Biomedical research is undergoing a sea change, driven in part by federal funding requirements that studies consider biological sex as a factor. Part two of this two-part Arizona Science Desk series explores this cultural shift.

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Despite known differences between the biological sexes in the prevalence, progression and prognosis of many diseases, female mammals — be they human or mouse — were long neglected in biomedical research.

Dangerous Assumptions

"For a long time, people kind of assumed that there weren't very many sex differences in a lot of disease processes, and this idea is now being challenged and overturned," said Arthur Arnold, whose lab at UCLA studies male and female biological differences.

Arnold said the assumption of similarity produced generations of research involving only a single sex — typically, male.

"People have studied mostly one sex; for example, in neuroscience research, the vast majority of studies have been on males and rarely have people compared males to females."

A paper in the medical journal "The Lancet" found only one in three biomedical studies included data on sex. In 2011, a study in "Neuroscience & Biobehavioral Reviews" found bias in eight of 10 biological fields, with male animal studies outnumbering female ones more than five to one.

"We just hadn't really seen it as a signal. We thought it's kind of noise in the system. And, all of a sudden, we have tools or abilities now to appreciate that, that, 'OK, now we actually see something,'" said Michael Berens, deputy director of the Translational Genomics Research Institute in Phoenix.

To make matters murkier, researchers often did not record the sexes of their test subjects, male or female.

"A huge swath of our molecular biology understanding of anything is in databases from cell lines that we don't know what sex the cell lines were," said Kristin Swanson, co-director of the Precision NeuroTherapeutics Innovation Program at Mayo Clinic in Scottsdale.

Swanson co-authored a paper with Berens describing sex differences in the brain cancer glioblastoma.

Source: The Lancet

"If we've historically just not tracked the right thing, you put you behind the eight ball when you're trying to interpret the new thing in the context of the old," she said.

Powering And Responsibility

Louise McCullough, chief of neurology at Memorial Hermann Hospital System in Houston, agrees. She was involved in the policy shift that now requires federally funded studies to either include males and females — or provide a valid reason not to.

"We have so much trouble translating our preclinical findings into effective therapies, and part of that problem may be, we haven't looked at both sexes," said McCullough.

But exploring sex as a biological factor in research takes more than just including male and female subjects.

"You have to design your trials appropriately. If you have a disease that acts differently in men and women, and you're giving a drug, you definitely need to power your study to look at the sexes independently," said McCullough.

"Powering" means designing an experiment to ensure a statistically valid result, and it depends strongly on who is included in the study population.

Swanson said federal standards stop short of such a requirement.

"They don't require you to either power your analysis, meaning make it statistically sound such that you could detect any difference, and they don't require you to do an analysis separately for males and females."

Cultural Shift

Still, everyone seems to agree that a change is underway.

"People are realizing that you really have to pay attention to sex and gender. It's important because it changes the way the pharmacodynamics, the way you respond to therapies, even the therapies you choose to use," said McCullough.

But it also seems clear that such an adjustment could require a significant cultural shift.

"In order to accept the new rules and to embrace them, people have to overturn their old idea that males, females aren't very different," said Arnold.

"In order to accept the new rules and to embrace them, people have to overturn their old idea that males, females aren't very different."
— Arthur Arnold, UCLA

Interest has grown with the push for personalized, or precision, medicine, in which prevention and treatment are tailored to the individual.

"We talk about personalized medicine as saving the world, and we can't tell the difference between a male and a female. It's a slight problem," said Swanson.

Still, some resist the change — and the expense and complexity it brings. Others worry pharmaceutical companies will drop certain drugs if they find they affect only one sex. Still others cite unavoidable social and political issues raised by sex-based medicine.

But to McCullough, it's all about finding answers.

"It's not about women's rights or, 'Yah-ha, I'm a feminist,' or anything like that. It's science. You can't ignore science. And science is telling us something."

Just what science is telling us is a tale that is still unfolding. But thanks to more inclusive approaches, we now have a better chance of hearing the full story.