Amanda Marcotte of Slate asked this question last year in her piece covering changes to NIH policies on sex of research animals and cells. In 2014, the NIH released a multi-phase plan to reach greater balance of male versus female animals in pre-clinical studies.
Until recently, most research was conducted on all-male cohorts of animals and cells—male was considered the default gender. Using all males avoided heterogeneous results and the ‘issue’ of the female menstrual cycle. Many researchers felt that for the bulk of experiments, sex would not play a significant role.
I became increasingly interested in this topic when a paper was published in June of 2015 that described biological differences in the development of pain between female and male mice. Findings by Jeffrey Mogil and Michael Salter’s research groups suggest that while pain in male mice is driven by microglial cells, pain in female mice is likely driven by T cells. My reaction was: “What?! How is it possible that pain sensitivity is driven by completely different cells in males vs. females?” (This was also the paper that made me reconsider one of my Aims during my PhD qualifying exam… I primarily study female rats because I am investigating a pathology that occurs in female patients at a ratio of 9 to 1.)
I’m glad others felt the same way. Dr. Salter told Chemical & Engineering News, “Every time I talk about this, I look at the audience, and I can tell they simply don’t believe it,” he says. “And I tell them, ‘I didn’t believe it either at first.’”
Beginning in the early 1990s, the NIH, with the influence of the Office of Research on Women’s Health, (check out their website for lots of interesting information!), pushed for increased inclusion of women in clinical trials. Today, half of clinical trial participants are women. With this change, a number of important findings came to light, including different effects of low-dose aspirin in males versus females and discrepancies in dosing requirements for many drugs. Despite these changes in the clinical realm, the lab rats and cells did not follow suit.
However, in the wake of new NIH grant requirements and heightened awareness amongst scientists, practices are beginning to change. In the last year or so, a swath of interesting results point to how important sex-balance is in pre-clinical and basic science research. Please note that overall these findings are quite preliminary. These are some of my favorites from a variety of fields.
- Different immune cells mediate mechanical pain hypersensitivity in male and female mice (Nature Neuroscience, June 2015)
- Individuality and Variation of Personal Regulomes in Primary Human T Cells (Cell Systems, July 2015)
- Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination (PNAS, January 2014)
- Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction (Aging Cell, June 2014)
- IL-4 Is Required for Sex Differences in Vulnerability to Focal Ischemia in Mice (Stroke, June 2015)
- Sex and Genetic Factors Determine Osteoblastic Differentiation Potential of Murine Bone Marrow Stromal Cells (PLOS One, January 2014)
How can your work support sex-balanced pre-clinical research? Include male and female animals in your work, mixtures of XX and XY cells in your cultures, and report your findings. More messy? Certainly. But some really cool (and important!) stuff is in that mess.
If you are interested in learning more about animal-based research and would like to hear from a vet that specializes in laboratory medicine, check out my piece from earlier this year.