and weary,” etc. Based on
the overlaps, scientists could then
reconstruct the original sentence:
“Once upon a midnight dreary, while
I pondered, weak and weary …” It
worked the same way with DNA.
48
The War over the Human Genome
And because the NIH already
had a chromosome map complete,
scientists then knew where each
gene fit on its chromosome.
Overall, the NIH’s method—
map things first and then
shotgun small pieces—was a
patient approach to sequencing
a genome, going paragraph by
paragraph, chapter by chapter.
Venter, in contrast, wasn’t patient.
His team loved the shotgun idea
so much that they decided to
skip the slow mapping step. In
other words, instead of dividing
 Lecture 5 The War over the Human Genome

a chromosome into chapters and NIH scientists were begrudgingly

paragraphs, they wanted to blast
the whole book into overlapping
smithereens right away. Then, they’d
whirlwind everything together all
at once using banks of computers.
The NIH had considered this
whole-genome approach but
dismissed it as slapdash—too
prone to leaving gaps and putting
segments in the wrong place.
impressed. They doubted, however,
that what worked for bacteria
would work for the much more
complicated human genome.
But computers and DNA sequencers
just kept getting faster. And Venter
gambled that if his team gathered
enough overlapping data and hired
top data scientists to run their
computers, they could beat the NIH.

Venter dismissed this concern. So, in May 1998, Venter started a

After all, this was the 1990s, when
computers and DNA sequencers
were getting exponentially faster.
And he soon had the opportunity to
show off the power of his approach.
By 1994, a biologist in Wisconsin
had been working 8 years to
sequence the first genome of a
fully living creature: a bacterium.
Suddenly, though, Venter’s team
jumped into the game. They began
zooming through the 2 million base
pairs of a different bacterium and
ended up finishing in just 1 year,
blowing by the Wisconsin group.
company called Celera to sequence
the human genome in just 3
years—4 years before the NIH
would finish. And Celera would
do it for $300 million, 1/10 of
the NIH’s $3 billion budget.
To do this, Celera would rely on 300
state-of-the-art DNA sequencers.
Each one cost $300,000 and was
capable of sequencing 900,000
base pairs every 24 hours. This
gave Celera more sequencing power
than the rest of the world’s biology
labs combined. In partnership
with Compaq and Sandia National

Former Human Genome Project leader James Watson

compared Craig Venter to Hitler invading Poland. And
most NIH scientists feared they’d fare about as well as
Poland had.

49
 Lecture 5 The War over the Human Genome

Laboratories, Celera would also However, a few key NIH scientists

build the world’s largest nonmilitary
supercomputer to process data.
Despite their years-long head start,
the NIH genome project was behind
schedule and over budget. By 1998,
the eighth year of the project’s
15-year timeline, the NIH had
sequenced just 4% of human DNA.
refused to back down from Venter.
This included Francis Collins, who
had taken over the project after
Watson. Collins had previously
done outstanding work at the
University of Michigan, discovering
the genes responsible for cystic
fibrosis and Huntington’s disease.

THE GENOME WAR

In announcing Celera’s plans,

Venter thought his company had
an exclusive deal on using the
$300,000 DNA sequencers. But
shortly afterward, Collins found
himself on a flight with an executive
from the company that made the
sequencers. Collins switched seats
to sit next to him. And by the
time they’d landed, Collins had
sweet-talked the executive into
supplying the NIH with the same
sequencers. Venter was livid.

Collins was also merciless about

keeping on schedule. Again,
the NIH was sending DNA
paragraphs out to different labs to

50
 Lecture 5
sequence them. But some labs fell
woefully behind. So Collins cut
them out of the project entirely.
And so, the genome war began:
Venter and Celera versus Collins and
the NIH. Naturally, the nastiness
of the war titillated the public and
dominated the headlines. But all the
while, solid science was emerging.
Despite their earlier success with
bacteria, Venter and Celera felt
they still had to prove that whole-
genome shotgun sequencing would
work on animal genomes, which
were much bigger and had far more
satellite repeats. And there was a
real worry that shotgun sequencing
would struggle to put all the
repetitious bits in the right order.
So, in 1999, Celera teamed up with
a group of academics to sequence
the 120 million base pairs of the
most important lab animal in
genetics: a fruit fly. To the shock of
many, Celera produced an absolute
beauty of a genome, and did so
amazingly quickly. At a scientific
meeting shortly afterward, geneticists
gave Venter a standing ovation.
In just a few months, scientists had sequenced
more DNA than they had in the previous 2
decades combined.
51
The War over the Human Genome
And once the human genome
work started in earnest, the pace
was breathtaking. Running neck
and neck, the NIH and Celera
each soon passed 1 billion base
pairs of human DNA—and then 2
billion. The NIH had once blasted
Venter for trying to sequence
DNA too quickly, but everyone
was playing Venter’s game now.
Amid the science, however, the
drama continued—both behind
the scenes and in public.
In March 2000, President Bill
Clinton and British Prime
Minister Tony Blair made joint
announcements that the human
genome belonged to all human
beings worldwide. Understandably,
people assumed that this coordinated
announcement was possibly
foreshadowing the elimination of
gene patents. As a result, investors
with money in biotech companies
stampeded. Celera alone lost $6
billion in stock value in just weeks.
Venter himself lost $300 million.
 Lecture 5
The NIH and Celera also continued
to publicly bicker. This appalled
President Clinton, as the Human
Genome Project was supposed to be
a milestone scientific achievement,
not a soap opera. So he told his
top science advisor to find a way
to make them work together.
The burden for this task fell on
a biologist named Ari Patrinos,1
who brought the 2 adversaries
together to broker a truce on May
7, 2000. The meeting did not go
well. Both sides mistrusted each
other, and there was lingering
anger. Yet after more meetings, the
anger dwindled. The men agreed
to stop taking shots at each other
in public. More importantly, they
decided to end their competition,
which had deteriorated into
a wasteful distraction.
The best way for everyone to
save face was to declare the race
a tie. Each team would also
publish a so-called rough draft
of the human genome based on
what they’d sequenced so far.
They agreed to announce the
tie at a joint press conference at
the White House on June 26.
1 Patrinos worked at the Department of Energy, which had started the first
iteration of the Human Genome Project in 1987 and still had a small team
contributing.
52
The War over the Human Genome
This was an incredible achievement.
It was less than a century since the
first gene for a human trait was
discovered and less than 50 years
since the discovery of the double
helix. Now, at the threshold of the
millennium, we could finally read
the full A-C-G-T blueprint of our
human heritage for the first time.
The 2 rough drafts of the human
genome appeared in early 2001.
And despite the so-called tie,
scientists continue to debate who
won the genome war, if anyone.
Rather than patent genes, the NIH
had been releasing all its DNA data
into a public database for anyone to
use, including Venter and Celera. In
fact, Celera acknowledged in their
rough draft that they’d been quietly
using the public data the whole time
to assemble their genome. Venter
wasn’t quite the independent rebel
he claimed to be. Additionally,
NIH scientists argued that Celera
never could have finished its rough
draft without the NIH maps to tell
them where to put the millions of
randomly shotgunned phrases.
 Lecture 5 The War over the Human Genome

Venter’s team angrily denied these However, Venter was no longer

charges. Then, they made some
countercharges of their own. They
argued that the NIH never would
have pushed to finish so quickly if
not for the threat of competition,
which is probably true. Furthermore,
the NIH had always portrayed
itself as the ones who didn’t care
about speedy sequencing, just
accuracy. But most scientists who
examined the 2 rough drafts side
by side proclaimed that Celera
did a much better job. The NIH
also ended up copying Venter’s
whole-genome shotgun approach
for later sequencing projects.
around to bother the NIH. After
various tussles with management,
Celera more or less fired Venter in
January 2002. When Venter left,
Celera lost interest in sequencing,
and the NIH claimed victory, loudly,
when it alone produced a final draft
of the human genome in 2003.
And the jockeying for status never
really ended. Someone will almost
certainly win a Nobel Prize someday
for the Human Genome Project—
but who? Only 3 people can win a
Nobel Prize for any one achievement,
and the public consortium led by
Collins included 249 authors on its
initial paper, whereas the Venter-
led paper had 285 coauthors. 2

Readings
Shreeve, The Genome War.
Sulston and Ferry, The Common Thread.
Venter, A Life Decoded.

2 Some of Collins’s top deputies could make legitimate claims for the Nobel
Prize, as could top figures on Venter’s team.

53
How DNA Controls Itself
and Shapes Our Culture
LECTURE 6

W hen the race to sequence the Human Genome ended in the

early 2000s, scientists located the roughly 20,000 genes that
make the proteins that run our bodies. But in reality, those 20,000
genes represent only 1% to 2% of all human genetic material.
And scientists still had to figure out what that remaining 98% did.
That ambitious goal has been the focus of another project, called
ENCODE (“Encyclopedia of DNA Elements”), whose purpose in
some sense is to finish the Human Genome Project by determining
what, if anything, most of our DNA does.

Return
to TOC

REGULATORY GENES

In the 1960s and 1970s, there 20% of the human genome

was a mistaken idea that all the
non-protein-coding DNA was
“junk DNA.” Work with forensic
DNA showed that even apparent
junk could be useful, since the
seemingly nonfunctional satellite
repeats provided markers of unique
identity in DNA fingerprinting.
But by 2012, the ENCODE
project had offered evidence
that at least some noncoding
DNA was biologically useful as
well. It suggested that at least
regulates the 2% that produces
proteins. That’s 10 times more.
And more than 80% of our
noncoding DNA is biologically
active, with most of that 80%
getting transcribed into RNA.
ENCODE scientists argued
that this meant that as much
as 80% of the human genome
may turn out to have functional
roles—roles not yet identified.

54
 Lecture 6 How DNA Controls Itself and Shapes Our Culture
The 80% claim proved controversial,
however. Just because some
DNA gets turned into RNA
doesn’t mean that this RNA has a
biological function. It could be the
equivalent of cell busywork—labor
that does nothing productive.
It remains an open question
whether the 80% figure is accurate.
Regardless, we now know that
some noncoding DNA does have a
purpose—namely, to regulate the
expression (or nonexpression) of
normal, protein-producing genes.
And whereas early waves of
genetics allowed us to understand
only diseases caused by single
point mutations, this next wave
opens the way to understanding
the on switches and off switches
that contribute to more complex
diseases, including cancer.
GENE-MUSIC INTERACTION
One example of genes interacting
with culture involves music. A few
studies have found that one key
musical trait—perfect pitch—
shows the same inheritance pattern
55
This deeper, more complete
mapping of our genome also
allows us to expand our horizons
even further, by considering the
interplay of DNA with things like
language and human culture.
To be sure, other animals do have
basic forms of culture and language.
But the richness and intricacy of
our languages and cultures make
them especially interesting, both
scientifically and practically.
At first glance, language and culture
might not appear to have much to
do with DNA and genes. But there
are profound connections there.
Genes drive culture in all sorts
of ways. And sometimes, culture
can even change our genes.
as a dominant gene, since people
with perfect pitch passed the
trait to 50% of their children.
 Lecture 6 How DNA Controls Itself and Shapes Our Culture

But other studies have found smaller
and subtler genetic contributions
for perfect pitch. They’ve also
found that this DNA must act in
concert with environmental cues,
such as music lessons, early in life
or people won’t develop the gift.1
Beyond the ear, physical traits
can also help boost individual
musicians. 2 A profound example
of gene-music interaction involves
the 19th-century Italian violinist
Niccolò Paganini, widely considered
the greatest violinist who ever lived.
There were some scientific reasons
why Paganini was amazing—
especially his hands, which were
unusually flexible. And because of
these unusual hands, Paganini had
a big advantage over other violinists.
He could stretch his hands incredibly
wide and perform unusual fingerings
that his peers struggled with. As a
result, he could play certain music
effortlessly, music that took his
peers ages to learn and that they
often couldn’t perform adequately.
From a modern perspective, it’s
almost certain that Paganini had a
genetic abnormality of some sort,
possibly Ehlers-Danlos syndrome.
Different mutations can cause
different variants of this syndrome,
but all of them leave people with
highly pliable connective tissue
and hyperflexible joints. In fact,
Paganini could bend his elbows the
wrong way and his knees backward.
Paganini’s life is a wonderful way
to expand how we normally think
about genetics. Science is usually on
one end of a spectrum, while music,
a fine art, is usually at the other end.
But science and fine art are
intertwined here. If you learn a little
about the music and a little about the
genetics, you can see a connection
between them. Knowledge of
music enhances our knowledge
of genetics, and vice versa.
Paganini’s life also offers a great
scientific lesson about the importance
of genes interacting with culture.

1 One study even suggested that all babies might be born with an ability to
process absolute pitch in some circumstances. But perhaps most babies
genetically switch off this predisposition early in life.
2 The Russian composer Sergei Rachmaninoff had gigantic hands—possibly
the result of a genetic disorder called Marfan syndrome—that could span 12
inches, a full octave and a half on the piano. This allowed him to play music
that would tear the ligaments of lesser-endowed pianists.

56
 Lecture 6
Imagine that Paganini had lived
100,000 years ago. He still might
have had superflexible hands, but
because stringed instruments didn’t
exist then, his amazing hands
wouldn’t have been useful in the
way that made him famous in the
19th century. He became a legend
only because he grew up in a culture
where string instruments existed and
were revered. Without that cultural
component in place, the genetic
mutation wouldn’t have mattered,
at least not in the same way.
Furthermore, Paganini had the right
temperament to take advantage
of his amazing hands. He was an
extremely hard worker, and he loved
playing and practicing music.
Genes don’t rigidly determine who we are. Our
personalities and traits and preferences depend
on our environments and cultures, too.
LANGUAGE AND INTELLIGENCE
Another aspect of cultural genetics
is language—and more broadly,
intelligence, since language is
one of the key tools that makes
us intelligent creatures.
It’s still very hard to sort through
and understand the hundreds,
or perhaps thousands, of genetic
How DNA Controls Itself and Shapes Our Culture
So it wasn’t just his amazing hands
that made him the best. Several
components had to come together:
his unique genes, the right culture,
and a temperament to take advantage
of those genes and culture.
People often want to draw a sharp
distinction between nature and
nurture—between genetic influences
and cultural-environmental
influences. But Paganini’s story
shows that we can’t separate the
2 so easily. Good scientists know
that nature and nurture work
together to make us who we are.
bits that contribute to human
intelligence. But we can say
something about what makes human
beings in general smarter than other
animals by comparing our DNA
with the DNA of chimpanzees
and other close primate relatives.
57
 Lecture 6
One key aspect of human
intelligence is language, and one
key gene involved in language
production is the FOXP2 gene.
FOXP2 is the gene for a transcription
factor called forkhead box P2
(FOXP2). Transcription factors
are proteins that bind onto
DNA and help control how
quickly DNA gets transcribed
into RNA. Transcription
factors can also silence DNA
sometimes, turning it off.
As far as transcription factors go,
the protein created by the FOXP2
gene is quite busy. It seems to
regulate hundreds of different
genes. In particular, it’s active
in fetuses and helps control fetal
development in the jaw, gut, lungs,
heart, and especially the brain.
All mammals have some version
of the FOXP2 gene, 3 and despite
millions of years of diverging
evolution in mammals, all versions
of the gene and the protein it makes
still look pretty much the same.
Remember that proteins are
made of amino acids. Compared
to the FOXP2 protein in mice,
human beings have accumulated
3 Bats seem to depend on the FOXP2 gene for echolocation.
How DNA Controls Itself and Shapes Our Culture
just 3 amino acid differences in
our FOXP2 protein out of 715
amino acids total. Intriguingly,
however, humans picked up 2 of
our 3 amino acid changes after our
evolutionary split away from other
great apes like chimpanzees. And
these changes allow the FOXP2
protein to interact with new genes.
Even more intriguingly, when
scientists created mutant mice with
the human version of FOXP2, the
mice had neurons that were shaped
differently, with more branches
and longer axes—especially in
a brain region that in humans
helps process language. This
showed that FOXP2 influences
brain structure and function.
Mutations in FOXP2 also have a
profound effect on people’s ability to
speak. In the 1990s, linguists began
studying 3 generations of a London
family known only, for privacy, as
58
 Lecture 6 How DNA Controls Itself and Shapes Our Culture
the KE family. In a simple pattern
of single-gene dominance, 50% of
the KE family members suffer from
a suite of language malfunctions due
to a mutation to their FOXP2 gene.
Because of the mutation, they have
trouble coordinating their lips, jaws,
and tongues when speaking, so they
stumble over most words. They
also struggle when asked to copy a
sequence of simple facial expressions,
such as opening their mouths
and sticking out their tongues.
Some scientists even argue that the
KE family’s problems extend beyond
motor skills to grammar. When
tested, most of them know that the
plural form of book is books, but
seemingly because they’ve memorized
that fact. When given invented
words like zoop, they can’t figure out
the plural. They see no connection
between book/books and zoop/zoops,
even after years of language therapy.
In the brains of affected members
of the KE family, the regions
that help produce language were
stunted and had low densities of
neurons. Scientists have traced
these deficits to a single A-for-G
mutation in the FOXP2 gene.
59
This tiny substitution altered just
one of the protein’s 715 amino
acids, but it was enough to prevent
the protein from binding to DNA
properly, which means the protein
can’t turn genes on or off at the right
moment during fetal development.
The result is language deficits.
But it’s too simplistic to say that
FOXP2 is the language gene.
Many genes contribute to brain
development, and many of them
probably contribute to linguistic
fluency, too. If nothing else,
FOXP2 can’t be the only language
gene, because even the most
afflicted members of the KE clan
can still speak some. They’re not
completely devoid of language.
Overall, then, while FOXP2 may
play an important role in the
genetic basis of language, there’s
more of this story to be written
in the years ahead as new things
about our DNA are learned.
For instance, Neanderthals have a
version of the FOXP2 gene that’s
very similar to that of humans. That
might mean nothing—or it might
mean that Neanderthals also had
the fine motor skills for language
or the cognitive wherewithal, or
perhaps both. Thus, although
Neanderthals disappeared tens of
 Lecture 6 How DNA Controls Itself and Shapes Our Culture

thousands of years ago, thanks to Two separate times since the

regulatory DNA, Neanderthals can
still speak to us in profound ways.
Beyond FOXP2, other individual
genes seem to have contributed to
our intelligence. For example, the
APOE gene is best known for its bad
variants, which increase the risk of
Alzheimer’s disease, but APOE4
plays a vital role in the normal
function of the body. In particular,
the APOE protein combines with
cholesterol and helps cholesterol
move through our bloodstreams.
But that’s not all this protein does.
To function properly, neurons in
the brain need to coat themselves
in fatty sheaths of cholesterol. This
cholesterol acts like rubber insulation
on wires, preventing the neurons
from short-circuiting or misfiring.
evolutionary lines of human beings
and chimpanzees split, the human
APOE gene has mutated, which
is how we got a total of 3 distinct
versions. Without the right APOE,
the brain gets less cholesterol
than it needs. And without that
cholesterol, brain signals running
down neurons can go awry.
Beyond APOE, some genes lead
to structural changes in the brain.
A gene named LRRTM1 helps
determine which exact patches of
neurons control speech, emotion,
and other mental qualities. This
in turn helps the human brain
establish its unusual asymmetry
and left-right specialization. Some
versions of the LRRTM1 gene even
reverse parts of the left brain and
right brain, which also increases
your chances of being left-handed.

