She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (45 page)

This tree, Weismann was quick to caution, was just
a “theoretical illustration.” He drew it only to convey his ideas about the crucial division between germ cells and somatic cells. But the picture inspired other biologists to look at the development of real embryos, and
draw trees of their own.

One of the first biologists to draw these cellular genealogies was a young American graduate student named
Edwin Grant Conklin. Conklin started his own artwork in the summer of 1890, when he traveled to the seaside village of Woods Hole, Massachusetts, to find something to study for his PhD. He ended up scraping slipper limpets off crab shells and harvesting their eggs. The limpet eggs were so big and transparent that Conklin could
observe them clearly under a microscope. He drew the portrait of a limpet egg, down to the nucleus and other structures within. He drew another when the egg divided in two. Each time the embryo divided, he made a new portrait in pencil, identifying each new cell according to its ancestor. His portraits changed from tiny batches of cells into large spheres, and then into more complex shapes.

“I followed individual cells through the development, followed them until many people laughed about it,” Conklin later recalled. “
They called it cellular bookkeeping.”

The hours that Conklin spent staring through his microscope made him an object of mockery in the lab. One day a fellow graduate student named Ross Harrison “
came behind me while I was anxiously studying some of the cleavage forms under the microscope and hung a crab on my left ear,” Conklin said. “That crab pierced the ear lobe and could not be taken off except by some of the other sympathetic people in the laboratory.”

Harrison sprinted away, and Conklin bolted in chase. “I ran for half a mile or more without catching him,” Conklin said.

Despite these distractions, Conklin managed to draw a prodigious number of images. When he got back to Baltimore, he numbered each cell so that readers could follow their multiplication from stage to stage. Conklin wrote a paper about the limpet's transformation, which he gave to his advisor, William Keith Brooks, to read. A few days later, Brooks brought the manuscript back to Conklin.

“Well, Conklin,” he said loudly, so that the other students in the lab could hear, “this University has sometimes given the doctor's degree for counting words; I think maybe it might give one degree for counting cells.”

The other students roared with laughter. “I certainly felt pretty small,” Conklin said.

The next summer, Conklin went back to Woods Hole and collected more limpets. One day, a professor named Edmund Beecher Wilson walked up to his lab table and said he had been doing a similar study on the larvae of leeches. Conklin and Wilson sat down together and compared their drawings. They were shocked to see how similar their embyros were, even
from their earliest stages of development. Wilson became Conklin's mentor, introducing him to other scientists and helping him publish his research in scientific journals. Conklin went on to draw painstakingly detailed embryos of other species, tracing the lineages of cells further than anyone had managed before.

As Conklin uncovered the lineages, he found a new way to tackle the centuries-old debate about how a single egg developed into a complex body. He could trace the division of cells as they produced tissues and organs. He watched generations of cells gradually part ways, committing to an existence as muscle or nerves, or some other tissue. In some cases, the fate of cell lineages was fixed at the start; in other cases, cells seemed to hold on to the capacity to take on a range of different final forms.

Conklin turned cell lineages into
an essential part of embryology. Later generations of scientists examined these embryonic pedigrees as they sought to understand
how
the cells reached their final identities, and how their identities became locked for life.

Although genetics was booming at the time, embryologists didn't think it could help them solve this mystery. They thought geneticists, who had yet even to show what genes were made of, were supremely arrogant to think they would be the ones to solve Aristotle's mysteries. “
The ‘Wanderlust' of geneticists is beginning to urge them in our direction,” Conklin's crab-wielding nemesis, Ross Harrison, warned an audience of embryologists in 1937. This “threatened invasion,” as Harrison called it, would lead only to nonsense. There was no way that simplistic explanations based on genes and their mutations could make sense of the majestic unfolding of development. Geneticists could busy themselves with finding mutations that changed the color of a fly's eye, Harrison said. He and his fellow embryologists were after bigger game: how the eye itself came to be.

Harrison was certainly right that, in 1937, geneticists didn't know enough to help explain embryos. But even as Harrison rallied his troops to man the university ramparts, a British embryologist was already thinking about how he could let the enemy in.
Conrad Waddington carried out experiments at the University of Cambridge, moving bits of tissue around
chick embryos to see if he could disturb their development. But he also had a philosopher's detachment. He could rise above the fine details of ectoderm and endoderm, and think in the abstract about how genes might guide development.

Each cell in an embryo, Waddington hypothesized, was a little factory.
It used its many genes to produce many proteins, some of which could spread to other cells. Different cells produced different proteins, creating complicated chemical blends that were different from one place to another in the embryo. The particular blend a cell was exposed to could cause it to take on a new identity as it developed.

Waddington shared Weismann's fondness for pictures. To illustrate the development of embryos, he drew a hillside shot through with forking valleys. He imagined a lineage of cells as a ball rolling down this landscape. The slope of the surface could guide it down one valley or another—committing to become a particular type of cell. Waddington had an artistic friend illustrate this landscape with two pictures, one looking down from above, and the other looking up from below. The underside of the landscape was anchored with guy wires, pulling down to create the valleys that drove cells to their final states.

Waddington liked to call this strange terrain the epigenetic landscape, borrowing the old language of Harvey and Aristotle. Waddington used the term, as he explained in a 1956 textbook, “for the theory that development is brought about through a series of cause interactions between the various parts.”

Waddington freely admitted that his epigenetic landscape was just an idea, one that was valuable mainly as a way to guide his thoughts. “Although the epigenetic landscape only provides
a rough and ready picture of the developing embryo, and cannot be interpreted rigorously,” he wrote, “it has certain merits for those who, like myself, find it comforting to have some mental picture, however vague, for what they are trying to think about.”

