Animal studies are the backbone of medical and scientific research. Because of animal testing, humans have developed vaccinations for smallpox, nearly eradicated polio, discovered chemotherapy, and made countless other innovations across the medical spectrum. But there’s a major flaw in the way we conduct these experiments: Far too many animal tests ignore biological sex entirely.
A new study from the Wellcome Trust Sanger Institute, published in Nature Communications, argues that too many animal experiments have failed to take into account sexual dimorphism—the traits that differ between sexes in a species, from size to bone density to coloring. This blind spot may be skewing the results of animal testing. And that could have big consequences for the conclusions that we take from animal studies and apply to humans.
Science has a long history of making incorrect assumptions about biological sex that skew testing on live subjects. For much of history, scientists have tended to regard female bodies as simply scaled-down versions of males, which meant that one could just test on men and draw conclusions about women’s medical needs. This has backfired repeatedly. In one notable case, in 2013, the US Food and Drug Administration had to cut the recommended dosage for zolpidem (Ambien) for women by half after it was discovered that taking a “normal” dose often resulted in serious overdoses for women.
At the same time, scientists thought female bodies were too complex and variable to be reliable test subjects, owing to monthly hormone cycles and menstruation. As it happens, male test animals show as much hormonal variation as female animals, so that argument has since been disproven. We also now know that the female body, in many ways, operates differently than the male body. New evidence this week shows that female brain patterns are more active than men’s, a revelation that joins a corpus of science proving that women, far from being “tinier men,” are a category unto themselves.
Women were also viewed as particularly vulnerable if experiments went wrong, both because of impacts on fertility and childbearing, and because of perceptions of greater physical “delicacy.” Up until 1993, American females of child-bearing age were banned from taking part in early research of any kind as subjects. As a consequence, male-centric trials have been the norm for much of medical history. Unfortunately for everybody, this exclusion has ignored the fact that female “imperfection” as test subjects doesn’t preclude women’s need for medical care. After all, sex has been shown to influence the development, progression, and symptoms of conditions like multiple sclerosis, strokes and migraines, asthma, and a host of other illnesses.
It’s been legally necessary to include women in clinical trials in the US since 1994. But progress has been slow. A study in 2009 found that compliance with the laws was still low in many published experiments. And the debate around sex, gender, and inclusivity has, until now, centered on humans, neglecting to consider how the issue may be replicated in animal research.
The Nature Communications analysis explicitly aims to explode some of the myths surrounding biological sex testing in animals—namely, that it’s unnecessary and a waste of resources. Sex doesn’t exert enough influence on our most favored experimental animal, the humble mouse, to require testing both males and females, right?
Au contraire, the results say. The scientists of the Wellcome Trust Sanger Institute looked at the many ways in which sexual dimorphism influences genetic traits in mice, using 14,250 normal mice (whose genetics were untouched) and 40,192 mutant ones (who had at least one gene “knocked out” for research purposes).
The study looked at two distinct types of traits. Qualitative traits, like eye color, are controlled by a single gene or small group of genes, and don’t really change in response to the environment. Quantitative traits, like metabolism or height, are controlled by a big group of genes and can be responsive to outside influences. The conclusion? A huge number of genetic traits in the mice showed distinct signs of influence by sex.
In normal or wild-type mice, 9.9% of qualitative traits and 56.6% of quantitative ones were influenced in some way by sex. And even in mutant mice with deliberately altered genes, 13.3% of qualitative traits and 17.7% of quantitative ones were sexually modified in some way. That, to put it mildly, is an experiment-altering amount of difference.
The problem in animal testing has been so frustrating for so long that the National Institute of Health took to Nature in 2014 to yell at scientists for not even bothering to use female lab animals—much less account for sex in their experiments. And now we know that the most commonly tested animals in medical history have bodies that react to sex differences across the genetic spectrum. The implications are pretty intense: This blindness has a direct impact on biomedical research, and might be part of the reason why progressing from animal trials to human medicine is so tricky.
Mice are also not the “typical mammal,” despite being sold as such to generations of biologists. And many findings for animals don’t necessarily apply to human beings. But if more experiments accounted for sex, we’d close at least part of the gap between the human and the animal.
The costs of neglecting female biomedical responses have been evident for a while now. Eight of the ten drugs withdrawn by the FDA between 1997 and 2001 (pdf) were taken off the market because of serious side effects for women, from birth defects in children to increased cancer risk. In most cases, the drugs were recalled after female patients went public with negative consequences. And evidence has shown that women’s bodies metabolize various medications in different ways, from antipsychotics to anesthetics—differences that have huge consequences for treatment and surgical practice.
Animal studies are meant to be the first line of exploration in discovering new ways to understand and conquer human disease. Leaving sex out of the equation means that women and men are both hobbled at the starting gate.