IN MEDIEVAL EUROPE, 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.
It’s hard to think of cancer having anything in common with a pink grapefruit. Yet they are both the product of mosaicism: living lineages of cells set off from the rest of a body by the mutations they inherit from their mother cells. Once scientists finally realized that cancer is a deadly form of mosaicism, they wondered how many other forms it might take.
As scientists looked more closely at how cells divide in the body, simple arithmetic hinted that mosaicism might be everywhere. A single fertilized egg will multiply into roughly 37 trillion cells by the time a person reaches adulthood. Each time one of those cells divides, it must create a new copy of its three billion base pairs of DNA. For the most part, our cells manage this duplication with stunning precision. If they make a mistake, one of their daughter cells will acquire a new mutation that was not present at conception. And if that daughter cell produces an entire lineage, a potentially vast pool of cells will inherit it, too. Based on estimates of the somatic mutation rate, some researchers have estimated that there might be over ten quadrillion new mutations scattered in each of us.
But simple arithmetic on its own could not reveal the precise nature of mosaicism. When a mutation arose in a cell, it might kill it. Our bodies might experience a kind of internal natural selection, favoring cells that retained the genome we started with as fertilized eggs. It was also possible that other mutations were harmless, accumulating without any effect for good or bad. Without technology to inspect DNA, researchers could not find out which possibility was true. They still managed to discover new examples of human mosaics, but only when those examples were impossible to ignore.
On August 5, 1959, for example, a baby was born at New York University Medical Center with both a penis and a vagina, and lacking testicles. The doctors extracted cells from the baby’s bone marrow to study their sex chromosomes. Out of twenty cells the doctors looked at, eight of the cells had an arrangement found in boys: one X chromosome and one Y. But twelve of the cells had only a single X chromosome.
The baby had started out as a zygote with an X and Y chromosome, the doctors realized. But at some point during pregnancy, a dividing cell in the embryo accidentally failed to pass on its Y chromosome to one of its daughter cells. Without a Y chromosome, the cell could not produce some of the proteins involved in developing the male anatomy. It divided and passed down its Y-free chromosomes to its descendants, giving rise to some female anatomical parts. The baby became a mosaic of XY and X cells.
As scientists worked out more details of how embryos developed, they recognized that other conditions were mosaicism as well. The lines of Blaschko, for example, were already present when babies were born, suggesting they were the result of some kind of genetic disorder. But geneticists could not trace the lines of Blaschko through family pedigrees, suggesting the mutation was not passed down from parents to children.
In 1983, a team of Israeli geneticists examined the chromosomes of a boy with lines of Blaschko running up and down the right side of his body. They collected epithelial cells that had been shed into his urine, skin cells from his arms, and white blood cells. The skin cells from his right arm had an extra copy of chromosome 18, as did half of his white blood cells. The rest of the cells were normal. The doctors concluded that a chromosomal mistake had arisen early in the boy’s development. It marked the start of a new lineage of cells, all of which carried the same extra copy of chromosome 18. Later, that lineage of cells differentiated into various tissues, including immune cells and skin cells. Only in the skin cells did the mutation produce a visible change.
Joseph Merrick proved to be a mosaic, too, but his case was especially hard to solve. For many years after Merrick’s death, doctors generally agreed that he suffered from neurofibromatosis, a hereditary condition that makes neurons prone to develop benign tumors. While Merrick did indeed have some of the symptoms of neurofibromatosis, some researchers noted that he had other symptoms that didn’t fit the diagnosis. Merrick’s feet, for example, developed moccasin-like overgrowths—a symptom not caused by neurofibromatosis.
In 1983, researchers recognized a few other people with Merrick’s precise combination of symptoms. Proteus syndrome, as they dubbed the condition, struck fewer than one in a million people. While Merrick’s disease now had a name, scientists didn’t yet understand its cause. In the early 2000s, Leslie Biesecker, a geneticist at the National Human Genome Research Institute in Bethesda, Maryland, led a search for its genetic basis. He and his colleagues collected samples from six people with Proteus syndrome—from diseased skin, as well as from healthy tissue and blood.