There are certain inheritable DNA mutations

that can cross-wire the sneeze reflex with
other parts of the brain, leaving people
sneezing uncontrollably—up to 43 times in a
row in one case.

4 Its full name is the apolipoprotein E gene, where apolipo means that it makes
a protein that binds to the fats, or lipids, in food.

60
 Lecture 6 How DNA Controls Itself and Shapes Our Culture
GENE SPLICING
Beyond individual genes, certain
functional changes to our DNA
also gave our brains a boost. One of
these functional changes involves
what’s called gene splicing.
Remember that when making
proteins, cells first turn DNA into
RNA. And that DNA-to-RNA
conversion is pretty rote. Cells
transcribe the DNA base by base,
skipping not a single A, C, G, or T.
But with the full RNA manuscript
in hand, cells narrow their eyes, lick
a red pencil, and start editing. This
editing consists mostly of chopping
out unneeded RNA. Cells then
stitch the remaining bits together to
make the actual messenger RNA.
Because the parts that are removed
were originally thought of as
intruders, the stretches of RNA
that get removed and discarded
are called introns. Meanwhile, the
stretches that get exported to the
final RNA are called exons. Overall,
the exon parts within your genes
that actually get translated into
proteins are called the exome.
While animals like insects and
worms contain only a few short
introns in their DNA, the cells
61
of mammals show more aptitude
here. We can sift through page
after page of needless introns
and never lose the thread of
what RNA we need to keep.
Dealing with excess RNA does
have disadvantages—namely, the
RNA-editing equipment in mammal
cells has to work lots of overtime.
The average human gene contains
8 introns to remove, each one an
average of 3500 bases long. That’s
30 times longer than the exons they
surround. The gene for the largest
human protein, titin, contains
178 exon fragments, totaling
80,000 bases, all of which must
be stitched together precisely.
The largest known human gene,
DMD, makes a protein called
dystrophin, which helps muscles link
with other tissue. Its gene contains
14,000 bases of coding DNA among
2.2 million bases of apparently
useless introns. An average human
gene can get turned into RNA and
then a protein in under an hour.
But with dystrophin, getting the
right RNA alone takes 16 hours.
 Lecture 6 How DNA Controls Itself and Shapes Our Culture

There’s a genetic splicing disorder in human skin

cells that can wipe out the grooves and whorls
of fingerprints, rendering people’s fingertips
completely bald.

Overall, all this extra splicing
expends incredible amounts of
energy, and any mistakes can ruin
important proteins. For example,
mistakes in the dystrophin gene
can cause muscular dystrophy.
So why do mammals have so many
long introns, despite the apparent
waste and danger? It’s because having
introns gives our cells versatility.
Different cells leave different
combinations of exons and introns
in place, and each variation makes
the final protein a bit different.
And these tweaks allow the protein
to work a bit better in different
environments within the body. In
other words, introns and exons
allow us to customize proteins, and
that gives our cells flexibility.
Human cells seem especially
reliant on DNA splicing. One big
difference between human DNA
and the DNA of other primates is
that our brain cells splice DNA far
more often, chopping and editing
the same string of bases for many
different effects. This appears
to help our brain cells specialize
even more than other primates.
Neurons are also unique in other
ways. Our neurons allow much
more free play for mobile DNA bits,
such as so-called jumping genes
that wedge themselves randomly
into our chromosomes, to move
around. Neurons remix DNA so
much, in fact, that some scientists
think that neurons have upended
one of the oldest dogmas in genetics:
that all cells in your body have
the same basic DNA, apart from
a few mutations. Neurons seem
to have much more variety.
Allowing jumping genes to freely
insert themselves changes the
DNA patterns in neurons, which
can change how they work. The
effect of these changes will vary:
Some might be for the worse, and
some will make no difference.
But some will be for the better.
Again, this provides variety. In fact,
the remixing of DNA in neurons
provides another source of the raw
variety that natural selection works
on: Neurons that function better
end up thriving and help our brains
run faster or more efficiently.

62
 Lecture 6 How DNA Controls Itself and Shapes Our Culture

Readings
Campbell, Waud, and Matthews, “The Molecular Basis of Lactose
Intolerance.”
Nudel and Newbury, “FOXP2.”
Sugden, Paganini.
Wade, Before the Dawn.

63
Microbes Manipulate Us,
Viruses Are Us
LECTURE 7

T he completion of the Human Genome Project led to 2 shocking

realizations. First, biologists realized that less than 2% of the DNA
in the human genome actually codes for the proteins that make and
run the human body. Second, it turns out that 8% of our genome is
not human at all; 250 million base pairs of our DNA are just old virus
genes that got inserted long ago and never got weeded out.1 Put
the 2 findings together and our “human” genome might look like it’s
4 times more virus than human.

Return
to TOC

THE WORLD OF MICROBES

Unlike everything else in nature, COVID-19 coronavirus, which is

there are many viruses that use RNA
instead of DNA to store genetic
information, including influenza,
polio, coronavirus, and Ebola.
Because RNA is typically single-
stranded, it’s far less stable than the
double helix of DNA. As a result,
the genomes for RNA viruses
never get very large. For example,
polio is just 7000 bases. Even the
at the upper limit of stability for an
RNA virus, is only 30,000 bases.
But among RNA viruses, there’s
also a more devious group,
including HIV, that infects a cell
differently. Most viruses do not
work this way, but these special
RNA viruses can coax the cell
into turning the virus’s RNA back
into DNA! For this reason, we call

1 Some rogue virus infiltrated our distant ancestor’s sperm or egg cell, which
produced a baby. And the lucky virus got to hitch a ride around indefinitely in
all of that baby’s descendants, including us today.

64
 Lecture 7 Microbes Manipulate Us, Viruses Are Us

these retroviruses. Even scarier,
the retrovirus then tricks the cell
into splicing that new viral DNA
into the host cell’s own genome.
In short, these retroviruses fuse
their virus genetic material with
the cell’s nonvirus genetic material.
This is the world of microbes, where
viruses can manipulate the DNA
of animals for their own ends. In
fact, some Machiavellian microbes
can even manipulate the minds of
animals to make us do their bidding.
But cells don’t “know” that the DNA
that’s been spliced into them is virus
DNA and not their own DNA. They
just see a string of As, Cs, Gs, and
Ts, so when it comes time to make
something from this DNA, the
cell’s machinery zips right along and
makes whatever the instructions say.
Unfortunately, these are actually
instructions to make more copies of
the virus. That’s how these viruses
reproduce—by tricking cells. And
they keep reproducing like this until
they kill the cell, at which point the
copied viruses burst free into the
rest of the body, where they infect
other cells and restart the process.
However clever, this strategy for
infecting cells might seem overly
elaborate. Why would an RNA
virus like HIV bother converting
itself into DNA first, when the
cell has to transcribe that DNA
back into RNA later to make
proteins? It seems convoluted.
This seems even more baffling when
you consider how nimble RNA
is compared to DNA. Free RNA
inside a cell can build rudimentary
proteins all by itself, whereas lone
DNA sort of just sits there. RNA
can also build copies of itself.
For these reasons, most scientists
believe that RNA probably predated
DNA in the history of life, since
early life would have lacked the fancy
machinery that cells have today.
Why the change? RNA does have
some disadvantages compared to
DNA. Most importantly, RNA is
flimsier. DNA is double-stranded,

Retroviruses show no respect for the line we’d

prefer to draw between “their” DNA and “our”
DNA. They rezone our genetic neighborhoods to
make room for themselves, and they never leave.

65
 Lecture 7
and the crucial A-C-G-T bases
are protected on the inside of
the double helix, with sugar and
phosphate on the outside. RNA
is a single strand. As a result, its
bases are exposed to assaults.
Also, RNA is ribonucleic acid, which
has an extra oxygen atom compared
to the deoxyribonucleic acid of DNA.
Oxygen is a reactive element, and if
an RNA strand grows too long and
gets tangled up with itself, oxygen
can react and cut the strand to bits.
Ancient cells that could switch to
DNA suddenly had a perfect way to
store information. This switch from
RNA to DNA was one of the most
important steps in the history of life.
EVOLUTION FROM RETROVIRUSES
A closer examination of the human
genome suggests that it might be
even more than 8% virus. After all,
so far, we’ve only been discussing
the 2% of our DNA that is coding
DNA for proteins, plus another 8%
we get from viruses. What about
the other 90% of our DNA?
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Microbes Manipulate Us, Viruses Are Us
In a way, it resembled the transition
in human cultures away from, say,
the spoken poetry of Homer to
written texts. With DNA, you don’t
get the RNA-like versatility—just
like written works lack nuances of
voice and gesture. But we wouldn’t
even have the Iliad and the Odyssey
today without papyrus and ink.
RNA is flimsy and temporary.
DNA lasts much longer.
So the advantage for retroviruses
that convert RNA into DNA after
infecting cells is that DNA is
sturdier, more enduring. Once that
DNA from the retrovirus gets inside
the host cell’s genome, it becomes
a permanent part of the cell.
In the 1950s, a geneticist named
Barbara McClintock made the
first observations of what are now
called mobile genetic elements
or transposable elements. These
are bits of DNA that can float
around on their own and burrow
into chromosomes at random.
They can even move from one
chromosome to another.
 Lecture 7
In all, mobile genetic elements make
up roughly 50% of our genomes.
These mobile bits linger inside every
cell we have, burrowing into our
DNA at random, like little ticks.
Sometimes they’re simply genetic
parasites, consuming resources and
doing nothing useful; sometimes
they regulate other genes or take
on some other useful job.
In fact, they may have been virus
parasites of some sort in the past and
got stripped down so far that only
a bit of DNA remains. Or perhaps
mobile genetic elements first gave rise
to viruses. Either way, they’re now a
permanent part of human beings.
Of all the old virus genes lurking
inside human DNA, very few of
them still function. The vast majority
of these genes have accumulated
fatal mutations and have been
disabled. But in some cases, these
virus genes still function inside us,
though perhaps with a new purpose.
In fact, some virus genes do vitally
important things inside our bodies.
For example, there’s strong evidence
that the placenta—the interface
between a mammal mother and
her fetus—originated in viruses.
2 One exception is duck-billed platypuses, which are warm-blooded mammals
that still lay eggs.
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Microbes Manipulate Us, Viruses Are Us
Across the animal kingdom,
placentas are practically a defining
trait of mammals. 2 Of the roughly
6400 species of mammals alive
today, more than 6000 have a
placenta, including the most
widespread and successful mammals,
such as bats, rodents, and humans.
Placental mammals have also
colonized diverse niches on Earth.
This suggests that placentas gave
mammals a big survival boost.
In particular, the placenta allows
a mammal mother to keep her
children warm inside her and gives
her the chance to run away from
danger with them. Growing fetuses
inside us also allows them to gestate
longer and develop energy-intensive
organs, such as a bigger brain.
And because mammals invest so
much energy in fetuses, many
mammal mothers feel more
incentive to nurture their children,
sometimes for years. The length of
this investment is rare among other
animals. And mammal children
reciprocate by forming unusually
strong bonds to their mothers. In
one sense, then, by enabling all
this, the placenta helped make
mammals caring creatures.
 Lecture 7 Microbes Manipulate Us, Viruses Are Us

What makes it even stranger is
that the placenta, in all likelihood,
evolved from retroviruses. But
from a biological standpoint, here’s
how the connection works.
One talent that viruses have is the
ability to clamp onto cells. They do
so by fusing their outer envelope with
the cell’s surface. This allows them to
inject genetic material into the cell.
Embryos clamp on in a similar way.
An embryo is a tiny ball of cells
that floats into the uterus. But it
doesn’t just float there. The embryo
anchors itself to the lining of the
uterus with special fusion proteins.
And the DNA that mammals use to
make fusion proteins for clamping
onto the placenta originally came
from DNA that retroviruses use
to attach onto host cells. The
DNA sequences are nearly letter-
by-letter identical. This is one
case where a virus inserted that
DNA in our ancestors, but it
turned out to be quite useful.
As a bonus, these viral fusion genes
seem to provide extra immunity for
the fetus. Specifically, the presence
of retrovirus proteins seems to
discourage other, potentially deadly
microbes from breaking through
the placenta, either by warning
them off or outcompeting them.

Viruses aren’t the only microbes that can

direct animal evolution. Bacteria can also
hijack the reproductive process, as has been
demonstrated for insects.
The Wolbachia bacteria, which infects insects
like wasps, can reproduce only inside females’
eggs. So Wolbachia scans the eggs it infects
and kills male larvae by releasing genetically
produced toxins. In certain species, Wolbachia
actually manipulates the genes that determine
sex in insects, converting male grubs it cannot
use into females.

68
 Lecture 7
MANIPULATING ANIMAL MINDS
Microbes can also manipulate animal
minds by stealing genes that produce
neurotransmitters and pumping
those neurotransmitters out. As a
result, they can influence thoughts
and direct behavior toward their own
ends. It’s spooky, but there really are
Machiavellian microbes out there.
Pregnant women aren’t supposed to
scoop kitty litter because doing so
puts them in danger of contracting
Toxoplasma gondii (T. gondii), which
is a one-celled protozoan, a living
organism similar to an amoeba
but bigger and more complex than
bacteria—and much bigger than a
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Microbes Manipulate Us, Viruses Are Us
virus. If a pregnant woman contracts
T. gondii, it can harm her fetus’s eyes
and brain or cause a miscarriage.
But T. gondii is more than just a
harmful parasite. It’s actually one
of the most fascinating microbes
we know about, with a fairly large
genome of 80 million base pairs.
T. gondii was originally a feline
parasite, but it can also infect a
wide range of creatures, including
monkeys, bats, whales, and chickens.
Wild creatures usually ingest T.
gondii through infected prey or feces,
while domesticated farm animals
absorb it indirectly through the feces
found in manure-based fertilizers.
 Lecture 7
Humans can ingest T. gondii
through food as well, and cat owners
often contract it through their skin
when they handle kitty litter.3
When T. gondii gets inside a
creature, it swims straight for the
brain, where it forms tiny cysts.
These cysts are especially common
in the amygdala, an almond-shaped
region in the mammal brain that
processes emotions, including
pleasure, anxiety, and fear.
This invasion of the amygdala has
especially profound consequences in
mice. Fear of cat urine is instinctive
in mice, even in lab mice that have
never seen a cat or other predator
in their whole lives. But mice with
T. gondii in their brains are actually
attracted to cat urine, especially male
rodents, whose amygdalas throb and
testicles swell when they smell cat
urine. This is the same response they
have to meeting female mice in heat.
These mice still fear the smell
of other predators. How does T.
gondii override mice’s instinct
to avoid cats specifically?
3 Overall, T. gondii infects roughly 10% of the US population and 33% of all
people worldwide.
4 When they’re inside humans, mice, and most other living creatures, T.
gondii reproduce asexually: They divide in 2 and essentially make clones of
themselves—identical copies.
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Microbes Manipulate Us, Viruses Are Us
T. gondii can reproduce sexually or
asexually4 but can only reproduce
sexually in the intestines of cats.
Like most organisms, T. gondii
craves sex. By making mice attracted
to cat urine, T. gondii effectively
lures the mice toward cats. Cats,
of course, are fine with this
arrangement. They pounce on the
mice and eat them—at which point
the mouse morsel ends up exactly
where T. gondii wanted to be all
along: in the cat digestive tract.
What made the possible influence
of T. gondii more convincing was
that scientists found that 2 of T.
gondii’s 8000 genes help make
the chemical dopamine, which
helps activate the brain’s reward
centers. It floods our brains with
good feelings. And T. gondii has 2
genes for this potent chemical.
When a mouse smells cat urine, a
signal inside the brain goes to the
amygdala, which processes emotion.
Normally, this signal would send the
mouse scurrying for cover. But in
mice brains that have been infected
by T. gondii, the signal prompts
 Lecture 7
the T. gondii in the amygdala to
start pumping out dopamine. This
pleasurable chemical overrides the
fear signal and causes the mouse to
move toward the danger, not away.
In other words, a gene in T.
gondii causes the mouse to do
something against its will—
something that benefits T. gondii
and leaves the mouse dead.
The effect of T. gondii on other
species, besides rodents, is an open
question. Dopamine is a common
neurochemical in mammals, so
T. gondii might also be steering
COLONIZING GENOMES
Protozoans like T. gondii
don’t colonize genomes. They
just steal a gene. But viruses
can colonize genomes.
In one variety of voles, a
type of rodent, the males are
usually polygamous. They
mate indiscriminately. But then
scientists infected their brains with
a specially tweaked DNA virus
in the lab. When infected with
this adenovirus—a virus family
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Microbes Manipulate Us, Viruses Are Us
other mammal prey toward cats,
including big cats. A 2016 study
of 33 chimpanzees in captivity
found that those with T. gondii
were not repelled by the urine of
leopards, a chimpanzee predator.
Even with creatures that aren’t
normally prey, such as human beings,
T. gondii might still be manipulating
their behavior. For example, perhaps
T. gondii could help explain the
phenomenon of cat hoarding. Just
like in mice, T. gondii can alter the
sense of smell in human beings. And
coincidentally or not, some hoarders
reportedly crave the odor of cat urine.
responsible for some strains of the
common cold in humans—the
voles turned into monogamists.
 Lecture 7 Microbes Manipulate Us, Viruses Are Us

This was a lab experiment, but
it proved that a virus can induce
monogamy, a radical change
in behavior for a species. And
if voles—which, like humans,
are mammals—can become
monogamous due to a virus, what
does that mean for us humans?
It’s one thing to find broken-down
virus genes leftover in our DNA. It’s
quite another to admit that microbes
might manipulate our emotions and
inner mental life through genetic
machinations. But some of them can.
in their cells that prevent the virus
from gaining access to cells. And
if an HIV pandemic began, these
HIV-immune people might evolve
into a new human species.5
Even more wildly, HIV, as a
retrovirus, could someday insert
its DNA into these new humans
in a permanent way, joining the
genome just like other viruses have.
HIV genes would then be copied
forever in our descendants—who
might have no inkling of the
destruction that HIV once wrought.