The pictures that Weismann, Conklin, and Waddington drew were
like visions from the future. They captured some of the overall truth of how we
develop, but they lacked the specifics. The three biologists made mistakes, albeit forgivable ones. Weismann, it turned out, was wrong to say that hereditary tendencies are divvied up between daughter cells. The DNA that encodes someone's genes is replicated in full each time a cell divides. What makes a sweat gland cell different from a taste bud cell is the combination of genes that are active in each of them, as well as the combination that is silent. And that difference can be passed down from mother cells to daughter cells.

It's an inheritance, but not of some particular mutation. It's the inheritance of a state, a configuration of life's network. And the first glimpse of how that network is configured came to a woman whose day job was to prepare for the apocalypse.

In the 1950s, hydrogen bombs were lighting up the world in test after test. It seemed as if nuclear war might not be far away. Movies distilled the anxiety and projected it onto theater screens. In
Godzilla
, a radiation-induced monster tramples Tokyo. The giant ants of
Them
slaughter people with formic acid.
The Day the Earth Caught Fire
imagines nuclear bombs pushing Earth out of its orbit around the sun.

Nuclear nightmares featured not just incineration but also a gruesome transformation of heredity. The people who did not evaporate in a blast would be pierced with radiation. It could damage cells deep in their bodies, causing radiation sickness and cancer. If an alpha particle crashed into an egg or sperm cell, it could alter the DNA inside, thereby extending nuclear war's ravages to future generations. The survivors might pass down the mutations to their descendants, along with the diseases they caused.

The British government decided it needed a lab to study this sort of damage, and it needed scientists like
Mary Lyon to work there. Lyon, a quiet, focused thirty-year-old geneticist, was hired in 1955 to work at the Radiobiological Research Unit of the Medical Research Council.

It was still rare for a woman to hold such a job. When Lyon had gone to the University of Cambridge to read zoology, she was allowed to receive only
a “titular” degree, even though she worked as hard as her male colleagues. Nevertheless, she made such a strong impression on her advisors that they helped her get a spot as a graduate student with Ronald Fisher, the geneticist who had combined Mendel and Galton's concepts of heredity into a new form in the 1920s.

Fisher turned out to be an irascible screamer who regularly threw graduate students out of his lab. But Lyon earned his respect, and he put her in charge of some of the mutant mice he studied.
She carried out elegant experiments to see how one mutation could give rise to different traits, such as a splotchy coat and a loss of balance. But she decided Fisher's rage-choked lab was too toxic for her to grow as a scientist. She was a fan of Conrad Waddington's new ideas about epigenetics, and so she went to the University of Edinburgh, where he had become the chairman of the biology department, to finish her PhD.

Lyon thrived scientifically in Edinburgh, staying on after finishing her dissertation to continue her research. Waddington provided his scientists with the latest technology, and they discussed the newest ideas about heredity and development. Though pensive and humble, Lyon nevertheless gained a reputation in Edinburgh for seeing right through scientific problems. She would politely challenge her male elders if she found their reasoning flawed. The friends Lyon made in Edinburgh grew accustomed to her long silences as she composed what she wanted to say next. Although she thrived as a scientist, her parents still couldn't understand why a woman would waste her time fussing over some odd mice.

“
They wanted me to get married at one point,” she later recalled in an interview.

“What did you think about that idea?” her interviewer asked.

“I didn't like it.”

The differences between the sexes came to dominate Lyon's own work. In Edinburgh, Lyon got the chance to study the first mice ever isolated with mutations on the X chromosome. She used them to explore how traits on the X and Y sex chromosomes were passed down. Lyon took her mice with her when the British government transferred her and other Edinburgh
biologists to the Radiobiological Research Unit near Oxford. There they were expected to uncover the genetic risks of nuclear warfare. After five years of intellectual ferment in Edinburgh, Lyon found the government bureaucracy in the unit stultifying. As much as she could, she “
always tried to stick to the mouse work,” she said.

One strain of mice she studied, called mottled, had a particularly intriguing form of heredity. The female mottled mice developed an assortment of colored patches randomly scattered across their coat. The male mice met one of two very different fates. Either they ended up with a uniform coat or they died before birth.

These clues suggested to Lyon that a deadly mutation lurked on the X chromosomes of mottled mice. Males died if they inherited it, because they carried only a single X. Females, with two X's, had better odds of surviving. If one of their X chromosomes lacked the mutation, they would develop normally.

Lyon suspected that the mutation was also responsible for the coat patterns of mottled mice. One normal copy of the X chromosome in males produced hairs with identical colors. Somehow, carrying two copies of X chromosomes gave females a mottled coat. Not only that, but the mottling developed into different patterns from one female mouse to the next.

Poring through earlier studies on the X chromosome, Lyon searched for evidence that could account for all these strange outcomes. She was led from the narrow question of mottled mice to a much deeper question about X and Y chromosomes.

With two copies of an X chromosome, a female ought to make twice as many proteins from their genes than a male. All those extra proteins ought to throw a female's biology into deadly chaos. The big mystery about X chromosomes, Lyon realized, was how females could be healthy with two of them, and males with just one.

Lyon realized that Canadian researchers had discovered a possible answer in the 1940s when they examined the cells of female cats. In every cell, they saw, one of the two X chromosomes was packed down into a dark clump. The other X chromosome remained open, like all the other
chromosomes. Perhaps, Lyon thought, females shut down one X in each cell, silencing its genes. As a result, they made only one chromosome's worth of X proteins, just like males.

There was just one problem with this explanation. It couldn't account for Lyon's mottled mice.

If the female mottled mice shut down one of their X chromosomes, they ought to end up with the two fates that the males met. Shutting down their normal X chromosome ought to cause them to die before birth. Shutting down their mutant X chromosome instead ought to give them a uniform coat of fur. Somehow, the females avoided both fates.