Talking about sex and gender doesn't need to be toxic

This episode discusses the evolving and intricate nature of research on sex and gender in a scientific context, emphasizing the importance of responsible and inclusive exploration in these areas.

1. Sex and gender research is essential but must be approached with nuanced methodologies that respect and incorporate socio-political contexts.
2. There's a critical need for scientists to use precise language to prevent the misuse and misinterpretation of scientific data regarding sex and gender.
3. Biological and social aspects of sex and gender are entangled, challenging simplistic binary categorizations.
4. Research must include diverse populations to ensure findings are comprehensive and applicable across different groups.
5. Scientific inquiry into sex and gender should not only answer existing questions but also challenge and expand the frameworks used to understand these categories.

1: Introduction

Lucy Odling-Smee introduces the topic and the importance of discussing sex and gender in a non-toxic way, highlighting the socio-political challenges surrounding this research. Lucy Odling-Smee: "To be clear, sex and gender exist beyond a simple binary."

2: Panel Discussion

Experts discuss their research backgrounds and the importance of integrating sex and gender considerations into scientific inquiry. Stacey Ritz: "I've moved away from immunological research to focus on how we incorporate sex and gender considerations."

3: Defining Sex and Gender

The panel explores the definitions of sex and gender, emphasizing the variability and complexity of these concepts across different scientific and social landscapes. Florence Ashley: "I use gender and sex largely synonymously and interchangeably."

4: Challenges in Research

Discussion on the challenges faced in current sex and gender research, including bias, inadequate categorization, and the impact of these factors on scientific validity. Peg McCarthy: "Sex differences throughout the brain have guided my research."

5: Future Directions

The conversation shifts towards how future research can better address the nuances of sex and gender, suggesting more inclusive and comprehensive study designs. Stacey Ritz: "We need to be paying attention to lots of variables."

1. Adopt inclusive language to ensure clarity and reduce biases in discussing sex and gender.
2. Educate and train new scientists on the importance of considering sex and gender in research.
3. Encourage rigorous peer review processes that scrutinize the handling of sex and gender in scientific publications.
4. Promote interdisciplinary collaborations to integrate diverse perspectives and methodologies in sex and gender research.
5. Fund studies focusing on underrepresented groups to enrich the understanding of sex and gender across different populations.

Ever since scientific enquiry began, people have focused mainly on men, or if studies involve animals, on male mice, male rats or whatever it may be. And this has led to gaps in scientists’ understanding of how diseases, and responses to treatment, and many other things might vary between people of different sexes and genders.
These days, mainly thanks to big funders like the NIH introducing new guidelines and mandates, a lot more scientists are thinking about sex and, where appropriate, gender. And this has led to a whole host of discoveries.

But all this research is going on within a sociopolitical climate that’s becoming increasingly hostile and polarized, particularly in relation to gender identity. And in some cases, science is being weaponized to push agendas, creating confusion and fear.

It is clear that sex and gender exist beyond a simple binary. This is widely accepted by scientists and it is not something we will be debating in this podcast. But this whole area is full of complexity, and there are many discussions which need to be had around funding, inclusivity or research practices.

To try to lessen fear, and encourage clearer, less divisive thinking, we have asked three contributors to a special series of opinion pieces on sex and gender to come together and thrash out how exactly scientists can fill in years of neglected research – and move forward with exploring the differences between individuals in a way that is responsible, inclusive and beneficial to as many people as possible.

People

Peg McCarthy, Stacey Ritz, Florence Ashley

Companies

Leave blank if none.

Books

Leave blank if none.

Guest Name(s):

Leave blank if none.

Content Warnings:

None

Nature Podcast
The Nature podcast is supported by Nature Plus, a flexible monthly subscription that grants immediate online access to the science journal Nature and over 50 other journals from the Nature portfolio.

More information at go dot nature.com plus.

Burrow
Burroughs furniture is built for the way you live, from ensuring easy assembly and disassembly to honoring highly requested new colors for the award winning seating, they always have their customers in mind. Their modular seating is made out of durable materials to last and grow with you. And with Burrow, you always get fast. Free shipping. Get up to 60% off during Burrow's Memorial Day sale@burrow.com. Acast that's burrow.com acast borough.com Acast.

Lucy Odling-Smee
This is a podcast extra from nature in which we're going to dive deep into a topic which is talked about a lot, but often in a way thats not productive evidence led or sex and gender after decades of neglect, research into sex and gender is increasing, but its happening in a socio political climate thats becoming ever more hostile and polarised, particularly in relation to gender identity. And in some cases science is being misinterpreted and weaponized to push agendas, creating confusion and fear. Fear.

