Authors: Carl Zimmer
A nurse called Keegan with the results. Not only were her sons not suitable as organ donors, but the HLA genes from two of them didn't match hers at all. It was impossible for them to be her children. The hospital went so far as to raise the possibility she had stolen her two sons as babies.
Since Keegan's children were now grown men, she didn't have to face the terrifying prospect of losing her children as Fairchild did. But Keegan's doctors were determined to figure out what was going on. Tests on her husband
confirmed he was the father of the boys. Her doctors took blood samples from Keegan's mother and brothers, and collected samples from Keegan's other tissues, including hair and skin. Years earlier, Keegan had had a nodule removed from her thyroid gland, and it turned out that the hospital had saved it ever since. Her doctors also got hold of a bladder biopsy.
Examining all these tissues, Keegan's doctors found that she was made up of two distinct groups of cells. They could trace her body's origins along a pair of pedigreesânot to a single ancestral cell but to a pair. They realized Keegan was a tetragametic chimera, the product of two female fraternal twins.
The cells of one twin gave rise to all her blood. They also helped give rise to other tissues, as well as to some of her eggs. One of her sons developed from an egg that belonged to the same cell lineage as her blood. Her other two children developed from eggs belonging to the lineage that arose from the other twin.
When Lydia Fairchild's lawyer heard about the Keegan case, he immediately demanded that his client get the same test. At first, it looked as if things were going to go against Fairchild yet again. The DNA in her skin, hair, and saliva failed to match her children's. But then researchers looked at a sample taken from a cervical smear she had gotten years before. It matched, proving she was a chimera after all. Fairchild got to keep her children.
The stories of Lydia Fairchild and Karen Keegan both ended happily. But they left the women with haunting questions not only about their families but about themselves. Fairchild's eggs, cervix, and perhaps some other tissues in her body all had a direct genetic link to her children. But what of the rest of her body? Was she partly their aunt, too? As for Keegan, were her sons half brothers to each other, with two sisters for their mothers? We use words like
as if they describe rigid laws of biology. But despite our genetic essentialism, these laws are really only rules of thumb. Under the right conditions, they can be readily broken.
Speaking years later to National Public Radio, Keegan admitted that telling her sons about the test results was the hardest part of the experience. “I felt that
part of me hadn't passed on to them,” she said. “I thought, âOh, I
wonder if they'll really feel that I'm not quite their real mother somehow, because the genes that I should've given to them, I didn't give to them.'”
It might have been some consolation to Keegan to learn that her sons were probably chimeras as well. They probably carried some of Keegan's own cells in them. And she was probably a twofold chimera, carrying some of her own children's cells inside her.
As an embryo's placenta draws in nutrients from its mother, it blocks the cells in her blood with a tight filter. But it's not perfect, and sometimes a mother's cells end up in the embryo. Other times, the traffic goes the other way.
It was in 1889 that
a doctor first took note of this traffic. A German pathologist named
Christian Georg Schmorl examined the bodies of seventeen pregnant women who had died of seizures. He noticed that their livers contained some “very peculiar” cells. Judging from their size and shape, Schmorl guessed they had originally come from the placentas of their unborn children.
It was easy to dismiss those cells as pathological, dislodged by the women's disorders. But in 1963,
Rajendra Desai and William Creger, two doctors at Stanford University, discovered that this traffic might be a regular part of pregnancy. They collected blood from nine pregnant women and spiked it with a drug called Atabrine. Although Atabrine was initially used to prevent malaria, it also proved to be useful to research scientists who wanted to track cells. Certain types of cells will swallow up Atabrine and then glow green under a fluorescent light.
Desai and Creger injected the women's Atabrine-treated blood back into their bodies and waited for them to give birth. The doctors then examined the umbilical cords of the babies. When they smeared the cord blood onto slides and lit them up, six of the nine babies glowed green. The mothers' white blood cells were crawling around the bloodstreams of their children.
