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Discussing the NIH Mandate to Study Sex as a Biological Variable in Basic Biomedical Research

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In one of my courses in the neuroscience Ph.D. program at Johns Hopkins, we recently discussed the 2016 National Institutes of Health (NIH) mandate requiring consideration of sex as a biological variable in grant applications to NIH agencies. Citing the success of the initiative to include both men and women in human clinical trials, the NIH hopes that including both male and female animals in preclinical studies will reveal sex differences in biological phenomena that could have relevance to human health.

Now, investigators who apply for NIH funding (and use vertebrate organisms in their research) must design studies that allow for examination of differences across sex, or they must explain why it is not practical or appropriate to include subjects of both sexes. The hope of the NIH is that investigators will analyze their data for differences across males and females and report these findings in their publications.

In our class discussion, led by fellow neuroscience students—Jessie Benedict and Lionel Rodriguez—we reviewed two opposing arguments published in the Journal of Neuroscience on the effectiveness of the NIH mandate. The first explains how studying sex as a biological variable will strengthen neuroscience research findings and improve our ability to translate the findings to human care. The second outlines the limitations of studying sex differences in animals to understand the multifaceted differences between men and women.

There are benefits of studying sex differences in vertebrate research. One is an enhanced understanding of a scientific phenomenon in the organism of interest. For instance, in a study characterizing a certain group of cells in the mouse brain, we can draw stronger conclusions about the purpose of the cells if we find that they function similarly in both male and female mice. Or, if there is a difference between males and females, that could be an indication that those cells contribute to the variability across individuals. Nevertheless, we cannot be too quick to call this a sex difference. Males and females can also differ greatly in size, body fat and activities such as grooming, which could be better determinants of the difference than sex.

Another benefit, and the one most advertised with the mandate, is an improvement for human health. It is well understood that men and women can have different manifestations (and underlying causes) for psychiatric diseases like addiction, depression, schizophrenia and bipolar disorder, and there is the possibility that men and women will respond differently to drugs designed to treat these diseases. The idea behind the mandate is that studying neuroscience principles in both male and female animals will develop insights into these differences between genders and lead to development of drugs that are better suited to men and women.

This second point is one that the second article highlights as suspect. Often, differences between male and female mice, for example, fail to hold up in humans. Indeed, our models of disease in nonhuman vertebrates are already imperfect, so sex differences observed in animal subjects are unlikely to reveal real differences that also occur in humans. This is particularly true when one considers that the differences between men and women extend well beyond biological sex—there is also gender identity, related to socialized expectations of masculinity and femininity. This complex process is not captured by studies of male and female model organisms.

Regardless whether the results of sex-specific animal studies can be directly translated to humans, we can learn a lot about a biological principle through comparison across males and females of the same species. Historically, surprisingly few studies have explored the role sex may play. The second article found that, in a year prior to the mandate, 28 percent of neuroscience research articles using rodents failed to even mention the sex of the subjects, and another 32 percent exclusively studied males. In order to fully understand the brain (or any biological system), it is prudent to look at the system across a variety of individuals, including those of different sexes. The NIH mandate should, at least, make researchers more conscious of which sexes they study and how they report the findings. With time, we will see whether the mandate will achieve its loftier goal of lessening disparities in men’s and women’s health.

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