Microbes that manipulate our Of course, saying that microbes

DNA might even be driving our
evolution in various ways—not
just forcing us to adapt, but also
directly changing our DNA.
Some scientists have speculated
about what would happen if HIV,
or another deadly retrovirus, ever
reached epidemic levels worldwide
and wiped out most people on Earth.
There is a small percentage of people
who are immune to HIV. The
virus gets inside their bodies but
doesn’t kill them, due to mutations
infiltrate “our” DNA may be nothing
but a species-centric bias. After
all, we stole the genes for making
placentas from viruses. And the
placenta might not be the half of it.
In 2009, scientists discovered
another well-known virus, called
the bornavirus, that’s active in
various animals, but also the human
brain. Based on its activity in the
brain, some scientists argue that the
bornavirus could be an important
source for adding variety to the DNA
that forms and runs our neurons.

5 These immune people couldn’t have sex with any nonimmune survivors
without killing them off, and any children from the union would have a good
chance of dying of HIV, too. These sexual and reproductive barriers would
slowly but inevitably drive the 2 populations apart.

72
 Lecture 7 Microbes Manipulate Us, Viruses Are Us

In the time of Charles Darwin, descent

from apes was a big surprise. Now we are
learning that the immediate ancestors for
some of our cherished traits are viruses.

Such variety is the raw material of
evolution, and lab tests have found
that bornavirus can somehow weave
itself into human DNA in as few
as 30 days. Inadvertently, then, the
bornavirus might have given human
beings an intelligence boost.
And if that’s true, then consider that
the microbes responsible for this
boost probably got passed around via
sex. In fact, that’s how many viruses
get passed around, both the ones
that make us sick and the occasional
one that benefits our evolution. This
means that if microbes really were
important for pushing evolution
forward, then sexually transmitted
diseases could be responsible in
some way for making us human.

Readings
Comfort, “The Real Point Is Control.”
Darnell, RNA.
McAuliffe, “How Your Cat Is Making You Crazy.”
Villarreal, “Can Viruses Make Us Human?”

73
How Epigenetics Turns
Genes On and Off
LECTURE 8

T here’s much more to genetics than DNA that codes for proteins.
Many noncoding stretches of DNA turn out to be important
for DNA regulation, which involves turning DNA on or off. Or it
involves turning the volume up and down on genes to vary how
active they are. But there’s also another type of DNA regulation
called epigenetics that’s perhaps especially important in humans. In
epigenetics, the underlying DNA sequence remains constant. What
changes is the activity of that DNA.

Return
to TOC

EPIGENETIC CONTROL AND SPECIALIZED

CELLS
In epigenetics, unlike other DNA
regulation we’ve seen, the genetic
code itself isn’t regulating the DNA.
Instead, epigenetics uses extra-genetic
signals, usually small molecules
that attach to the DNA. These
signals then affect how cells access,
read, and use the DNA. Overall,
you can think about DNA genes as
hardware, while epigenetics is the
software that runs on top of genes.
Organisms use epigenetics to
turn genes on and off in several
ways, but the most common
ways involve attaching small
molecules, such as methyl groups.
Methane gas is a close relative of the
methyl groups. The chemical formula
for methane, whether it comes
from cows or natural gas, is CH4:
1 carbon and 4 hydrogens. Methyl
groups are almost the same: CH3.
And because the methyl groups are
missing the fourth hydrogen, they

74
 Lecture 8
are very eager to bond to something.
Most often they bond to cytosine,
especially when it’s next to a guanine.
And when cells allow a methyl CH3
to stick onto a bit of DNA, the
cellular machinery generally ignores
that section of DNA. As a result, that
methylated DNA won’t translate into
RNA and won’t make new proteins.
Another type of epigenetic
change involves modifying
the proteins that help bundle
DNA. Remember, chromosomes
contain proteins as well as DNA.
Those proteins, called histones,
carry epigenetic information.
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How Epigenetics Turns Genes On and Off
Histones are essentially spools. Just
like a tailor wraps thread around
spools, cells wrap DNA around
histones. But if methyl groups, or
other small molecules, bond to
the histones, this can alter when
or how the cellular machinery
gets at the DNA. So, again, that
DNA might be silenced, which
would prevent translation into
RNA or the making of proteins.
In summary, cells turn DNA
off by adding methyl groups
directly to DNA or by using other
molecules to control how and
when DNA spools and unspools
around histones, and cells can
turn DNA back on by doing the
opposite: removing methyl groups
or reversing the histone spooling.
 Lecture 8
Epigenetic control gives creatures
flexibility. One fundamental
example of this flexibility is the
fact that we have specialized cells.
Every cell in your body essentially
has the same DNA. But your heart
and liver and brain cells sure don’t
act or look the same. Epigenetics
is part of the reason why.
All cells have the same instruction
book—the DNA. What’s different
is that each type of cell in your
body has certain genes turned on
inside it and certain genes turned
off, based on the patterns of methyl
groups and histone spooling. In other
words, epigenetic controls prevent
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How Epigenetics Turns Genes On and Off
some cells from reading certain
parts of the instructions. Liver cells
read some passages, brain cells read
other passages, and so on. The end
result is specialized cells, specialized
tissues, and specialized organs.
In 2015, the NIH completed a
reference map for epigenetic markers
in 111 different types of human
cells and tissues. So how cells end
up specializing—becoming liver or
kidney or brain cells—is one well-
established aspect of epigenetics.
But what really excites scientists
about epigenetics is another
aspect: how even the environment
can turn genes on and off.
 Lecture 8 How Epigenetics Turns Genes On and Off

EXPERIENCES AND ENVIRONMENTS

Scientists now know that our
experiences and environments can
add or subtract methyl groups;
that is, environments can change
some aspects of how DNA works.
Epigenetics can also spool or unspool
DNA in ways that affect human
genes. Drugs like cocaine and heroin
seem to spool and unspool the DNA
that regulates neurotransmitters.
And if drug users continue using,
that DNA can become permanently
mis-spooled, becoming an epigenetic
contributor to addiction.
Again, these are not genetic changes
to DNA, even though DNA is
involved, because the underlying
A-C-G-T string remains the same.
But there are de facto mutations
to the genes, which is why we
call this epigenetic change.
And just like with other
mutations, we accumulate more
and more unique epigenetic
changes as we age, based on our
experiences and environment.
Epigenetic changes also explain why
twins turn out differently. Despite
having identical DNA, twins have
different experiences, which can
mark their genes in unique ways and
produce both physical and mental
differences. And the twins will grow
more and more distinct every year.1

Incidentally, the detective-story trope of one

twin committing a murder and both of them
getting away with it—because DNA fingerprints
can’t tell them apart—might not hold true now.
First, whole-genome sequencing can search for
rare mutations. Second, if the life experiences
of the twins have differed sufficiently, a simple
test of the murderer’s epigenome could
condemn him or her.

1 When US astronaut and twin Scott Kelly spent a year on the International
Space Station, he was closely monitored for epigenetic changes. And
researchers were surprised to find the rate of change increased during the
last 6 months, suggesting that astronauts in space for more than a year might
experience even more changes. Just as intriguing, all but about 800 genes
had returned to preflight conditions 6 months after his return to Earth.

77
 Lecture 8
There’s one key difference
between genetics and epigenetics
that we’ve skipped over.
Again, epigenetic changes involve
turning genes off and on in different
cells in our body, such as the neurons
in our brains. But we don’t pass
down the DNA in body cells to
our children. We pass down only
the DNA in sperm and egg cells—
which can also acquire epigenetic
markers. But normally, as soon as
an egg and sperm unite, the embryo
erases all epigenetic information
there. This allows you to become
you, unencumbered from what
your parents did or experienced.
At least that’s been the theory.
But epigenetic changes can
sometimes get smuggled down
to new generations. And because
these epigenetic changes are
often the result of environmental
experiences, that means that
people can sometimes inherit the
biological memories of what their
mothers and fathers experienced—
or even what their grandmothers
and grandfathers experienced.
Early in the 21st century, scientists
reported an example of epigenetic
inheritance found in a farming
village called Överkalix in northern
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How Epigenetics Turns Genes On and Off
Sweden. In the 1800s, about 70%
of households there had 5 or more
children, and about 25% had 10
children or more. And most of
those mouths had to be fed on just
a few acres of poor farming soil.
It didn’t help that the weather often
laid waste to corn and other crops
there. During some stretches, such as
in the 1830s, the crops died almost
every year. But every so often, there
was an abundance of food, and even
families of 15 could gorge themselves.
This history was fairly typical
in northern Scandinavia, and it
probably would have gone unnoticed
except for one thing. In the 1990s,
some Swedish scientists started
reviewing birth and death records
in Överkalix to figure out whether
environmental factors like a lack
of food for pregnant women could
predispose their children to long-
term health problems. And because
famines had happened repeatedly
in Överkalix during its history, the
scientists had an opportunity to
study these effects on a wide scale.
Early modern kings of Sweden
demanded crop records from every
parish to prevent anyone from
cheating on taxes, so agricultural
data existed for Överkalix from well
before 1800. The Swedish scientists
 Lecture 8
could then compare this crop data
with the meticulous birth, death,
and health records that the local
Lutheran church had always kept.
Some of what the Swedish team
uncovered made sense. For
instance, there was a strong link
between maternal nutrition during
pregnancy and a child’s future
health. Other findings, however,
made them scratch their heads.
Most notably, they discovered a
robust link between a child’s future
health and the father’s diet.
Obviously, fathers don’t carry babies
to term, so any effect must have
slipped in through a father’s sperm.
Even more strangely, the child got a
health boost only if the father faced
deprivation. If the father gorged
himself, his children lived shorter
lives with more diseases like diabetes.
The influence of the fathers turned
out to be so strong that scientists
could trace it back to the father’s
father, too; that is, if the grandfather
had been deprived of food, the
grandson would benefit. These
weren’t subtle effects, either. If
the grandfather had binged, the
grandson’s risk of diabetes increased
fourfold. If the grandfather had
tightened his belt, the grandson
lived an average of 30 years longer!
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How Epigenetics Turns Genes On and Off
Remarkably, this was a far
greater effect than deprivation or
abundance had on the grandfather
himself. Grandfathers who were
deprived, grandfathers who
gorged, and grandfathers who
ate just right all lived to the same
average age, 70 years. Only their
descendants were affected.
This multigenerational influence
didn’t make any genetic sense.
Famine couldn’t have changed
the father or grandfather’s DNA
sequence, since that’s set at birth.
But the influence did make
epigenetic sense, since binging or
near-starvation can easily flick genes
on and off, masking or unmasking
DNA that regulates metabolism.
The real question was how
these epigenetic marks got
smuggled between generations.
And scientists found a clue in
the timing of the starvation.
The health of a man’s future child
or grandchild was not affected by
a lack of food during puberty, nor
did a lack of food during infancy or
during peak fertility years make any
difference. All that mattered was
whether a male binged or starved
right before puberty, during what’s
called his slow growth period.
 Lecture 8 How Epigenetics Turns Genes On and Off

During this period, from about
9 to 12 years of age, males begin
setting aside a stock of cells that
will become sperm. So, if the slow
growth period coincided with a feast
or famine, the pre-sperm cells were
apparently imprinted with unusual
epigenetic patterns—patterns that
the actual sperm would carry as well.
Scientists are still working out the
molecular details of what exactly
happened. But a handful of other
studies about paternal epigenetics
have lent support to the idea that
sperm epigenetics has profound
and inheritable effects in humans.
For example, men who take up
smoking before the age of 11 are
more likely to have overweight
children, especially overweight boys,
than men who started smoking later.
That’s true even if the grade-school
smokers quit smoking sooner. 2
Such results have forced
scientists to revise their previous
assumption that a zygote wipes
clean all epigenetic makers inside
a newly formed embryo.

2 Similarly, in Asia and Africa, hundreds of millions of males chew the pulp of
betel nuts, a cappuccino-strength stimulant. And these men have children
with twice the risk of heart disease and metabolic ailments.

80
 Lecture 8 How Epigenetics Turns Genes On and Off

GENOMIC IMPRINTING
Other lines of evidence also
support the idea that zygotes
aren’t completely scrubbed of
epigenetics. Take so-called
parent-of-origin effects.
All of us have 2 copies of every gene.
One copy resides on the chromosome
we inherited from our mother; one
copy resides on the chromosome
we inherited from our father. And
unless one of those genes contains
a mutation, in theory they should
be equal. There’s no real reason for
a cell to prefer one over the other.
But in practice, cells do have
preferences. Some genes behave
differently, depending on
whether they come from our
mother or our father, because
of epigenetic differences.
that will grow up fast and pass its
genes on early and often. Mothers,
on the other hand, would want to
temper the igf genes. Otherwise,
the baby might grow too large and
crush her insides or kill her in labor
before she has other children.
So, like a married couple fighting
over the thermostat, sperms
tend to snap their igf genes into
the on position, while eggs tend
to snap their igf genes off.
This epigenetic process is called
imprinting. This is why the offspring
of a male lion and a female tiger,
a so-called liger, is especially big,
while the offspring of a male tiger
mating with a female lion, called
a tigon, is not nearly as hefty.

Consider the igf (“insulin-like

growth factor”) gene, which
makes children in the womb
grow fast and hit their size
milestones earlier than normal.

From an evolutionarily selfish point

of view, fathers would want both
of a child’s igf genes blazing away.
This will produce a big, hearty baby

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 Lecture 8
THE EPIGENETICS RACE
Epigenetics can also potentially
explain one mysterious aspect of
certain diseases: why some people
who have what seem like deadly
mutations never actually develop
the diseases or show symptoms.
Even before the Human Genome
Project ended, 2 teams of scientists
started another race, this time
looking at epigenetics and
other individual differences.
The Human Genome Project had not
been the genome of any one person
in particular. It was a composite
genome, made of DNA from several
different people. It was an average
genome that omitted and smoothed
over any individual variations.
The new race involved sequencing
the first full genome of an individual,
so this meant sequencing twice
as many bases as in the previous
race. That’s because this would
include both the mother and
father’s genetic contributions as
well as every epigenetic mutation
that makes a person unique.
3 By posting their genomes online, both men left their personal biology open
to scrutiny. Scientists across the world could pore through their DNA letter by
letter, looking for genetic flaws or embarrassing revelations.
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How Epigenetics Turns Genes On and Off
One team, dubbed Project Jim,
decided to sequence James Watson.
Another team, led by Craig Venter,
decided to sequence Venter’s genome.
This time, the big science rivalry
between Watson and Venter could
not have been more personal.3
Venter’s team had a big head start.
They started their work around 2002
and ended up spending close to $100
million on his genome. The Project
Jim team, meanwhile, didn’t jump
into the game until 2007. But they
took advantage of new, lightning-
fast sequencers and computers to
catch up to the Venter team quite
quickly. And they managed to
sequence Watson’s genome for 50
times less money: just $2 million.
Surprisingly, this second competition
also ended in a tie. The 2 teams
posted their sequences online
within days of each other, during
the summer of 2007. The pure
speed of the Project Jim approach
wowed the world. But Venter’s
sequence proved more accurate,
as it had during the original race
to sequence the human genome.
 Lecture 8 How Epigenetics Turns Genes On and Off

Scientists found that Venter So why didn’t they suffer these

had genes that inclined him
toward alcoholism, blindness,
heart disease, and Alzheimer’s,
among other ailments. Yet Venter,
even in his 70s, had skirted all
of these health problems.
Similarly, scientists noted 2 places
in Watson’s genome where he had
2 copies of devastating recessive
mutations. One was for Usher
syndrome, which leaves victims
deaf and blind, and one was for
Cockayne syndrome, which stunts
growth and prematurely ages
people. Yet Watson lived to be more
than 90 years old without showing
any hint of these problems.
diseases and ailments? There’s
no reason to think Watson and
Venter are special, either. A naïve
perusal of anybody’s genome
would probably turn up all sorts of
potential sicknesses and diseases.
Yet most of us dodge the hazards.
The answer to this mystery might
lie in DNA regulation from within
the DNA itself. There are huge
swaths of our genome that don’t get
turned into proteins but that still
have biological functions. These
noncoding sections regulate the
coding sections and contribute
to health and illness in ways we
don’t yet understand. Perhaps

According to current estimates, humans have around

20,000 genes coding for proteins. That’s fewer
protein-coding genes than some onions have! So how
do human beings get by with so few genes?
Human beings have deeper and richer cultures than
other animals, and we live in complex, fast-moving
environments. And that culture imprints itself on our
genes in part through epigenetics. In other words,
epigenetics gives us more biological flexibility when
responding to our environments than we’d normally
have. So it’s not just the sheer number of genes, but
how you use them, too.

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 Lecture 8 How Epigenetics Turns Genes On and Off

they can even pick up the slack
for mutated genes and prevent
negative biological effects.
Similarly, epigenetic controls affect
our health in all sorts of ways. One
major source of epigenetic changes
to our DNA is our diet. Eating
right can add or remove methyl tags
and spool or unspool DNA around
histones to help keep us healthy.
Smoking and exercise can change
epigenetic markers, too. So perhaps
Watson and Venter escaped what
seemed like sure genetic damage
because of their epigenomes.
There’s no question that your
genetics influences your health.
But so does your epigenetics.

Readings
Angrist, Here Is a Human Being.
Epigenetics (series), Nature Reviews Genetics.
Moore, The Developing Genome.

84
Apes, Humans, and
Neanderthals
LECTURE 9

I n the first 2 decades after the Human Genome Project, several

thousand additional species had their genomes sequenced,
including dozens of so-called reference-quality sequences that
provide a basis for research. For the first time, we are now in a
position to understand, for instance, why most animals have the
same basic body plan. And we could also track differences. Among
the most revealing genomes for humans has been the chimpanzee
genome. The 2005 Chimpanzee Genome Project revealed genetic
differences in how primates transmit nerve signals and hear, for
example. There were also results from studying the Neanderthal
genome, which shocked scientists by providing long-lost evidence of
breeding between humans and Neanderthals.

