A call for balance

NIH to require grant applicants to report cell, animal sexes in preclinical studies

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BETHESDA, Md.—In the latest step of a journey toward more balanced studies, the U.S. National Institutes of Health (NIH) has announced that, moving forward, grant applicants will be required to report the sex of the animals and cells used in preclinical studies. Janine A. Clayton, director of NIH’s Office of Research on Women’s Health (ORWH), and Francis S. Collins, director of the NIH, detailed the need for more balanced research and the NIH’s plan for engendering such changes in a recent Nature commentary.
Science has shown that sex plays an undeniable role in the biological responses to disease and medicine. This can be seen in several conditions, such as heart attacks, substance abuse, multiple sclerosis and depression, in which symptoms and condition severity vary between the sexes. Drug reactions can also differ, as with aspirin, and require different dosages, as with zolpidem. A 2007 study published in Pharmacological Research, “Gender differences in drug responses,” noted that women tend to experience higher rates of adverse drug reactions than men.
As for the in-vitro side of things, even male and female cells have been shown to have disparate reactions to chemical and microbial stressors.
“These intrinsic differences are hormone-independent but also exhibit further variation on differentiation and exposure to sex hormones,” wrote Collins and Clayton. “It is well known that many neurological conditions are sexually dimorphic, and cell-culture studies have demonstrated that male (XY) and female (XX) neurons respond differently to various stimuli. Male neurons are more sensitive to stress from reactive oxygen species and excitatory neurotransmitters; female neurons are more sensitive to some stimuli that prompt the programmed cell death known as apoptosis. Data support distinct cell-death signaling in female and male neurons with potential applications in treatments for stroke, brain injury and other conditions.”
The NIH has taken a number of efforts to encourage a balance of the sexes in later-stage research over the years. The ORWH was established more than 20 years ago, when the Congressional Caucus for Women’s Issues, women’s health advocacy groups and NIH scientists and leaders concurred that excluding women from clinical research hampered science and was a disservice to women.
Some years later, in 1993, the NIH Revitalization Act was passed, which required the inclusion of women in NIH-funded clinical research; now more than half of all participants in NIH-funded clinical studies are women. Last year, the ORWH launched a program that offers supplemental funding to existing grants for the addition of “subjects, tissues or cells of the sex opposite to that used in the original grant, or to increase the power of a study to analyze for a sex or gender difference by adding more subjects of either sex to a sample that already includes both males and females.”
Unfortunately, balance has continued to be absent in earlier research stages.
There are multiple causes for the disparity in terms of in-vivo animal experiments; many researchers prefer male animal models due to the mistaken belief that the effects of the oestrus cycle on female physiology skew results, while other studies might prefer female animals, as they, unlike males, are not prone to fighting if housed together.
Not everyone feels that the requirement of equal numbers of models of both sexes is the way to solve the problem, however. Brad Bolon, a veterinary pathologist at Ohio State University, commented to Nature that such a requirement could be costly, as researchers might have to double the number of animals they use to get results of statistical significance for both sexes. A more direct method to encourage greater equality of this nature, he posited, would be for journals to require the reporting of variables such as sex in the methods sections of papers.
That is one of a number of plans the NIH has for addressing this imbalance; though it does not control publication of sex and gender analyses of NIH-funded research, Clayton and Collins said the organization “will continue to partner with publishers to promote the publication of such research results.” Moving forward, the ORWH will continue its work with the U.S. Food and Drug Administration in co-funding the Specialized Centers of Research on Sex Differences program, an initiative that supports interdisciplinary collaborations on the influences of sex and gender on health.
The NIH is also crafting policies that will require applicants “to report their plans for the balance of male and female cells and animals in preclinical studies in all future applications, unless sex-specific inclusion is unwarranted, based on rigorously defined exceptions,” and will use data-mining techniques to monitor compliance with sex and gender inclusion policies in the preclinical research it funds. Implementation of the policies is expected to begin in phases as of October 2014, said Clayton and Collins, and the NIH’s review process will be modified to coordinate with applicant requirements.

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