Instead of looking for large changes in chromosomes, the scientists used a newer method, called exome sequencing. They decoded all the protein-coding stretches of their genome—about 37 million bases of DNA per cell. Biesecker and his colleagues found that all six subjects had the same mutation in common. It struck a gene called AKT1, which is known to be important in controlling the growth of cells. But the mutation was present only in some of their cells, and not others. The mixed results suggested that Proteus syndrome was a case of mosaicism.
Biesecker’s team then turned to twenty-nine other people with Proteus syndrome. They sequenced the AKT1 gene from cells in a variety of their tissues, too. The scientists found the same mutation in the diseased skin of twenty-six of the subjects. But the scientists couldn’t find the mutation in any of the white blood cells they examined.
Beisecker and his colleagues reared some of the cells in flasks to see how the mutation affected them. They found that it didn’t shut AKT1 down. Just the opposite: It made the gene even more active, spurring skin and bone to grow more—precisely what you’d expect from a mutation that could produce the Elephant Man. It was the first time scientists used exome sequencing to find the cause of a mosaic disease. And once the researchers knew what gene was responsible for Proteus syndrome, they could search for a drug that could attack it. Biesecker and his colleagues found one, which they began testing with promising results. Now that Joseph Merrick’s disease had finally been revealed to be a case of mosaicism, it may one day become curable.
As scientists have pinned down the genetic causes of more mosaic diseases, they are building a chronicle of our inner heredity. A mutation may arise at any stage of development, from the first division that splits a zygote in two, to the last mitosis before death. Depending on when it strikes, a disease may affect a few cells or many. A skin disorder called CHILD strikes early, just as an embryo’s cells are dividing the body into its left and right sides. It produces a body that’s half-dark, half-light. The lines of Blaschko arise much later, as an embryo’s skin starts to develop. Epidermal cells stream in rivers from the body’s midline over the surface of the body. If they pick up a mutation to their pigment genes, they will trace lines across the skin.
The timing of development is so powerful that it can cause the same mutation to produce a different kind of mosaicism, depending on when it arises. A condition called Sturge-Weber syndrome causes a cluster of devastating changes to the head. It can trigger an aggressive bloom of blood vessels that push down dangerously hard on the brain. Depending on where the vessels press, they may cause epileptic seizures, paralyze one side of the body, or cause intellectual disability. If the blood vessels push against the eyes instead, they can cause glaucoma. Sturge-Weber syndrome also creates a massive pink birthmark across as much as half the face. It looks like an extravagant version of a port-wine stain.
The resemblance to port-wine stains is so strong that some scientists have wondered if the two conditions are related. In 2013, Jonathan Pevsner of the Kennedy Krieger Institute led a study to find out. They took a sample of pigmented skin from three people with Sturge-Weber syndrome, along with samples of their unpigmented skin and blood. Pevsner and his colleagues extracted the DNA from the different tissues and sequenced their entire genome. In each patient, they discovered that the pigmented skin cells shared the same mutation to the same gene, called GNAQ. Following up with twenty-six other people with Sturge-Weber syndrome, they found twenty-three had the mutation as well in their altered skin.
Having found the genetic basis of Sturge-Weber syndrome, Pevsner turned his attention to port-wine stains. When he and his colleagues examined the stains on thirteen people, they discovered the same mutation to GNAQ in twelve of them. Their study suggests that the two conditions arise from the same mutation but take on different forms depending on when it appears during development. Sturge-Weber syndrome occurs if the mutation takes place early in development. As the mutant cells divide, they can turn into skin, blood vessels, and other tissues. If the mutation arises in GNAQ later in development, it becomes limited to skin cells, causing only port-wine stains. The two conditions differ only in time.
Conditions like port-wine stains and Proteus syndrome brought mosaicism to the body’s surface and made it visible. More recently, scientists have searched for buried mosaicism hidden from view. Annapurna Poduri, a pediatric neurologist at Harvard, investigated a brain disorder called hemimegalencephaly. In people with this condition, one of the brain’s hemispheres becomes massively swollen, leading to severe seizures. The fact that the disease affected only half the brain raised the possibility that it was a case of mosaicism.