To be clear, sex and gender exist beyond a simple binary. This is widely accepted by scientists and is not something well be debating in this podcast. But this whole area is full of complexity and there are many discussions which need to be had around funding, inclusivity or research practices.

So to try to lessen fear and encourage clearer, less divisive thinking, nature has commissioned a search series of opinion pieces about sex and gender, spearheaded and edited by Lucy Odling Smee. And in this podcast we've invited three of the authors of those pieces, Peg McCarthy, Stacey Ritz and Florence Ashley, to come together and thrash out how scientists can fill in on years of neglected research and move forward exploring the differences between individuals in a way that's responsible, inclusive and beneficial to as many people as possible.

So without further ado, let me hand you over to Lucy Odling, Smee and the rest of the panel.

Lucy Odling-Smee
So first of all, I wonder if you could all introduce yourself and give us a brief overview of your work and why you got interested in sex and gender. Stacey, let's start with you.

Stacey Ritz
Sure.

Stacey Ritz
Thanks Lucy. I'm Stacey Ritz. I'm an associate professor in the department of pathology and molecular medicine at McMaster University.

To this work on the incorporation of sex and gender considerations into health research on a pathway that started as a laboratory scientist myself, I was looking at the molecular and cellular origins of allergic disease in the respiratory tract. And that was occurring at a time when I was developing heightened sensibility about the importance of sex and gender in health research. In fact, it was around the time that the Canadian Institutes of Health research established their institute of Gender and Health. And thinking about it in terms of my own work, engaging with a lot of the feminist literature on sex, gender and science, and trying to translate some of the insights that I was reading into my work in the lab proved to be really challenging.

And I kind of spent more and more time reading and more and more time thinking about it. And it ultimately became more interesting to me than the research that I was doing itself. And over the course of a number of years, I moved away from the immunological research. And my focus now is on how do we incorporate sex and gender considerations when we're doing experimental biomedical research.

Stacey Ritz
Peg eye fatigue hi, I'm Margaret go by Peg McCarthy. I'm a professor in the department of pharmacology at the University of Maryland School of Medicine in Baltimore, Maryland. I'm also the director of the Maryland Institute for Neuroscience Discovery. And I started my career with a really keen interest in how the brain controls behavior and how evolution sculpts that relationship between brain and behavior. And if you want to look for where you're going to get the strongest impact of evolutionary forces on brain and behavior relationships, it's in the realm of reproduction, reproductive behavior, and reproductive physiology. So I started my career looking at these aspects of reproduction and comparing and contrasting males and females, using the laboratory rat as my animal model. I've since then expanded, as has the field of neuroscience, far beyond reproduction. When I started, neuroendocrinology was a very niche field that was considered sort of a set aside to the rest of neuroscience. But we've since discovered that there are sex differences throughout the brain. And so my guiding light, my mantra, is to compare and contrast males and females for its heuristic value, because it creates a sort of contrast agent in which I can reveal new cellular and molecular mechanisms of just how the brain constructs itself. By using this natural tool of comparing males and females, and over the years, I found a number of novel ways that synapses are formed, how cell number is controlled, how dendrites are branched, et cetera.

Just by using this approach of comparing males and females.

Florence Ashley
Florence so, I'm Florence Ashley. I am an assistant professor at the University of Alberta Faculty of Law and John Dosseter Health Ethics center. I'm a transdisciplinary researcher focused online bioethics as it relates to trans people. And so my interest in research around gender has really started around addressing misinformation and improving both clinical care and research for trans communities. And that's really where I came into this topic.

Lucy Odling-Smee
So one thing that really struck me in working on this series is the degree to which different people mean different things when they talk about sex and gender.

And I know this is a discussion that could last a long time, and we've got a lot to talk about, but I do think it may be worth starting with a brief overview. So, for each of you, how do you or your community go about defining these terms? Florence, perhaps we could begin with you on this one.

Florence Ashley
Yeah, so, surprisingly, perhaps. And part of this is due to my philosophical background and also legal background, I first of all use gender and sex largely synonymously and interchangeably. And by and far, when I try to be accurate, I just don't use those terms. I instead focus on what it is exactly that I'm talking about. Am I talking about gender identity? Am I talking about gender assigned at birth? Am I talking about sexual traits or hormonal profile or chromosomes or anything else? Gender modality, gender expression, sexual orientation, and all of these things, which is really a mosaic of.

