By Eric Goldscheider / Published September 11, 2014

Five years ago, Annaliese Beery, now an assistant professor of psychology at Smith, took time away from her primary research interests to do some research on research.

This spring her curiosity contributed to a major procedural shift and the unveiling of a new policy at the U.S. National Institutes of Health that closes a major gender gap in research and addresses sex bias in cell and animal studies. The policy will be introduced in phases beginning in October.

Beery and her thesis-adviser-turned-colleague Irving Zucker, professor emeritus of psychology and integrative biology at the University of California, Berkeley, wanted to see if they could document the extent to which scientists who work with animals in preclinical biomedical research selectively study males versus females.

Their research confirmed what they knew anecdotally. They systematically combed through methods sections and online supplements of 1,900 scholarly articles in prominent journals in 10 biomedically relevant subdisciplines of biology such as neuroscience, pharmacology and endocrinology. “The punch line was that we have a vast overrepresentation of male subjects and a vast underrepresentation of female subjects in our basic animal research studies,” says Beery.

Just as important, many experimenters didn’t even report the sexes of the animals they used, which she says is “astonishing.” She and Zucker also found that “even when male and female subjects were included, two-thirds of the time the results were not analyzed by sex.”

A related question is, does the sex of the subject matter in these studies? This, says Beery, is not an ideological question, but one that requires a hard look at how outcomes in the lab translate into an understanding of biology. In other words, does a sex bias in the use of lab animals yield findings only relevant for one sex?

The answer to the first question turns out to be yes, it does matter. “There are striking and scary stories of where basic biology for some biomedical processes is different between males and females,” says Beery. For instance, pain processing in female mice is modulated by a receptor pathway that is not involved in male mice, and there is evidence that suggests the same is true in human females. Thus research focused on males may miss important therapeutic targets.

Eight of 10 drugs removed from the market related to bad side effects are done so because of their effects on women, according to a recent survey.

The true extent to which sex matters when studying nonhuman research subjects will become better understood in coming years in the wake of a policy shift at the National Institutes of Health.

Janine Clayton, director of the NIH Office of Research on Women’s Health, and Francis Collins, NIH director, unveiled the new policy in May. They wrote in a commentary published in the journal Nature that, starting this October, the government funding agency will “require applicants to report their plans for the balance of male and female cells and animals in preclinical studies in all future applications, unless sex-specific inclusion is unwarranted, based on rigorously defined exceptions.”

This, explains Beery, doesn’t mean researchers will be compelled to use an equal number of male and female animals in all cases. But they will be required to think about, document and justify their choices. “It is very thoughtfully worded in terms of making sure that we actually learn about female biology in an important way,” she says.

Beery is quick to point out that she can’t take credit for the new NIH policy, which has been part of a wider conversation in the scientific community. But the articles on the subject that she wrote with professor Zucker in 2010 and 2011 are widely cited in that discussion and in fact are in the first two footnotes in the NIH’s recent policy announcement. She found out about the announcement days before its official release, when reporters started calling her for comments.

The new policy, which will be rolled out in phases beginning this October, goes even further than addressing sex bias among animal subjects.

“We focused in our review article on animal studies at the level of the whole organism,” says Beery. “We didn’t even count how many studies were done on male or female tissues or cell lines. But there are even biochemical differences at the level of the cell. The new NIH mandate says you also have to consider the sex of your cell lines, which I think is a bold move and a good one.”

Clinical studies on humans are more likely to include an even balance of women and men since a 1993 mandate that NIH-funded research must account for the sex of enrollees. Extending that to preclinical studies on animals is important, says Beery, because to ignore biological differences related to sex in basic research undermines the foundation of later research.

The convention of experimenting mainly on male animals goes back to the 1920s and a belief that females were less stable as research subjects because of their estrous cycle connected to ovulation. Some scientists argued that experimenting on female animals would require more specimens to account for variations in hormone levels and thereby drive up costs.

Newer research shows that this argument “doesn’t hold up,” says Beery. “Female rodents might be more predictably variable across the estrous cycle, but they are not more variable than males.”

Beery’s collaboration with Zucker on this subject came out of a talk he presented, “Why Study Weird Species and Two Sexes?” Initially their research focused on both prongs of this question designed to get researchers to think about reasons for introducing more diversity into the animals they use in research.

“We originally wrote the article to be about sex and species bias but the reviewers were so interested in the sex bias part that they said, don’t dilute the message,” says Beery.

Now, four years later, the message is clear: overreliance on male research specimens, or worse yet, not even keeping track of the sex of animals used in experiments, can lead to skewed results.

Clayton and Collins, in their recent Nature article, called the lack of attention to how sex can affect the outcome being measured in an experiment a “blind spot” in how science is conducted.

That blind spot extends down to basic research, which constitutes the building blocks of new knowledge. Now that this blind spot is being addressed, does Beery expect to see a cascade of new findings illustrating the fundamental differences between male and female sex cells, down to the chromosomal level?

“I can’t say I want that to happen; it certainly makes our lives a lot easier if there are fewer sex differences,” she says. But she suspects that important, heretofore not understood differences will come to light. “Science is a process of taking our ideas about how things work and revising them over time,” she says. “I will continue to be interested in this question, and I might even do a follow-up study to see where this leads us over the years.”

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When the U.S. National Institutes of Health announced a new policy in May aimed at eliminating sex bias in preclinical biomedical studies, many health advocates and researchers who had been calling for change—including Smith professor Annaliese Beery—were pleased.

“Even though the biomedical model is to drill deep—and it’s easiest to drill deep if you are drilling deep on one thing—diversity can teach us things that are important not to leave out,” she explained.

Beery, in fact, subsequently became a prominent voice in the media coverage that followed, as she had been a co-author in two papers that examined the state of male/female subject use and pointed to an overreliance on male animals and cells in preclinical research.

NIH cited those papers in its announcement.

Here are some of the national media stories in which Beery was interviewed and quoted:

Chronicle of Higher Education: NIH to Require Gender Balance in Subjects of Animal Studies

Reuters: U.S. Health Agency to Erase Sex Bias in Biomedical Studies

Science Magazine: Needed: More Females in Animal and Cell Studies