Return
to TOC

OUR APELIKE ANCESTORS

A few key genes in every embryo
play cartographer for other genes;
that is, they map out our bodies
front to back, left to right, and top
to bottom. Insects, fish, mammals,
reptiles, and other animals all share
many of these genes, especially
a subset called Hox genes. The
ubiquity of Hox genes in the animal
kingdom explains why most animals
worldwide have the same basic body
plan: a cylindrical trunk with a single
head at one end, an anus at the other,
and various appendages in between.
Scientists refer to DNA that appears
in the same basic form in many
species as highly conserved1 DNA.

1 Highly conserved DNA is so named because creatures are very conservative

about changing it. For DNA, being highly conserved is a good indication that
the DNA is vital.

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 Lecture 9
Some Hox and Hox-like genes
are so conserved between species
that scientists can actually remove
them from, say, chickens, mice,
or flies and swap them between
species—and the genes more or
less function the same. Creatures
don’t mess with their Hox genes
because they lead to catastrophic
birth defects. The vast majority of
creatures with Hox mutations die.
Given that most animals have the
same basic body plan, why can’t
different animals interbreed? Or
could they? After all, if you can
swap different Hox genes in and
out and if DNA itself is universal
to life, what’s to stop different
creatures from hybridizing,
especially closely related ones?
These questions occurred to a Soviet
biologist in the 1920s named Ilya
Ivanovich Ivanov, whose career
included the successful breeding
of antelopes with cows, guinea
pigs with rabbits, and zebras with
donkeys. And he saw questions
about interbreeding as a new way
to test the most controversial aspect
2 According to documents that a Russian historian of science unearthed, it was
then–secretary general of the Communist Party, Joseph Stalin, who approved
the funding for Ivanov’s work.
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Apes, Humans, and Neanderthals
of Charles Darwin’s theory of
evolution: that human beings had
descended from apelike ancestors.
To test his ideas, Ivanov came up
with one of the most unethical
experiments in the history of science.
He decided to mate human beings
with apes to see if he could produce
offspring, “humanzees.” The Soviet
Union supported Ivanov’s work with
a $10,000 grant in 1925 (roughly
$150,000 a century later). 2
At the time, Ivanov had good reason
to think that he could succeed
in breeding humans and apes.
Scientists knew that human and
ape blood showed a remarkable
degree of similarity. And Ivanov
was already an expert on artificial
insemination in animals; that’s how
he had created antelope-cows, guinea
pig–rabbits, and zebra-donkeys.
We can find similar cross-species
hybrids in nature as well. Lions
can mate with tigers, sheep with
goats, and polar bears with grizzlies.
Some of the resulting offspring are
sterile—genetic dead ends. But of
the more than 300 mammal species
 Lecture 9
that “outbreed” naturally, 33% can
produce fertile children. Even mules
can have children sometimes.
Apes and humans had diverged
millions of years ago, but that
divergence point was not greater
than the divergence point for
other species that had successfully
crossbred. So Ivanov had high
hopes for producing “humanzees.”
He started the project at a primate
research station in what’s now
Guinea in West Africa. The first
experiments took place in February
1927, when Ivanov inseminated 2
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Apes, Humans, and Neanderthals
young female chimpanzees with
a syringe full of human sperm.
To do so, he and his assistants
had to bind the chimps in nets.
The chimps already lived in filthy,
crowded conditions, so given all the
stress they were under, it’s no surprise
that they didn’t get pregnant. But
when these experiments failed,
Ivanov didn’t just give up. He
decided to visit a local colonial
hospital and impregnate female
humans with chimpanzee sperm.
And he wanted to do this without
telling the women involved.
 Lecture 9
Thankfully, the director of the
hospital put the kibosh on that
work, and Ivanov left Africa in
July 1927. Back in the Soviet
Union, he began seeking out
Soviet women to volunteer to
be inseminated by a 26-year-old
orangutan named Tarzan.
Incredibly, Ivanov found a volunteer.
Her name survives today only as
“G.” But before Ivanov could bring
her in for insemination, Tarzan
died of a brain hemorrhage. And
before Ivanov could round up
another ape, the Soviet secret police
arrested him for unknown reasons
and exiled him to Kazakhstan.
He died there shortly after being
released from prison in 1932.
After Ivanov’s arrest and death,
his scientific agenda disintegrated.
Few other scientists had the skill
to inseminate monkeys. Plus, no
other country but the Soviet Union
had been willing to trash ethical
guidelines and fund such work.
As a result, scientists have done
virtually no research on human-
ape hybrids since the 1920s. Even
today, scientists don’t know for sure
whether “humanzees,” however
unlikely, would be possible.
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Apes, Humans, and Neanderthals
For one thing, human sperm can
pierce the outer layer of an ape
egg cell in the lab, the first step in
fertilization. For another, human
and chimpanzee chromosomes look
similar on a macro scale. In fact, if
you mix human and chimp DNA in
a solution and heat it up, the double
helixes will unwind. And when
things cool back down, human DNA
strands have no problem embracing
ape DNA strands and zipping back
up with them. They’re that similar.
That said, there are good reasons to
think that breeding humans with
chimpanzees is impossible. Some
of this evidence comes from the Y
chromosome, which helps produce
sperm in males. In wild populations,
female chimps commonly have
sex with several males in a short
time. Therefore, sperm competition
is intense, and evolution has
remade the male chimpanzee’s Y
chromosome from top to bottom.
In human males, by contrast, the
Y chromosome has stayed pretty
similar for the past few million years.
This brings up an interesting point:
We humans often think about
ourselves as evolving away from
chimps—as if we’ve improved since
the split while they’ve stayed the
same. But with sperm production
at least, chimpanzees have left
 Lecture 9
human beings in the dust. And
these changes in sperm production
might make chimp sperm
incompatible with human eggs.
In fact, research using the Orangutan
Genome Project in 2011 showed
that both humans and orangutans
NUMBER OF CHROMOSOMES AND
BREEDING
Chimp-human hybrids might fail
for other reasons. One big reason
is that each species has a different
number of chromosomes.
89
Apes, Humans, and Neanderthals
have retained some genes that
chimpanzees lost. Similarly,
humans share some snippets
of DNA with bonobos that we
don’t share with chimpanzees.
Determining the number of
chromosomes that humans have was
pretty hard for scientists for most
of the 20th century. But in 1955,
scientists finally nailed down that
humans have 46 chromosomes.
 Lecture 9
But as often happens in science,
solving one mystery only opened
up another mystery: While humans
have 46 chromosomes, chimps
and orangutans and gorillas all
have 48. How did humans end
up with 2 fewer chromosomes?
It took a lot of research, but we’re
pretty sure here’s what happened.
With the exceptions of X and
Y, human chromosomes are all
referred to by a number, where
chromosome 1 is the longest, 2 is
the next longest, and so on, down
to the stubs of chromosome 22.
Around a million years ago, in
some fateful man or woman, 2
ancient human chromosomes—
let’s call them 2A and 2B—
accidentally fused together at
their ends. It was like buckling
one belt onto another. This fusion
of A with B created the second-
largest chromosome for humans,
which we call chromosome 2.
Fusions like this are not uncommon.
They occur even today, in roughly
one of every 1000 people. And most
of these fusions go unnoticed because
they don’t upset anyone’s health.3
3 The ends of chromosomes, called telomeres, often contain no genes, so
nothing gets disrupted.
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Apes, Humans, and Neanderthals
However, one fusion by itself can’t
explain the drop from 48 to 46. If 2A
fused with 2B, that left the person
with 47 chromosomes, not 46.
And even after the drop to 47, the
person still had to pass on the fused
chromosomes—a serious barrier.
Scientists eventually puzzled
out what happened. Let’s go
back a million years, when most
protohumans had 48 chromosomes.
But imagine there’s one person with
47. Let’s call this person Jill, although
it might well have been a male.
Having an odd number of
chromosomes will cripple the
viability of Jill’s eggs. Overall, in
someone with an odd number of
chromosomes, 66% of her children
die in the womb and just 16%
inherit the fusion. Plus, any child
who inherits the fusion would
then face the same terrible odds
trying to reproduce. That’s a low-
probability recipe for spreading
the fusion, which is also stuck
at 47 chromosomes, not 46.
What Jill needs is a Jack with
the same 2 chromosomes fused
together. The odds of 2 people
 Lecture 9
meeting who have the exact
same chromosome fusion are
low—except in inbred families.
Relatives share a high percentage
of DNA. As a result, in inbred
families, there’s a good chance of 2
people meeting who have the same
fusion. And while the odds of Jill
and Jack having a healthy child
remain low, every so often—one
in every 36 times—a child would
inherit both fused chromosomes,
giving it 46 total chromosomes.
And here’s the payoff. Junior and
his 46 chromosomes would have
a much easier time having viable
children. Remember that the
fusion itself doesn’t harm your
health; lots of healthy people
worldwide have fusions. It’s only
reproduction that gets tricky, since
fusions can lead to an excess or
deficit of DNA in embryos.
But because Junior’s 46 chromosomes
are an even number, he wouldn’t
have any unbalanced sperm cells.
Each sperm would have exactly
the right amount of DNA to run a
human, just packaged differently.
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Apes, Humans, and Neanderthals
As a result, all his children would
be healthy. And if his children
start having their own children—
especially with other relatives who
have 46 or 47 chromosomes—the
fusion could start to spread.
Scientists know that this fusion
and inbreeding scenario isn’t
just hypothetical, either. In
2010, a doctor in rural China
discovered a family with a history
of inbreeding. And among the
various overlapping branches of
the family tree, he discovered a
male with 44 chromosomes.
In this family’s case, the 14th and
15th chromosomes had fused.
And, consistent with what was
just described, prior generations
of the family had a brutal record
of miscarriages in their past from
fetuses with the wrong number
of chromosomes. But from that
wreckage emerged a perfectly healthy
man with 2 fewer chromosomes
than every other person on Earth.
 Lecture 9 Apes, Humans, and Neanderthals

Something similar probably it is difficult, which means that

happened deep in our past in Africa,
causing the drop from 48 to 46.4
And all of us today are the result.
Overall, then, it’s not impossible for
creatures with different numbers
of chromosomes to breed. But
Ivanov’s experiments to create
“humanzees” probably wouldn’t
have worked. That said, it’s a
virtual certainty that human beings
did breed with another species in
the recent past: Neanderthals.

NEANDERTHAL AND DENISOVAN DNA

The first Neanderthal skulls skulls for deformed humans, but

were unearthed in Belgium in
1829. Similar skulls turned up in
Gibraltar in 1848 and Germany’s
Neander Valley (or, in German,
Neander Thal) in 1856. At first,
many anthropologists mistook the
they eventually realized they had
something new on their hands.
Initially, Neanderthals were classified
as archaic human ancestors, before
eventually being shunted off
onto their own, terminal branch
on the tree of life. And that’s

4 While it’s certainly possible that the fusion of 2 chromosomes long ago gave
humans a big survival boost, allowing that DNA to spread widely, a more
plausible explanation is that human beings suffered a genetic bottleneck.
In other words, either some great catastrophe or a series of smaller, but still
bad, events probably wiped out most human beings on Earth, except for a
few small tribes. Inbreeding would have become more common. And when
our population rebounded afterward, whatever genes those lucky survivors
happened to have would spread far and wide—including a chromosome
fusion.

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 Lecture 9 Apes, Humans, and Neanderthals

What did we learn by sequencing

Neanderthal DNA?
Neanderthals likely had reddish hair and pale skin.
Sequenced genomes showed type O blood, which
is the most common blood type in humans. And
like most humans around the world, they probably
couldn’t digest milk as adults.

where things stood until around
2010, when geneticists started
examining Neanderthal DNA.5
Shockingly, the Neanderthal
genome revealed clear evidence
that humans and Neanderthals
interbred with each other and
produced viable children. Those
children, in fact, are the ancestors
of many human beings alive today.
Here’s how that DNA got inside
human beings. After migrating out of
Africa many thousands of years ago,
clans of human explorers eventually
wandered into Neanderthal
territory in the Middle East. Boys
met girls, hormones took over, and
pretty soon, little “humanderthals”
were running around.
And when these human explorers
pushed onward into Europe and Asia,
they carried the Neanderthal DNA
with them in their clan. As a result,
all people of non-African descent—
that is, people who trace their roots
to Europe, Asia, or the Americas—
have Neanderthal DNA today.
In most people, it’s a few percent
of their total DNA—equivalent
to the amount you inherited from
each great-great-great grandparent.
It’s not clear what all the
Neanderthal DNA does in humans,
but some of it apparently helped fight
off new diseases. This was necessary
then because human beings were
moving out of Africa and colonizing
new lands with new microbes.
Neanderthals had already been living
in those lands for millennia and

5 DNA can survive in bones and other organic remains for tens of thousands
of years, especially in cold climates. To be sure, DNA isn’t as hardy as bone.
It often deteriorates and starts to break down into fragments. But thanks to
technologies developed during the Human Genome Project, scientists can
often piece those fragments together into a coherent genome.

93
 Lecture 9 Apes, Humans, and Neanderthals

had acquired immunity. Getting prominent jaws and wide hips.

Neanderthal DNA through breeding
was therefore a shortcut to gaining
resistance for humans, rather than
enduring centuries of dying off.
And it’s not just Neanderthal
DNA that human beings
are carrying around. There’s
also Denisovan DNA.
The Denisovans are named after
a cave in Siberia where, in 2008,
scientists found a knucklebone
of a young girl who died tens of
thousands of years ago. At first, it
seemed Neanderthal. But DNA
extracted from the knucklebone
showed enough distinctions to count
as a separate line of hominins.
This was the first extinct species
ever discovered almost entirely
through genetic, not anatomical,
evidence. Such evidence suggests
that Denisovans probably looked
somewhat like Neanderthals, with
But Denisovans probably had
wider faces and longer jawbones.
The Denisovans are sometimes
called cousins of the Neanderthals,
but they remain mysterious today.
But glimpses of their DNA appear
in modern humans. For instance,
there are traces in the Melanesians,
the people who originally settled
the islands stretching 2000 miles
from New Guinea to Fiji.
Apparently, as the proto-Melanesians
were making the long haul from
Africa to the South Pacific, they ran
into Denisovans somewhere. And
just like with Homo sapiens and the
Neanderthals before, the 2 groups
interbred. Today, Melanesians have
up to 8% non–Homo sapiens DNA.
In addition, people with ancestry in
Tibet have Denisovan DNA. Tibet
lies in the Himalayan mountains and
is one of the most elevated regions
on Earth. As a result, Tibetan people

Because Neanderthal DNA exists in so many

human beings today, some scientists argue
that technically, Neanderthals haven’t gone
extinct. In fact, we can currently reconstruct
most Neanderthal DNA based solely on the
bits we find scattered about in different
human beings.

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 Lecture 9 Apes, Humans, and Neanderthals

have several genetic adaptations As scientists continue to catalogue

for altitude to help them survive.
And they inherited some of these
genetic adaptations 6 directly from
Denisovans, who had lived in the
mountains before them. Without
interbreeding, people from Tibet
likely couldn’t have thrived there.
On a genetic level, then, modern
human beings are a mix of at least
2 other species: Neanderthals and
Denisovans. And there could be
more. Evidence began to turn up in
2020 that native West Africans—
who mostly lack Neanderthal and
Denisovan DNA—had their own
liaisons in the past with other,
now-extinct archaic hominins.
human diversity around the world,
DNA memories of other liaisons
could surface in other groups. The
work of analyzing commonalities
and differences among species is
now accelerating. In 2018, the
Earth BioGenome Project began
efforts to sequence the genomes for
some 1.5 million species. As such
work advances, it seems inevitable
that we’ll assign more and more
of “our” DNA to ancestors we
share with other creatures.

Readings
Pääbo, Neanderthal Man.
Reich, Who We Are and How We Got Here.

6 For instance, because there’s less oxygen higher up, people produce more
red blood cells at altitude to deliver as much oxygen as possible to cells.
That’s why endurance athletes train in the mountains. Unfortunately, more
red blood cells can also lead to deadly blood clots. But one adaptation
from Denisovans helps people in Tibet avoid blood clots even with high
concentrations of red blood cells.

95
How DNA Reveals
History
LECTURE 10

G enetics has already rewritten the story of human migration

across the world by showing us that we interbred with species
like Neanderthals. DNA can also shed light on later migrations, on
archaeology, and on more recent human history, including the lives
of historical celebrities like King Tut.

Return
to TOC

HUMAN ORIGINS

Because human beings arose a few
hundred thousand years ago, it’s
often difficult to tell what exactly
happened. But examining DNA
from ancient humans can support or
refute certain theories or even open
up whole new vistas to explore.
Perhaps most importantly, DNA
confirmed that human beings first
arose in Africa. Well into the 1900s,
a few holdouts had insisted that
humankind actually first arose in
India or East Asia. But it’s a general
rule of biology that species show the
most genetic diversity in the land
of their origin, because that’s where
they’ve had more time to accumulate
mutations and new genes.
And that’s exactly what scientists
see in Africa. Humans in Africa
have far more genetic diversity than
humans in the rest of the world
combined.1 Anthropologists of
the 19th century used to lump all
African peoples into one single race,
but in truth, the rest of the world’s
genetic diversity is more or less
just a subset of African diversity.

1 African peoples have 22 versions of a particular stretch of DNA that helps

regulate insulin, and of those 22 versions in Africa, the rest of the world has
just 3 versions total.