Of concepts that have historically, oftentimes been kind of reduced down into either gender or sex as categories. And these are just such large terms that I try as much as possible to avoid using them as articulating categories for categorizing individuals or entities. And instead, when I talk about gender and sex, I'm usually talking more broadly about the institution or the regulation of gender, sex or research into gender sex. But when it comes to applying it to individuals or to entities, I tend to use, to try to use more kind of precise and narrow terminology to avoid any potential confusion.

Lucy Odling-Smee
Stacey, what's your take on this?

Stacey Ritz
My take has changed over the years. I think if I think back to the ways that biomedical sciences has sort of taken up the terms of sex and gender, there's been a real emphasis in the last 2025 years of trying to make clear distinction between the concept of sex and the concept of gender, because they had been often used synonymously in the literature, still quite often are used synonymously in the biomedical literature.

And there was an effort to try and make a conceptual distinction between these terms that would allow for more recognition that the kinds of phenomena that we see when we're doing scientific research are not all based in biological origins, that there are certainly sex and gender related patterns that we see in human health that have biological contributions, but also have social, political, cultural, economic kinds of contributions. And the effort to distinguish between sex and gender in biomedicine was largely about trying to broaden that recognition beyond a sort of biological essentialist frame that everything is biology.

A lot of the ways that scientists are enjoined to think about sex and gender is to try and distinguish them. And the sort of general definitions that are offered tend to emphasize that sex is the biology, gender is the social.

And I think that is an important and useful starting point for thinking about sex and gender, especially for people who are sort of new to the field and new to thinking about these things.

At the same time, my thinking around sex and gender has certainly evolved a lot in the last number of years, to the point where I really try and refrain from offering some sort of a generalizable definition that we can sort of frame and hang on the wall and say, here's what sex is, here's what gender is. And I'm much more inclined to define the frameworks for thinking about sex and gender that I'm using in any particular instance and to recognize the entanglement and the interactions between the biological and the social, that gender and sex aren't as neatly separable as the sexist biology. Gender social framing would have it, trying to dissolve some of the hard lines between sex and gender, between male and female, while still recognizing the material realities of our biological bodies and how they operate in any given instance.

Lucy Odling-Smee
Peg, what's your take?

Stacey Ritz
Yeah, just as sort of a little bit of a contrast to both Stacey and Florence in the purely animal laboratory rat and mouse world, we sort of purposefully exclude gender. We say that animals don't have gender, and we often debate about it and everything. But to me, it's like gender. Gender identity is something you have to be able to tell me whether or not you think you are a male or a female. If you can't tell me, then I can't assume that you have gender. So the most parsimonious thing is to assume that animals have no gender, and therefore, they have only a sex. Now, that doesn't mean that everything is absolutely deterministic by your sex chromosomes and your hormones, because we know that there are additional contextual constructs, such as housing situations, influence of stress, even the gender, actually, of the investigator. But to me, the point of not assigning gender to animals is in order to recognize the complexity of the human condition, which includes gender in all aspects of health. And to say, we're only carving out this corner, right? This aspect of biology, is that so that we and it is the onus on the biomedical researchers, ultimately, when translating to humans, that you bring in all of gender and entanglement with sex and all of its complexities.

But when I'm studying my rats, I'm studying their sex, and that has limitations.

But it also provides a rigor that. And we have to, in our rigor, has to include acknowledgement of these other variables that sometimes scientists like to say are representative of gender. I sort of feel that a little bit dishonors the complexity of the human situation. And so I hew very closely to just sex. And, in fact, one of the things that me and my colleagues often do when reviewing manuscripts is we find that investigators new to the study of sex differences often refer to their rats and mice as having gender because they're squeamish about the term sex and always wanting to correct that, that, no, you don't have boy, girl, man, woman, rats and mice.

Stacey Ritz
Right.

Stacey Ritz
That's a human construct.

Stacey Ritz
If I can follow up a little bit on that, Peg, I think synthesizing some of the other things from Florence as well is that emphasizing that gender goes beyond just the idea of gender identity, that I see this a lot with my students in the last ten years, for example, that students are much more likely to come to class these days with a clearly developed sense about gender as being equivalent to gender identity. And one of my first tasks in that class is actually to sort of back it up and say, actually, there's more to gender than simply gender identity, that there's all kinds of social structures, performances, roles, norms that are part of what we mean when we're talking about gender beyond just identity itself.

