She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (47 page)

When cells divide, one of the most obvious things their daughter cells can inherit from them is their shape. In an embryo's nervous system, many neurons become long and spindly, with two slender branches extending out from a tiny cell body containing DNA. And when they divide, their daughter cells end up long and spindly as well.

These cells are the sensory neurons, which let our bodies feel. Buried in the skin of your thumb, for example, are feathery nerve endings connected to a sensory neuron that reaches from the thumb to the base of the hand, bends around the elbow and heads up to the shoulder before finally reaching a swelling of neurons around the spinal cord. The pain of scraping your thumb on a thorn is relayed along the two branches to the spinal cord, where it gets passed on to other neurons headed for the brain.

Leila Boubakar, a neuroscientist at the University of Lyon, and her colleagues wondered how it was that sensory neurons inherited their two-branch shape from their two-branched precursors, known as neural crest cells. Carefully observing neural crest cells divide under a microscope, they saw something remarkable happen: The neural crest cells got rid of their two branches before dividing, leaving behind only their blob-shaped cell bodies. But as soon as a neural crest cell divided, its daughter cells sprouted two new branches from the same sides as the ones that had sprouted from their mother cell.

To figure out how this was happening, the scientists added glowing tags to some of the proteins inside the neural crest cells. They discovered that the cells laid down what Boubakar and her colleagues call a “molecular memory” of their two-branch shape. It is a memory that can be inherited by their daughter cells. Before the neural crest cells start to divide, they move special proteins called septins to the base of their two branches. After the branches die back, the clusters of septins remain, marking where the branches had been.

The neural crest cell then divides into two sensory neurons, each of which inherits a septin mark. At that mark, each of the new neurons sprouts a new branch. Boubakar's experiments suggest that the septins then travel
to the opposite side of the new sensory neuron. There the septins form a new cluster, which marks the spot where the second branch on the new neuron will grow.

Boubakar's research shows how heredity can incorporate more than genes. When cells divide, everything inside them is a living legacy to their descendants. It is unquestionably true that sensory neurons inherit genes from their mother cells. But that genetic inheritance alone does not explain why like engenders like inside our nervous system. Sensory neurons do not inherit their shape from their mother cells simply by inheriting genes for septins and other molecules. The mother cell's proteins carefully orchestrate the renewal of its branches in its offspring.

By the time my daughters were born, they had developed sensory neurons throughout their bodies. They had also developed virtually all their other cell types: red skeletal muscle cells and white skeletal muscle cells; white fat cells and brown fat cells; liver lipocytes and Paneth cells of the intestines. But when they were born, my daughters were far from finished growing.

Throughout their childhood, many of their cell types continued to multiply. Most by now were deep in Waddington's canyons, their inner heredity now relentlessly rigid. I'm grateful for this tight epigenetic control. It kept their eyes from turning to kidneys, their fingernails from growing teeth. As I worked on this book, Charlotte and Veronica reached their mature height, determined in part by hundreds or thousands of genetic variants they inherited from Grace and me, combined with the influence of a twenty-first-century American environment rich in sunlight and pizza. As they approached their final height, all their cell lineages slowed down in a harmonious braking. Their full-size lungs now fit snugly in their properly sized rib cages. Their earlobes do not graze the floor.

But some of their cells went on giving rise to new types, and this creative flame will flicker on throughout their lives. Some parts of the human body perpetually renew as old cells die and new ones develop to take their
place. In people in their thirties, the average fat cell is only eight years old. Red blood cells
survive for only four months. Skin cells last just a month; taste buds, ten days; stomach lining, as little as two.

Scattered through the human body are
hidden refuges of stem cells that can replenish these short-lived cells. In our long bones, our pelvis, and our sternum are cavities of bone marrow. The stem cells they harbor can divide into two kinds of cells, called myeloid cells and lymphoid cells. The myeloid cells have their own lineage, which branches into red blood cells as well as platelets and bacteria-gobbling immune cells called macrophages. The lymphoid cells have a different tree: They develop into T cells, which can command infected cells to commit suicide, and B cells, which make antibodies that can precisely attack certain pathogens. The stem cells lurking in the stomach lining rebuild it as old cells slough off. The same renewal happens in our skin.

