Starting in October, biomedical researchers will have to counterbalance their use of male animals and cells with the equivalent in female biological tissues and test subjects. At least that's what they'll have to do if they want to get funding from the US National Institutes of Health (NIH), the largest source of medical-research funding in the world. This change, NIH researchers announced in Nature today, will help close the sex gap that continues to exist in preclinical research — the research stage in which drugs and medical interventions are tested on animals and biological tissues — and will "ensure that the health of the United States is being served by supporting science that meets the highest standards of rigor."

Using male animals is the norm

Over the last two decades, researchers have identified a plethora of differences in the way women and men react to various drugs and develop diseases. Women, for instance, are more susceptible to multiple sclerosis than men, even though their symptoms are less serious. And some drugs, such as the sleeping aid Ambien, need to be prescribed in different doses depending on a patient's sex. But preclinical research continues to include a majority of male animals and tissues. In fact, many trials don't include female animals at all. This, some researchers say, might explain the higher rate of adverse drug reactions seen in women today.

Janine Clayton, co-author of the Nature article and associate director for NIH research on women's health, said in an email to The Verge that "using male animals and cells is by and large the status quo right now," even though a number of studies have shown that "sex is a fundamental variable that should be considered from the very start."

Clayton points to studies showing that women and men respond differently to techniques for smoking cessation, such as nicotine patches. Clayton also points to the fact that men and women show different blood vessel patterns, which explains why women can exhibit very different symptoms than men during a heart attack. "Learning this, and understanding what this means, has allowed us to act fast for women, saving lives," she said. This statement comes off as encouraging, but it also hints to a much starker flip-side, one where scientists might have discovered these differences earlier had they included more female tissues at the preclinical stage.

Blame it on their hormones

Jeffrey Mogil, a pain researcher at McGill University in Montreal who regularly works with animal subjects, says that researchers avoid using female animals because many believe that female test subjects introduce more variability in their data. Clayton echoed Mogil, stating that some scientists "assume that using female animals is problematic due to the fact that female animals cycle hormonally." Numerous studies have disproved these beliefs — including a study published by Mogil's team in 2005 — but the male-centered practice persists.

"I guess if you go back far enough it was sexism," Mogil says, but scientists today mostly just "do experiments the way they were taught to do experiments." This, the researcher explains, includes using mostly male animals — even though the convention is "probably unethical, when you come right down to it."

It's "probably unethical."

The changes mandated by the NIH will be rolled out progressively, because the agency wants to ensure that scientists can properly adjust their experimental designs. "To help scientists understand and adapt to the changing policies, we will create training modules on experimental design," Clayton said. "Of course, we will also monitor compliance with new policies and perform data analysis to track our progress." Researchers will be compliant with the NIH's new policies if they report how they intend to balance the use of male and female cells and animals in their proposals. They may also be compliant if they can demonstrate that "sex-specific inclusion is unwarranted," the NIH researchers wrote, "based on rigorously defined exceptions."

Yet NIH-funded research isn't the only scientific sphere where changes need to occur. "We don't operate in a vacuum," Clayton said. "The entire scientific community has a stake in this game." Scientific publishing should also be reformed, she said, because many journals don't require researchers to consider the effect that an animal's sex might have had on their analyses.

This won't address all sex differences

Furthermore, the NIH changes might not be enough to account for all the sex differences that can influence preclinical research. A study recently published by Mogil's team, for example, demonstrated that male experimenters provoke a fear response in rodents that female scientists do not — meaning an animal killed by a male researcher might present stress-related chemicals in its cells that an animal killed by a female researcher would not. One might therefore argue that the sex of the human who killed the lab mice should also be included in a research proposal, along with the sex of the animals themselves.

"As our biomedical knowledge base grows and technology advances," Clayton said, "smart science reveals gaps." Because sex and gender differences continue to represent a blind spot for many scientists, more research should look into these differences at the preclinical stage, she said. "That's why we are calling on scientists to turn their head, and check that blind spot."