World Health Organization photograph of a person's hand holding a petri dish. (Paul Almasy/National Library of Medicine | Courtesy of WHO)

Sex and Gender in a Petri Dish

The HeLa cell line, infamously derived in 1951 from the tumor of Henrietta Lacks, was cultured and immortalized to provide standardized research material for scientists, generating an astonishing 74,000 scientific publications. HeLa, originating from “female” cells, became the most widely used cell line in twentieth century biomedical science, including in critical areas such as cancer research. Should men be concerned that so much basic biological research occurred in “female” materials?

Last year, the NIH introduced a new policy requiring all preclinical research — studies in cells and tissues, cell lines, and model organisms — to include both male and female specimens. Widely celebrated as a victory for women’s health, proponents raised parallels to the women’s health movement’s fight to include women in clinical research a quarter century earlier.

Until the 1990s, women were often excluded from clinical medical trials. An androcentric medical model presumed that white males represented all humans. Because women of reproductive age were considered potentially pregnant, they seemed especially vulnerable to risks of clinical research, and it was thought unethical to include them in trials. Additionally, many asserted that women’s ovarian cycles would introduce too much variability into research. As a result, women were denied participation in life-saving treatment trials, such as HIV drugs in the 1980s. Then, when drugs hit the market only having been tested in men, there were sometimes unexpected reactions and side effects in women. This situation was rectified in the early 1990s, when after a decade of women’s health activism, Congress directed the NIH to establish the Office of Women’s Health Research (OWHR) and required all clinical studies to include both men and women.

Illustration by Katie Scott, for Janine A. Clayton & Francis S. Collins, "Policy: NIH To Balance Sex In Cell and Animal Studies," Nature (May 14, 2014).
Illustration by Katie Scott, for Janine A. Clayton & Francis S. Collins, “Policy: NIH To Balance Sex In Cell and Animal Studies,” Nature (May 14, 2014).

The new policy is slated to go into effect in January of 2016. Supporters, such as the Society for Women’s Health Research, argue that studying sex differences at the preclinical stage is necessary to advance understanding of persistent women’s health problems such as the 50-70% higher rate of reported adverse drug events in women compared to men.1

But will requiring study of sex in basic laboratory research produce meaningful and relevant science for remedying health disparities between men and women? Our Harvard-based working group of feminist scientists and science studies scholars spent a year reading and discussing the primary documentation supporting the new policy. In a recent article in Proceedings of the National Academies of Sciences, we argue that as an approach to addressing health disparities between men and women in adverse drug events, the policy is misguided.

We make two main points. First, there is limited evidence that the differences in adverse drug events experienced between men and women are largely due to intrinsic sex-specific biological factors. Instead, there is strong evidence that other factors mediate this health disparity. This includes women’s on average lower body weights (leading to overdoses), women’s higher rates of polypharmacy (taking more than one medication at a time), the tendency of women to live longer and hence to have complications related to age, and women’s greater likelihood to see a doctor and to report adverse outcomes. Sex variables in cells and mice cannot capture these embodied and gendered dimensions of human male and female health disparities. To fully understand and address the problem of higher rates of adverse drug events in women, we need biomedical institutions and funders to incentivize researchers to study the interaction between sex and gender in embodied humans.

"Human sex is not simply a chromosome complement." (Chromosome banding highlighting Y chromosome/National Human Genome Research Institute | Public domain)
“Human sex is not simply a chromosome complement.” (Chromosome banding highlighting Y chromosome/National Human Genome Research Institute | Public domain)

Second, while we support basic biological research — for example, on how XX and XY cells may differ — we argue that research should be hypothesis driven, with sex difference considered thoughtfully as an experimental variable, rather than added wholesale to all preclinical research studies. Human sex is not simply a chromosome complement. In the body, cells live in a hormonal milieu and engage in constant physiological dialogue with the environment. How well in vitro cells can model this dynamic and multidimensional quality of biological sex is not known. For example, some XY cell lineages have replicated so many times that the Y chromosome has been lost in many tested samples. Are these cells still representative of “male” cells? We would like to see in vitro cells validated as models of sex in humans before mandating sex difference research in these materials.

To be sure, in well-designed, hypothesis-driven studies, animals and cellular material can advance our understanding of sex disparities in health. One example is differences in lung development in preterm infants. Male infants born at the threshold of viability are more susceptible to lung diseases than female infants. In order to uncover the influence of sex, researchers developed experimental models to carefully consider the interaction of genetics, hormones, age, and developmental tempo during fetal lung maturation. These researchers used preclinical animal models and materials, yet they did not simply add sex to existing models. Instead, they started with hypotheses built to investigate sex differences.

Unmoored from hypotheses generated by human sex/gender research, and with no requirement for validated laboratory models, we believe that the NIH mandate to study sex in preclinical materials is likely to contribute to the proliferation of unreplicable data on male-female comparisons with little meaning for human health. The NIH now appears to have quietly acknowledged how complicated it might be to operationalize sex at the level of preclinical research materials. When the new policy goes into effect with the January 2016 grants cycle, the NIH will require study of sex differences only in preclinical vertebrate animal studies, remaining silent on sex in cellular materials.

To truly advance understanding of male and female disparities in health outcomes, our public institutions would be wiser to invest in stronger studies of the interaction of sex- and gender-related variables in living, embodied human men and women of diverse ages and genders. Advocates have used the banner of women’s health to promote the new NIH mandate. But requiring study of sex in all preclinical materials will not redress pressing women’s and men’s health inequalities. The true nod to the legacy of the women’s health movement would be an NIH policy that places the many interacting social and biological factors in human women’s and men’s health disparities at the center of scientific investigation.

Further Reading

Notes

  1. Approximately 5% of emergency room visits are related to adverse drug reactions, and women have 50-70% more of these adverse drug reactions than men do (see Marius Rademaker, “Do women have more adverse drug reactions?,” American Journal of Clinical Dermatology 2 (2001): 349-351). Return to text.

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