Sex differences lie at the core of biology. They are the driving force of evolution, and in many cases they are fundamental in health and medicine. The study of sex differences is important work, and more of it should be done. But a new National Institutes of Health policy intended to drive research in sex differences is a major step in the wrong direction.
The policy, which requires NIH-funded scientists to use equal numbers of male and female animals and cells in their studies, is about politics, not science. In January, Representatives Nita Lowey of New York and Rosa DeLauro of Connecticut wrote to Francis Collins, director of the NIH, expressing concern that women's health was being put at risk because biomedical researchers often prefer to use male animals for experiments. Apparently their message came through clearly. In May, Collins and Janine Clayton, associate director for Research on Women's Health at the NIH, announced in Nature that in all experiments funded by the agency, scientists must use equal numbers of male and female animals or cells and investigate the differences by sex. This directive will affect nearly every researcher. “The exception will be truly an exception, not the rule,” Clayton stated at a press conference. (Scientific American is part of Nature Publishing Group.)
On the surface, this rule sounds reasonable enough. Why not include males and females in every study? In fact, the rule would be a huge waste of resources.
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Say a scientist wants to test a blood pressure drug. One group of lab rats (the experimental group) is treated with the new compound, and the other (the control group) receives sugar pills. After treatment, researchers measure the mean blood pressure in both groups as well as the amount of variation surrounding each mean. The variation around the mean, usually a bell-shaped distribution, is important. The more variation in the results, the harder it is to conclude that any differences between the control and experimental groups are meaningful. Scientists therefore take great care to minimize the amount of variation—for example, by using only specific purebred lines of animals of the same age and often the same sex (male or female, depending on which sex minimizes variance in the particular experiment).
If scientists must add a second factor—sex—to their experiment, two things happen: the sample size is cut in half, and variation increases. Both reduce the researchers' ability to detect differences between the experimental and control groups. One reason variation increases is the simple fact that males and females are different; these differences increase the range of scores, just as they would if males and females competed together in Olympic weight lifting. The result is that when males and females are mixed together, scientists might fail to detect the beneficial effect of a drug—say, one that reduces blood pressure in males and females equally well.
In their Nature commentary, the NIH officials argue that scientists exclude females by “convention” or to avoid variability caused by hormonal cycles in females. This is not accurate. Scientists have enormous practical and financial incentives to use both sexes of animals in their studies: doing so cuts animal costs in half. Transgenic animals in particular are rare, are difficult to breed and can cost thousands of dollars apiece. As a consequence, scientists exclude one sex from a study when it is necessary—when there is reason to suspect that the results will differ between sexes, possibly for trivial causes, such as if a male rat might run a maze faster than a female.
It is critical to understand biological differences between the sexes. But understanding sex differences is much more complex than the NIH mandate would suggest. Modifying experiments to include both males and females costs money and requires a duplication of time and effort—time that researchers might not have to spare or that might be better spent conducting other research—that is rarely practical or scientifically warranted. A much better way is to fund opportunities specifically designed to study sex differences. If the NIH makes sex research a priority and earmarks money to support it, scientists will apply. For precedent, look to the Obama administration's recent projected $4.5-billion BRAIN Initiative, which has unleashed a flood of brain research. The new mandate does just the opposite: it compels all researchers to study sex regardless of the objective of their study, and it provides no additional funding to do so.