For decades, scientists have embarked on the long journey toward a medical breakthrough by first experimenting on laboratory animals. Mice or rats, pigs or dogs, they were usually male: Researchers avoided using female animals for fear that their reproductive cycles and hormone fluctuations would confound the results of delicately calibrated experiments.
That laboratory tradition has had enormous consequences for women. Name a new drug or treatment, and odds are researchers know far more about its effect on men than on women. From sleeping pills to statins, women have been blindsided by side effects and dosage miscalculations that were not discovered until after the product hit the market.
Now the National Institutes of Health says that this routine gender bias in basic research must end.
In a commentary published on Wednesday in the journal Nature, Dr. Francis Collins, director of the N.I.H., and Dr. Janine A. Clayton, director of the institutes’ Office of Research on Women’s Health, warned scientists that they must begin testing their theories in female lab animals and in female tissues and cells.
The N.I.H. has already taken researchers to task for their failure to include adequate numbers of women in clinical trials. The new announcement is an acknowledgment that this gender disparity begins much earlier in the research process.
“Most scientists want to do the most powerful experiment to get the most durable, powerful answers,” Dr. Collins said in an interview. “For most, this has not been on the radar screen as an important issue. What we’re trying to do here is raise consciousness.”
Women now make up more than half the participants in clinical research funded by the institutes, but it has taken years to get to this point, and women still are often underrepresented in clinical trials carried out by drug companies and medical device manufacturers.
Partly as a result, women experience more severe side effects from new treatments, studies have shown. The Food and Drug Administration last year told women to cut in half their doses of the sleeping pill Ambien, for example, because new studies showed they metabolize the active ingredient more slowly than men do.
Although statins are the most widely prescribed drugs in America, they were tested mostly in men, and evidence of their benefit to women is limited. Indeed, women respond differently from men to a broad array of treatments, and often do not derive the same benefits from them as men.
The ideas for new treatments are often generated in the laboratory, where gender bias in basic biomedical research and neuroscience is ingrained.
Bias in mammalian test subjects was evident in eight of 10 scientific disciplines in an analysis of published research conducted by Irving Zucker, a professor of psychology and integrative biology at the University of California, Berkeley. The most lopsided was neuroscience, where single-sex studies of male animals outnumbered those of females by 5.5 to 1.
Contrary to the conventional wisdom in laboratories, there is far more variability among males than among females on a number of traits and behaviors, Dr. Zucker has found. Yet even when researchers study diseases that are more prevalent in women — anxiety, depression, thyroid disease and multiple sclerosis among them — they often rely on male animals, according to another analysis led by Dr. Zucker, who has written extensively on gender bias in scientific research.
Jill Becker, a senior research scientist at the University of Michigan who studies gender differences in addiction, has found that women increase their drug use much more rapidly than men and that the hormone estradiol plays a critical role in the escalation, especially during ovulation.
Nonetheless, researchers studying escalating drug use in rats and mice rely almost entirely on males, she said.
“One of the underlying assumptions has been that females are simply a variation on a theme, that it isn’t a fundamentally different mechanism, that if you’ve learned about the male you’ve learned enough to deal with both males and females,” she said. “We’ve discovered that’s not always the case.”
The N.I.H. is directing scientists to perform their experiments with both female and male animals, and grant reviewers will take the balance of each study design into account when awarding grants. (If the subject is gender-specific, like ovarian cancer or prostate cancer, then the rule will probably not apply, Dr. Clayton said.)
Researchers who work with cell cultures are also being encouraged to study cells derived from females as well as males, and to do separate analyses to tease out differences at the cellular level.
“Every cell has a sex,” Dr. Clayton said in a telephone interview. “Each cell is either male or female, and that genetic difference results in different biochemical processes within those cells.”
“If you don’t know that and put all of the cells together, you’re missing out, and you may also be misinterpreting your data,” Dr. Clayton added. For example, researchers recently discovered that neurons cultured from males are more susceptible to death from starvation than those from females, because differences in the ways their cells process nutrients.
N.I.H. officials will start rolling out the new policies in October, and the details are still being ironed out. But they are likely to be met with resistance from scientists who fear increased costs and difficulty in performing their experiments.
“There’s incredible inertia among people when it comes to change, and the vast majority of people doing biological research are going to think this is a huge inconvenience,” Dr. Zucker said.
Studying animals of both sexes may potentially double the number required to produce meaningful results, some experts say.
Kathryn Sandberg, director of the Center for the Study of Sex Differences in Health, Aging and Disease at Georgetown University, said she was concerned researchers would “just throw in one or two females” and then conclude that “everything is the same.”
“If they do it, but don’t do it correctly, then it’s going to lead to misinformation,” she said.
Margaret McCarthy, a neuroscientist at the University of Maryland School of Medicine who studies sex differences, agreed that the new policies will meet resistance. “The reactions will range from hostile — ‘You can’t make me do that’ — to, ‘Oh, I don’t want to control for the estrous cycle,’ ” she said.