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A lack of female animal models in research has led to a clear failure to scientifically study sex differences. In 2017, Susanne Wolf, a neuroscientist from the Max Delbruck Center (MDC) in Germany, contacted organisations medicating against eye diseases to ask them if they had kept records of drug response for different genders.

Wolf wanted to see if there was data on treatment response in males and females as part of a study she was conducting on sex differences in the immune system.


The clinics simply responded that there had been no safety issues in their trials. On gender response, they remained quiet and refused to provide further information.

This confirmed something that Wolf suspected. Although it has been evident for some time that male and female immune systems behave differently in the disease spectrum — there are five times more men with autism, for instance, while women are three times more likely to get multiple sclerosis— the lack of female animal models in research has led to a clear failure to scientifically study sex differences.

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We shouldn’t read too much into the clinics’ reluctance to provide data, clarifies Wolf. “It is a big claim, and probably not the right one, to say that the wrong medication was given to patients,” she says. “But there is definitely a fear among clinicians to be blamed for it.”

In a paper published yesterday, Wolf shows that the underlying reason why male and female brains are equipped differently to fight pathologies that cause nerve damage, such as multiple sclerosis or Parkinson’s disease, lies in immune cells found in the brain, called microglia. “Microglia function differently depending on sex,” she says. “Male microglia are more numerous and larger, so arguably they react faster and stronger in the case of an attack. But on the other hand, they tend to overreact and wear themselves down more easily than female microglia.”


While it cannot be said that the male nor the female brain is better equipped to face neurological disease, continues Wolf, it is clear that they are differently equipped.

This is problematic. To treat the same disease, different drugs have never been tested specifically for men and for women. That is partly because pharmaceutical companies developing new drugs have historically privileged undertaking studies on male mammals. She says: “If you are only using male models to research and then develop drugs to treat immune diseases, then clearly it will have an impact on the way we treat women because you will not have been producing drugs that are appropriate for everybody.”

Neuroscience ranks particularly badly. Research has shown that single-sex studies of male animals outnumbered those of females 5.5 to 1 in that field. The consequence of that is that we may have been administering certain medication to men and to women that were not adapted to the way their immune system functions.

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Gina Rippon, professor of cognitive neuroimaging at the Aston Brain Centre, and writer of soon-to-be published The Gendered Brain, explains that the failure to carry out research on female mammals is the primary cause of the so-called “sex bias” in science.


Another reason why female mammals have received less or no attention in scientific research is also a pragmatic one. Females, indeed, are affected by sexual hormone cycles that interfere with research – and that means more work for the scientists that need to measure them and take them into account in case they have impacted the animals’ reactions to tests.

However, according to Wolf, ensuring that sex differences are investigated – especially when creating new medication – should be a scientific responsibility.

She says: “I can sympathise with the temptation to use male models, because it is more complicated to work with female ones. But I don’t think it is justification enough. If you want to really see what is going on with your medication, I believe that you are compelled to conduct research on both sexes.”

In fact, according to consumer organization DrugWatch, women have almost twice as many chances of developing an adverse reaction to medication than men do.

This is why research organisations have been trying to implement policies to ensure that male and female mammals are equally used for research. In 2014, the National Institutes of Health (NIH) passed a rule that obligated researchers to have a valid explanation when using single-sex animal models. The European Commission similarly started the Horizon 2020 campaign – a research and innovation program stretching over seven years with the objective, among others, of including gender differences in research.

For Rippon, while it is key that the scientific community does more research into sex differences to ensure that both men and women receive treatments that are more adapted to them, this comes with the danger of such a process becoming political. “One of the concerns is that quite often people jump to interpretations of sex differences to prove that there are biological differences between men and women,” she says. “It’s not too many steps before people claim that, because there are differences in male and female immune systems, there must be differences in their brains, too.”


The amalgam between sex differences and psychological differences is quick to happen, but that shouldn’t stop a change that is necessary to science, claims Wolf.

“Now that we know this, we have to take it into consideration,” she says. “It would be a terrible loss scientifically to ignore it. And I think things will change, because awareness is growing – this kind of topic is en vogue in the media.”

Whether medical companies have been appropriately handling sex differences in medication seems to be a mystery that remains to be solved. And with a record-high 64.7 million items of antidepressants having been prescribed in the UK in 2016, it better be solved as soon as possible. And it starts with resolving the gender mammal gap in the lab.