96

Genetics can also help us understand
how human beings spread across
the rest of the globe. Our DNA,
essentially, kept a travelogue.
For Asia, genetic analysis has
revealed 2 distinct waves of
colonization. Many scientists think
that one wave, which occurred
65,000 years ago, skirted India and
led to the settlement of Australia by
the aborigines. A second wave then
filled in the rest of Asia and led to
humanity’s first-known population
boom 40,000 years ago. At that
point, 60% of humankind lived
on the newly booming Indian,
Malay, and Thai peninsulas.
And eventually, these Asian
populations gave rise to people who
traveled even farther. The first people
in Oceania had roots somewhere
near Taiwan, while the first Native
Americans have roots in Siberia.
In addition to understanding
the movement of people, genetic
evidence can help us understand
the emergence of uniquely human
traits as well as cultural innovations
like clothing and farming.
Roughly 1.2 million years ago, a
mutation in a gene called MC1R
gave rise to darker skin in humans,
and darker skin suggests that we
97
Lecture 10 How DNA Reveals History
were becoming hairless. Then,
a million years later, roughly
200,000 years ago, a genetic
mutation allowed the hair on our
heads to grow indefinitely long,
unlike the hair on other apes.
Then, not long afterward, humans
began wearing animal skins as
clothes. Scientists determined this
by studying lice. At first, humans
had just one species of louse, in our
hair. But it eventually split into hair
lice, which live only on scalps, and
body lice, which live only in the
clothing we made from animal skins.
Because DNA mutations accumulate
at a steady rate over time, by
comparing the DNA of head
lice with the DNA of body lice,
scientists could work backward
and determine when body lice
and head lice diverged—roughly
170,000 to 190,000 years ago.
So around then may be when
we started wearing clothes.
As for farming, it’s widely believed
that this practice first arose in the
Middle East at least 11,000 years
ago and spread from there. But
archaeologists always wondered
exactly how farming spread. Did
farmers themselves move into
new territory and replace hunter-

gatherers? Or did the technology
alone spread as hunter-gatherers
adopted a new way of life?
In Europe at least, the answer is
becoming clear. Preliminary DNA
evidence from ancient bodies—
some from right before the spread
of farming and some from right
after—suggests that it wasn’t just
the technology alone spreading. It
was mostly people moving in and
taking over new lands. We know
this because right after the onset
of farming, genes that originated
with people close to the Middle East
suddenly show up in bodies buried
in Europe, thousands of miles away.
THE NEAR EXTINCTION OF HUMANS
Perhaps the most dramatic
information about our past
that has been illuminated by
DNA comes from reliable DNA
evidence showing that human
beings very nearly went extinct.
One thing that stands out about
modern humans is our lack of
genetic variety. Estimates suggest
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Lecture 10 How DNA Reveals History
The most dramatic evidence that
farming people replaced hunter-
gatherer people comes from Great
Britain. Surprisingly, based on
DNA evidence, the first settlers
of Great Britain probably had
black skin but also bright-blue
eyes. The famous Cheddar Man,
for instance, a 10,000-year-old
skeleton found in a cave in England,
almost certainly had those traits.
Although there was some
interbreeding, Cheddar Man’s
hunter-gatherer people were largely
replaced by light-skinned settlers
whose roots ultimately trace back
to modern Turkey. These later
people were also the farmers who
built Stonehenge in England.
that there are roughly 150,000
chimpanzees alive and around the
same number of gorillas. Compare
that with nearly 8 billion humans.
Yet human beings have significantly
less genetic diversity than chimps
and gorillas. This suggests that in
the past, the worldwide population
of humans had crashed, bottoming

out quite low. Had the Endangered
Species Act existed way back when,
Homo sapiens might have been
that era’s pandas or condors.
Some scientists linked the human
population crash to a huge volcanic
eruption near Lake Toba in
Indonesia 75,000 years ago. At its
peak, the Toba eruption was ejecting
millions of tons of vaporized rock
into the air every second—up to
2000 times more than the Mount
Saint Helens eruption of 1980.
Other scientists have argued against
the Toba eruption as the cause of
any population crash. They theorize
that other, more localized events
like droughts or diseases might
have devastated our population
through a series of smaller blows.
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Lecture 10 How DNA Reveals History
How bad did things get? Answers
vary, but estimates of a few
thousand adults are common.
Perhaps our superior brains helped
us survive, through innovations
like clothing or fire or tools.
Perhaps some of us found hospitable
climates and weathered any
catastrophes there. Or perhaps
a few of us just got lucky.
We tend to think about the
emergence of modern human beings
as triumphant—something like
that National Geographic sequence
of hairy hominids rising off their
knuckles and standing on their feet.
But our DNA tells a more humbling
story. Nature may have almost wiped
us out, like so many dinosaurs, with
very little regard for our big plans.
 Lecture 10 How DNA Reveals History

ANSWERS FROM KING TUT’S DNA

King Tut was the famous teenage
pharaoh of ancient Egypt whose
reign marked the end of an entire
line of pharaohs. His father was
another famous pharaoh, Akhenaten.
But certain details about Akhenaten
have always puzzled Egyptologists.
In particular, public art during
Akhenaten’s rein always made him
look pretty strange. Archaeologists
have noted his almond-shaped
head, spidery arms, chicken legs
with backward-bending knees,
gigantic lips, concave chest, and
huge potbelly. No one quite knew
what to make of this art—especially
since other creatures, such as birds,
are usually depicted realistically.
But some Egyptologists decided
that these pictures were evidence
of a congenital deformity. And
frankly, this wasn’t a bad guess,
since there was a lot of incest in the
pharaonic line. As further evidence,
Akhenaten’s son Tut showed signs of
physical deformities as well. Among
the many treasures in Tut’s tomb,
archaeologists found 130 walking
canes, many showing signs of wear.
Unable to resist, doctors have
retroactively diagnosed Tut and
Akhenaten with all sorts of ailments,
including elephantiasis and
Marfan syndrome. 2 But however
suggestive, each diagnosis suffered
from a lack of hard evidence.
Both Akhenaten and Tut’s mummies
exist today, and in 2007, Egypt 3
allowed scientists to withdraw DNA
from 5 generations of mummies.
This included Tut, Akhenaten,
and Akhenaten’s wife, the famous
Queen Nefertiti, who many people
suspected was Tut’s biological
mother. When combined with
meticulous CT scans of the corpses,
this genetic work helped resolve some
mysteries about Tut’s life and times.
The study turned up no major
genetic diseases in Akhenaten or
his family. This hints that the
Egyptian royals probably had no

2 This is a disorder marked by elongated connective tissue.

3 The Egyptian government had long hesitated to let geneticists test
Akhenaten and Tut’s mummies. To do genetic tests, you have to drill
into mummy tissue, which destroys a small bit of the carefully preserved
tissue. The study of ancient DNA was also kind of iffy at first, plagued by
contamination and inconclusive results.

100

major physical defects or obvious
genetic syndromes. So then what
about the art from Akhenaten’s
reign, which showed several strange
physical traits? The absence of a
major genetic disease suggested
that these pictures probably
weren’t striving to be realistic.
They were probably propaganda.
Akhenaten apparently decided that
his status as pharaoh lifted him so
far above the normal human rabble
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Lecture 10 How DNA Reveals History
that he had to inhabit a new type
of body in public portraits. Some of
Akhenaten’s features—such as a big
head and a distended belly—also
call to mind fertility deities. Perhaps
he wanted to portray himself as
the womb of Egypt’s well-being.
All that said, the mummies that were
tested did show subtler deformities,
such as clubbed feet and cleft palates.
And each succeeding generation
had more such defects to endure.

Tut, of the fourth generation,
inherited both a clubfoot and a
cleft palate. He also seemed to have
congenitally weak bones; he broke
his femur when he was young, and
bones in his foot atrophied because
of poor congenital blood supply.
Scientists realized why Tut suffered
so much when they examined
his genes. Recall that we all have
in our genomes highly repetitive
sections of DNA called satellites.
And because you inherit some
satellites from your mother and
some from your father, they offer
a good way to trace lineages.
Unfortunately for Tut, he inherited
the same DNA satellites from
his mother and his father. That’s
because Tut’s mother and father
in turn had the same mother and
father; in other words, his mother
and father were brother and sister.
So Akhenaten’s most famous
wife might have been Queen
Nefertiti. But when it came time
to produce an heir for the throne,
Akhenaten apparently turned
from Nefertiti to his sister, and the
result was King Tut. And pretty
4 Each child ended up as a small mummy in Tut’s tomb, next to his gold mask
and walking sticks.
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Lecture 10 How DNA Reveals History
soon, this incest compromised
Tut’s immune system—and
helped end his family dynasty.
Akhenaten died when Tut was just
9 years old, meaning that Tut was
a boy when he assumed the throne.
And he was plagued by illness
during his reign. We know this
because geneticists found scads of
malaria DNA inside Tut as well. He
probably had a weak immune system
due to his incestuous genes, and he
ended up dying at the age of 19.
Perhaps saddest of all for the royal
line, Tut died without leaving
any heirs. That’s because he
compounded his own genetic defects
by taking his own half sister as his
wife. Their only known children
were stillborn at 5 months and 7
months old—probably because
they were genetically unviable. And
with the death of those babies, 4
Tut’s dynasty came to an end.
DNA shed light on 14th-
century Egyptian art,
history, politics, and funeral
practices, among other
things.

THOMAS JEFFERSON’S CHILDREN
The American president Thomas
Jefferson’s DNA revealed some
fascinating contradictions
about his views on slavery.
As far back as 1802, hostile
newspapers were suggesting that
Jefferson had fathered several
children with a slave named Sally
Hemings. Even Jefferson’s friends
admitted that Hemings’s sons
looked uncannily like him.
Historians later determined, through
diaries and other documents,
that Jefferson was in residence at
Monticello 9 months before the
birth of each of Sally’s children.
And Jefferson emancipated each
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Lecture 10 How DNA Reveals History
of the 4 surviving children when
they turned 21, a privilege not
extended to other slaves.
However, Jefferson always
denied fathering any children
with Hemings, and many
contemporaries didn’t believe
it, either. Some pointed to other
Jefferson males as the father. To
get to the bottom of this, scientists
in the late 1990s investigated
the family’s Y chromosome.
In males, the Y chromosome gets
passed down intact from father to
son, so it offers a good way to trace
paternal lines. Jefferson himself had
no recognized sons, but male relatives
of his, such as his uncle, did have a
family line with an unbroken string
of sons down to the present day.
Similarly, there’s an unbroken
string of males alive today that
can trace their heritage back to
one of Sally Hemings’s sons. So
geneticists tracked down members
of both families in 1998 and
compared their Y chromosomes—
and they were perfect matches.
Of course, the test proved only
that a Jefferson male had fathered
Sally Hemings’s children, not

which specific one. But given the
additional historical evidence,
a case for the father being
Thomas Jefferson is strong.
Overall, Jefferson fathered at least 6
children with Hemings, including
one in 1808—during the last
year of his 8-year presidency and
6 years after the first allegations
appeared. This reveals either
enormous hubris or sincere devotion
to Sally (or perhaps both).
GENGHIS KHAN AND KING RICHARD III
Ever since the revelations from the
Jefferson research, Y-chromosome
testing has become increasingly
important in historical genetics. For
instance, this type of testing has
revealed that Genghis Khan, head
of the Mongolian empire, is the
ancestor of an incredible 16 million
men alive today. This is because
whenever the Mongols conquered
new territory, they fathered as many
children as possible with local women
to tie them to their new overlords.
As a result, central Asia is littered
with Genghis’s descendants today.
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Lecture 10 How DNA Reveals History
Yet, like many of the English
monarchs he despised, Jefferson
disavowed his bastard children
in public to salvage his political
reputation. Also typical for his time,
Jefferson publicly opposed marriages
between black people and white
people, pandering to fears of racial
impurity. All in all, it seems like a
damning account of hypocrisy in one
of our most philosophical presidents.
As for the female ancestors, all
humans have a separate collection
of DNA in our cells’ mitochondria,
which reside outside the nucleus,
where most DNA is kept. Molecular
biologist Lynn Margulis first
suggested in the 1960s that this
separate store of DNA proves that
mitochondria—which provide
power for cells—actually used to
be separate, free-living creatures.
And only over time did our cells
tame and colonize them, to the
point where mitochondria can’t
live outside our cells and our cells
can’t live without mitochondria.

Margulis was eventually proved
correct. And today, mitochondrial
DNA can again provide insights
into human heritage. In 1987,
mitochondrial DNA revealed
that Neanderthals were not the
direct ancestors of humans.
Note that mitochondrial DNA
gets passed only from mothers to
their infants, because embryos
get mitochondria only from
egg cells. Males do not pass
on mitochondrial DNA.
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Lecture 10 How DNA Reveals History
And because mitochondrial DNA
averages one mutation every 3500
years—almost like clockwork—
scientists have used this “molecular
clock” to estimate that every
human being now on Earth can
trace their maternal ancestry to a
single woman who lived in Africa
170,000 years ago. This so-called
mitochondrial Eve wasn’t the only
woman alive then, but she is the
most recent common matrilineal
ancestor of all people alive today.
 Lecture 10 How DNA Reveals History

And just like the Y chromosome geneticists confirmed his identity—

allows us to trace lineages,
mitochondrial DNA does as well.
In 2013, the skeleton of the English
king Richard III was uncovered
beneath a parking lot, and
and a diagnosis of scoliosis—by
comparing mitochondrial DNA
from the bones to the mitochondrial
DNA of a few living descendants
of his sister, Anne of York.

When it comes to DNA analysis, not everything

that can be done should be done. There are
ethical concerns as well as privacy issues.
For example, many famous people have
descendants alive today who share a large
fraction of their genes, and these descendants
might not appreciate having their own DNA
outed merely because of a famous ancestor.

Readings
Hawass, “King Tut’s Family Secrets.”
Monticello, “Thomas Jefferson and Sally Hemings.”
Reilly, Abraham Lincoln’s DNA and Other Adventures in Genetics.
Sykes, Seven Daughters of Eve.

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CRISPR’s Rise, Promise,
and Peril
LECTURE 11

A recent tool called CRISPR-Cas9 has made DNA editing much

easier and cheaper than it had been previously. We might do
amazing things with CRISPR, such as cure diseases and resurrect
extinct species. But there are also legitimate fears. In 2018, CRISPR
was used to edit human embryos in China. And some people fear
that without careful control, we could see a new version of the awful
eugenics movement that became so influential in the first half of the
20th century.

Return
to TOC

THE RISE OF CRISPR

In Spain in 1989, a biologist named letters of the second half are

Francisco Mojica was studying
bacteria in a salt marsh along the
coast, collecting the microbes and
analyzing their DNA. He found
mostly normal DNA. But one
thing struck him as strange. Next
to one gene, he spotted 5 small,
identical stretches of DNA clustered
together, each 30 bases long.
What’s more, the identical stretches
were a DNA palindrome—a word or
phrase that reads the same forward
and backward (such as taco cat). In a
DNA palindrome, the “backward”
complementary bases. For instance,
G-A-A-T-T-C would be a 6-letter
DNA palindrome, because the other,
complementary side of the strand
would read C-T-T-A-A-G, which
is the original strand backward.
The 30-letter palindromes were
interspersed among other stretches
of DNA, all 36 letters long. These
nonrepeated sections are now
called spacers. And that’s the
pattern Mojica found: clusters of
palindrome-spacer, palindrome-
spacer, repeating over and over. The

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full name that came into use was
clustered regularly interspaced short
palindromic repeats—abbreviated
CRISPR, which became shorthand
for any technology making
use of palindromic repeats.
Mojica had no clue what his short
palindromic repeats in the DNA did.
But some quick research revealed
that a similar palindrome-spacer
pattern appeared in dozens of other
microbes from around this world.
Why would these very different
bacteria have the same DNA?
In the 1990s, Mojica every so
often would type the palindrome
or spacer sequence into an online
DNA search engine called BLAST
(basic local alignment search tool),
which contains DNA sequences
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CRISPR’s Rise, Promise, and Peril
from lots of different organisms.
These included the organisms in
which Mojica had already found
the palindromes and spacers. But
with BLAST, you can also compare
DNA sequences in one organism
to the DNA of other organisms.
After searching in BLAST for spacer
sequences for a long time and getting
nothing, Mojica got a hit in August
2003 for a new organism besides
the bacteria he already knew about.
But strangely, the hit he got was
in a virus. Apparently, his bacteria
and a virus shared some DNA.
Puzzled, Mojica searched for some
other spacers he’d seen in bacteria
and got more hits—in more viruses.
He searched for more than 4000
different bacterial spacers. Overall,
 Lecture 11 CRISPR’s Rise, Promise, and Peril

he got 88 hits from viruses. And immunity in bacteria, they decided

then he noticed something even
more striking—the key to the whole
mystery. In the majority of the cases,
the bacteria that contained the virus
spacers were immune to the viruses
that matched. He realized that he
was looking at a virus defense system.
to investigate: How do bacteria use
the short palindromic repeats to edit
their own genes and fight off viruses?
They found that the CRISPR
defense system involves 2 steps:
recognizing viruses and killing them.

When Mojica reported his results s The key to recognizing

in 2005, he didn’t know how
bacteria did it, but his work
showed that bacteria edit their own
genes to fight against viruses.
The next breakthrough came from
what might seem an unlikely place:
a yogurt plant in Wisconsin.
Bacteria make yogurt by culturing
milk to give it a sour tang. But the
bacteria in the vats of the yogurt
plant of the Danisco company
in Wisconsin kept getting wiped
out by viruses. The Danisco
company was losing money.
So when microbiologists at the
company heard that CRISPR
sequences were associated with
viruses is the spacers between
the palindromes. Whenever
bacteria survive a virus attack,
they take some viral DNA and
store it as a spacer. It’s basically a
genetic mugshot that helps them
recognize the virus next time.
s To then kill viruses, bacteria use
a special enzyme, such as Cas9,
which can cut DNA like scissors.
However, the enzyme scissors can’t
just cut DNA willy-nilly, or else
the bacteria’s own DNA might get
shredded. But the mugshots solve
this problem. The bacteria use the
DNA mugshots to build an RNA

Some people hail genetic engineering as an exciting

idea, a way to fix diseases and tackle some of the biggest
problems that humankind faces. Other people, though,
fear genetic engineering, calling it a Pandora’s box that
could plummet us into biological dystopia.

