News & Events

Guest Director's Letter: Considering Sex as a Biological Variable in NIH-Funded Preclinical Research

NIH NIAMS NIAMS
Special Announcement
August 20, 2015

I am delighted to introduce Janine Clayton, M.D., Director of the NIH Office of Research on Women’s Health. Dr. Clayton is leading the NIH’s initiative to ensure that NIH-funded investigators consider sex as a biological variable in their pre-clinical research.

If you have comments or questions, please send them to Anita Linde, M.P.P. lindea@mail.nih.gov.

Stephen I. Katz, M.D., Ph.D.
Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases

Guest Director's Letter: Considering Sex as a Biological Variable in NIH-Funded Preclinical Research

Dear Colleagues:

Over the past year, NIH has invested considerable time and effort toward ensuring that federally funded research that affects human health is the best it can be: both rigorous and reproducible. But there’s another "R" — NIH-funded research must also be relevant.

Photo: Janine Clayton Dr. Janine A. Clayton, NIH Associate Director
for Research on Women’s Health; Director,
NIH Office of Research on Women’s Health

Preclinical research, which is performed in model systems such as animals, intends to test the waters for ideas that will ultimately be used as treatments in people. And at the most basic level, people — and animals — come in two forms: female and male. As such, sex is a basic biological variable, and it is encoded in our DNA, giving us XX/XX chromosomes (females) or XX/XY chromosomes (males). Sex, and gender (a psychosocial construct), affect us from head to toe. Both can affect health and influence how diseases appear and progress, and they also factor into the development of safe and effective drugs and other interventions.

However, although women now comprise roughly half of the participants in NIH-funded clinical trials, the same is not true for preclinical research. A majority of animal studies have focused on males, and investigators studying cell models have often ignored the sex of the animal from which the cells were obtained. For the most part, looking for differences between males and females has been a blind spot in biomedical research, leaving gaps in our knowledge. But another roadblock has been the female estrous, or reproductive hormone, cycle. Many scientists have perceived that female hormonal cycling introduces too much variability into study design, but good science cannot ignore this physiological reality. Moreover, male animals have other, equally variable characteristics such as dominance hierarchies — meaning they fight when housed together. In fact, on the whole, males are slightly more variable than females, as shown by a recent meta-analysis.

Pain is one particular gap area in which the majority of preclinical research has been performed in male animals, but exciting new findings reveal that different immune cell types mediate certain types of pain in males and females. This new work shows how important it is to study both sexes in research on pain--an unfortunately common symptom of many chronic ailments and a significant issue in women’s health.

In June 2015, the Office of Research on Women’s Health and the Office of Extramural Research announced in the NIH Guide that, beginning in fall 2016, scientists must account for the possible role of sex as a biological variable (SABV) in vertebrate animal and human studies. In short, applicants will be asked to include SABV information in the Research Strategy section of applications, and study sections will be reviewing this information.

Let me say that NIAMS and its grantees have been longstanding leaders in this area, so this may not be news to you. Years of high-quality research considering both sexes has given us new insights into many health issues within the NIAMS mission: autoimmune disorders like lupus and rheumatoid arthritis, osteoarthritis, and bone and joint health, just to name a few. So thank you for so much excellent science that has considered both sexes, and that has delivered findings that are at once fascinating and vitally relevant to the health of women.

"Turning discovery into health." At NIH, we speak this, we write this, we think this. It is indeed the end-goal of taxpayer-funded biomedical research. Our work must have relevance for all Americans: women, men, girls, and boys. In 2015, we must make every research dollar count, and studying both sexes is an excellent way to achieve this goal.

Sincerely,

Janine A. Clayton, M.D.
Associate Director for Research on Women’s Health
Director, Office of Research on Women’s Health
National Institutes of Health