Some stem cells generate new tissue only in an emergency.
So-called satellite cells, nestled in our muscles, will produce new muscle cells to help repair damage. If you cut your hand, stem cells lurking in hair follicles will make new skin cells that crawl to the wound and heal it over.

Stem cells need to hide in their refuges to cling to their special nature. There they can swim in a pool of chemical signals, ensuring that the right network of genes stays turned on. In these refuges, the stem cells perform the same magic trick over and over again. They divide in two: One daughter cell goes on dividing to become mature types of cells, while the other is yet another stem cell. The cells manage this feat by
manipulating the way their daughter cells inherit their molecules. Stem cells don't simply split up their molecules fifty-fifty. They move certain proteins and RNA molecules to one side but not the other. When they split in two, one of the new cells inherits a combination of molecules that allow it to stay a stem cell. The other cell flips its network to a new wiring and takes on its new identity.

One of the most important places where new cells develop is also
one of the last places where they were discovered: in the brain. In fact, generations of neuroscientists were convinced that the neurons in the brain stopped dividing altogether shortly after birth. In order for us to learn, the neurons
in our brains only grew new connections and pruned their old ones. In 1928, the Nobel Prize–winning neuroscientist Santiago Ramon y Cajal put the dogma of the twentieth century into a simple declaration: “
Everything may die; nothing may be regenerated.”

It wasn't until the late 1900s that this dogma started to crack. Some of the most elegant evidence of adult neurogenesis was made possible by the fact that everyone on Earth is partly made up of nuclear fallout.

Aboveground nuclear testing started in the mid-1950s, and was carried on until the 1963 Partial Test Ban Treaty. Each explosion sent neutrons racing through the atmosphere, sometimes crashing into nitrogen atoms and converting them into carbon-14. By 1963, carbon-14 had reached twice its level before the testing had begun. As plants absorbed carbon dioxide from the air, they incorporated extra carbon-14 into their leaves and stems and roots. The animals that ate those plants also accumulated high levels of the isotope. Plants absorbed it into their leaves and stems, and animals that ate the plants absorbed it into all their own tissues. Those animals included people alive at the time. They used the carbon-14 to build many new molecules. The RNA molecules and proteins sooner or later got torn apart and recycled. But the DNA remained unchanged. Ever since 1963, the carbon-14 level in the atmosphere has been dropping toward the level it was before the Atomic Era.

In the early 2000s, Jonas Frisén, a cell biologist at the Karolinska Institute in Stockholm, realized he could use carbon-14 levels in brain cells to estimate their age to within a couple of years. He and his colleagues began studying people who donated their bodies to science. They clipped bits of tissue from different regions of the brain and measured the levels of carbon-14 in them. By checking the year of their birth, the scientists could determine how old they were when the neurons had formed.

At first, the results confirmed the dogma. Frisén and his colleagues looked at the cerebral cortex, the thick outer layers of the brain that carry out much of our higher-level thinking. The neurons there dated all the way back to people's birth. But then the scientists looked to a small region tucked deep in the brain called the hippocampus. They were curious about it
because scientists have long known that the hippocampus is vital for learning and for laying down long-term memories.

Because the hippocampus was so small, their initial tests weren't sensitive enough to measure carbon-14 levels accurately. It wasn't until 2013 that Frisén and his colleagues were finally able to take the measurements. Some of the neurons in the hippocampus turned out to be young. In fact, the scientists calculated, seven hundred new neurons were added to each hippocampus every day.

Adding seven hundred neurons to the eighty billion in an adult human brain is like dumping a tablespoon of water into an Olympic-size swimming pool. Yet some scientists suspect
this tiny infusion may make an important difference to how our brains work. When mice are prevented from growing new neurons in their hippocampus, they take longer to learn how to make their way through a maze or how to press on a screen to get a reward of food. New neurons may make it possible to erase old, faulty memories and form new ones. In other words, Weismann's genealogy of our inner heredity may extend from the moment of conception to the last lesson we've learned.