And then the question that peg raised around whether or not animals have gender, I think, is such a. Such an important and timely question, because I think it's one of the things that is a real difficulty in thinking about animal research and cell research. As you said, Peg, we don't know what kinds of gender identity animals might have, but certainly we do know that animals have social influences and outside external influences on their biology and on their behavior. But given the ways that a lot of the framing around the terms sex and gender have evolved over the last 25 years in biomedical context, there's definitely this hesitation to use the term gender for animals. And I see a lot of value in that, because I think it's really important that we don't start slipping between thinking that what we see in terms of gender in humans is equivalent to what we see in terms of social, environmental experiences of animals, the kinds of meanings and the kinds of power dynamics that function in human gender are probably very different and may not have an equivalent to animals. At the same time, I think that there's sort of a vacuum of the language that we have for talking about what that means when we're talking about laboratory animals.

Florence Ashley
Yeah.

Stacey Ritz
To me, it's a safeguard against us over interpreting what we see in our animals as being directly relevant to humans. I mean, of course the biology of an animal is relevant to the biology of a human. Now, we could model things like gendered expectations. We can model dominance hierarchies. We can go in and pluck out a dominant male and disrupt the social network and things like that. So we can model them. But we live in a highly, highly gendered world from the moment we're born, if not before. To say that that exists in animals, I think, is, to me, the cost of that is greater than the potential cost, is greater than the potential benefit.

Stacey Ritz
No, I agree. What dominance means to a rat is probably very different from what dominance means to a human and the way that that gets processed and the way that that has implications for health.

Florence Ashley
And I do wonder if we're not, even when using sex already doing that kind of over interpretation and kind of projection on animals in the sense that, like, I wonder to which extent it's useful to even use a term that's kind of shared between non human animals and humans, given especially that the term sex has such a long history being used as a social and not a legal category, that it raises question of, like, what does it do about to humans and to how we think about humans when we use sex as a term for animals as well. And one thing that comes to mind is all of these laws are trying to define legal sex and biological sex. And one thing that happened in my home province of Quebec in Canada was that the government proposed having administrative documents that essentially have different, like, have both gender identity and sex sex on them. And of course, the big concern was like, well, yeah, but then you're one outing trans people, but two, misgendering a lot of trans people by labeling them as, say, female when they're trans men and vice versa. And here we can see that move as being partly grounded on this idea of, like, oh, we have sex as this biological category that is relatively fixed and that is shared with animals as well. And so there is a question to, I think, as to the extent to which perhaps we might not even want to use the same terms for non human animals and for humans.

Lucy Odling-Smee
I think I was right in predicting that this would take a book length.

We could have the entire podcast dedicated to this. So, over the past decade or so, sex differences in things like health have started to be taken more seriously in the research community.

Peg, I wonder if you could just give us some examples of particularly striking findings and maybe some sense of how these results have come about.

Stacey Ritz
First, it's important to recognize why this has become to attention, and that's because in the preclinical world, and by preclinical, I mean people who are studying cells or animals, laboratory animals in particular, not animals in the wild, were never held to account as to what was the sex of their animals. And there was a sort of a naturally occurring shift towards, in most disciplines studying all male animals, with the interesting exception of immunology, where they studied all female animals for very kind of ironic reasons, in the case of neuroscience, overwhelmingly male, because of studies in the 1990s that showed that the fluctuating hormones across what was the equivalent of the human menstrual cycle in a rat actually changed brain physiology, changed synaptic formation, that caused the entire field to shift entirely to males so that they could avoid the complexity of hormones.

Then they made the assumption that males hormones were like steady eddy, rock solid, never changed across the day, the season, or anything. Immunology. On the other case, they all studied mice, and they found out that the male mice were really aggressive, so you couldn't house them together, so they would kill each other. And the investigators are charged by the cost per cage, and so that they could get more mice per cage if they just studied females. And the entire discipline of immunology, preclinical work has been founded on female animals. So now large funding agencies like the NIH or the Canadian Health Research foundation have insisted that investigators either must include both sexes in their work, or they must acknowledge why they're not kind of thing.