As plausible as this was as an idea, it would be hard to test. Poduri and her colleagues couldn’t simply draw blood from people with hemimegalencephaly or snip off a bit of their skin. The mosaic mutation might be hiding only in the brain.
Poduri and her colleagues took advantage of surgeries that people may get to treat hemimegalencephaly. Surgeons will sometimes remove part of the overgrown hemisphere, or take it out completely. The scientists were able to examine brain tissue taken from eight people. In the first sample they looked at, some of the cells had a lot of extra DNA. It turned out that in those cells, a long stretch of chromosome 1 was duplicated. In other cells from the same patient, chromosome 1 was normal. When the scientists looked at a second patient, they once again found another duplication of DNA in the same region of chromosome 1.
That region contains an intriguing gene called AKT3. Looking back at earlier studies on the gene, Poduri and her colleagues found that a loss of AKT3 sometimes led babies to develop abnormally small brains. Perhaps, they thought, an extra copy of the gene might push brains in the other direction. Poduri and her colleagues sequenced the AKT3 gene in brain tissue from six other people with hemimegalencephaly. One of them had a mutation in AKT3, but only in about a third of his brain cells.
Hemimegalencephaly probably gets its start early in the development of embryos, when neurons are climbing up cellular ropes to build the brain. The neurons divide as they climb, and a mutation arises in the AKT3 gene, or perhaps another gene that helps it. While other neurons eventually stop dividing, the mutant neuron’s lineage does not. Its proliferation is not the runaway growth of a tumor. Instead, the extra neurons spread out across a hemisphere, nestling in among normal cells. Even though they make up only a small fraction of the total neurons, they somehow trigger some hemisphere-wide damage.
The genetic differences that mosaicism creates between our cells are far fewer than the differences between two people. If I could compare cells from my left and right hands, they would not be genetically identical, but they would be vastly more similar to each other than to any cell from my brother, Ben. Yet a somatic mutation that alters even a single base can have a profound effect on our health while eluding our best medical tests. To diagnose a standard hereditary disease—one that was already present in a zygote—geneticists can look at the DNA of any cell in a patient. But in a mosaic disease, one cell cannot stand in for all cells.
In 2013, doctors at Lucile Packard Children’s Hospital Stanford in Palo Alto, California, discovered how vexing mosaicism can be when a woman named Sici Tsoi gave birth to her third child, a daughter named Astrea. The first clue that Astrea had a problem came in the thirtieth week of pregnancy. Tsoi’s obstetrician noticed something peculiar about the baby’s heartbeat. “The beat was long and short and long and short,” Tsoi explained to me.
It was possible, Tsoi’s doctors worried, that Astrea had a hereditary disorder known as long QT syndrome. Normally, the heart beats by releasing regular bursts of electric charge across its muscles, causing them to contract. After each beat, the heart moves charged atoms through tunnels in its cells to build up a new charge. In about one in two thousand births, babies are born with defective tunnels. Some don’t develop enough of them; others produce deformed tunnels that can block the flow of charged atoms. These defects can slow down the heart’s recharging, creating long lags between beats, and throwing off the heart’s precise choreography of electric waves. Left untreated, the chaos caused by long QT syndrome can be fatal.
A definitive diagnosis of long QT syndrome would require putting electrodes directly on Astrea’s chest after birth. For the time being, Tsoi’s doctors kept tabs on Astrea’s fetal development with a twice-weekly echocardiogram, using ultrasound to monitor her heartbeat from a distance. The longer the doctors could extend the pregnancy, the healthier Astrea would be after birth.
In her thirty-sixth week, Tsoi’s doctor spotted a suspicious buildup of fluid around Astrea’s heart. It might be a sign that she was experiencing heart failure. They decided Tsoi would need to have an emergency caesarean section.
