Of mice and (wo)men

This month the National Institutes of Health (NIH) announced that scientists who use animals must now incorporate both males and females in their studies. Clinical studies of human subjects have had this requirement (albeit only for the final, Phase III trials) for more than two decades, but until now, scientists who study nonhumans have done so by and large with males, under the belief that experiments are simpler without those fussy hormone cycles that afflict females.

This announcement has made international news. But why? After all, most experiments are performed on mice and rats, animals that seem so distant from us in nearly all aspects that any differences arising from sex might seem negligible.

Except they’re not. Like it or not, rats and mice aren’t that different from us. Experiments using rodents were essential for nearly all we know of our own basic biology and for advances in treating disease. So the sex of mice does matter. And that’s crucial because diseases don’t adhere to equal-opportunity doctrines.

Immunological diseases such as multiple sclerosis, nervous system disorders such as autism and Parkinson’s disease, and the manifestation of heart disease, to name a few examples, show significant differences between the sexes — differences that can be recapitulated and understood by studying rodents. Studies limited to males may miss important therapeutic approaches helpful to females or, worse yet, suggest detrimental ones. As noted by the Society for Women’s Health Research, the Government Accountability Office found that from 1997 to 2000, 80 percent of the drugs taken off the market had disproportionately adverse effects for women.

Sex-specific differences in brain biology have important ramifications for all human beings, not just those unfortunate to have specific diseases. For example, we all have to deal with stress and the anxiety it promotes. Research from rodents has identified critical signaling molecules and mechanisms in the brain that mediate our responses to stress and lead to the expression of anxious states. Many of these molecules, such as corticotrophin releasing factor and brain-derived neurotrophic factor (BDNF) show striking differences between female and male rodents. Such discoveries garnered from rodent studies of both sexes have provided fundamental insights into sex-specific differences in anxiety disorders — disorders that are far more prevalent in women than in men.

These differences have important implications for general health as well. Take exercise, for example. It’s hard to pick up a magazine, surf the Web or watch TV without the benefits of exercise being extolled, not just for losing weight or cardiovascular conditioning but also for peace of mind. Research has shown that exercise decreases anxiety-like behaviors, a result tied to increases in BDNF. However, nearly all that research has been performed on male mice and rats. In the few studies in which females were studied, the relationship was far more equivocal. In many cases, exercise neither decreased anxiety nor altered BDNF in females.

So does that mean women should stop exercising? Of course not, but it does mean that if your husband comes home from the gym relaxed and released from the day’s trials and tribulations and you don’t, that may reflect a difference, not a deficit, in your biological makeup. Beyond the gym, understanding sex-specific differences in the brain circuits of rodents provides us with a better understanding of how men and women may deal differently with the many other challenges and stresses of our jobs, personal relationships and family demands.

The announcement from Janine Clayton and Francis Collins heralding the change in NIH policy has already met with criticism. Some critics suggest the news reflects feminists and women’s studies nuts run amok; others worry this policy will impose significant increases in costs on a scientific community already squeezed by retreating NIH support. 

The latter is a credible concern, and one hopes the NIH policy will show flexibility in execution. But overall, the NIH is to be congratulated for addressing a deficiency that has been evident for well over 20 years. Let’s hope that studies incorporating both Minnie and Mickey go far in pushing the boundaries of science for everyone.