She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (48 page)

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.