When Tsoi woke up in her hospital room after the delivery, she expected a nurse would bring Astrea to her bedside. Hours passed without a glimpse of her new daughter. Tsoi asked her husband, Edison Li, to go to the neonatal intensive care unit. He came back saying that there were so many doctors surrounding Astrea that he couldn’t even see her.
The next day, Tsoi’s doctor visited her with forms to sign. “Then I realized it was something serious,” Tsoi said. Her doctor explained that Astrea did indeed have a severe form of long QT syndrome and had gone into cardiac arrest shortly after birth. It was hard for Tsoi to make sense of all the medical terminology, but she understood that surgeons were going to have to operate on Astrea’s day-old heart to save her life.
After Tsoi and Li signed the forms, the surgeons implanted a cardioverter defibrillator in Astrea’s heart. When her heartbeat lurched out of control, the defibrillator delivered an electric shock that reset her heart and established a normal rhythm again.
Astrea’s medical team included a pediatric cardiologist named James Priest from Stanford Medicine’s Center for Inherited Cardiovascular Disease. Priest sent some of Astrea’s blood to a genetic testing company to see if they could find the cause of her long QT syndrome. Rather than look for a single mutation, Priest ordered a so-called panel test that could search for mutations on a number of genes that are firmly tied to long QT syndrome. The panel’s results might tell Priest which kind of tunnel was altered in Astrea’s heart. Some tunnels pump sodium atoms, while others pump potassium. Different drugs for long QT syndrome work better on different tunnels.
But Priest was keenly aware of the limits of the panel test. For one thing, it was slow. He might have to wait a couple of months to finally get the results back—a vital window during which Astrea might benefit from being put on the right kind of drug. Priest also knew that about 30 percent of patients with long QT syndrome got no genetic diagnosis at all from panel tests. Scientists at the time were still a long way from identifying all the genes that can, when mutated, give rise to long QT syndrome. Thus, nearly a third of patients ended up in what doctors call genetic purgatory.
In 2013, Priest and his colleagues were beginning to sequence the entire genomes of some of their patients to better understand their diseases. Rather than inspect one gene at a time, they wanted to look at all genes at once. When Priest talked about Astrea’s case with his fellow scientists, they realized that genome sequencing might be both quicker and more thorough than the standard panel test. But they knew such an experiment would have no guarantees of success.
Priest spoke to Tsoi and Li, explaining what he wanted to do. “Everybody’s genome is like a book with 23 chapters,” he told them. “You have two copies of each chapter, one from your dad and one from your mom. Whole genome sequencing looks for everything. It looks for missing chapters, missing paragraphs, every misspelled word.”
Tsoi and Li gave their consent, and Priest drew some blood from Astrea—now only three days old. He shipped it to Illumina, which rushed the job. Six days later, Priest got all their raw data. He set up a program to assemble the short reads into Astrea’s entire genome, and then he searched through it for mutations that might be responsible for her long QT syndrome.
Astrea had millions of variants, of course, but Priest was quickly drawn to one in particular. She carried a rare mutation of one copy of gene called SCN5A. That particular gene encodes sodium tunnels in the heart, and Priest himself had found that, in another patient, a mutation at precisely that same spot caused long QT syndrome. “It totally hit me over the head,” said Priest. “I wasn’t going to find anything better.”
The next day, Priest informed Tsoi and Li of his discovery. Astrea, now only ten days old, was put on a drug to treat sodium channels. Priest then went back to Astrea’s genome to wrap up the case, to confirm his diagnosis before writing up the results.
And that’s when his story fell apart.
The Illumina technicians had sequenced Astrea’s genome as they had mine and thousands of other people’s. They broke open her white blood cells and chopped up the DNA inside. They then made many copies of those fragments—known as reads—and sequenced them all. Priest had used his computer to figure out where each read sat in Astrea’s genome. Because the sequencer made so many reads, around forty of them lined up at every spot in her DNA. On average, half of the reads in a gene came from one copy of a gene, and the remaining ones came from the other. Priest found the SCN5A mutation in eight out of thirty-four reads. It wasn’t a perfect fifty-fifty split, but it was close enough, Priest decided. He assumed that one copy of her SCN5A gene had the disease-causing mutation.
