We have always known that many types of biological research can be confounded by sex differences, and this is usually believed to be secondary to hormonal disparities between the sexes. In fact, that is why when we are investigating a particular pathway, mechanism, behavior, etc, we frequently carry out the studies in a single sex, and typically the male, unless there is a specific reason to study females. The NIH Revitalization Act in 1993 required that women be included in clinical research. It seems we are now moving down that path in preclinical studies as well where NIH will start requiring NIH-funded research to consider sex differences in the experiments. NIH is currently developing policies to ensure that applicants have a balanced male-female approach. It is expected that they will start rolling out these new policies before the end of 2014.

I understand that we may be missing crucial information by not comparing differences between males and females. Indeed, understanding why men and women have differing susceptibilities to a particular disease, say multiple sclerosis, may very well help us discover treatments and uncover disease mechanisms. But is having NIH enforce such comparative studies going a bit too far?

I recently posed this question to Dr. James Nelson, Professor of Physiology and the Barshop Institute for Longevity and Aging Studies. Dr. Nelson’s research focuses on the role of endocrine systems in aging. His response is below:

” It’s a challenging one. I agree with you that it is disturbing to have the NIH impose a blanket requirement on research to include both sexes in all studies. I have a natural distaste for being told what to do — and I think many others among us do as well. On first blush, I would agree that we should include samples from both sexes in our studies. It’s logical because the evidence is strong that there is sexual dimorphism in many biological traits. However, each research proposal is unique and there are always resource limitations and competing research priorities to be considered in the complex art of designing experiments. For example, if all NIH research proposals are required to use cells, tissues, and animals of both sexes, the question must be asked: how will that affect the rate at which we progress in our understanding of biological systems, since the costs for doing a given experiment will increase markedly, if not always two-fold. Indeed, one model suggested by Collins and Clayton is the “four core model”, in which 4 groups are studied: XX gonadal female, XX gonadal male, XY gonadal male, and XY gonadal female. One study they cite demonstrates sex differences in neuronal traits (there are many more referenced in the citation), the differences were often quantitative, not qualitative. Knowing these differences is important ultimately to understand the basis for sex differences in biological phenomena, but is it necessary to know in all studies — a requirement that would arguably slow progress in understanding basic mechanisms? The challenge is how to balance the need for, and benefit derived from, more studies of sex differences in biological phenomena against the significant costs–both financial and scientific– associated with doing so. Good policy requires compromise, taking into consideration competing interests and, most importantly, capitalizing on the creativity that wells from the diversity of individual intellects. Perhaps a compromise would be to require research portfolios of Institutes to have at least 10, 15 or 20% of grants include sex difference studies. Another idea would be to initiate RFA’s for sex difference studies. The RFA mechanism would capitalize on our greatest resource, individual scientists — challenging them to develop novel hypotheses and approaches. These and other policy instruments are more likely to advance our understanding of the mysteries of sexual dimorphism than would a blanket requirement for sex difference study in all proposals.”

A letter from Francis Collins, Director of the NIH, and Janine Clayton, the Director of the NIH Office of Research on Women’s Health, discussing this issue in more detail recently appeared in Nature.

What are your thoughts?