The battle of the sexes in biomedical research

Women’s rights activist Elizabeth Cady Stanton decreed that “all men and women are created equal,” a proclamation necessary to win women the right to equal representation in the eyes of the government. Ironically, I believe we now need to realize just how differently men and women are created in order to secure a new set of rights for women, that of equal representation in preclinical biomedical research. It isn’t news that males and females are biologically different (duh), but historically, scientists have conducted studies predominantly on male mice, presuming those discoveries would be applicable to both men and women; unsurprisingly, current research is pointing out the many flaws in this logic. In May of last year (2014), the National Institutes of Health (NIH), the agency that is charged with allocating government funds to research grants, announced policies that would require basic scientists to use both male and female mice in their studies.  The announcement of these policies included the following reasoning:

"The over-reliance on male animals and cells in preclinical research obscures key sex differences that could guide clinical studies. And it might be harmful: women experience higher rates of adverse drug reactions than men do. Furthermore, inadequate inclusion of female cells and animals in experiments and inadequate analysis of data by sex may well contribute to the troubling rise of irreproducibility in preclinical biomedical research, which the NIH is now actively working to address."

As with most changes in funding policies, there was pushback on the NIH’s new policy. Including both male and female mice would almost certainly increase variability, resulting in more time and resources spent on answering experimental questions. As a sixth year graduate student, I whole-heartedly agree that no scientist wants to see those two factors increase. One suggested solution was to increase allocated funds for studies specifically designed for “sex differences research.” This essentially would give scientists the allowance to presume what may or may not differ between the sexes. My personal experience over the past months calls bullshit.

I use mice as a model system to study cells of the sympathetic nervous system, which regulates the “fight or flight” response we experience when faced with a stress trigger (i.e. a big exam, public speaking, or a swerving car).  Specifically, I examine how signaling through a specific protein helps sympathetic neurons develop connections with another type of neuron. There’s no reason to think there would be sex differences in the basic circuit that I study—both males and females have these cells, both males and females develop the same inter-neuronal connection, and that connection functions similarly in both males and females  to control pupil dilation, increased sweating and increased heart rate, among other things. However, after a relatively long struggle with results that didn’t always add up, I discovered the missing piece of the puzzle: male and female mice have inherently different expression patterns of that specific protein in sympathetic neurons. Imminently, this means that I can move forward with my experiments and have cleaner data by examining results according to gender. But I’m intrigued—what does this mean more generally for how cells of the sympathetic nervous system connect to form circuits and thus function? And I’m hooked on the possibility that differences between the sexes may be more common than most scientists currently think.

Supporting my new take on sex differences is an interesting article on pain I recently came across in the journal Nature Neuroscience from Jeffrey Mogil’s lab.  For years, Mogil has called for equal representation of male and female mice in pain research, and his recent paper illustrates the point that males and females have differences even in unsuspected areas such as chronic pain. Essentially, the study demonstrates that drugs that work in male mice to help reduce hypersensitivity to pain do not reduce hypersensitivity to pain in female mice. Why?  Because the pain causing mechanism is fundamentally different between the sexes. This is an important finding because one of the drugs used in the study was actually used in a clinical trial for neuropathic pain—a clinical trial that included both men and women. This work underlines a major flaw in studying only one sex in basic science studies. Adding fuel to the painful fire is the fact that women make up the majority of chronic pain patients. How is studying only male mice fair to those women?

My own experience and current publications are pointing to the fact that we, as scientists, cannot predetermine which biological systems will show sex differences. It seems clear that preclinical studies need to do their due diligence and include both genders in order to provide information that would be relevant to both men and women. The new NIH policies may not be perfect in how they are requiring this, but it seems to me that every researcher should remember that sex matters, so that all men and women patients can be duly represented.