I
N MEDIEVAL
E
UROPE
, travelers making their way through forests would sometimes encounter a terrifying tree. A single branch sprouting from the trunk looked as if it belonged to a different plant altogether. It formed a dense bundle of twigs, the sort that people might fashion into a broom to sweep their floors. The Germans called it
Hexenbesen.
The word was later
translated into English as witches'-broom. Witches supposedly cast spells on trees to grow brooms, which they used to fly across the night sky. They could summon forth other branches as nests for sleeping. Elves and hobgoblins used the nests, too, as did the evil spirits who traveled about to sit on people's chests and give them nightmares.

In the nineteenth century these terrors faded, and plant breeders began using these rare, strange growths to create entirely new cultivars. Cuttings from monstrous branches could take root and grow into trees of their own, producing seeds that would grow into a new generation of plants with the same monstrous shape. Some of today's most popular landscaping plants got their start as witches'-broom.

Dwarf Alberta spruce, a tree that grows only ten feet high, is a common sight in suburban yards. But it originated from white spruces that grow as tall as ten-story buildings in northern Canada. In 1904,
a pair of Boston horticulturalists visiting Lake Laggan noticed that a white spruce there had sprouted a witches'-broom. Seeds had fallen from the freakish branch to the ground, where they had grown into squat little shrubs. The horticulturalists
took some of the shrubs home with them and dubbed them
Picea glauca
“Conica,” or dwarf Alberta spruce. The only trouble these shrubs cause their owners is that they sometimes reclaim their ancestral glory. Sometimes a branch will jut out from a dwarf Alberta spruce and race upward, taking on the titanic shape of its giant predecessors back at Lake Laggan.

Plant breeders didn't have to go into the north woods to find witches'-broom, however. They could look in their own orchards and gardens. When they spotted an odd branch,
they dubbed it a bud sport. In the early 1900s, a Florida farmer found a notable bud sport while inspecting his grove of Walters grapefruit trees. Tree after tree bore white fruit, except one. On that tree, the farmer spotted a branch weighed down with pink fruits. From that single bud sport,
all pink grapefruits descend.

To make sense of witches'-broom or bud sports, scientists had to study how plants grow. As plant cells divide, the daughter cells inherited the same hereditary factors that were in the mother cell. In some cases, a cell would change, and its descendants would inherit its new quirk. Those cells might produce a new branch, complete with leaves, fruit, and seeds. But bud sports could alter plants in other ways, too. As a red sunflower bloomed, half of it might grow yellow leaves. Sometimes an ear of corn developed a patch of dark kernels. A pale red apple might develop a wedge-like stripe of green running down one side, right next to a stripe of umber.

Charles Darwin would pore through issues of the
Gardeners' Chronicle
to find new reports of bud sports. He noted branches on cherry trees that bore their fruit two weeks after the rest of the branches. His curiosity was piqued by the story of a French rose that mostly produced flesh-colored flowers but also grew a branch covered by deep-pink blossoms.

As he struggled to make sense of heredity, Darwin believed studying these sports could help. They seemed to contain the same mysterious power of generation as seeds or eggs. Sports were not mere freaks, deformed by a cold snap or a disease. Something triggered a drastic change inside them, Darwin declared, like “
the spark which ignites a mass of combustible matter.”

Half a century later, it became clear that this combustible matter lay in the chromosomes of the plants. When plant cells divided, they usually
produced identical copies of their genetic material. But on rare occasion, one of the new cells would mutate, and its own descendants within the plant would inherit that mutation.

“It appears that a change in the hereditary constitution of the cells has occurred in the soma or body,” the biologist
T. D. A. Cockrell wrote in 1917, “without having any connection with the process of sexual reproduction.” Cockrell called this change a somatic mutation. He coined the term to distinguish it from a germ line mutation—a mutation that germ cells could pass down to the next generation.

When Cockrell investigated somatic mutations, scientists knew so little about genes that it was hard to say exactly how they occurred. One possibility was that newly formed pairs of chromosomes got entangled and swapped parts. The strange stripes on apples—known as twin spotting—might occur because a cell had two copies of a gene for color. One copy might be a light variant, the other dark. When the cell divided, it accidentally bequeathed two dark variants to one daughter cell, and two light ones to the other. When those cells multiplied, their daughters would inherit those new combinations. And since they grew next to each other, the result would be dark and light stripes.