Priest followed up on the genome sequencing with a more focused exam of Astrea’s DNA. He pulled out the SCN5A gene from some of Astrea’s white blood cells and made millions of copies of it so he could examine it in fine detail. He expected to find a fifty-fifty split between the normal version and the mutant one. But he found no mutation at all. It was as if he had examined two different babies, one with a lethal mutation and one without it. “I was just flabbergasted,” he said.
Priest wondered if there was some unusual heredity in Astrea’s family that had tricked him. Neither Tsoi nor Li showed any sign of having long QT syndrome. They never had any problems with their hearts, and Priest found that their EKGs were normal. It was possible that one of them carried an extra broken copy of SCN5A. Sometimes a mutation will trigger the accidental duplication of a gene but in a form that can’t make a protein. Perhaps Astrea had inherited a so-called pseudogene of SCN5A, and perhaps Priest had mistaken it for her working version. If that was the case, then SCN5A would have nothing to do with Astrea’s ailing heart, and Priest would be back at square one. He’d have to start a new search for her long QT mutation.
To search for a pseudogene, Priest sequenced DNA from Tsoi and Li. Instead of sequencing their entire genomes, he sequenced only their protein-coding genes. Again, he ended up empty-handed. Neither of Astrea’s parents had a pseudogene for SCN5A.
Finally, Priest considered the most extreme possibility: that Astrea was a mosaic. Perhaps the SCN5A mutation was only in some of her cells but not others. To investigate this possibility, Priest brought Astrea’s blood to Stephen Quake. Quake, a Stanford scientist, had developed a way to sequence a genome from a single cell. Rather than throwing together DNA from millions of Astrea’s cells, he could inspect them one at a time.
Quake and his team inspected thirty-six of Astrea’s blood cells. In three of them, they discovered a mutation on one copy of the SCN5A gene. In the other thirty-three cells, both copies of the SCN5A gene were normal.
Quake’s test confirmed that Astrea’s blood was a mosaic. To get a broader survey of her mosaicism, Priest and his colleagues also examined cells from her saliva and urine. Now they had samples of cells that had developed from the three germ layers. (Blood comes from the mesoderm. The lining of the mouth comes from the ectoderm. And the urinary tract develops from the endoderm.)
In all three tissues, the scientists found the SCN5A mutation in between 7.9 and 14.8 percent of Astrea’s cells. She was a mosaic through and through, in other words. And she must have become one before she had developed the three germ layers, when she had been just a ball of cells. One cell in that embryonic ball had mutated, and when it divided, it passed down that mutation to its descendants. The cells that inherited the errant SCN5A gene ended up mixing into all three germ layers.
As Priest and his colleagues were deciphering Astrea’s mosaic nature, she recovered well enough from her surgery for Tsoi and Li to take her home. The drugs Priest had recommended kept her long QT syndrome under control, and she enjoyed a happy infancy. One day, when Astrea was seven months old, Tsoi’s phone rang.
“I got a call from the doctor, and she asked if Astrea was doing okay,” said Tsoi. Astrea was right in front of her, playing with toys, Tsoi said.
It turned out that Astrea’s defibrillator had just shocked Astrea’s heart. It had sent a wireless message to her doctors to let them know. They needed to get Astrea back into the hospital as quickly as possible. “I couldn’t absorb that information fast enough,” said Tsoi.
When the Stanford doctors examined Astrea, they discovered that her heart had become dangerously enlarged—another risk posed by SCN5A mutations. Astrea would need a new heart in order to survive. Not long after Astrea came back to the hospital, her heart stopped, and her doctors struggled to bring her back, clamping a mechanical pump to her heart to keep it functioning.
“On the night that she was almost gone,” Tsoi said, “I was thinking, ‘If it’s too hard or it hurts too bad on her, it’s okay, just go.’”
