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NIH to Ensure Equal Study of Sexes in Preclinical Research

Adapted from a story that originally appeared on the Alzforum.

May 20, 2014. The National Institutes of Health (NIH) has announced policies to ensure that males and females receive equal representation in preclinical research. Announcing the agency’s plans in a joint comment published in Nature on May 15, Janine Clayton of the NIH Office of Research on Women’s Health (ORWH) and NIH Director Francis Collins wrote that they aim to balance the study of not only male and female animals, but male and female cells, as well. A majority of preclinical studies use male material only. This skews understanding of disease and creates possible deleterious effects to women at the receiving end of such data, i.e., in clinical trials and approved drugs, the authors wrote. The new NIH policies stipulate that grant awardees use both male and female animals and cells in their research. They will be phased in beginning October of this year.

“Sex makes a difference,” Clayton told Alzforum. “You’re basically getting a half-truth if you don’t look at both sexes for a disease that affects both sexes. We want to know the whole story, and that’s what we’re asking.”

Thanks to women’s health advocacy groups such as the Society for Women’s Health Research (SWHR) and NIH leaders, the passage of the NIH Revitalization Act in 1993 required that women be included in clinical research. Preclinical research got a pass, however, and research continues to favor male animals, in part due to concerns about confounding influences of the estrous cycle. However, as Clayton and Collins noted in the commentary, a recent meta-analysis reported that female mice showed no more variability in experimental outcomes than male mice in studies that spanned their hormone cycle (see Prendergast et al., 2014). Beyond endocrinology, researchers have leaned primarily on male mice simply out of convention, they wrote.

The new policies will require all NIH grant applicants to provide for equal use of female and male model systems in their research proposals. The agency will offer training materials to NIH staff, trainees, and grantees on how to design sex-balanced experiments. Furthermore, the NIH will partner with research journals to ensure that gender balance is taken into account when studies are published. Initially, the NIH will award supplements to existing grants to facilitate the addition of experiments using animals or cells of both sexes.

“In terms of therapeutics, this is a step toward understanding, from the very beginning, what may or may not work for both men and women,” said Phyllis Greenberger of SWHR. She added that the shift has been a long time coming, and that a more balanced approach is important for acquiring a basic understanding of the biological differences between men and women.

How might this affect researchers studying Alzheimer's or other neurodegenerative diseases? Michael Greicius of Stanford University in California praised the move. “I think it’s high time. [The new policy] makes good sense both in terms of clinical relevance but also in terms of biology and understanding complex diseases,” he said. Greicius’ work helped to show that the effects of the ApoE4 allele raise the risk of AD much more in women than men (see Altmann et al., 2014).

“I think most neuroscientists have presumed that sex differences in non-reproductive parts of the brain, if they exist, are subtle variations on a common theme,” Catherine Woolley of Northwestern University in Evanston, Illinois, wrote in an email to Alzforum. “Yet, we found a sex-specific mechanism at work in the hippocampus. It is hardly subtle when something occurs in one sex and not the other.”

Michael Sasner of the Jackson Laboratory in Bar Harbor, Maine, agreed the new gender policies are a step in the right direction. He also said he hoped the NIH would step up funding to cover the cost of additional experiments beyond the announced supplements to existing grants. Gender differences are pervasive in mouse models of disease, particularly those that involve the immune and vascular systems, such as AD, Sasner said. “Wherever people have looked, they’ve seen differences,” he said. Examples include mouse models of APP overexpression, such as the 5xFAD, APP23, and Tg2576, in which female animals face a greater amyloid plaque burden or faster deposition (Bhattacharya et al., 2014; Sturchler-Pierrat and Staufenbiel, 2000; Callahan et al., 2001). Many papers, such as the recently published description of APP knock-in mice (see Saito et al., 2014), don’t report the sex of the animals used in experiments, Sasner said, an omission he hopes will change along with more detailed reporting of genotype and genetic background information.

Existing efforts to standardize preclinical drug studies already call for gender matching of mice, but are not universally applied (e.g., Shineman et al., 2011).—Jessica Shugart.

Clayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature. 2014 May 15; 509(7500):282-3. Abstract