As geneticists studied these peculiar plants more carefully, they gave them a new name: mosaics. The name hearkened back to the ancient artworks composed of thousands of tiny colored tiles. Nature created its mosaics from cells instead of tiles, in a rainbow of different genetic profiles.

Plants first brought mosaicism to our attention, but in the early 1900s, scientists started to appreciate that
animals can be mosaics, too. Their attention might be caught by a parakeet with a splash of dark plumage across one wing, a rabbit with a peculiar white patch of fur.

But modern science was slow to recognize that we humans are mosaics as well. It's not as if human mosaics were invisible. Some were downright impossible to miss. Human mosaics might be born with port-wine stains on their face. Others looked as if a charcoal artist had applied stripes and checkerboards to their skin (a condition that came to be known as the lines of Blaschko, named for the
German dermatologist Alfred Blaschko, who first described the condition in 1901). One human mosaic
even became a celebrity in Victorian England. He called himself the Elephant Man.

When Joseph Merrick was born in 1862, he seemed heathy and normal. But within a few years, his forehead began to swell forward like a ship's prow. His feet became nightmarishly large, and his skin grew rough, lumpy, and gray like an elephant's. As his appearance altered, his parents became convinced that his deformities were the result of his mother's being knocked over by an elephant at a fair while she was pregnant with him.

Merrick went to school until he was thirteen and then found work rolling cigars in a factory. His deformities continued to worsen, his head broadening out until it was thirty-six inches in circumference. His right arm expanded into a paddle-like shape, forcing him to quit his job. He tried to work as a peddler, but the authorities soon revoked his license because they deemed him too grotesque.

Merrick decided to follow the examples of Charles Byrne, the Irish Giant. He turned himself into an attraction, traveling around England as the Elephant Man. His manager, Tom Norman, would warm up the crowds by warning them about what they were about to see: “
Brace yourselves up to witness one who is probably the most remarkable human being ever to draw the breath of life.”

In London, Merrick exhibited himself in a shop across the street from the Royal London Hospital. Medical students came to gawk, and eventually a doctor at the hospital, Frederick Treves, followed them over. He was startled by “
the most disgusting specimen of humanity I had ever seen,” as he later recalled. He persuaded Merrick to visit the hospital and be examined by the hospital doctors. But after a few inspections, Merrick decided he felt like “
an animal in a cattle market,” and stopped going.

Merrick's business tapered off, prompting him and Norman to try their luck on the continent. Things didn't go much better there, and soon Norman abandoned Merrick, who was then robbed of all his possessions. Destitute and filthy, he managed to make his way back to England in 1886, whereupon Treves set up an apartment for him in the hospital.

When Treves first met Merrick, he'd thought the Elephant Man was intellectually disabled. But in the comfort of his new home, Merrick
flourished. He wrote poetry, made cardboard dioramas, and received visits from aristocrats. Alexandra, Princess of Wales, brought him a signed photograph of herself and sent him a Christmas card each year. Merrick enjoyed this happy existence for four years before dying at age twenty-seven in his bed. It is likely he died when his massive head fell back suddenly, severing his spinal cord.

Try as he might, Treves never figured out Merrick's condition. He brought in medical experts, who speculated Merrick might be suffering from a nervous system disorder. Merrick's death did not quench Treves's curiosity: He had plaster casts made of much of Merrick's body, and had his bones bleached and boiled. Treves observed that the growths on Merrick's skeleton were enormous, and yet he could see they were not tumors. No one in Merrick's family had suffered his condition, making it unlikely that it was inherited. And, most puzzling of all, his deformities were scattered in random patches across his body. The other parts of his body were entirely normal.

Merrick's case, along with the lines of Blaschko and port-wine stains, were all dramatic examples of mosaicism, but their true nature remained hidden for decades. Part of the reason for this oversight was the lack of scientific tools, but there were other reasons for the lag. As scientists studied the genetic variations among people, they gave little thought to the genetic variations
within
each one.