And so the question is, has that had an impact? What would have been the discoveries? Partly, it was also that the mandate came about in the United States because of failed clinical trials in which they found out that there was overwhelmingly adverse events in women, not compared to men. And when they went back and looked at the preclinical work, discovered that all the research had been done on males. When they repeated the experiments on females, they discovered that the adverse effects were there, and so they could have been avoided all along. The examples that get the most players just sort of dosing about drugs, but I don't think those are the important ones that we're discovering, is that across the lifespan, your relative risk of a mental health disorder is going to be based in humans on your gender, with early life injuries having worse outcomes for young males than young females. And we can then replicate that in our animal models. And by early life injury, I mean like asphyxia at birth. I mean inflammation in utero or early in life inflammation. And these events put you at cerebellar damage. They put you at higher risk for autism spectrum disorders, attention deficit disorders, schizophrenia, etcetera. All of those disorders have some gender bias in their diagnostic rates, so their prevalence is partly influenced by gendered aspects in society. But they also, we believe, have an underlying biological underpinning, which we can model in our animals, getting down to the actual signaling molecules and the events in the developing brain that are leading to this greater susceptibility in males.

Females are susceptible as well, but not as much. There also appears to be a female resilience. So if we can find out what is the resilience factors in females, what are the risk factors in males, we can actually help both by this kind of basic biological research.

Florence Ashley
Another problem that arises is that you're kind of opening up to risk of, like Simpson's paradoxes when you're looking at overall data without actually stratifying by subgroup, because the actual effect, in fact, direction can be different between subgroups, and yet the overall data have the opposite direction depending on the structure of studies and things like that. So not only is it a danger for particular subgroup, but it can actually lead to the completely wrong conclusion for any subgroup.

Stacey Ritz
Absolutely, totally agree we should be paying attention to lots of variables, and I totally agree with that. But I think excluding sex as a variable, it is the first, most sort of practical variable. I completely agree with you, Florence, and I know Stacey feels the same way, that we should then also break down into things like, what is it sex related to hormone levels or sex chromosomes, or all various aspects of sex and gender. But at the start, it's an imperfect but useful sorting tool.

Florence Ashley
It kind of ties into the broader kind of map territory problem, where we have to find what is the appropriate level of nuance. Because on one hand, you have too much nuance. Well, you basically have raw data, and that's completely useless. But if you're over evacuating nuance, then you end up with a binary model that doesn't tell you what you even need to know. And so a lot of it is about this fundamentally partly subjective process of figuring out what is the actual best level of nuance that you can get and set aside those that you have good reason to think, won't really be particularly useful, and would actually end up producing results that are not particularly usable.

Stacey Ritz
I agree completely, Florence, and I think it speaks to what I think about as sort of a paradox or a dilemma around experimentation, is that experimentation itself is an incredibly powerful tool for generating knowledge. That particular method can allow us to establish cause and effect relationships in ways that other forms of research are much more limited. At the same time, experimentation generally requires us to have categories and have controls. It's geared toward trying to create a degree of simplification so that we can generate those relationships. I see that there's almost an inherent tension between the kind of drive to that simplification that gives experimental methods their power and the recognition of the complexity of sex and gender, which are not. I don't think they're easy to reconcile with that, with that experimental paradigm. And I think one of the ways that we can deal with that, practically, is to address some of those kinds of things that you were speaking to Florence about, thinking about. What exactly is it that is the thing that we think is important here? Is it the sex category itself, or is there something that's associated or affiliated or correlated with that sex category that is actually the mechanistic driving factor?

There are different ways of approaching this, and there's no single right way that this is the way that you do research on sex or gender. And, you know, that's reflected in different jurisdictions, too, in terms of the ways that the policies are articulated. So, in the canadian context for the CIHR, the requirement for researchers is not you must include males and females, or you compare males to females. The requirement is you must explain how you are accounting for sex and gender.

And if you're not, you have to have a really good reason why not. And so, you know, that that paradigm asks something slightly different of researchers than mandates to say, you must include males and females, or you must take this approach. So, you know, there are different ways of approaching these questions, and they will generate different kinds of insights.

Stacey Ritz
And I just want to, like, agree with what Florence said, that the challenge is where to draw the line between what is the useful variables to incorporate, and partly it's not all going to be done in every single study. So some studies are just going to say, I divided my mice into the male and female mice, and I found a difference, and full stop. And they're going to publish that, and they're never going to explore why another researcher might come along and say, well, I wonder if that difference has to do with hormones, or does it have to do with housing conditions, and they'll actually carry it to the next level. So let's say they find out it's hormones. The next researcher comes along and says, I'm really interested in what are the genes that are being changed in their expression profile by those hormones, because that's the way science works. So we have to be careful not to try to say that every study has to incorporate all of the complexity of just even sex, right? Because it is a very broad category. I often, when people show me an amazing sex difference in adult animals, I say, well, does that have its origins in development or is that adult circulating hormones? And they say, I don't know, and I don't care. I'm moving on. And I say, well, I care, so maybe I'll study it, you know, because that's the way science works, right? To me, sex is like. It's like the term evolution. Oh, this is the result of evolution. Well, we all know evolution doesn't have agency, right? Evolution is a compilation of forces of natural selection, mutation, et cetera, et cetera.

