Siblings

Tethered for life: How brothers and sisters really shape you.

The You in Me

Image: Fraternal Twin Sisters
LINKED BY BIRTH Eight-year-old fraternal twins Zellie (left) and Lula (right) likely share each other's cells.
Peter Hapak
It should have been a routine paternity test. In late 2002 Lydia Fairchild—a mother of two and pregnant with a third child—applied to the state of Washington for welfare assistance. Because she already received child support from her sometime boyfriend, Jamie Townsend, state law required a court hearing to determine how much welfare support she was eligible for. The state demanded a paternity test as well, to prove Townsend was the father, so he and Fairchild both submitted cells from a cheek swab. A few weeks later, Fairchild got a call from the social services department. Officials there wanted to chat. In person.

When she arrived, officials shut the door. Fairchild sensed hostility and says they peppered her with odd, insinuating questions. Finally, they revealed the reason for the interrogation. The DNA test had proved Townsend the father. But it ruled Fairchild out as the mother—and, she says, the state no longer believed the children were really hers.

Stunned, Fairchild drove home and dug up her children’s birth certificates, as well as pictures of herself during her earlier pregnancies. She called her mother and broke down crying. The state meanwhile had her submit DNA to a second lab. Within weeks, it confirmed the results from the first lab.

Things got messy after that, as a routine court case deteriorated into a probe of Fairchild’s relationship to her children. State prosecutors didn’t know if she’d acted as a surrogate or perhaps even abducted the children, and Fairchild was afraid the state would investigate her for welfare fraud. She also feared social services would take her children away, and she made furtive arrangements to hide them if need be.

The judge in the case hoped Fairchild’s impending due date might clear things up. He appointed a witness to monitor the birth from the delivery room and to watch blood being drawn from Fairchild and her baby, for more tests. Fairchild agreed to this—but once again failed the test. Her DNA indicated that the baby who’d just emerged from her birth canal wasn’t hers.

Prosecutors were dumbfounded. One of them began searching the medical literature and came across an eerily similar case from 1998, involving a woman in Boston who needed a kidney transplant. She and her three sons had undergone DNA testing to find a suitable donor. Instead, they found out that she couldn’t possibly be the mother of two of them. Genetically, in fact, they appeared to be the offspring of her husband and her brother, the boys’ uncle.

On a hunch, her doctors examined the DNA in a thyroid nodule she’d had removed years before. Oddly, the thyroid DNA matched the DNA of all three sons. From this lead, doctors determined that the woman had a rare condition called chimerism; due to a prenatal twist of fate, she was a genetic blend of two people with different cells. As a result, the cells in some tissues (her skin and blood) and those in other tissues (her thyroid and reproductive organs) had different DNA.

After this revelation, Fairchild submitted more cells for DNA testing, but this time from all over her body, including her cervix. The plan worked. The cervical DNA looked different from the skin and blood DNA she’d submitted before—but it matched her children’s DNA perfectly. Like the Massachusetts woman, Fairchild was declared a chimera, and after 16 months of legal hell, her children were officially hers again.

Chimerism is a strange beast. Scientifically, it’s the persistence of cells from two (or more) people in one body. Firm numbers remain elusive, but most—if not all—humans are probably a little chimeric, since mothers and fetuses commonly exchange cells during pregnancy. Such chimeric cells can invade organs throughout the body, including the brain, and scientists have found tantalizing links between chimerism and autoimmune diseases, in which the body’s immune system attacks its own tissue. Beyond strictly medical issues, chimerism also raises psychological questions about child development, sexual identity, mother-child bonding, and even what constitutes the self.

Image: Kaja, Nando, Ivo and Mileva
PIECES OF YOU Kaja and Nando and their children, Ivo, 4, and Mileva, 1.
Peter Hapak
Large-scale chimerism, à la Lydia Fairchild, occurs when a fraternal twin vanishes inside the womb during the first weeks of pregnancy. Fraternal twins come from two separate eggs and therefore have different DNA, like regular siblings. Sometimes, one fraternal twin “consumes” the other by absorbing its cells.

The resulting singleton baby is a mosaic of different DNA in different organs. A chimera from one male and one female twin can become a hermaphrodite; if twins are the same sex, the child might have patches of skin or eyes of different colors, but otherwise will probably appear normal. In the absence of extensive DNA testing, he or she will probably never know.

Such stealthiness makes it hard to determine how prevalent chimerism is. A few scientists claim that one-quarter of all twins end up being singletons, but most cite far lower numbers. Regardless, the number of chimeras is probably growing: In vitro fertilization increases the odds of having fraternal twins by about thirtyfold and is also associated with an increased risk of chimerism.

That increase has alarmed some legal thinkers. They envision situations where a chimeric male rapist, for instance, goes free because the sperm DNA collected at the crime scene doesn’t match the skin or blood DNA he submits to the police. For now, these scenarios remain theoretical, and aside from Lydia Fairchild, just about the only real-life case involving chimerism was more of a farce. A professional cyclist charged with blood doping—injecting himself with someone else’s red blood cells to boost his endurance—claimed the foreign cells inside him must have come from a long-vanished twin in his mother’s womb. The panel hearing his plea didn’t buy it.