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 Lecture 11
guide, which is complementary to the
virus DNA. It therefore recognizes
the virus DNA and latches onto it.
The RNA guide and the enzyme
scissors are now yoked together, with
the guide pulling the scissors along.
So whenever a virus invades, the
guide locks onto the complementary
virus DNA. And only when the
guide is locked onto that virus
DNA can the scissors start snipping.
Overall, then, the mugshot-guide
system is a safety measure. It ensures
that only the virus DNA gets
snipped, and only at a specific point.
A TALE OF TWO LABS
In 2011, a microbiologist working
in Vienna named Emmanuelle
Charpentier attended a scientific
conference in Puerto Rico.
Charpentier studied flesh-eating
bacteria and had come across the
CRISPR defense system in one
of those bacteria. She realized
that what the bacteria were doing
could be an amazing gene-editing
tool, and not just in bacteria. So
she tracked down a biochemist at
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CRISPR’s Rise, Promise, and Peril
Once the yogurt team understood
how bacteria store viral DNA and
use the scissors enzyme to kill
viruses, they figured out how to
identify good bacteria for dairy
production. They’d sequence the
DNA mugshots and use only bacteria
that had a defense against some
common, troublesome viruses.
Dairy makers had been preselecting
the best bacteria since at least 1990.
But now they understood that the
better strains of bacteria became
advantageous over other bacteria
by editing their own genomes.
the conference whose lab studied
CRISPR: Jennifer Doudna of the
University of California, Berkeley.
Before their meeting, Doudna and
everyone else had only studied
CRISPR within bacteria. But
bacterial DNA is a string of A-C-
G-T bases, just like any other
organism’s DNA. That meant the
enzyme scissors should be able to
cut animal and plant DNA, too.
 Lecture 11 CRISPR’s Rise, Promise, and Peril

And instead of relying on the virus
mugshots to tell the scissors where
to cut, Doudna and Charpentier
realized they could swap in their
own RNA guide. That way,
the scissors could cut the DNA
at any point they chose. The 2
women agreed to join forces.
Doudna and Charpentier built their
own guides and proved in 2012
that this human-made CRISPR
could edit DNA in test tubes.
The next question at that point was
whether—and how well—CRISPR
would work in the more complicated
environments of living cells.
Doudna and Charpentier weren’t
the only ones trying to use CRISPR
for editing beyond bacteria. There
was also a geneticist named Feng
Zhang. By 2011, which is when
Zhang first heard about CRISPR,
he had been searching for years for a
better way to edit DNA. He plunged
into more than a year of research
into tweaks to make CRISPR
editing more targeted and efficient.
When the paper by Doudna and
Charpentier on editing DNA
appeared, it was a blow for Zhang.
He’d been scooped. But he took
comfort in one thing: Doudna and
Charpentier had succeeded only
in test tubes, not living cells.
So Zhang worked like a maniac
for several months. And in the
end, he won the race to edit
human cells with CRISPR. He
published his results in January
2013, just weeks before Doudna’s
lab succeeded at the same task.
After this, the competition
between the labs only became
more intense. Doudna’s lab and
Zhang’s lab both filed for patents
on their CRISPR techniques. In
2017, Zhang’s lab won the patents.
But in 2018, the Patent Office
reopened the case, and hundreds of
other institutions, companies, and
researchers around the world jumped
in with their own applications.

Because only 3 scientists can win a Nobel

Prize for a particular discovery, several
people will probably get left out of a Nobel
Prize for CRISPR. Scientists who have claims
here include Mojica, the Wisconsin yogurt
scientists, Charpentier, Doudna, and Zhang.

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 Lecture 11 CRISPR’s Rise, Promise, and Peril

APPLICATIONS OF PRECISION GENOME

EDITING

The applications for precise editing CRISPR could also make it

of the genome are almost endless.
Fixing diseases is an obvious one.
Injecting someone with the
CRISPR guide and scissors could
potentially patch up their genetic
mutations and cure them. Most
modern medicine treats symptoms;
CRISPR could treat root causes.
Other applications are a little
wilder. Some scientists are trying
to grow human organs inside pigs
to help ease our chronic shortage of
organ donors. We can’t transplant
pig organs directly into humans
because our immune systems would
reject and attack the organs. But
if we could tweak pig DNA with
CRISPR and delete the pig DNA
that codes for proteins that provoke
an immune response in humans,
then the pigs’ kidneys, livers, and
hearts could survive in humans.
possible to bring creatures back
from extinction. Though you’re
probably familiar with this idea from
Jurassic Park, it wouldn’t work with
dinosaurs, who died out so long ago
that their DNA, even when trapped
in amber, has long since deteriorated.
But resurrecting more recent
creatures, such as mammoths, isn’t
so farfetched. Mammoth remains
are not uncommon in Siberia, and
the pelts and bones there contain
mammoth DNA.1 But this
scenario overlooks some ethical
issues. All pachyderms, including
mammoths, are intelligent and
highly social creatures, which means
that the first few mammoths would
probably be intensely lonely.
In fact, although CRISPR is
a brilliant DNA-editing tool,
it’s not perfect. It still makes
mistakes sometimes. Some of
these off-target effects may have

1 Getting mammoth DNA is only the first step. Even if you rebuild the entire
mammoth genome in a lab, you would need a mammoth egg cell to put the
DNA into and a mammoth womb to grow it in. Because close relatives of
mammoths are elephants, scientists have proposed starting with an elephant
embryo and tweaking its genes. The result would be a mammoth-elephant
hybrid that would look and perhaps act like mammoths.

112
 Lecture 11
no medical consequences, but
others probably will, including
potentially severe birth defects.
These issues become even more
fraught with species closer to
humans. In theory, scientists have
all the genetic information they’d
need to resurrect Neanderthals, 2
too. Scientists could tweak a
human embryo’s DNA to be more
Neanderthal-like and implant
the egg in a human womb. Nine
months later, you’d effectively
have the first Neanderthal to
walk the Earth in 40,000 years.
ANOTHER EUGENICS MOVEMENT?
The word eugenics means “good
birth” or “well born.” Many early
eugenicists had backgrounds in
breeding farm animals, and they
wanted to apply the same principles
to human beings. We take great
pains to breed good cattle and horses,
they argued. Shouldn’t we be even
more careful with our own kind?
2 Remember that humans and Neanderthals once interbred—that’s how similar
we are biologically.
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CRISPR’s Rise, Promise, and Peril
But would that first Neanderthal
child be an outcast? Could
a Neanderthal ever find any
place in human society?
CRISPR also makes it possible to
revive or edit infectious diseases from
the past. In fact, genetic sequences
for smallpox and other diseases
are already publicly available.
But perhaps most controversially,
CRISPR gives us the ability to
edit our own DNA—which
for some people brings up the
haunting specter of eugenics.
So they encouraged people
who were physically robust and
mentally sound to have as many
children as possible to help good
traits spread. Future generations,
they assumed, would be smarter,
healthier, and happier as a result.
Eventually, just like with farm
animals, county fairs started
sponsoring “fitter family”
 Lecture 11 CRISPR’s Rise, Promise, and Peril

competitions, at which parents of inheritance in 1900. Negative

would parade their children across
the stage and be awarded prizes, just
like pigs that win a blue ribbon.
Promoting fitter families became
known as positive eugenics.
But there’s also negative
eugenics, which has a much
more sinister history.
traits suddenly seemed easy to
explain: Poor people were presumed
to have bad genes, and those bad
genes were presumed to pass to
their children. Eugenicists even
built family trees and tried to use
Mendel’s laws of inheritance to
follow traits they didn’t like, such as
sassiness or poor dressmaking skills,
from generation to generation.

While positive eugenics encouraged
healthy families to have more
children, negative eugenics tried
to prevent other families—usually
poor and minority families—
from having children at all.
Supporters framed negative eugenics
as a way to improve society. They
claimed that poor people committed
more crimes, drained resources
from the government, and spread
diseases. Eliminating such people
would therefore benefit everyone.
The eugenics movement was already
underway in the late 1800s, but
negative eugenics took off with the
rediscovery of Gregor Mendel’s laws
Today, the flaws in this work seem
obvious. There’s no such thing as a
gene for poor dressmaking, and one
person’s sassiness is another’s spunk.
In addition, the traits that eugenicists
condemned reflect an upper-class
bias against the poor. Even more
importantly, in attempting to make
everything genetic, eugenicists
completely neglected the role
of the environment and society
in shaping behavior—and we
now know that the environment
can even affect our genes.
But the eugenicists built their family
trees anyway. And once they’d made
up a supposed genetic basis for a bad

Prominent eugenics supporters included the

inventor of the telephone, Alexander Graham
Bell, who helped organize the First International
Conference on Eugenics in 1912.

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 Lecture 11 CRISPR’s Rise, Promise, and Peril

trait, the next step was obvious to
them. They wanted to eliminate the
trait—by preventing people from
having babies. This led to a series
of notorious sterilization laws.3
By the mid-1920s, doctors had
already sterilized a total of 3000 US
men and women. Even the Supreme
Court gave its blessing to eugenics in
1927 with the Buck v. Bell decision, 4
which opened the floodgates for
negative eugenics. Eventually, 33
states passed eugenics laws, and
more than 60,000 American men
and women were sterilized.5
And the United States was only
the start. When Adolf Hitler rose
to power in Germany in 1933, the
Nazi Party looked to the American
eugenics movement for inspiration.
In particular, they used American
sterilization laws as models in their
crusade to sterilize hundreds of
thousands of Jews and other groups
they regarded as “undesirable.”
But at the Nuremberg trials
after the war, when American
prosecutors went after Nazi doctors
for sterilizing people, the Nazis
flung the charges back in their
faces: If your own Supreme Court
declared sterilization legal, they
said, how can you charge us with
crimes? The Americans didn’t have
a good answer, but they convicted
several of the Germans anyway.
Many people fear that precision
genome editing could kick off
another eugenics movement. Even
attempts to engage in positive
eugenics leave some people feeling
queasy. This is especially because
CRISPR could greatly accelerate
whatever changes are selected. Rather
than rely on the slow process of
selecting who breeds with whom,
new eugenicists could alter an
embryo’s genome in a few hours.
Plus, genome editing could do active
harm. A study of CRISPR in 2018
found deletions of many thousands
of bases and complex rearrangements

3 Indiana passed the first sterilization law in 1907, followed by several other
states.
4 Speaking for an 8-to-1 majority, Justice Oliver Wendell Holmes Jr., a believer
in eugenics himself, argued that a young woman named Carrie Buck should
be sterilized for the good of society. He based this decision in part on
arguments that Buck’s mother and baby were also low-functioning.
5 Many victims didn’t even know they were being sterilized. In some cases,
doctors lied and told them they were having their appendix removed.

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of bases not removed—either Some people also object to

of which might have adverse
medical effects, depending on
which bases were affected.
Many argue that we should subscribe
to the precautionary principle: that
in the face of uncertainty, avoiding
irreversible changes is best.
But it’s also important to avoid
scaremongering. CRISPR-Cas9 has
kick-started a search for even better
techniques. Some may be a more
precise form of the enzyme scissors.
Some may insert desired genes into
DNA without cutting, instead using
bacterial “jumping genes.” Other
techniques may even skip DNA
entirely and instead modify the RNA
that is downstream from DNA.
CRISPR gene editing because
they fear a human monoculture;
that is, they fear that if people are
allowed to choose from a menu
of features regarded as desirable,
then everyone in the future will
end up looking much the same.
But human beings find a huge range
of things appealing and attractive.
So why would we all suddenly
want our children to look alike?
For some of the more complex traits
humans might want to promote,
such as intelligence,6 there are more
practical obstacles. DNA editing
has certainly become easier. But you
still have to know what DNA to
target and what you want to swap
in. And in many cases, we simply
don’t know what DNA to swap in.

Readings
Black, War against the Weak.
Doudna and Sternberg, A Crack in Creation.
Lander, “The Heroes of CRISPR.”
Okrent, The Guarded Gate.

6 A 2018 study estimated that more than 500 genes are linked to intelligence.
And even if we understood the connections between the relevant genes,
we would still be a long way from being able to reprogram intelligence into
someone’s DNA.

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How DNA Redefines
Medicine and Our Future
LECTURE 12

S ome of DNA’s most hidden stories involve disease. Despite

the hype and hope surrounding the Human Genome Project
in 2000, scientists now know that curing diseases takes a lot more
than just sequencing DNA. Only a few genetic disorders, such as
cystic fibrosis and sickle cell anemia, can be traced to a simple, well-
understood mutation in a single gene. Most diseases have far more
complex genetic components. And when we look beyond diseases
caused by a single gene, the biggest genetic disease is probably
cancer.

Return
to TOC

CHIMNEY-SWEEPERS’ CANCER

At a cellular level, cancer is a
problem of the individual versus
the collective—of individual cells
versus the trillions of cells that
collectively make up a human body.
To be healthy, cells need to ingest
nutrients and grow. Most cells also
divide and make more copies of
themselves. Ingestion, growth, and
division are basic biological drives.
However, healthy cells strike a
balance with those drives—some
growth, some division, but not
too much for any one cell. If one
individual cell gets selfish and tries
to grow and divide as fast as it can
and make a billion copies of itself,
that will harm the rest of the body
by diverting nutrients and resources
away from all the other places
they’re needed more. In fact, when
cells do start multiplying out of
control, they can turn into tumors.
We normally don’t think about
cancer as a genetic disease. But
in fact, all known types of cancer

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 Lecture 12
involve flaws in our genes, whether
inherited flaws or flaws in DNA
caused by our environment.
Sometimes people inherit genetic
flaws from their parents, and some
of that inheritance can contribute
to cancer. Probably the best-
known example of inherited genes
contributing to cancer are the
BRCA genes, mutations in which
increase a woman’s risk of breast
cancer.1 BRCA cancers tend to
attack women early in adulthood
in a way that’s aggressive and often
deadly. Also, these cancers often hit
3 or 4 women in a single family.
But while BRCA mutations are
inborn, for other cancers, the DNA
flaws are not inborn, as far as we
know. They’re primarily caused by
something in the environment.
This discovery—that someone’s
environment can cause cancer—
traces back to the chimney sweeps
of 18th-century London. And while
the type of cancer they came down
with was rare, understanding this
one type of cancer reveals a lot
about how cancers work in general.
1 The BRCA genes help repair breaks in the DNA double helix. But when those
genes can’t function properly, cancer happens.
How DNA Redefines Medicine and Our Future
The life of an average chimney
sweep was nasty, brutish, and short
on hygiene. Most sweeps were
paupers, and they usually started
their careers very young, sometimes
at 3 or 4 years old. Chimneys had
become mandatory after the Great
Fire of London in 1666. But most
people couldn’t afford a big, grand
chimney, just a small one. Some
were just 9 inches by 14 inches. And
the only people who could fit inside
such tiny chimneys were children.
Chimney sweeping was awful
work. The sweeps would spend
all day, every day, climbing up
and down chimneys to clean soot
and grime. They often wore no
clothes. Sometimes they even
had to put out fires inside the
chimneys—at 4 years old!
But perhaps the worst part about
being a chimney sweep, on top of all
the hardship and indignity, was that
child sweeps often got cancer later
in life. They’d get tumors on their
scrotums. This is such an extremely
rare form of cancer that doctors used
to call it chimney-sweepers’ cancer.
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 Lecture 12 How DNA Redefines Medicine and Our Future

The scrotal tumors looked like among chimney sweeps. Even

small warts. Sweeps called them
soot warts. And because of the
shame and embarrassment of scrotal
cancer, it took a long time for
doctors to figure out the cause.
Not until the 1770s did a soon-to-
be-famous British doctor named
Percivall Pott finally piece together
what was going on. While treating
the poor in London, Pott noticed
an outbreak of scrotal tumors
worse, the cancer often metastasized
and migrated into the abdomen,
where it attacked other organs. 2
Pott guessed—correctly, we
now know—that something in
chimney soot was causing the
cancer. After all, very few men
aside from chimney sweeps ever
came down with scrotal tumors.

2 The pain got so bad that patients sometimes cut off parts of their own
scrotums with a knife or razor, just for some relief.

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 Lecture 12 How DNA Redefines Medicine and Our Future

Unfortunately, when Pott sounded This discovery about chimney sweeps

the warning about soot and scrotal
cancer in 1775, most treatment
options were crude. One option
involved spreading arsenic paste
over the scrotum, which killed skin
cells and caused the skin with the
warts to slough off. The other main
option was genital surgery, which
in the days before anesthesia was
painful, crude, and unpopular.
As for prevention, doctors told
chimney sweeps that they should
bathe regularly. Or even better,
English chimney sweeps could have
copied their colleagues in continental
Europe, who wore special clothing
to work. People also began inventing
mechanical devices to clean
chimneys in place of young boys.
Unfortunately, like with most
reforms, change was slow to come.
Sweeps ignored the guidelines
about bathing. The use of boys
under 8 was not outlawed until
the late 1700s, and many bosses
ignored the rules, especially in rural
England, until the mid-1800s.
added to a growing awareness among
doctors at the time that cancer could
be tied to someone’s lifestyle and job.
Studies like this are now part of a
field called occupational medicine,
which investigates how your career
and livelihood can affect your health.
And Pott’s work became one of the
foundational studies in the field.
The Pott study was also the first
time that anyone had ever linked
cancer to a specific chemical: soot.
But what exactly in the soot caused
cancer? Why was there a decades-
long gap between when the sweeps
were cleaning chimneys as children
and when they got cancer as adults?
And why didn’t all chimney sweeps
get cancer? In other words, why did
some of them avoid this disease?
The answers to all of these
mysteries can be found in our
DNA—specifically, a stretch of
DNA on human chromosome 17.

Even by the standards of the 1700s, chimney

sweeps were pretty lax about bathing. They were
going to get filthy dirty tomorrow, too, so why
bother bathing today, or wearing clean clothes?

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 Lecture 12
MUTATIONS AND CELL GROWTH
There are 2 types of mutations
that drive cancer.
s The first are mutations that
promote cell growth—and rapid
multiplication. And a mutation to
this promoter DNA is like holding
down the accelerator on your car.
s The second are mutations that
undercut the system of checks
and balances that limits excessive
growth and sets rules for how
often cells are allowed to divide.
Normally, these rules are also
encoded in certain stretches of
DNA. A mutation to this checks-
and-balances DNA is like having
your car’s brakes cut; there’s
no way to slow down. Growth
is no longer curbed, and cells
can multiply out of control.
Because out-of-control growth is so
deadly, evolution has added another
layer to the system of checks and
balances as an extra precaution. We
all have certain watchdog proteins
inside us that scour cells and monitor
3 Cells really do commit suicide, especially when they’re already damaged.
Within the body, no one cell is more important than the collective. And p53
is the protein that makes the call about when to sacrifice an individual cell for
the greater good.
How DNA Redefines Medicine and Our Future
the stretches of growth-curbing
DNA for damage. One protein in
particular is a vital watchdog: p53.
If p53 finds some moderate damage
to the growth-curbing DNA, it
emits a signal that summons certain
handyman proteins, which fix the
damage to eliminate the potential
for out-of-control growth.
Sometimes, however, the p53
protein finds massive amounts of
damage—something that’s not
easy to fix. In this case, p53 doesn’t
summon a handyman. Instead,
it kicks off a series of chemical
reactions that force the cell to kill
itself.3 Because p53 is so vital to
our DNA health, it’s sometimes
called the guardian of the genome.
Overall, the p53 protein works quite
well in monitoring our DNA for
damage and eliminating the potential
for out-of-control cell growth. But
there’s also a huge security flaw.
Because our bodies manufacture
the p53 protein, this means that our
bodies need to store the instructions
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 Lecture 12 How DNA Redefines Medicine and Our Future

At different points in our evolutionary history, human

beings have even benefitted from excessive cell growth.
Most great apes have a certain stretch of DNA that’s
roughly 3200 base pairs long. Chimpanzees have it,
for instance. But at some point after the human and
chimpanzee lines split several million years ago, humans
lost that DNA.
What probably happened was that our cells made a
mistake one day and forgot to copy that stretch of DNA.
The stretch of DNA that didn’t get copied in humans
seems to stop the excessive growth of brain cells, which
can help prevent brain tumors. But when that DNA
disappeared and that constraint was lifted, we humans
ended up with lots more brain cells than before and
much bigger brains overall.

for making p53. And our bodies the benzo[a]pyrene in the soot
store these instructions in the form would get rubbed deep into their
of DNA—on chromosome 17. skins and get inside their bodies.