Astrea recovered and regained her strength. And a few weeks later, a donated heart became available. Astrea underwent transplantation surgery, and she was back home again after a few days. The first few months at home were rough for the entire family, with Astrea throwing up constantly. But gradually she recovered. Except for having to take anti-rejection drugs three times a day, Astrea got her childhood back. She listened over and over again to songs from the movie Frozen. She did cartwheels with her sister.
For Priest, Astrea’s heart transplant gave him a chance to find out once and for all if mosaicism had been to blame for her condition. After surgeons removed her heart from her body, they clipped off some pieces of muscle for Priest to study. On the right side of the heart, he and his colleagues found that 5.4 percent of the cells had mutant SCN5A genes. On the left, 11.8 percent did. Little grains of mutant cells were mixed in with the ordinary tissue. Priest and his colleagues built a computer simulation of Astrea’s heart with those levels of mutant cells and let it beat. The simulated heart thumped irregularly, in much the same way Astrea’s did.
Astrea had lost her mosaic heart, but the rest of her body remained a genetic mix. Yet now her SCN5A mutations could no longer threaten her life. Priest was left wondering how many other cases of long QT syndrome are actually the result of mosaicism like Astrea’s. “It’s hard to say I’ll be involved in such an interesting case for the rest of my life,” Priest said.
The search for the causes of diseases has uncovered a number of cases of mosaicism. But scientists have also discovered some people in which mosaicism can heal.
A team of Dutch dermatologists and geneticists described the first case of mosaic healing in 1997. They examined a twenty-eight-year-old woman whose skin was so fragile that even a gentle rubbing would raise blisters. This painful condition is caused by a mutation to a gene called COL17A1. Normally, skin cells use this gene to make a type of collagen that makes them stretchy.
Both of the woman’s parents were carriers. They each carried a mutation on one copy of their COL17A1 gene. (They had different mutations in different locations—a detail that will turn out to matter tremendously in a little while.) Because each parent also had a normal copy of the COL17A1 gene, they could still make enough collagen to keep their own skin healthy.
The woman had the bad luck to inherit each parent’s bad copy of the gene. Those defective copies were present when she was still a fertilized egg. They were passed down to every cell that zygote gave rise to. When she developed skin, her skin cells needed to switch on her COL17A1 gene to make collagen. The gene failed at its job, and she was left with skin that couldn’t stretch.
Remarkably, however, the woman’s doctors noticed that she had a few patches of normal skin on her arms and hands. They didn’t blister when they were rubbed. The woman had been aware of some of the patches for as long as she could remember. Others had emerged more recently and were expanding. When the doctors looked at the molecular makeup of her healthy patches, they found healthy collagen.
Looking closely at the DNA in her cells, the geneticists figured out how these patches had developed. Each arose from a single faulty skin cell. Before it divided, the cell duplicated its DNA. And during that duplication, it mutated in a peculiar way: It swapped a section of the COL17A1 gene between its chromosomes.
When the two daughter cells pulled away from each other, one cell no longer carried the woman’s mutation from her mother. It had been replaced by the working portion of her father’s COL17A1 gene. Now altered, the cell could make collagen again. And when it divided, its daughter cells inherited a working version of the gene as well. The woman’s mosaics had repaired her defective genes.
Since that initial discovery, scientists have found more genetic diseases partially cured by mosaics. Their list now includes hereditary forms of other skin diseases, along with anemia, liver disorders, and muscular dystrophy. The growing inventory of mosaicism—causing diseases or healing them—raised the question of just how mosaic humans are in general. The definitive answer would come from breaking down people into their 37 trillion cells and sequencing every base of DNA in each one. For now, scientists are only carrying out rough surveys. But even these preliminary studies have come to one clear conclusion: We are all mosaics, and we have been so pretty much since our beginnings.
In the first few days of an embryo’s existence, over half of its cells end up with the wrong number of chromosomes, either by accidentally duplicating some or losing them. Many of these imbalanced cells either can’t divide or do so slowly. From their initial abundance, they dwindle away while normal cells create their own lineages. If the supply of chromosomes is too abnormal—a condition called aneuploidy—then the mother’s body will sense trouble and reject the embryo altogether.