Far more common than large-scale chimerism is microchimerism, chimerism on a tiny scale. Microchimerism can result from bone-marrow transplants, poorly prepared blood transfusions, and twins exchanging cells in utero; there’s also evidence that breast-feeding might pass cells from mother to child, and some scientists speculate that unprotected sex might be a contributor. But by far the most common cause of microchimerism is pregnancy.

According to traditional thinking, the placenta acts as a barrier between a mother and a child in the womb, preventing an exchange of cells between them. But recent research has revealed that the placenta is more porous than previously believed, says Kirby Johnson, a biologist at Tufts University. “Now we know a mother and her baby have to be linked. Cell-based communication is essential for a healthy pregnancy.”

Overall, the placenta allows for a lot of two-way traffic, with fetal cells stealing into Mom, and maternal cells slipping into Child. (Even tumor cells can cross over, and there are a few well-documented cases of mothers giving cancer to fetuses.) After cells cross over, some get rounded up and killed by the new host’s immune system. Many, however, take root in the other body, burrowing into the heart, liver, kidneys, spleen, skin, pancreas, gallbladder, and intestines, among other places. Most of these organs house tens to hundreds of interlopers per million normal cells, but the lungs can tolerate thousands of foreign cells per million. Fetal cells do an especially good job of colonizing Mom’s body since they often have the power, much like stem cells, to turn into multiple types of tissue, depending on where they find themselves.

At first, researchers assumed that microchimeric transplants would harm the recipient. Most scientists who study microchimerism also study autoimmune diseases, which occur in women three times more often than in men. Scientists have reasoned that perhaps a mother’s immune system, in trying to exterminate fetal cells inside her, inadvertently causes collateral damage to her own tissue. Or perhaps the fetal cells, surrounded by foreign tissue, rebel and attack the mother. Studies have indeed linked high levels of microchimeric cells to some forms of lupus, cirrhosis, and thyroid disease. Twin studies have also found higher levels of microchimerism in females with multiple sclerosis.

Image: Dylan, Ray, Sherbina & Sahana
HE CONTAINS MULTITUDES Dylan, 9, and family (from left): Ray, Sherbina, and Sahana, 2.
Peter Hapak
Still, there’s at least as much evidence that microchimeric cells prevent certain ailments. Scientists have documented cases where chimeric cells slowed diabetes and liver disease, for instance. The fetal cells, because of their stem cell–like powers, might actually repair damaged tissue: They’re essentially a transplant of younger, healthier cells into depleted organs. Even more intriguing, microchimerism might help protect against certain types of cancer. Women with breast cancer, for instance, generally have lower levels of microchimerism than women who don’t develop the disease, suggesting a possible role for fetal cells in helping our bodies to detect and destroy tumors. Similarly, when patients with certain types of leukemia receive a transfusion of a nonrelative’s cord blood (blood collected shortly after birth, from the placenta or umbilical cord) rates of relapse drop. This occurs because the cord blood contains maternal immune cells that women develop in response to pregnancy, and which fight the cancerous cells in the recipient.

Determining the effects of crossover cells gets even trickier with the brain. Until recently, scientists didn’t even know whether microchimeric cells could invade the brain, says Johnson, in part because of the blood-brain barrier—a cellular firewall that seals the brain off from the body proper, much like a fetus in the womb. But last year a team of researchers, led by immunologists William Chan and J. Lee Nelson at the Fred Hutchinson Cancer Research Center in Seattle, proved that the blood-brain barrier is just as leaky as the placenta. Their demonstration of microchimerism in the human brain—the first—“is very encouraging” and should finally open research into how microchimerism might affect brain function and brain diseases, says Gerald Udolph, a biologist at the Institute of Medical Biology in Singapore.

Chan and Nelson’s team ran DNA tests on the brains of 59 women who died between the ages of 32 and 101. To make things simple, they searched for a gene found only on the male Y chromosome. (Women shouldn’t have any Y-chromosome DNA, so finding it would provide strong evidence of the presence of microchimeric cells.) Overall, the scientists found DNA evidence for male cells in 63 percent of the subjects, distributed in multiple brain regions. One woman who tested positive had died at 94, well past child-bearing age, meaning the male cells had stuck around for at least half a century.

Where did the male DNA appear in the brain? All over. About half of the parietal and temporal lobe samples studied contained male DNA; occipital and frontal lobe samples contained it at lower rates. Male DNA was found in 40 and 35 percent of thalamus and hippocampus samples, respectively, and 90 percent of samples of the medulla, the part of the brainstem just above the spine. These shouldn’t be taken as absolute numbers, because the team had small sample sizes, and they didn’t even try to search for microchimeric cells from female offspring. But the wide distribution is important, Udolph says, because it shows that fetal cells “might be able to contribute functionality to many, or maybe all, brain areas. The homing to multiple brain sites also might demonstrate that these cells are plastic.”

