Progress In Considering Sex As A Biological Variable

9:07 minutes

Back in 2013, Charles Hoeffer from the University of Colorado Boulder was studying memory and learning in mice. He was looking at a specific protein in the brain called AKT1, which helps mice forget an old task and learn a new one. In humans, a mutation in that protein has been linked to disorders like schizophrenia, Alzheimer’s and depression.

But in a follow-up study, Hoeffer did something different. He included both male mice and female mice, and then tested them separately. As expected, he discovered that male mice had a much tougher time learning the task when AKT1 wasn’t working. But in female mice, he found the unexpected: It didn’t make any difference whether the protein was removed or not. In other words, the sex of the mouse became an important variable that affected the outcome of the research.

Hoeffer’s study is one example of considering sex as a biological variable (SABV) in pre-clinical research. And in 2016, the National Institutes of Health’s Office of Research on Women’s Health made it an official policy for researchers applying for funding. 

But that didn’t change things overnight. Five years later, the approach is still catching on in many areas of research. Chyren Hunter, from the Office of Research on Women’s Health, joins Ira to discuss the progress that’s been made, and what lies ahead for the effort to make pre-clinical research more inclusive.

Further information on the NIH’s policy on sex as a biological variable is on its website.

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Segment Guests

Chyren Hunter

Chyren Hunter is associate director for basic and translational research in the Office of Research on Women’s Health at the National Institutes of Health, in Bethesda, Maryland.

Charles Hoeffer
Charles Hoeffer is an assistant professor of integrated physiology at the Institute for Behavioral Genetics at the University of Colorado Boulder.

Segment Transcript

IRA FLATOW: This is Science Friday. I’m Ira Flatow. Several years, ago Dr. Charles Hofer was studying memory and learning in mice. He was looking at a protein in the brain that helps mice forget an old task and learn a new one.

CHARLES HOFER: To be honest, I had pursued a lot of research prior to this only using male mice because it was more cost-effective.

IRA FLATOW: As expected, he found that male mice had a much tougher time learning a task when the protein wasn’t working. But in a new experiment, he tried something different. He added female mice, tested them separately, and found the unexpected. In female mice, it did not make any difference whether the protein was removed or not. In other words, the sex of the mouse became an important variable. It affected the outcome of the research.

CHARLES HOFER: Once we saw that, we couldn’t let it go. In some ways, it would have been really easy to just pursue male data, but it was too promising a scientific avenue to pass up.

IRA FLATOW: A significant discovery, and Dr. Hofer might not have caught it if it weren’t for a new policy from the National Institutes of Health requiring researchers to consider an animal sex in preclinical research.

CHARLES HOFER: There isn’t a lot of consideration for sex as a biological variable. So I really think it hasn’t permeated research to the level that I think it should. I’m wondering how widespread this is, how overlooked sex differences really are in research.

IRA FLATOW: My next guest is playing a critical role in implementing the policy first published five years ago. Dr. Sharon Hunter is associate director for basic and translational research and the Office of Research on Women’s Health at the National Institutes of Health in Bethesda, Maryland. Welcome to Science Friday.

SHARON HUNTER: Thank you, Ira. Happy to be here with you today.

IRA FLATOW: If this policy was enacted five years ago, why do so few researchers know about it?

SHARON HUNTER: Well, I would say that like an ocean liner turning, getting individuals aware of the policy takes time and effort. Researchers are busy. But they do know now that if they’re going to apply for an NIH grant, they must address SABV.

IRA FLATOW: Let’s talk about as SABV, Sex As a Biological Variable. What does that mean in the context of this NIH policy?

SHARON HUNTER: Great question. Thank you. I always like to first start with definitions. And as you said, SABV is an abbreviation for sex as a biological variable. We know that every cell has a sex, and so do the cells that make up our tissues, and so do the tissues that make up our organs and the organs that make up our cardiovascular and other systems. So consideration of sex is a constant in our biological makeup. And therefore, it’s very important to consider how sex has involved in health and disease.

