Mandate comes with opportunities, challenges, little funding, and few details
In many scientific fields, the study of the body is the study of boys. In neuroscience, for example, studies in male rats, mice, monkeys and other mammals outnumber studies in females 5.5 to 1. When scientists are hunting for clues, treatments or cures for a human population that is around 50 percent female, this boys-only club may miss important questions about how the other half lives.
So in an effort to reduce this sex bias in biomedical studies, National Institutes of Health director Francis Collins and Office of Research on Women’s Health director Janine Clayton announced in May a new policy that will roll out practices promoting sex parity in research, beginning with a requirement that scientists state whether males, females or both were used in experiments, and moving on to mandate that both males and females are included in all future funded research. The end goal will be to make sure that NIH-funded scientists “balance male and female cells and animals in preclinical studies in all future [grant] applications” to the NIH.
In 1993, the NIH Revitalization Act mandated the inclusion of women and minorities in clinical trials. This latest move extends that inclusion to cells and animals in preclinical research. Because NIH funds the work of more than 300,000 researchers in the United States and other countries, many of whom work on preclinical and basic biomedical science, the new policy has broad implications for the biomedical research community. And while some scientists are pleased with the effort, others are worried that the mandate is ill-conceived and underfunded. In the end, whether it succeeds or fails comes down to interpretation and future implementation.
At a broad level, it might make sense to study only males when examining biological processes. After all, females have hormonal cycles that vary over time, from the roughly-28 day cycle in humans to the four-day cycle in rats. These hormones affect everything from the immune system to cognitive processes. So there are fewer variables when you have only males in your study population.
But cutting out the females has led to major knowledge gaps. “Even though it has been clear for some time that males and females differ on many measures of neurological and physiological function, research on females continues to lag far behind research on males,” says Jill Becker, a behavioral neuroscientist at the University of Michigan in Ann Arbor. “This has led to false assumptions about things work in females due to lack of knowledge.”
Studying only one sex also presents problems as preclinical studies in cells and animals move into clinical trials in humans. Treatments in males don’t always apply to treatments in females, notes Irving Zucker, a behavioral neuroendocrinologist at the University of California, Berkeley. “Sex is probably the most significant neglected variable you can think about,” he says. “When females show greater sensitivity to painful stimuli, it doesn’t make sense that 80 percent of pain studies in rats and mice are done on males.”
One high-profile example is the sleep drug zolpidem, prescribed in the United States as Ambien. In 2013 the Food and Drug Administration released a safety announcement stating that women might be more sensitive to the drug’s side effects than men, and recommending that women be given half the previously recommended dose. Had there been a better balance of males and females in the clinical studies, it is possible that this difference would have been caught much earlier.
Both Zucker and Becker applaud the new mandate for sex balance in early studies. “Including females will require many labs to think more broadly about their approach, so as to include females in a cost-effective way,” says Becker. “These changes will be good for science in the long run.”
But others are worried the new policy is underfunded and under-planned. Douglas Fields, a developmental neuroscientist at the National Institute of Child Health and Development, is concerned that “the current approach hasn’t given enough thought to the realities and practicalities” of including both sexes in experiments. (Fields, who authored a critique of the new policy, spoke with me as a public citizen, not as a representative of his employer.)
“Sex bias in a social sense is just inexcusable and wrong,” Fields explains. “But in experimental design it’s often about exclusion, to exclude things until you come down to an experimental and a control group that will allow you to detect a difference.” He is concerned about the extra variables that the policy could introduce into experiments, not to mention the extra animal and analyses that might be necessary to investigate possible sex differences in every experiment. And if scientists have to evaluate every experiment for sex differences, they would have to include an extra aim (a section proposed for experiments) for each research grant they submit, with a huge increase in time and materials.
But female animals may not, in fact, introduce any more variability in the data than males do. And Zucker notes an important difference between studying both sexes and studying sex differences. The policy doesn’t mean that all scientists need to dig into every result they get that shows a difference by sex. Instead, they just have to establish whether the sexes respond differently to a particular experiment. Zucker than explains that other scientists could follow up on the sex differences, while the original scientists continue to pursue their primary research questions.
If there are no differences between males and females in the first experiment, Zucker says, scientists simply need to keep including animals of both sexes in follow-up experiments. “Scientists don’t need to repeat all experiments in males and in females,” he explains. “They just need to include females and males in all of their aims. Anyone who’s advocating the extra-expensive aim isn’t paying attention.”
Mike Taffe, a neuropharmacologist at Scripps Research Institute in La Jolla, Calif., is skeptical of an approach that would find a difference between sexes and not study it further. He is concerned that every scientist will, in fact, have to pursue sex differences as they arise. “It’s one thing to say, OK, I’m just going to run groups of male and female rats,” he says. “But if a difference is found, then all of a sudden even more groups of animals are involved. You want to compare the sexes, not just describe a difference.” He says the idea of just describing variability among the sexes and then leaving it alone would represent a weak scientific investigation.
Fields is also concerned that scientists not used to studying sex differences will not be able to adapt to the new policy with good scientific rigor. “Done properly, research on sexual dimorphism is difficult and time consuming and highly specialized,” he says. “To expect everyone to do this is really to be dismissive of the importance of research on sex differences.”
Finally, there are concerns about the funding available to carry out sex-balanced studies. The Office of Research on Women’s Health has announced more than $10 million in supplements to currently funded research, intended to provide resources for scientists to add the opposite sex to their experiments. But if extra animals, personnel and experiments are required to achieve sex parity in studies, much more funding per grant would certainly be needed. “Supplements are great and people will do those studies and publish them,” Taffe explains. “But there is no way the NIH budget would double or quadruple to reflect the increased number of animals needed to study both sexes. Without funding and personnel, the pace of science in fields that suddenly need to study both sexes will slow.”
In the end, most agree that females do need to be studied as much as males. The question comes down to how, exactly, those studies should take place. Should males and females be studied side by side, all the time, as the NIH policy is planning? Or should studies of sex differences be separately funded and separately focused?
Instead of a broad policy, Fields and Taffe prefer a series of incentives for scientists to research sex differences, rather than a mandate that applies to all research. “I share the goals of the current approach, but my concern is that it will fail and cause a backlash among the public and undermine the effort,” Fields says.
Zucker points out that there have been repeated pleas to study females and sex differences, and says these have been “all but ignored over several decades.” He says that a sweeping sex-inclusion policy is necessary to achieve real parity in research. Keeping funding for females separate would ensure they will never be equal.
No matter how the policy is interpreted, the message is clear: It’s time to include females in all studies. If this means that every NIH-funded scientist is required to become an expert on both the sexes, it means huge increases in time for experiments and the personnel and materials to carry them out. There are many questions still unanswered, from how big the policy change will really be to how NIH is prepared to pay for it. But in the meantime, it’s made some scientists consider looking toward the female side of studies. “The policy does seem sweeping,” Taffe acknowledges. Still, he says, the threat of the policy has made him look more closely at using females in his studies. “Of course I wasn’t against it before,” he notes. “But this was enough to push me the last little bit.”