It is hard to think of another explanation for how a scientist could correctly realize that cancer is a form of mosaicism in 1902, only to die years later before other researchers proved he was right.

In the late 1800s,
Theodor Boveri carried out a series of studies on chromosomes that assured his place in the history of science. His experiments made clear, for example, that chromosomes carry hereditary factors. Boveri did most of this work on sea urchins at a marine biology station in Naples. He would carefully inject sea urchin sperm into eggs and then observe them develop, duplicating their chromosomes with each division.
After a few years of this research, Boveri and his wife, Marcella, got an idea for an experiment. They wondered what would happen if they injected two sperm instead of one into a single sea urchin cell. The result, they discovered, was chaos.

The extra DNA delivered by the two sperm overwhelmed the fertilized egg, leaving it unable to separate all its chromosomes into equal sets. When the egg divided, some of its daughter cells ended up with more chromosomes than others. Some even ended up with no chromosomes at all. The aberrant cells continued to copy their chromosomes and divide. Eventually they broke apart into embryonic fragments, and some of those clumps of cells continued to develop. Some became healthy sea urchin larvae, while others ended up as deformed pieces of tissue.

Observing this chaos, Boveri wondered if it was akin to cancer. In the late 1800s, biologists who studied tumor cells under microscopes noticed their chromosomes had odd shapes. They couldn't see the chromosomes well enough to understand the precise nature of those differences. But they saw enough to speculate that chromosomes had something to do with cancer.

Now looking at sea urchin cells run amok, Boveri had an insight of uncanny brilliance. In order to grow normally, he reasoned, cells needed to inherit the same set of chromosomes as their ancestors. If some disturbance ruined the process, cells might end up with too many chromosomes or too few. Many of these mutant cells would die. Sometimes these cells would multiply at an unnatural rate. Their daughter cells inherited the same abnormal chromosomes, and continued to proliferate. The result would be a tumor.

As soon as Boveri floated his theory, he faced intense opposition. “
The skepticism with which my ideas were met when I discussed them with investigators who act as judges in this area induced me to abandon the project,” he later said. Boveri set the idea aside for twelve years, only making it public in 1914 in his book
Concerning the Origin of Malignant Tumors.
Even then, he was met with skepticism. Boveri died the following year, never knowing if he was right.

It would take until 1960 for scientists to observe chromosomes carefully enough to test Boveri's theory. David A. Hungerford and Peter Nowell
discovered that people with a form of cancer called chronic myelogenous leukemia were missing a substantial chunk of chromosome 22. It turned out a mutation had moved that chunk over to chromosome 9.
The altered chromosomes drove cells to become cancerous.

Like Boveri before them, Hungerford and Nowell could observe only the large-scale changes that occurred in chromosomes. Later generations of scientists would gain the technology necessary to study cancer cell DNA at a finer scale,
sequencing entire genomes from tumor cells. And when they looked closer, they found that far smaller changes than the ones Hungerford and Nowell had observed could also drive cells toward cancer.

Healthy cells make a number of proteins that guard them against becoming cancerous. Snipping out a short stretch of DNA or misreading a single base in their genes disables these guards and lets the cells run wild. Some genes, for example, make proteins that regulate how quickly cells grow and divide. Shutting down one of these genes may be like disabling the brakes in a car rushing downhill. A succession of mutations can then push the descendants of a cell farther down the path to cancer. They can make precancerous cells invisible to the immune system, which continually searches for new tumors. They can make the cells send out signals that lure blood vessels their way, feeding their wild growth.

Each new generation of cancer cells inherits these dangerous mutations, and by the time they've produced a full-blown tumor, it may harbor thousands of new mutations not shared by healthy cells. These mutations can allow cancer cells to thrive at their host's expense, but they can also damage the cells themselves. Mutations to the DNA in mitochondria, which generate a cell's fuel supply, can leave it without enough energy to grow. Cancer cells can solve this particular dilemma with a bold change to their DNA:
They steal mitochondrial genes from healthy cells to replace their own damaged set.