So the policy primarily talks about preclinical research, but we also talk about how SABV is related to gender. And so as we get more information about sex and gender, perhaps there will be progress that can be made along the consideration of sex and knowledge about how to improve treatments for all of us.

IRA FLATOW: In the history of research, why wasn’t this something that was known about years ago or taken for granted that we need to include sex when we talk about research?

SHARON HUNTER: Yes. That’s a question I get a lot. So I will say, however, that there are a cadre of investigators that always have considered the sex differences or the influence of sex in their research fields. But I’ll say that for a number of reasons, researchers– maybe for convenience, they predominantly use male subjects, or when they were using female and male subjects, they didn’t analyze the data by sex. So that’s a problem.

And so researchers are now aware that not including sex, we actually lose lots of information. And this policy helps to get that word out and make scientists aware that the study of SABV is important, and it improves rigor and transparency of research. And the more we study SABV, the better the science and the better the health for all of us.

IRA FLATOW: If researchers were not including female– let’s say lab rats– in their studies, was that showing up when you went to create a medicine or a technique that both men and women were using? Did it say, hey, look, there’s a difference in men and women here?

SHARON HUNTER: Absolutely. So for instance, between 1997 and 2000, 8 of the 10 drugs that were pulled from the market were drugs that had more adverse side effects in women. So perhaps what’s happening is that because the preclinical studies did not use both males and females, the studies in humans did not have enough information to create a treatment that would not have adverse effects in women.

IRA FLATOW: When this requirement was first proposed and published by the NIH, what kind of response did you get from the scientific community?

SHARON HUNTER: In the few short years since the policy has been implemented, there have been positive changes. For instance, there was a very large study that was funded by NIH called the GTEx study. And that study recently found that there are over 13,000 genes that are expressed differently between the sexes.

Now, this GTEx study has been going on for some time, and now, recently, they have looked at the differences between the sexes. And so they found over 13,000 genes that are differently between the sexes. And moreover, there are sex bias patterns on how these genes are regulated in over 50 bodily functions. So these findings are exciting, and they may be seen as a foundational starting point to pursue personalized medicine.

IRA FLATOW: Well, it looks like the policy is working then. Wouldn’t you say?

SHARON HUNTER: Absolutely, the policy is working. I will say that we do not have full implementation. And we do know that we do need to do more. And I can’t do it alone. We need other funders. Because after all, this is an NIH policy, so there are other funders of biomedical research that do not have this policy.

Also, closing the loop on SABV is the engagement of journal editors because journal editors publish the data of scientists. And we hope that these journal editors would require researchers also to consider SABV before their information is published. Because again, the more we know about SABV, the better the science, the more rigorous the science, and the bigger the knowledge base. And that goes to creating better health for all of us.

IRA FLATOW: Well, as you gather more information about SABV, do you think there might be any revisions or tweaks to the policy?

SHARON HUNTER: Well, right now, I think that– as I said, as we go along– the policy was enacted a few short years ago. And right now, we’re really focusing on getting the word out. And what we’re hoping is that when we get the word out, we won’t see publications that talk about the gender of mice, because I do see those publications. So first, we really need to get the word out.

And I’m happy to say that one of the ways that we’re doing that is we have created a free online course called the SABV Primer. And it talks about why we needed a policy, the background to the policy, and importantly, what the policy does not do. So the ORWH and the NIH is making every effort along many lines to make sure that investigators consider sex as a biological variable.

IRA FLATOW: Well, we know we have many scientists who are in their labs listening to Science Friday when they’re doing their work. The radio is in the background, or they’re listening on podcasts. So maybe the word will get out.

SHARON HUNTER: Well, and I would ask that investigators, when they’re considering a research project– when you don’t consider sex as a biological variable, you might have data that’s hiding in plain sight.

IRA FLATOW: Thank you very much, Dr. Hunter, for taking time to be with us today.

SHARON HUNTER: All right. Take care.

IRA FLATOW: Dr. Sharon Hunter is associate director for basic and translational research. That’s in the Office of Research at Women’s Health at the National Institutes of Health in Bethesda, Maryland.

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