Upsetting the status quo is never easy, especially when it comes to scientific research. Just ask AstraZeneca duo Natasha A. Karp, Associate Principal Scientist/ Biostatistician and Neil Reavey, Associate Director, Research Assurance, who explore ways of overcoming the issue of sex bias in a paper entitled, “Sex Bias in Preclinical Research and Exploration of How to Change the Status Quo.” Originally published in the British Journal of Pharmacology last fall, the paper contends that sex should be considered as a biological variable in preclinical research and furthermore, sex bias is a factor affecting replicability in research outcomes. Finally, the pair offers up strategies on overcoming sex bias in preclinical research and ultimately reversing the status quo. Scientist.com recently caught up with co-author Natasha A. Karp to discuss the topic of sex bias in preclinical research, its effects and how researchers can overcome it.

Scientist.com: When you use the term, “sex bias,” in your research, what are you referring to precisely?

NK: The issue is an endemic failure in research to consider sex as a source of variation.  This can be seen in published in vivo studies, which are predominately conducted on one sex.  In manuscripts where data are collected on both, scientists typically pool the data.  Within the in-vitro arena, sex bias refers to a lack of awareness that the source of the cells in term of sex can significantly impact the behavior of the cells.

Scientist.com: How big of a role would you say sex bias plays in the reproducibility crisis?

NK: The replicability crisis, impacting all areas of science, is a methodological crisis with factors contributing from all stages of the research process.  The reality is that it’s impossible to know how large a role it has in the replicability crisis but certainly it has an impact.  For example, failure to consider sex as a biological variable means researchers often omit the sex of the animals or cells in published manuscripts, and if the effect is sex specific, then independent researchers will not be able to replicate the finding.  At times, it has been shown that researchers have allowed sex to confound the experiment meaning the differences could be due to the underlying sex differences in the data, or it could mask an effect of interest.  The pooling of data likewise could impact the study.

Scientist.com: At one point, you use the drug, zolpidem as a case study for the potential dangers of sex bias in research. Can you think of any other real-world examples of what could happen if sex bias continues to go unchecked?

NK: In 2007, a paper published in Journal of Cell Biology was reporting research from the University of Pittsburgh, where they were working to develop a treatment for Duchenne muscular dystrophy.  They were investigating the potential of an injection of muscle-derived stem cells instigating muscle regeneration in a mouse model of the disease.  They found that the cell sex considerably influenced the regeneration abilities and proposed it was an innate sex related differences in the cells’ stress response.   Luckily the researcher spotted and investigated the heterogeneity in response.  This example demonstrates the potential missed opportunity and the value of including both sexes in our research both in vivo and in vitro.

There are limited examples, as the studying of one sex is endemic in preclinical research.  We can see the impact of this in clinic, as women are 1.6 times more likely to experience an adverse drug reaction than men, which is mirrored in the observation that 8 out of 10 drugs withdrawn from the US market between 1997 to 2000 were due to greater health risks for women.  These were significant and described as including life-altering, disfiguring surgical complication, birth defects in babies or drugs triggering the onset of chronic disease.

Scientist.com: Of the factors making research organizations resistant to change, which stands out as the most prevalent to you?

NK: I feel that it is misconceptions that are embedded in our scientific culture.  These urban legends have an air of authority to them but are not based in fact but are accepted as truths.  For the in vivo community, they result in the researchers feeling that ethically they cannot justify the study of both sexes.  When working with animals, it is frequently believed that studying both sexes would double the sample size and that female animals are more variable than males, requiring more animals.  Within the in vitro community, it would be the misconception that once you remove the circulating hormones the sex of a cell is irrelevant.

Scientist.com: Why do you feel so strongly that change needs to start at the top, with leadership, vs. the individual researchers?

NK: For over 20 years, manuscripts have been raising the issue of the sex bias in our research pipeline, and yet little change to date has occurred.  We, the research community, need to acknowledge that this isn’t a minor change.  To embrace sex as a biological variable, we have to change how we design experiments, how we analyze data and how we present the data.  There are practical issues, unique to each experiment, to resolve, such as the pheromones of female rodents potentially impacting behavior of males.  To not follow the current norm is challenging, but to make substantial improvement we must embrace change.  Leaders can provide impetus that studying two sexes is a priority and adds value.   We will only see real change when it becomes the new cultural norm.

To read the entire paper, “Sex Bias in Preclinical Research and Exploration of How to Change the Status Quo,” click here.