Three years later,
Desai and colleagues in Boston ran the reverse experiment. They took advantage of blood transfusions that fetuses sometimes get when they develop anemia in the womb. Desai added Atabrine to
blood that was to be transfused into seven fetuses. A few hours after the procedure, he drew blood samples from the mothers. In almost every case, Desai found green-glowing white blood cells and platelets that had been injected into the fetuses. The mothers were becoming chimeras, taking on their children's blood.
Desai's experiments proved that the placenta was a leakier barrier than scientists had previously thought. But it was hard to know just how significant the migrant cells were in their new homes. Perhaps they simply died out soon after making the crossing. It would take three decades for other scientists to show that these cells can endure, and that mothers can become permanent chimeras with their children.
These results had their origins in a failed attempt to come up with a test for Down syndrome. In the 1970s, the only way to test for Down syndrome was to pierce the amniotic sac surrounding a fetus with a needle and draw off some fluid. The fluid contains some cells shed by the fetus, which geneticists could inspect to look for chromosomal abnormalities. But this test, known as amniocentesis, had many drawbacks. It sometimes falsely indicated a fetus had Down syndrome, and it sometimes failed to find genuine cases. Making matters worse, inserting a needle into the uterus put women at greater risk of a miscarriage.
A Stanford University researcher named Leonard Herzenberg decided to invent a blood test to take the place of amniocentesis. He would draw blood from pregnant women, whichâas Desai had shownâcontained some cells from the fetus. He could then examine the fetal cells without ever disturbing the woman's pregnancy.
The big challenge of Herzenberg's project was to find a way to separate fetal cells from maternal cells that was both quick and accurate. Herzenberg and his students figured out how to put fluorescent tags on the HLA proteins that sit on the surface of cells. They used only tags that would attach to the HLA proteins a child inherited from its father and not shared by its mother. That step would ensure that only the child's cells would glow.
In 1979, Herzenberg and his students demonstrated that they could use
new method to sort the cells of a fetus out of the bloodstream of its mother. To improve the method even more, one of Herzenberg's students,
Diana Bianchi, carried on research at Tufts University. In her own lab, she came up with a new strategy. Herzenberg had tagged lots of different types of fetal cells. Bianchi developed a tag that would mark only the stem cells that give rise to red and white blood cells. In adults, these stem cells are locked away in bone marrow and never slip into circulation. Any stem cells in a pregnant woman's blood would almost certainly have been shed by her fetus.
Bianchi crafted a new set of molecular tags, which she successfully used to fish out fetal stem cells. She was delighted with her successâuntil some of the pregnant women she had studied started giving birth.
From some of the women, Bianchi had drawn out stem cells with Y chromosomes. This was to be expected from women who were pregnant with boys. But when some of these women gave birth, their babies turned out to be daughters.
Even more startling to Bianchi were the results of a control experiment she ran on women who were not pregnant. Some of those women had Y chromosomes, too. All of them, Bianchi learned, had given birth in the past to sons.
As a search for a blood test, Bianchi's study was a bitter failure. She could not reliably isolate fetal cells from a current pregnancy. But Bianchi got a fabulous consolation prize: She discovered that fetal cells can survive for years in women.
Bianchi decided to keep studying these cells by finding more mothers with sons. The women she selected for her research had never had a blood transfusion or an organ transplant. Out of eight such women, Bianchi found fetal cells with Y chromosomes in six of them. One of the women with Y chromosomes had a twenty-seven-year-old sonâmeaning that his cells had remained established in her body for over a quarter century.
When Bianchi wrote up her results, they were rejected by three journals. The reviewers complained that it didn't make sense that fetal cells could endure for so long in another person's body. Finally,
Proceedings of the National Academy of Sciences
agreed to publish her results in 1996. “Pregnancy may thus establish a long-term, low-grade chimeric state in the human female,” Bianchi and her colleagues wrote.
