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Ideas | Viviane Callier

How gender makes a difference in disease


Many diseases affect one sex disproportionately. Women, for instance, get autoimmune diseases more often than men do, whereas men are at higher risk of non-reproductive cancers such as lung, colon, and kidney cancers. But the question has always been why.

In a recent paper in Trends in Genetics, evolutionary biologist Melissa Wilson and her colleagues at Arizona State University propose an intriguing hypothesis based on our deep evolutionary history.

From egg-laying ancestors, mammals evolved a new way to reproduce that involved a uterus and placenta. The evolution of pregnancy required the immune system to walk a tight line between fending off pathogens while tolerating the placenta — genetically foreign fetal tissue that invades the mother’s uterus.


“Pregnancy is a super dynamic immunological event,” says Andrea Graham, an ecological and evolutionary immunologist at Princeton who was not involved in the study. “Basically, successful pregnancy in mammals requires quite an incredible array of immune gymnastics.”

For most of human history, women were either pregnant or lactating almost constantly from menarche to menopause, so their immune systems were always hanging in that careful balance. That’s no longer true in our modern societies, where women have fewer children and generally have them later in life. Without the placenta and fetus to dampen immune cell activity, women’s immune systems could more easily fall into overdrive, leading to autoimmune symptoms.

Add to this the well-known “hygiene hypothesis,” which is the idea that in our modern, industrialized societies, we are no longer exposed to the microbes and parasites that we co-evolved with for thousands of years. Those microbes and parasites found ways to recalibrate our immune systems, toning down the inflammatory responses of our bodies to ensure their own survival, and protecting us, too, from the consequences of a too-strong immune response.

The fact that women in modern societies no longer spend most of their reproductive years pregnant, along with this relatively recent lack of parasites, has left our immune systems bereft of key regulators. This could explain the higher incidence of autoimmune disease in women, the researchers argue.


Immune hypervigilance, however, may provide such advantages as better surveillance and culling of cancer cells, which could explain why many non-reproductive cancers have higher incidence in men. The idea also could explain anecdotal observations, for instance, that women on the whole tend to respond better to cancer immunotherapy than men, Wilson says.

Now the researchers are working to test several predictions. For example, women who have had many pregnancies are predicted to have lower rates of autoimmune disease than those who have had no pregnancies.

If their hypothesis is confirmed in forthcoming studies, it could have big implications for human health. For instance, it would mean that pharmacologically “tricking” the body into “thinking” it has had a pregnancy could be a strategy to alleviate autoimmune symptoms, Wilson suggests. In fact, some hormonal birth control methods work by mimicking pregnancy, and it might be possible to use them to rein in autoimmune symptoms, Graham adds, though she cautions that there isn’t enough data yet and applications to medicine are still far afield.

Although recently developed, the idea, which the researchers call the Pregnancy Compensation Hypothesis, brings together well-established observations from different fields, says anthropologist Amy Boddy at University of California Santa Barbara: “It is really novel and exciting because it opens up the door to study some of these complexities from a different angle.”


Wilson and her colleagues believe taking an evolutionary perspective could bring completely new approaches to treating not just autoimmune disease in women, but a variety of modern diseases.

“Evolution shaped our bodies, and it still does. It is going to be game-changing when we connect with clinicians to change how we think about health,” Wilson wrote by e-mail. “Many ‘diseases’ are actually natural bodily responses, as a consequence of hundreds of thousands, or millions of years of evolution.

“When we can stop treating these classes of diseases as if they are malfunctions of the body, and understand how they came to be, and how they’re the body’s natural response to our industrialized environment, I think we’ll start to make leaps of progress in improving quality of life,” Wilson wrote.

Viviane Callier is a science writer based in San Antonio, Texas. She holds a PhD in biology from Duke University. In addition to her journalistic work, she does some freelance contract work for the National Institutes of Health, which funded part of the research reported in this article.