About 65 million years ago, shortly after the time of the dinosaurs, a new critter popped up on the evolutionary scene. This “scampering animal,” as researchers described it, was likely small, ate bugs, and had a furry tail. It looked, according to artistic renderings, like an especially aggressive New York City rat. And it had a placenta, an organ that grows deep into the maternal body in order to nourish the fetus during pregnancy.
The rodentlike thing would become the common ancestor of the world’s placental mammals, with descendants that include whales, bats, dogs, and humans, among many other species. And today, the placenta might hold the key to one of the most enduring mysteries in human medicine: Why do women suffer much higher rates of autoimmune disease than men do?
Autoimmune diseases turn people’s own immune systems against their bodies. In the United States alone, women represent 80 percent of all cases of autoimmune disease. Women are 16 times more likely than men to get Sjogren’s syndrome, in which the immune system goes after the glands that make tears and saliva, and nine times more likely to have Hashimoto’s thyroiditis, in which it sets its sights on the thyroid. Sjogren’s forced Venus Williams to drop out of the U.S. Open in 2011. The singer Selena Gomez underwent a kidney transplant after suffering complications from lupus, which is eight times more common in women than in men.
Some scientists now think the placenta itself might be the reason why women are so disproportionately affected. In a paper published last week in the journal Trends in Genetics, Melissa Wilson, an evolutionary biologist, along with her colleagues from Arizona State University, put forward an explanation called the “pregnancy-compensation hypothesis.” It suggests that women’s immune systems are engaged in a fierce tug of war with placentas, even when the organs aren’t actually present.
Here’s how the theory goes: Women—and all other placental mammals—evolved such that they would be pregnant for many of their adult years. Before the advent of birth control, that was pretty much the fate of the female sex. In modern hunter-gatherer populations, Wilson told me, it’s not uncommon for women to have eight to 12 children each.
Though bearing so many babies might sound grueling, women’s bodies evolved to cope. When the placenta grows during pregnancy, the organ sends signals to the mother’s immune system to change its activity so that the mother’s body doesn’t eject the placenta and the fetus. This might even mean turning down the immune system in some ways, or for some periods of time. Turning down the immune system too much, though, risks leaving women sensitive to pathogens, which would also be bad for the fetus. So instead the mother’s immune system ramps up in other ways throughout adulthood, Wilson and her colleagues think, so as to remain vigilant against germs even when some of its parts become dormant during pregnancies.
Things get complicated, however, when those pregnancies don’t actually occur. Women today tend to have far fewer children—fewer than two on average in the United States, according to the CDC. Wilson reasons that without a more or less constant pushback from placentas during pregnancies—the pushback that women’s immune systems have evolved to anticipate—the immune system can get too aggressive, too ramped up. It starts looking for things to attack that aren’t dangerous, which is how autoimmune diseases set in.
For millions of years, minus the past 100, “the immune system was expecting to have exposure to a placenta,” Wilson says. Imagine if you’re pulling on something heavy, and then the rope snaps. “If you suddenly don’t have that heavy thing anymore,” she says, “you’re gonna go off the moon.”
This is certainly not the first theory for why women suffer from more autoimmune disease than men do. One has to do with a protein called BAFF; another has to do with the fact that women have two X chromosomes instead of one. The way Wilson sees it, the pregnancy-compensation hypothesis synthesizes many of the previous theories into one and provides the evolutionary explanation behind them. “They were all right,” she says. “But everyone was looking under their own streetlight, and we just waited for it to be daytime.”
Wilson says that so far, no one has come forward to attack her for being wrong, despite the seeming boldness of this theory. Several experts I spoke with—even those who have competing theories for the sex difference in autoimmune disease—say Wilson’s theory might fit with what we already know. “I would say there’s not one theory that explains all [autoimmune diseases],” says Nikolaos Patsopoulos, an assistant professor of neurology at Brigham and Women’s Hospital. “This isn’t Lord of the Rings.” Still, he says, “this theory puts together a lot of things we know that are true and some that we’re still trying to understand.”
Johann E. Gudjonsson, a professor of skin molecular immunology at the University of Michigan, found that women have more of a molecular switch called VGLL3 in their skin than men do, and that all this VGLL3 might be what causes a heightened immune response in women. In this case, then, the VGLL3 might be how the body ramps up the immune system, but the pregnancy-compensation hypothesis might be why it does so.
Similarly, Hal Scofield, a professor of pathology and medicine at the University of Oklahoma, says that it appears there are lots of genes involved in the immune response on the X chromosome, and because women have two X chromosomes while men have only one, women have more of those immune genes. The placental theory that Wilson’s team devised could be the reason this happens. Because women have to have strong immune systems that buck against the placenta, they evolved to produce more genes involved in the immune response. “I don’t think there’s any way out of thinking that placental pregnancy has to have influenced the evolutionary immune system,” Scofield told me.
Not everyone I reached was impressed by the paper. David Hafler, a professor of neurology at the Yale School of Medicine, told me, “Ideas are cheap. It’s data which is hard to get.” In other words, sure, the pregnancy-compensation hypothesis is an interesting idea, but it still has to be tested.
Wilson says there are opportunities to do just that. Scientists could try to determine whether the number of pregnancies a woman has is predictive of her risk of autoimmune disease. If Wilson’s theory holds, women who have more pregnancies should have a lower risk. Or scientists could study the differences between mammals in the wild and zoo animals, which are sometimes on birth control, to determine whether they have differences in their autoimmune function.
Some people might take Wilson’s findings to mean that women should simply be pregnant all the time, but that’s far from the takeaway here. Pregnancy, after all, also carries major health risks, and not all women want to have 12 kids. And Wilson’s findings suggest that women’s extra-strong immune systems might protect them in some cases. Women are less likely than men to get certain kinds of nonreproductive cancers, for example.
Wilson says that the hope is to eventually learn what it is in the immune system that’s trying to respond to the placenta, and to target that thing with vaccines or treatments. More research could mean major improvements in the way women’s autoimmune diseases are treated. “I’ve never been more excited about an idea than I am about this,” Wilson told me. “This is the first time that I can see my work having a direct impact in the next 10 years on human health.”
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