But what happens if the DNA for Benzo[a]pyrene wouldn’t do much

making p53 suffers a mutation? In
other words, what happens if the
watchdog for DNA damage itself
gets damaged? In that case, the body
won’t produce any p53 protein, and
that vital security check falls apart.
And here’s where we get back to
the chimney sweeps. Soot contains
a chemical called benzo[a]pyrene,
which is also found in tobacco smoke
and many grilled or overcooked
meats. When the sweeps were
scrambling up and down inside the
tiny chimneys and getting dirty,
damage by itself, but unfortunately,
our bodies metabolize it into another,
related chemical called benzo[a]
pyrene diol epoxide (BPDE ). If
BPDE finds its way into your cells,
it goes straight for the cell nucleus,
where DNA is stored. It then
shoulders its way into the double
helix, breaking apart the rungs of the
ladder. A kink forms that damages
the DNA and prevents the cell from
reading it and making whatever
protein it’s supposed to make.

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 Lecture 12
This BPDE damage would be bad
enough on its own, no matter where
it appeared in the genome. But
for some reason, BPDE prefers to
shoulder its way into the gene that
makes p53. As a result, in people
exposed to BPDE—such as the
chimney sweeps—the guardian of
their genome gets knocked out.
But getting p53 knocked out didn’t
instantly lead to cancer. In fact,
you virtually never get cancer
from a single mutation. Some
of the positive mutations need
to be flipped on—the ones that
promote too much cell growth.
4 Not all tumors are malignant. Some are benign, meaning that they won’t
invade nearby tissue or spread to different parts of the body.
How DNA Redefines Medicine and Our Future
And even with the p53 gene
damaged, you still have the rest of
the system of checks and balances to
monitor your cells for out-of-control
growth. There’s redundancy built in,
and the brakes aren’t quite cut yet.
You still have a fighting chance.
But losing p53 is a huge blow.
That’s because a cell loses much of
its ability to fix major mutations.
The loss of p53 also decreases the
odds of a highly damaged cell
committing suicide, which can
shut down potential tumors4 early
on. Half of all human cancers are
known to involve damage to this
one guardian of the genome.
Overall, then, chimney sweeps
got cancer because a chemical
in chimney soot disabled a vital
cancer-fighting gene called p53.
We can also now explain the decades-
long gap between when chimney
sweeps were exposed as boys and
when they came down with cancer as
adults. That’s because even after p53
got knocked out, other mutations
needed time to accumulate.
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 Lecture 12
In fact, this need for the
accumulation of mutations can
also explain why some women
who inherit BRCA mutations
develop breast cancer and some
don’t.5 All women born with
BRCA mutations are vulnerable to
cancer. But other mutations also
need to accumulate, which takes
time. And if other mutations don’t
accumulate, a woman can get
lucky and avoid breast cancer.
The same goes for genes linked to
other types of cancer, too. This is
an area of active research, and the
number of necessary mutations
varies by cancer type. Some cancers
require just a few mutations. Others
seem to require a dozen—some
inborn and some accumulated over
your lifetime. And environmental
factors often drive those mutations.
For example, radon and other
radioactive substances bombard
cells with radiation and increase
the risk of cancer by shredding the
double helix of DNA. Similarly,
chemical substances, such as
those in cigarettes, can also cause
cancer by breaking DNA.
5 Like the p53 gene, BRCA genes help repair DNA breaks. This includes
fixing breaks in the DNA that helps suppress tumors. So when BRCA genes
malfunction, tumor suppression is weakened, and tumors are more likely.
How DNA Redefines Medicine and Our Future
These other substances don’t target
specific DNA the way that BPDE
targets the p53 gene. There’s a wider
range of possible targets. But what’s
the same is that if you’re exposed,
things in your genome will start
breaking, and eventually some
cancer-fighting genes might get
disabled and a tumor could result.
By contrast, genetic diseases with
only a single mutation involved are
likely to be much simpler to treat.
In 2020, for instance, scientists
used CRISPR to delete a single
large genetic mutation in a patient
with an inherited form of blindness.
Drops containing the CRISPR
gene-editing machinery were inserted
just beneath the patient’s retina.
If the treatment works, that’s also
very encouraging news for other
ailments that arise from single
genetic mutations, such as cystic
fibrosis and sickle cell disease.
Scientists would probably package
a CRISPR guide and scissors into a
virus that’s been doctored to make
it harmless. They’d inject the virus
into the person’s bloodstream, and
the virus would penetrate cells and
deliver the guide and scissors.
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 Lecture 12
And in cases where the DNA
mutation needs to be replaced
with a healthy sequence, the virus
would also contain copies of the
PERSONALIZED MEDICINE
For many other diseases, including
cancer, this is one realm where
personalized medicine could make a
huge difference. Rather than give the
same drug to everyone, doctors could
fix your specific DNA. The patch
would be tailored and unique to you.
In fact, we can see signs of such
personalization already. Many
women with breast cancer have
certain genes sequenced to determine
exactly what type they have in
order to tailor their treatment,
since not all types of breast cancer
respond to the same drugs. We’ll
likely see more and more tailoring
of drug use in the future.
Still, things might not be as simple
or rosy as that. The scenario of
viruses delivering CRISPR scissors
assumes that everything will go
perfectly—which it probably
won’t, especially not at first.
How DNA Redefines Medicine and Our Future
healthy DNA to insert. After the
scissors cut the bad DNA out,
the cells’ own machinery would
then patch the healthy DNA in.
Genomes are complicated. Changing
bases in one location can have effects
elsewhere in the DNA. Tweaking
one gene will almost certainly lead
to unintended consequences.
And for diseases that have strong
environmental components or aren’t
wholly genetic, it’s less obvious how
CRISPR-style edits would help.
For example, ailments like diabetes
and heart disease are similar in
that we know there must be genetic
components—family trees tell us
so. But it’s been very difficult to
pin down exactly which genes are
to blame and also to determine
how lifestyle or environmental
factors might contribute to
harmful genetic change.
Also, many processes in the body
involve dozens, or hundreds, of
genes. A mutation in any one of
those genes could cause problems.
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 Lecture 12
And again, things like diet and
exercise and smoking can all
contribute to your susceptibility, too.
So in these cases, with diseases that
are both genetic and environmental,
gene-editing tools like CRISPR
might not be a magic fix.
And, as with any powerful new
technology, patching—or even
trying to improve DNA—can have
serious ethical ramifications.
There’s a big difference between
altering the DNA of an adult and
altering the DNA of an embryo.
With an embryo, the changes have
an entire lifetime to operate. Those
changes can also be passed on to
any descendants. With the adult,
you’re just fixing body cells, not
the sperm and egg cells, so any
changes won’t counteract past life
experiences and won’t get passed
along to the next generation.
Dronsfield, “Percivall Pott, Chimney Sweeps and Cancer.”
Mukherjee, The Emperor of All Maladies.
Shapiro, How to Clone a Mammoth.
How DNA Redefines Medicine and Our Future
In December 2015, a summit
organized by the US National
Academies of Sciences, Engineering,
and Medicine declared that
“modified cells should not be used to
establish a pregnancy.” But by 2017,
the academies had begun to open
the way for exceptions for medical
conditions with no other options.
And while fixing diseases might be
noble, some of CRISPR’s nonmedical
uses have murkier justifications.
What about using gene editing to
produce babies with a certain eye
or hair color or to make babies
taller or significantly smarter?
And even though we’re nowhere near
being able to produce genius babies
with gene editing, we’re much closer
now than we were before CRISPR.
Readings
126
 Multiple-Choice Quiz
1. Why did Gregor Mendel succeed in
discovering the gene while other scientists
(including Charles Darwin) failed?
a. He used pea plants, which had binary traits.

b. He made tens of thousands of observations of plants

grown in his greenhouse.

c. He studied each trait independently.

d. All the monks at Mendel’s abbey were devoted to helping

Mendel understand the gene.

2. Genes and DNA were both discovered in

the German-speaking area of Europe in the
1860s. So why did it take scientists nearly a
century to link them and realize that DNA
was the hereditary material?
a. Chromosomes contain both proteins and DNA.

b. Proteins originally seemed like smaller molecules than

DNA molecules.

c. The protein “alphabet” seemed smaller than the DNA

“alphabet.”

d. Techniques for finding the building blocks of DNA had

made DNA seem like a very small molecule.

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to TOC

127
 Multiple-Choice Quiz

3. What did the Hershey-Chase blender

experiment reveal?
a. That proteins contain phosphorus

b. That DNA contains sulfur

c. That viruses can infect bacteria

d. That DNA is the genetic material

4. What was wrong with Watson and Crick’s

initial DNA model?
a. It was upside down.

b. It was inside out.

c. It used 3 helixes.

d. It didn’t have enough water molecules attached.

5. What was Erwin Chargaff’s contribution to

the discovery of the double helix?
a. He championed Watson and Crick as brilliant and
promising young scientists.

b. He denied Linus Pauling a passport to attend a scientific

meeting.

c. He took crucial x-ray photographs of DNA.

d. He determined that DNA always contains equal amounts

of A and T and of C and G.

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 Multiple-Choice Quiz

6. Why is the discovery of the double helix so

controversial, even today?
a. Because Maurice Wilkins showed James Watson a
photograph that Rosalind Franklin had taken without
Franklin’s permission

b. Because Franklin was denied a Nobel Prize on account of

her sex

c. Because Watson later made nasty comments about

Franklin’s personality and appearance

d. Because Watson and Crick won most of the glory for the
discovery and Franklin was neglected

7. What did Marshall Nirenberg discover?

a. That DNA is a double helix

b. That sickle cell disease is caused by a point mutation

c. That cells read DNA in triplets

d. That specific triplets code for specific amino acids, with

no apparent rhyme or reason to it

8. Which of the following are mutations?

a. Substituting one base for another

b. Inserting bases

c. Deleting bases

d. Accidentally repeating a stretch of bases several times in

a row

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 Multiple-Choice Quiz

9. Which of the following was a step in

sequencing DNA during the US federal
government’s Human Genome Project?
a. Mapping chromosomes

b. Blasting DNA in overlapping fragments

c. Reading the order of the A, C, G, and T bases

d. Figuring out what the DNA does inside living creatures

10. Why was Craig Venter so controversial?

a. His flamboyance and media-hungry personality rubbed
people the wrong way.

b. He worked for a private company that wanted to patent

genes.

c. He recklessly proposed shotgunning DNA.

d. He refused to meet with Francis Collins at first to broker

a truce.

11. What does Niccolò Paganini’s story help

illuminate about genetics?
a. That having flexible hands will instantly make you an
amazing violin player

b. That some people are more naturally gifted than others

c. That both our genes and our environment work together

to make us who we are

d. That nurture is more important than nature

130
 Multiple-Choice Quiz

12. What can studying the FOXP2 gene teach us?

a. That we’ve finally discovered the language gene

b. That language has at least some genetic basis

c. That highly conserved DNA never changes

d. That Neanderthals could speak language just like us

13. What is (are) the difference(s) between RNA

and DNA?
a. RNA is double-stranded; DNA is single-stranded.

b. RNA lacks an oxygen molecule on its sugar backbone

whereas DNA doesn’t.

c. DNA is more versatile at building things than RNA.

d. DNA almost certainly predated RNA historically.

14. What have viruses contributed to the human

genome?
a. Genetic switches that help us digest starch in our mouths

b. Genes that make us attracted to cat urine

c. Genes that help produce a placenta during pregnancy

d. Lots of old, broken-down DNA with no apparent purpose

131
 Multiple-Choice Quiz

15. What are some ways that cells turn DNA on

or off?
a. Spooling it around histones

b. Chopping up the DNA and throwing it away

c. Spitting DNA outside their membranes to be excreted in

the urine

d. Sticking propane-like molecules on DNA.

16. What things can epigenetics help us explain?

a. Why cells with the same DNA behave differently

b. Why parents’ lifestyle and choices can affect a future

child’s health

c. Why identical twins usually aren’t totally identical

d. Why the environment can permanently alter DNA in

future generations

17. What are some features of the Hox genes?

a. They’re highly conserved between plants and animals.

b. They build our bodies directly, much like construction

workers would.

c. They appear in a sequence, with the first Hox genes

building our most important structures, such as the brain,
and later Hox genes building less vital structures.

d. Mutations in the Hox genes often give rise to wild

creatures like chimeras with extra heads on their bodies.

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 Multiple-Choice Quiz

18. Why would it be unlikely for humans and

chimps to interbreed?
a. We’re different species, so it’s impossible.

b. The chimpanzee Y chromosome and chimpanzee sperm

differ markedly from human sperm, making conception
difficult.

c. We have different numbers of chromosomes.

d. We’re much smarter than them, and it’s gross anyway.

19. What are some things we’ve learned from

genetics about the deep history of human
beings?
a. That farming spread in Europe more through people
replacement than the diffusion of technology

b. That humankind’s first-known population boom

happened in Europe, thanks to farming

c. That human beings have a large worldwide population

and high genetic diversity

d. That human beings have been wearing clothes for

millions of years, based on evidence from lice

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 Multiple-Choice Quiz

20. What did scientists learn from sequencing

King Tut’s DNA?
a. That his father had bizarre genetic diseases, due to incest
in pharaonic lines

b. That Tut suffered from malaria

c. That Tut was sterile

d. That DNA testing ancient remains can replace most

archaeological work

21. Who should win the Nobel Prize for CRISPR?

a. Francisco Mojica, who more or less discovered the
CRISPR defense system in bacteria

b. The Wisconsin yogurt scientists who figured out how

CRISPR worked by cutting DNA

c. Emmanuelle Charpentier and Jennifer Doudna, who

proved that CRISPR could edit DNA in test tubes

d. Feng Zhang, who showed that it could work in actual

cells

22. What were some of the flaws of eugenics as a

supposed science?
a. Practitioners often let their biases against poor and
minority people cloud their judgments.

b. Practitioners had a simplistic view of genes and genetics.

c. Practitioners genetically engineered people to become

sterile.

d. Practitioners claimed that intelligence has a basis in

genetics, which is completely false.

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 Multiple-Choice Quiz

23. What are some of the genetic hallmarks of

cancer?
a. Mutations to a single gene like p53 often cause cancer.

b. Cancer is often driven by promotor DNA that promotes

out-of-control cell growth.

c. Cancer is often driven by damage to checks-and-

balances DNA that slows cell division.

d. Cancer always runs in families.

24. How does p53 help protect us against

cancer?
a. It repairs mild to moderate breaks in the DNA double
helix.

b. It produces toxins similar to chemotherapy drugs and

poisons tumors.

c. It helps expel nasty carcinogens like chimney soot from

the body.

d. It forces cells with massive DNA damage to commit

suicide.

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 Quiz Answer Key
1. a, b, and c. Despite working alone, Mendel succeeded in
discovering the gene for 3 reasons: He picked an organism—
the pea plant—that had binary traits; studied each trait
independently (unlike Darwin); and carefully recorded
many observations over multiple plant generations.

2. a and d. Scientists knew that chromosomes were

involved in heredity since they got passed down from
parents to children in sperm and egg, but chromosomes
contain both DNA and proteins. Boiling DNA in acids to
discover a DNA “alphabet” of just 4 bases (A, C, G, and
T) had also inadvertently resulted in fragments of DNA
that were smaller than known protein structures, and
proteins were also gradually revealed to have a much
bigger “alphabet” (20 amino acids) compared to DNA.

3. d. Scientists already knew that viruses can infect

bacteria before Hershey and Chase. The duo simply took
advantage of that fact to set up a clever experiment. By
using DNA with radioactive phosphorus and proteins
with radioactive sulfur, they determined that viruses
inject only DNA as genetic material into bacteria.

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to TOC

136
 Quiz Answer Key

4. b and c. Watson and Crick’s initial model was an inside-

out triple helix, with the DNA bases (A, C, G, and T) on
the outside. We now know that DNA is a double helix and
that the bases are protected on the inside. Also, Watson
and Crick didn’t know enough about DNA to even take
water molecules into account; they had to learn that
fact (among other things) from Rosalind Franklin.

5. d. Chargaff actually thought Watson and Crick were kind of

buffoonish; he called them a “variety act.” But his discovery
that DNA always contains equal amounts of A and T, and
of C and G, proved crucial to the duo. This implied that
DNA comes in pairs—hence a double helix. It also hinted at
the complementary base-pairing that’s so crucial for DNA.
Chargaff had actually told Pauling this information before
Watson and Crick learned about it, but Pauling blew him off.

6. a, c, and d. Watson and Crick would not have made

their discovery without Franklin, but at least initially, they
alone won all the glory. (Historians have since rectified
things.) And Watson’s portrayal of Franklin was so one-
sided that he later apologized for it. Franklin did not
share in Watson, Crick, and Wilkins’s Nobel Prize, but not
because of her sex. She had actually died a few years
before the prize, and only living scientists are eligible
for it. But her death contributed to her initial neglect.

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 Quiz Answer Key

7. d. The double helix nature of DNA was discovered

without Nirenberg. Linus Pauling discovered that sickle
cell disease is caused by a point mutation, while a
team led by Francis Crick proved that cells read DNA
triplets. Nirenberg’s contribution was mapping out
which specific triplets coded for which amino acids.

8. All of the above. Any change to the DNA sequence

is technically a mutation, although some mutations have
little to no effect, while others are deadly. Substituting
one base for another is a point mutation. Inserting or
deleting bases is a frameshift mutation. Repeating
stretches several times in a row leads to the so-called
satellites that are used in DNA fingerprinting.

9. a, b, and c. Unlike Craig Venter’s Celera company, the NIH

invested time and effort into mapping chromosomes—
determining where genes stopped and started on each
chromosome. They then divided each chromosome in
segments and sent the segments to different labs. The labs
would break the segments into overlapping fragments and
then sequence the order of the A, C, G, and T bases. But the
Human Genome Project did not attempt to figure out what
the DNA inside us does. That work is ongoing even now.