But a surprising number of embryos can survive with some variety in their chromosomes. Markus Grompe, a biologist at Oregon Health & Science University, and his colleagues looked at liver cells from children and adults without any liver disease, most of whom had died suddenly, by drowning, strokes, gunshot wounds, and the like. Between a quarter and a half of their liver cells were aneuploids, typically missing one copy of one chromosome.
A trained expert can spot aneuploid cells with a microscope. Finding smaller mutations—such as short deletions, duplications, or single-base changes—has required far more sophisticated technology. In 2017, for example, researchers at the Wellcome Trust Sanger Institute in England sequenced the entire genomes of immune cells they got from 247 women. In each volunteer, the scientists found around 160 somatic mutations, each present in a sizable fraction of her cells.
Because these somatic mutations were so common, the researchers suspected they arose early in development. To test the idea, they sequenced the genomes of cells from other tissues in the women. They could find most of the somatic mutations in a fraction of those other cells, too. Based on their research, the Sanger scientists estimated that an embryo gains two or three new mutations every time its cells double. As those new mutations arise, embryonic cells pass them all down to their descendants as a mosaic legacy.
Christopher Walsh, a geneticist at Harvard who studies mosaicism in the brain, wondered how extensive mosaicism is in our neurons. To find out, he and his colleagues got hold of tissue samples from three people who underwent brain surgery. From each sample, they isolated around a dozen neurons and then sequenced the genomes of each one. They then looked for somatic mutations that set each neuron apart from other cells in the brain, as well as the rest of the body.
Every neuron, Walsh found, was a mosaic. It carried around 1,500 single-nucleotide variants, a unique genetic signature that set each neuron apart from the cells in other parts of the body. These mutations accumulated gradually, through many generations of dividing neurons. Recent mutations were shared by only a few neurons, while older ones were shared by many.
It occurred to Walsh that he could use the mutations to reconstruct the cell lineages of the brain—not to watch the lineages grow forward as Conklin had, but to work his way back up their branches like a genealogist, back to the womb.
To make this trip, Walsh and his colleagues studied a seventeen-year-old boy who had died in a car accident. The boy’s family donated his body for scientific research. Walsh got hold of frozen pieces of the boy’s brain, and his team plucked 136 neurons from the tissue. They then sequenced the entire genome in each cell. As a point of comparison, they also sequenced DNA from other organs in the boy’s body, such as his heart, his liver, and his lungs.
Scanning the trillions of bases they sequenced, the researchers spotted hundreds of somatic mutations in each neuron. Many of the mutations were shared by some of the neurons, but not all of them. Some were found in only a few of the neurons, and some were unique to a single cell. The researchers used this pattern to draw a genealogy of the brain, linking each neuron to its close cousins and its more distant relatives. Walsh and his colleagues found that the cells belonged to five distinct lineages, the cells in each one inheriting the same distinctive mosaic signature.
The shared mutations must have all arisen when the boy was still an embryo, when the neurons in his brain were still multiplying quickly. But Walsh got even deeper insights into the development of the boy’s brain when he compared the neurons to cells from his other organs. One lineage of neurons also included cells from the boy’s heart. Other lineages included cells from other organs.
Based on these results, Walsh and his colleagues pieced together the biography of the boy’s brain. When he was just an embryonic ball, five lineages of cells emerged, each with a distinct set of somatic mutations. Cells from those lineages migrated in different directions, becoming different organs—including the brain.
The cells that joined to become the brain were transformed into neurons. And these new neurons wandered throughout the brain before settling down and dividing a few more times. That’s why Walsh and his colleagues could find neurons belonging to different lineages sitting near each other. The boy’s brain ended up divided into millions of patches of tiny cellular cousins.
Mosaics were once the stuff of superstitions, of freak shows. Then they gained recognition as diseases, both rare and common. Now we can see them everywhere. A single genome can no longer define us, because our inner heredity toys with DNA, altering just about every piece of genetic material we inherit. Even in our skulls, we grow a witches’-broom.