chromosomes. And all these crucial differences have been underestimated when it comes to developing, testing, and implementing medical advancements.
I first discovered the depth of this problematic chasm while I was in the early stages of developing my first antibiotic directed to fight against multidrug-resistant superbug microorganisms such as methicillin-resistant Staphylococcus aureus (MRSA). Years before researchers actually test a drug or treatment on humans, they are required by government agencies like the Food and Drug Administration (FDA) to go through a preclinical stage of research. This often involves using cells and nonhuman animals to produce evidence that the proposed treatment is both efficacious and safe.
When it comes to metals such as zinc and iron, the male and female body have different intake requirements.* Given that some of my antibiotic compounds were metal-based, I wanted to test specifically whether there would be any experimental differences in the results between male and female mice.
As I alluded to in the introduction, the problem was that I couldn’t easily get any female mice. I was perplexed when I found out that normally only male mice were used to perform these types of early infectious model experiments.
The FDA did publish a document, all the way back in the year 1987, that provided guidance about the use of both sexes of animals in clinical trials for scientists seeking approval for a new drug or treatment. It stated the following: “Both sexes of animals are to be included in pre-clinical drug safety studies for products targeted for use by both sexes.” The only issue was that it was a suggestion rather than a regulation. This particular suggestion didn’t have to be followed to get a drug approved by the FDA.
I learned that if I wanted to secure an equal number of male and female mice for my studies, I would actually have to special-order the female mice, as most research-animal breeding facilities didn’t readily keep them in stock at the time. Understanding for the first time how unusual it was to request female mice, I realized that the majority of my colleagues were simply using male mice to conduct their preclinical research.
Ordering the female mice would delay the start date of my experiment by many months, throwing my project behind schedule. I wish I had waited. As I was to discover years later when I finally included both female and male mice in my preclinical research studies, the experimental results obtained from only using male mice were different. This differential finding required me to rethink and rework some of my subsequent drug-design strategies. And if that was my experience, maybe the results that other scientists were getting from using only male mice in very early drug discovery accurately predicted clinical outcomes only half the time.
* * *
INCLUDING FEMALE MICE in preclinical research may not entirely solve this problem either. Most of the female mice that are used today in research have been inbred for many generations. That means that unlike human females, who have two vastly different X chromosomes in all their cells, inbred female mice have two identical X chromosomes instead (in effect making them almost like male mice genetically). The implications are that inbred female mice do not have the genetic diversity of human females or female mice that have not been inbred, nor do they benefit from genetic cooperation in the same way. So even if we begin using more female mice in research, we will need to take this important nuance into consideration.
Only relatively recent clinical research has begun to take genetic sex into account. Research in the 1980s and 1990s that was looking at new drug applications (the first step in the long and arduous process of drug approval) found that although women were included in clinical trials, their numbers were still overall underrepresented in many of the studies.
This discrepancy prompted the National Institutes of Health in 1993 to finally require the inclusion of women in NIH-funded clinical research. The latest study to tackle the issue of the inclusion of women in clinical trials looked at about 185,000 clinical trial participants and found no evidence of a significant underrepresentation of women. That’s good news—an important step in the right direction. But since most of our prior medical research essentially ignored the differences between the sexes, we still have a lot of refining to do.
Even with the inclusion of women in clinical trials, the sex and gender differences when it comes to drugs and medical procedures haven’t yet been fully addressed by all those