“Becca! Becca! I have something to tell you!”
During a conference coffee break in 2019, I looked up to see a long-time colleague approaching me with what appeared to be great urgency. What could his exciting news be? I wondered. He looked at me and beamed. “I studied a female!”
On the surface, you might not think that the simple act of performing an experiment on a female mouse should be cause for such celebration. But for decades, most behavioral neuroscientists routinely excluded female animals from their research under the false assumption that the daily hormonal fluctuations associated with the estrous cycle would make it difficult to interpret their data. Those of us who were explicitly interested in studying sex differences in brain function were told that we needed to “control” for the influence of ovarian hormones on our experimental measures, as if the endocrine system were some kind of external confound and not a fundamental component of an animal’s physiological state.
Thanks to advocacy efforts led by scientists and staff at the National Institutes of Health’s Office of Research on Women’s Health (ORWH), in 2016 the NIH implemented what was arguably one of its most consequential new policies, “Consideration of Sex as a Biological Variable” (SABV). The policy stated that basic science grants submitted to NIH must propose to use equal numbers of male and female animals in their experiments, as part of a broader initiative to improve rigor and reproducibility across biomedical research. As basic science findings make their way up the translational pipeline, knowing how universally the discoveries we make at the bench might apply in the clinic is critical. Because both the prevalence and symptoms of dozens of disorders—from Parkinson’s disease to post-traumatic stress disorder—can vary according to a person’s sex, identifying underlying mechanisms that may be sex-dependent could be a big step toward improved personalized medicine.
At first, the policy rollout was met with resistance—many saw it as an unwelcome requirement to reallocate their funds to pay for additional animals. But slowly things began to change. Like my proud colleague, some scientists chose to adhere to SABV in good faith and found that not only was studying females not as complicated as they had imagined, but that doing so allowed them to uncover exciting new sex differences in the brain that could lead to novel therapeutics. SABV in neuroscience research was becoming normal (dare I say cool?) instead of niche, and I couldn’t have been happier.
Enter the second Trump administration, which within the first two weeks of taking office had largely scrubbed the ORWH website of SABV-related content, including helpful resources to assist those newly attempting to bring females into their work. No explanation for the cuts was provided, but given that words such as “sex,” “female” and “women” (but not “male” or “men”) appeared on a list of “woke” topics that could cause grants at the National Science Foundation (the other major scientific research funding agency in the United States) to be flagged for review, one might speculate that decisions here were similarly motivated.
SABV’s future as an official NIH policy remains unclear. But even if it is ultimately stricken from the record entirely, let’s keep doing it.
W
itnessing the SABV cultural shift in my field has brought me a great deal of joy and satisfaction. Five years ago, I assembled a “sex differences”-themed panel for a conference on stress and alcohol research, hoping to convince attendees how important SABV was for their work. The conference was canceled that year because of the COVID-19 pandemic and rescheduled for 2023, with our panel slotted for the final day. I did not expect to hear about research in females until then, but to my pleasant surprise, at least half of the speakers in the other panels presented data from males and females, often highlighting unexpected sex differences in their findings. When I finally took the podium to introduce my panel, I started by saying, “I’m thrilled to see that this panel was entirely unnecessary.”The SABV sea change has been palpable at more recent meetings too, to the point where it seemed that scientists who presented data collected only in males felt the need to make excuses or explain why they continue to take such an outdated approach.
Today, the fate of SABV hangs in a confusing state of limbo. The formal notice of the policy, dated June 2015, remains available on the NIH.gov website. But the accompanying Guidance Document was labeled a “historic document” late in February and has since been removed entirely. For myself and dozens of colleagues who have spent the past 10 to 20 years working to convince the neuroscience community of the value of SABV—and to finally see the needle move in the right direction—to have so much expunged in the course of a few weeks has been crushing. Years of progress, erased with the click of a button.
The disruptions to NIH operations over the past two months have been mammoth, unlike anything most of us have witnessed in our lifetimes. In March, $250 million in federal grants was canceled at Columbia University, halting work on hundreds of projects and stripping Ph.D. students of their stipends. Many of us feel helpless and scared for our future as scientists, wondering whether our work will even be allowed to continue. Right now, it is all the more important that those of us lucky enough to keep our research programs alive focus on what we can control: the integrity of the knowledge we generate in the lab and share with the world.
More than ever, demonstrating to the taxpaying public that neuroscience research will have long-term benefits for everyone is of the utmost urgency. Most nonscientist audiences I’ve spoken to are astounded when I tell them that historically, females have been excluded from biomedical research. “But we’re half the population!” many women exclaim in disbelief. Although the paths from basic science discoveries to clinical application will likely not divide neatly according to sex, keeping SABV practices in place will ensure that our findings lead to treatments that help as many people as possible.
With almost 10 years of the initiative behind us, we’ve reached a point where I believe most neuroscientists recognize that adhering to SABV in our work is the right thing to do, both for scientific rigor and translational relevance of our findings. Even in the absence of formal instruction to do so, we should continue to hold our colleagues accountable for SABV practices in grant and paper review and lead by example in our own labs, using equal numbers of male and female animals in most, if not all, experiments. Maintaining these standards in the face of the uncertainties that lie ahead—stalled grant reviews, budget cuts and the likely confirmation of a new NIH director who does not seem to care much for public health—is one way we can ensure that the value of our work to the public does not waver.