Still, the study raises more questions than it answers. Chan and Nelson don’t know whether the male DNA they found came from neurons or other brain cells, much less whether the invading cells affect memory, perception, or other facets of the mind. Nevertheless, animal studies provide a glimpse of what such cells might be doing.

Experiments by Udolph have shown that in mice mothers, fetal cells become full-fledged neurons and function in cognitive processes. Despite their different DNA, there’s no evidence yet that those neurons can cause mothers to think differently, he says, but this influx “can be regarded as a naturally occurring form of a ‘stem-cell transplantation’” that might repair defects in the brain and restore normal function. On a more general level, given all the two-way cellular traffic, “the dogma of every cell in our body being genetically identical has to be revised,” he says.

Nelson and Chan’s paper also explored a potential link between microchimerism and Alzheimer’s disease. The more a woman gives birth, the higher her risk of Alzheimer’s disease. Nelson reasoned that perhaps an accumulation of fetal cells in the brain might contribute to the condition. Surprisingly, the study found the opposite: Women had a 60 percent lower chance of having Alzheimer’s if their brains hosted male microchimeric cells. Nelson cautions that later studies could significantly alter the picture, but for now microchimerism doesn’t appear to be a cause. If the results hold up, they may provide a new lead for slowing or preventing Alzheimer’s disease.

Microchimerism might also play a role in child development. A fetus in the womb is exposed to more than just its mother’s cells. A woman also has cells from her mother stowed away in her organs, from her long-ago fetal days. So every pregnant woman has at least three generations of cells inside her. If a mother-to-be has been pregnant before, cells from the firstborn baby could be in the mix as well. In fact, there’s good evidence that older siblings can bequeath their cells to younger siblings via the womb.

This sibling hand-me-down could have real consequences. As the fetus grows week to week, certain genes turn on and off, and cells produce different biochemicals and behave in different ways, depending on what developmental stage they’re in. But cells from an older sibling who has already gone through later stages of prenatal development might be too “old” for the fetus’s body, Nelson says, and might not behave appropriately if incorporated. Perhaps that means nothing. But birth interval and birth order do seem to affect certain aspects of development. Males are more likely to be homosexual, for instance, if they have older biological brothers. Scientists currently attribute this effect to a possible immune response by the mother, but perhaps the older brother’s cells play a role as well. What’s more, the closer the birth date between two biological siblings, the more likely the younger one will be autistic: A birth interval of less than a year increases the odds threefold. No one knows what role (if any) microchimerism might play in sibling development—or in brain function. “It’s a wide-open question,” says Nelson. But low levels of foreign cells can affect how organs function, she notes, so it’s at least biologically possible. Tufts’s Johnson adds that it’s now legitimate to ask whether microchimeric cells could affect even cherished human faculties like memory and learning.

We usually think about a body containing only one person. Our cells even produce special markers on their surface to distinguish self from nonself. But in chimeras like Lydia Fairchild, cells from two distinct people inhabit the same body: She’s almost her own cellular twin. Cases like hers fascinate scientists because they upend our notions of identity.

Microchimerism “changes the way you look at the entire human experience,” says Johnson. We naturally form tight bonds with our mothers, he notes, “and to have that bond moving from ‘you’re in my thoughts’ to ‘you’re present in me’ is a powerful thing. You’re taking a relationship and turning it into something physical.”

Image: Miriam, Barbara and Alison
LIKE MOTHER LIKE DAUGHTER From left to right: Miriam, Barbar and Alison.
Peter Hapak
The mother-child relationship is especially poignant for Johnson. He began studying microchimerism in 1999, a few years before his own mother died of an autoimmune liver disease. During that time, he constantly shared his discoveries with her, including early evidence that microchimeric cells can fight diseases, not just cause them. So as his mother’s illness progressed, they took comfort in the possibility that his cells were battling on her behalf inside her, prolonging her life at least a little.

Even now, Johnson can take solace from another fact: Because of the two-way exchange of cells in the womb, he almost certainly has some of his mother’s cells secreted away inside him still. In some sense, then, she isn’t quite gone. “When you’re with someone in the end of her days, something that passes through your mind is immortality,” he says. “And to me immortality isn’t measured by living forever, but by influence.” Because his mother’s cells continue to act inside him, contributing to how his body—and perhaps even mind—work, his mother has achieved a sort of “perpetual cellular influence,” he says—a modest sort of immortality.

Few people ever face the kind of identity or legal crisis that Lydia Fairchild did. But as far as chimerism goes, all of us exist on a continuum with her. We each carry a little bit of someone else inside us, and their cells influence almost every organ in our bodies. When describing what this all means, Nelson likes to quote from Walt Whitman’s Song of Myself. Despite the title, the poem does not limit itself to one narrator or perspective. It encompasses a much wider view of the self, and some of its most celebrated lines presage the new biological and psychological reality of chimerism. “Every atom belonging to me as good belongs to you,” Whitman wrote. And, “I am large, I contain multitudes.” Thanks to microchimerism, so do we all.