To distinguish this new form of chimerism from other ones, Bianchi coined a new term:
. In the years since her paper came out, other scientists confirmed that most mothers experience microchimerism. Y chromosomes were the easiest markers for this condition. But some researchers also began looking in mothers for other segments of DNA from their children. Their research has revealed that all pregnant women have fetal cells in their bloodstream at thirty-six weeks. After birth, the fraction drops, but
up to half of mothers still carry fetal cells in their blood decades after carrying their children.
These microchimeric cells swim against heredity's current,
a legacy in reverse. Other forms of chimerism play different games with heredity. Very often, a mother's cells will infiltrate her children's bodies, where they can endure and grow long after her death. According to one estimate,
42 percent of children end up with cells from their mothers.
Chimeras even create side flows in heredity. At the University of Copenhagen, scientists got
blood samples from 154 girls ranging in age from ten to fifteen. They cracked open the cells in the blood and searched them for Y chromosomes. In 2016 they reported that twenty-one girlsâmore than 13 percentâhad them. Because the girls did not have sons of their own, the scientists concluded that their Y-chromosomeâcarrying cells originated in their brothers, were left behind in their mothers after birth, and then made their way into the bodies of the girls while they were still fetuses. It's also possible that the cells came from male fetuses that their mothers miscarried or had aborted.
Charting the full scope of microchimerism is difficult, because foreign cells can work their way remarkably far into the nooks and crannies of the human body. Just because chimeric cells aren't present in blood doesn't mean they're not hiding in some hard-to-reach organ. The best way to hunt for chimeras is to cut open a cadaver.
a group of researchers at Leiden University in the Netherlands did just that. They searched Dutch hospitals for tissue samples taken from women who had been pregnant with boys when they died, or who had died
within a month of giving birth to sons. The researchers found twenty-six such women and collected samples from their kidneys, livers, spleens, lungs, hearts, and brains. At least some of the women had their son's cells in every organ. Out of seventeen hearts they examined, five were chimeric. Out of nineteen lungs, all nineteen were. The cells of their sons were also in their brains, five for five.
Autopsies of older women have also shown just how long fetal cells can endure in a mother.
Lee Nelson, a rheumatologist at the Fred Hutchinson Cancer Research Center, and her colleagues examined the cadavers of fifty-nine women who died, on average, in their seventies. In 63 percent of the women, the scientists found Y chromosomes in their brains.
Fetal cells don't simply migrate around their mothers' bodies. They sense the tissue around them and develop into the same types of cells. In 2010,
Gerald Udolph, a biologist in Singapore, and his colleagues documented this transformation with a line of engineered mice. They altered the Y chromosomes in the male mice so that they glowed with the addition of a chemical. Udolph and his colleagues bred the mice, and then later they dissected the brains of the mothers. They found that the fetal cells from their sons reached their brains, sprouted branches, and pumped out neurotransmitters. Their sons helped shape their thoughts.
Chimeras took much the same scientific path as mosaics: from monster to fluke to fixture. And as scientists came to recognize that a substantial fraction of humanity are amalgams of cells from different individuals, they wondered
what effects their divided inheritance had on them.
In 1996, Lee Nelson proposed that microchimerism might make some mothers sick. With half their genetic material coming from their father, fetal cells might be a confusing mix of the foreign and the familiar. Nelson speculated that being exposed to fetal cells for years on end could lead a woman's immune system to attack her own tissues. That confusion might be the reason that women are more vulnerable to autoimmune diseases such as arthritis and
To test this possibility, Nelson and Bianchi collaborated on an experiment. They picked out thrity-three mothers of sons, sixteen of whom were healthy and seventeen of whom suffered from scleroderma. Nelson and Bianchi found that the women with scleroderma had far more fetal cells from their sons than did the healthy women. Other scientists who carried out similar studies got the same results for a number of other diseases. These findings aren't definitive proof that microchimerism made these women sick, however. It was also possible that the diseases came first, and the fetal cells only later flocked to the diseased tissues, where they could multiply.