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 Quiz Answer Key

10. a and b. Venter was certainly flamboyant and loved

attention, and many scientists viewed his company’s
choice to patent genes as a threat to basic research—
they wanted all data freely available. Venter did
propose shotgunning DNA, but so did the NIH. Venter
simply wanted to shotgun the whole genome right
away and skip the NIH’s slow, cautious chromosome-
mapping steps. And it was actually Collins who
refused to meet with Venter at first, not vice versa.

11. c. Paganini’s genetic disorder gave him amazingly flexible

hands, but that alone didn’t make a legendary violin player.
He also worked very hard and lived in an environment that
nurtured and rewarded his gifts. Contrary to popular belief,
it doesn’t make much sense to talk about nature versus
nurture with DNA and genetics—that’s an outdated belief.
Scientists now speak about nature and nurture: how specific
DNA gets expressed (or doesn’t) in specific environments.

12. b. Mutations in the FOXP2 gene leave people with

huge language deficits, suggesting at least a partial
genetic basis for language. But there’s no such thing
as a single “language gene.” Many genes contribute.
FOXP2 is indeed highly conserved in mammals, but it
does change sometimes. Neanderthals had a humanlike
version of FOXP2, and they were a lot smarter than
scientists traditionally gave them credit for. But we
can’t know for sure whether they could speak.

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 Quiz Answer Key

13. None of the above. DNA is a double-stranded

molecule that lacks an oxygen atom at a key point
on its sugar (hence the name de-oxyribose nucleic
acid). And while DNA simply stores information,
RNA is far more versatile and can do things like
build proteins. That versatility explains why most
scientists think RNA predated DNA in life’s history.

14. a, c, and d. Viruses did give us DNA that helps us break

down starches and that helps us construct a placenta.
Certain retroviruses have also inserted many long stretches
of broken-down DNA that appears to do nothing but take
up space—up to 8% of our DNA overall. But the cat urine
connection involves not a virus but a protozoan, Toxoplasma
gondii. Plus, T. gondii appears to have stolen the dopamine-
producing gene from animals, not vice versa, and its
overall effect on human behavior remains speculative.

15. a. Cells don’t normally chop up DNA and throw it

away, nor do they spit out the DNA. Cells do wrap
it around histones to silence it. And they do tag it
with methane-like molecules (called methyl groups),
but not with anything resembling propane.

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16. a, b, and c. Epigenetic tags and spools silence some DNA

in embryonic and fetal cells. That’s why liver and kidney
and brain cells, despite having the same DNA, all behave
differently. Lifestyle choices and environmental experience
(e.g., smoking or starvation) can also flip genes on and
off with epigenetic tags—and in some cases, alter the
expression of genes in future children. However, there’s no
evidence so far that epigenetic tags (unlike, say, a mutation)
can permanently alter DNA in all future generations.

17. None of the above. Hox genes are highly conserved

within animals; plants lack them. Hox genes do not build our
bodies directly, like construction workers; rather, they act
as managers, instructing other genes on what to do. The
Hox genes do appear in a sequence, but the first ones build
things near the top of the body, with each subsequent gene
building something a bit lower; they’re arrayed spatially, not
in order of importance. And while mutations to these genes
can lead to awful birth defects, extra heads are not common
and most creatures with Hox mutations die in the womb.

18. b and c. Differences to chimp sperm and the different

number of chimp chromosomes, among other reasons,
make “humanzees” unlikely. But while different species
often can’t interbreed, it’s not impossible. Tigers and
lions can have children, for instance. And however
gross it seems, that has nothing to do with reproductive
biology—nor does the potential parents’ intelligence.

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 Quiz Answer Key

19. a. Farming did spread in Europe several thousand years

ago mostly due to human beings moving in and taking
over land, but the world’s first-known population boom
happened much earlier, roughly 40,000 years ago, in
Southeast Asia. The lice evidence revealed that human
beings adopted clothes less than 200,000 years ago,
not millions. And while human beings do have a high
population, we actually have very little genetic diversity
overall, thanks to genetic bottlenecks in our past.

20. b. DNA testing revealed that Tut’s father did not have any
known genetic diseases. But due to incest in the pharaonic
lines, Tut himself did seem to have a compromised
immune system, which probably reduced his ability to
fight off malaria. And while Tut was not sterile—he got
his half sister/wife pregnant at least twice—the incest
probably did harm the viability of those children. DNA
testing can reveal amazing things about an era, but
it’s just one tool of many that archaeologists have.

21. All right, this was a trick question. Any or all of these
answers are viable, since every one of these scientists
made valuable contributions and helped CRISPR become
a vital tool. The real problem, as most scientists see
it, is that only 3 scientists can win a Nobel Prize for a
given discovery—a stricture that’s a relic of an older,
much-less-collaborative era. In fact, many scientists
would prefer to see that limitation dropped, but so
far, the Nobel Prize Committee has refused.

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 Quiz Answer Key

22. a and b. In retrospect, eugenicists were clearly prejudiced

against certain classes of people and pushed for their
sterilization (but they sterilized them with medical
procedures, not genetic engineering). Eugenicists also
constructed bogus family trees that claimed to find genes
for traits like shiftlessness and poor dressmaking skills.
Complex cultural traits and skills might have a genetic
basis, but not always, and they’re rarely traceable to
one gene. As for intelligence, it does have something
of a genetic basis, though scientists debate about how
big the contribution is. Regardless, intelligence is only
moderately correlated with success in life, with factors
like perseverance being equally, if not more, important.

23. b and c. Cancer usually results from a combination of

mutations that both push down the accelerator on out-
of-control growth and cut the brakes on the checks and
balances that stop excessive cell division. But cancer
never results from a single mutation, even to an important
gene like p53. Cancer can run in families, and ultimately
cancer is a genetic disease, but lifestyle and environmental
factors—or just plain bad luck with mutations—can
lead to cancer in people with no family history of it.

24. a and d. Often called the guardian of the genome,

p53 prevents cancer mostly by repairing damaged
DNA and initiating suicide among cells whose massive
DNA damage might lead to tumors one day. It cannot
produce toxins or expel potential carcinogens.

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 Bibliography
This course is substantially based on portions of the book The
Violinist’s Thumb: And Other Lost Tales of Love, War, and Genius,
as Written by Our Genetic Code (Little, Brown and Company,
2012), supplemented by later research and the newer books in
this bibliography. Different from the course, The Violinist’s Thumb
is organized to answer 16 major questions, such as, Why did
life evolve so slowly and then explode in complexity? How did
humans get such grotesquely large brains? and What’s our most
ancient and important DNA? But like this course, the book takes
a sweeping look at the history of DNA, considering everything
from the genes we share with microbes to how DNA can influence
music and language and culture today, taking a narrative, story-
driven approach to illuminating the most important molecule in
biology.

For a cutting-edge and often controversial take, try David Reich’s

Who We Are and How We Got Here: Ancient DNA and the New
Science of the Human Past (Vintage Books, 2019). Reich has been
at the forefront of the field of paleogenetics: the delicate process
of extracting DNA fragments from old specimens and using this
DNA to infer things about deep human history. Paleogenetics has
reinvigorated, if not reinvented, several branches of archaeology.
And while Reich has come under fire at times for his claims, his
deep knowledge of the field makes his views worthwhile.

Though less directly about DNA, one book that repays close
attention is Jim Endersby’s A Guinea Pig’s History of Biology
(Harvard University Press, 2007). Each chapter focuses on a
different model organism for study—from the fruit flies and corn
of early genetics to the zebra fish and genetically engineered
oncomouse of today—and details why exactly that organism led
to each specific breakthrough. It’s also chock-full of lively details
about the scientists involved in each case.

One other book that’s especially recommended is James

Shreeve’s The Genome War: How Craig Venter Tried to Capture
the Code of Life and Save the World (Ballantine books, 2004).

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In writing this book, Shreeve got full access to the inside players
on the Human Genome Project, especially the flamboyant Craig
Venter. It has great breakdowns of all the science involved—
both the genetics and biochemistry—but also the computing
breakthroughs that enabled scientists to sequence more DNA
in a few years than had been sequenced in the previous century
combined. But really it’s the unforgettable characters, the heroes
and villains alike, that drive this book.

Angrist, Misha. Here Is a Human Being. HarperCollins, 2010.

Talking about the human genome can get abstract sometimes. But
Angrist brings it all home, on the level of human beings.

Black, Edwin. War against the Weak: Eugenics and America’s

Campaign to Create a Master Race. Dialog Press, 2012. Eugenics
remains a black eye on American history. Here’s how the science of
so-called racial betterment advanced as far as it did.

Campbell, Anthony K., Jonathan P. Waud, and Stephanie B.

Matthews. “The Molecular Basis of Lactose Intolerance.” Science
Progress 88, no. 3 (2005). Fills in gaps about how a swath of
humankind came to embrace one of the most unlikely mutations in
evolutionary history: the ability to digest the milk of other species.

Carlson, Elof Axel. Mendel’s Legacy. Cold Spring Harbor Laboratory

Press, 2004. Fully detailed dive into the history of genetics.

Chargaff, Erwin. Essays on Nucleic Acids. Franklin Classics, 2018. A

direct peek into the mind and work of one of the key players of early
DNA research, but someone who’s often forgotten from that era.

Comfort, Nathaniel C. “The Real Point Is Control.” Journal of the

History of Biology 32 (1999): 133–162. Barbara McClintock won
a Nobel Prize in 1983. Yet her contributions are still somehow
underrated. Comfort lays out all the scientific details.

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 Bibliography

Darnell, James. RNA: Life’s Indispensable Molecule. Cold Spring

Harbor Laboratory Press, 2011. A full account of how RNA makes
life run—and why it is truly the indispensable molecule for life.

Doudna, Jennifer A., and Samuel H. Sternberg. A Crack in Creation:

Gene Editing and the Unthinkable Power to Control Evolution.
Houghton Mifflin Harcourt, 2017. We wouldn’t have CRISPR
without Doudna. Dive in to a future Nobel Prize winner’s account
of her vital contributions to CRISPR.

Dronsfield, Alan. “Percivall Pott, Chimney Sweeps and Cancer.”

Royal Society of Chemistry, February 28, 2006, https://edu.rsc.org/
feature/percivall-pott-chimney-sweeps-and-cancer/2020205.article.
Percivall Pott’s investigation of chimney-sweepers’ cancer remains a
sad monument today—a pioneering exploration of cancer, yet a sad
monument to the limits of medicine in previous ages.

Endersby, Jim. A Guinea Pig’s History of Biology. Harvard University

Press, 2007. A history of biology in general, but wonderful chapters
on the filthy fruit fly room at Columbia.

Epigenetics (series). Nature Reviews Genetics, January 1, 2018. https://

www.nature.com/collections/jgywtpkhrv. If you’re into the nitty-
gritty details, here’s how epigenetics works, top to bottom.

Hager, Thomas. Force of Nature: The Life of Linus Pauling. Simon

& Schuster, 1995. The definitive biography of perhaps the greatest
scientist that no one knows about—a double Nobel Prize winner and
brilliant thinker.

Hawass, Zahi. “King Tut’s Family Secrets.” National Geographic,

September 2010, https://www.nationalgeographic.com/
magazine/2010/09/tut-dna/. The godfather of Egyptology explains
what DNA evidence can reveal about perhaps the most famous
pharaoh in history, King Tut.

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 Bibliography

Henig, Robin Marantz. The Monk in the Garden. Houghton Mifflin

Harcourt, 2001. A definitive biography of one of the most unlikely
scientists in history. Both entertaining and insightful.

Lagerkvist, Ulf. DNA Pioneers and Their Legacy. Yale University

Press, 1999. Details the story of many lesser-known, but still vital,
figures in the history of DNA research.

Lander, Eric S. “The Heroes of CRISPR.” Cell 164, no. 1–2 (January
14, 2016): 18–28. https://www.sciencedirect.com/science/article/pii/
S0092867415017055. An insider on the Human Genome Project lays
out the main players in arguably the most fundamental advance in
genetics since the discovery of the double helix.

Maddox, Brenda. Rosalind Franklin: The Dark Lady of DNA.

HarperCollins, 2003. Few figures in science history have sparked
as much scientific controversy as Rosalind Franklin has. This book
looks beyond the icon and brings the complex woman to life.

McAuliffe, Kathleen. “How Your Cat Is Making You Crazy.” The

Atlantic, March 2012, https://www.theatlantic.com/magazine/
archive/2012/03/how-your-cat-is-making-you-crazy/308873/. OK, it
sounds crazy—how could a little microbe so deeply affect the human
mind? But Toxoplasma gondii is a unique critter, and even if you
don’t buy it all, this account will make you think twice.

Monticello. “Thomas Jefferson and Sally Hemings: A Brief

Account.” https://www.monticello.org/thomas-jefferson/jefferson-
slavery/thomas-jefferson-and-sally-hemings-a-brief-account/. The
Jefferson estate at Monticello long resisted the idea that a beloved
president almost certainly fathered children with his slave. But it
finally accepted this notion—and laid out all the details of Thomas
Jefferson and Sally Hemings’s long affair.

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 Bibliography

Moore, David S. The Developing Genome: An Introduction to

Behavioral Epigenetics. Oxford University Press, 2017. How will
epigenetics affect you as an individual? Here’s a great guide to sort
all that out.

Mukherjee, Siddhartha. The Emperor of All Maladies: A Biography

of Cancer. Scribner, 2011. The definitive biography of cancer. If you
want to understand human genetic diseases, read this book.

Nudel, Ron, and Dianne F. Newbury. “FOXP2.” Wiley

Interdisciplinary Reviews: Cognitive Science 4, no. 5 (2013): 547–560.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992897/. The
FOXP2 gene has entered the pantheon as one of the vital genes that
might have made us human. It’s not the only language gene, but it
did appear to play an important role in quickening our language
abilities.

Okrent, Daniel. The Guarded Gate: Bigotry, Eugenics and the Law
That Kept Two Generations of Jews, Italians, and Other European
Immigrants Out of America. Simon and Schuster, 2019. Okrent is
a gifted writer on all sorts of vitally American topics. He brings a
keen eye and his sharp critical pen to this account of how eugenics
reshaped American immigration.

Pääbo, Svante. Neanderthal Man: In Search of Lost Genomes. Basic

Books, 2015. Pääbo pioneered the study of ancient genomes. He’ll
almost certainly win a Nobel Prize someday, and here’s his personal
account of navigating the genomes of our lost hominin cousins.

Portugal, Franklin H. The Least Likely Man: Marshall Nirenberg and

the Discovery of the Genetic Code. MIT Press, 2016. The title says it
all. No one would have guessed that Marshall Nirenberg would go
down in history. But every cell in your body obeys the DNA/RNA/
protein rules he discovered.

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Reich, David. Who We Are and How We Got Here: Ancient DNA and
the New Science of the Human Past. Vintage Books, 2019. A sweeping
overview of what we can discern about human beings based on all
the little details in our genomes.

Reilly, Philip R. Abraham Lincoln’s DNA and Other Adventures in

Genetics. Cold Spring Harbor Laboratory Press, 2000. Reilly sat on
the board that ultimately decided not to test Lincoln’s DNA. His
essay on the behind-the-scenes discussions is illuminating. And the
rest of the book reflects his deep place in the early days of genetic
testing.

Shapiro, Beth. How to Clone a Mammoth: The Science of De-

Extinction. Princeton University Press, 2016. What will genome
research bring us in the future? How will we handle the power
we’ve given ourselves? Shapiro lays out the consequences of what we
can—and should or should not—do with our newfound genome
knowledge.

Shreeve, James. The Genome War: How Craig Venter Tried to

Capture the Code of Life and Save the World. Ballantine books, 2004.
A funny, embarrassing, riveting account of the legendary battle
between Celera and the government’s Human Genome Project.

Sugden, John. Paganini: The Illustrated Lives of the Composers.

Omnibus Press, 1986. As long as people play violins, we’ll revere
Niccolò Paganini. Here’s his strange, painful life, laid out in full.

Sulston, John, and Georgina Ferry. The Common Thread. Joseph

Henry Press, 2002. Sulston directed the British branch of the
Human Genome Project and was something of a wild man—
hacking into DNA decoders and fighting back Craig Venter at
every turn.

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Sykes, Bryan. Seven Daughters of Eve: The Science That Reveals Our
Genetic Ancestry. W. W. Norton, 2002. A classic text on the deep
history of human beings and how we can all trace our ancestors back
to a few unknown but pivotal women in history.

Venter, Craig. A Life Decoded. Penguin Books, 2007. Venter’s

biography. He uses his own genome to try to illuminate different
aspects of his personality and life. A book as unconventional (and
uneven!) as Venter himself.

Villarreal, Luis. “Can Viruses Make Us Human?” Proceeding of

the American Philosophical Society 148, no. 3 (2004). http://www.
somosbacteriasyvirus.com/canviruses.pdf. It’s hard to think that
viruses are as much a part of our genetic heritage as anything else is.
But Villarreal’s account proves just how important they have been.

Wade, Nicholas. Before the Dawn: Recovering the Lost History of Our
Ancestors. Penguin, 2007. Wade has plowed into some trouble for
controversial views, but this book blends archaeology and genetics
insights in a most inspiring way.

Wambaugh, Joseph. The Blooding: The Dramatic True Story of

the First Murder Case Solved by Genetic “Fingerprinting.” Random
House, 1995. A riveting account of one of the first practical uses of
DNA technology: the inside story of how British scientists tracked
down a killer using a revolutionary new technology called DNA
fingerprinting.

Watson, James. Genes, Girls, and Gamow: After the Double Helix.
Cold Spring Harbor Laboratory Press, 2002. Watson’s follow-up to
his first, seminal book (The Double Helix: A Personal Account of the
Discovery of the Structure of DNA). A look at the wild, confusing,
fruitful era shortly after the discovery of the DNA double helix.

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———. The Annotated and Illustrated Double Helix. Simon &

Schuster, 2012. One of the most controversial scientific books ever
written. Watson later apologized for parts of it, but it remains one of
the canonical works about the discovery of DNA.

Wilkins, Maurice. Maurice Wilkins: The Third Man of the Double

Helix—An Autobiography. Oxford University Press, 2003. Watson
and Crick are legends, but few people remember Wilkins, who
shared the Nobel stage with them. A book that gives a complex but
important scientist his due.

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