The same thing with sex. It doesn't have agency. It's a catch all category. And then we have to drill down into what are the mechanisms if we care.

Lucy Odling-Smee
So that's something that's worth exploring. We talked about the different definitions of sex and gender, but even with the term sex, we could be talking about a lot of different things.

Florence Ashley
There's something to be noticed about how science is sometimes just as much art as it is science, especially when it comes to study design. And, I mean, that plays a role even in, you know, everywhere in science, even with, like, things like the replication problem and things like that. But in terms of, like, studies around sex, what I would really love is for the studies to at least have this reporting of how they actually categorized the individuals or the animals in the study and whether they had any edge case. Because sometimes you're reading a study and they're like, oh, well, you know, male, female. I'm like, yeah, but how did you decide which one you actually put in that category? Because it's going to be very different based on whether you're using chromosomes, whether you're just looking at the gonads, whether you're looking at a production of gametes, whether you're looking at all of these different factors, which is like, sex is such a broad category that includes so many biological traits in the way that it's used in science. And oftentimes they don't tell us which ones they actually use. And at a minimum, I'm not saying that they should have to do the whole justificatory work of figuring out why they care about hormones versus something else in each individual study. Sometimes they just. They don't know because they don't know what could have a relevant impact. But at the very least, I feel like it should be standard to report how they did that categorization so that we can take that data and interpret it better and with more sensitivity and also figure out what, if any, follow up studies need to be done.

Stacey Ritz
This emphasis on category and the concept of category, I think, is really important in this realm because I think, on the one hand, it's important to recognize that categories are decisions. You know, we have created categories, or we have decided that certain differences are salient and that we want to categorize individuals in these different ways. So categories are decisions, especially when we're talking about sex category or gender category. They aren't based on one single trait.

They're based on a constellation of elements. And some people will define them in one way for one purpose and for a different way for another purpose, but in every way, they're a decision. And at the same time, I would want to emphasize that categories are useful and important for human cognition and decision making, but they are also, they're not mechanisms. So when we find a difference between comparing two categories, that tells us that there's something going on there, but it doesn't tell us about the mechanism that actually links it. And I think that is one of the important things to highlight here, is that we can do research where we're comparing two categories and identifying a difference. But I am really reluctant to take big policy level or clinical decision making level kinds of decisions on the basis of something where we don't understand the mechanism because we don't know who within those categories that mechanism may or may not apply to.

Stacey Ritz
True, true. But I always, when I lecture the medical students, I talk about nsaids, right? Nonsteroidal anti inflammatory drugs, which aspirin is the most famous. And we didn't know the mechanism of action of aspirin until the 1980s, but we sure used it a lot. So, I mean, I'm, you know, Stacey, you know, I'm a complete mechanism person. I believe in mechanisms, but sometimes we can't even. We don't know the mechanisms, and it's still a very useful thing to do. Back to Florence. Saying, though, that, that researchers need to report how they are determining sex and even more importantly, gender. I completely agree, and I would say it's always been sort of as just sort of self evident, you know, like, I looked at the genitalia, you know, or I ordered ten males and ten females from Charles river. So that's what I've got.

And I agree that it's important for rigor that we should start to report those things more carefully, particularly if you're doing anything with embryonic animals. Did you do it based on dissection? Did you look at the sex chromosomes? Did you look for genes on the Y chromosome, etcetera? Those are important things for enhancing rigor. And I don't see how any scientists.

Stacey Ritz
Could object, especially when you're talking about cell culture research as well. There becomes all these really interesting complications about reporting sex and making a determination of the sex of the cells. You know, they're cells that came from known donors, and you know, that the. The sex category in that donor. But having cultured them in the lab forever and ever and ever, their chromosome changes and becomes very totally driven.

Stacey Ritz
Exactly. And actually, there's a huge problem emerging in the organoid field, which is a, you know, really burgeoning new area that organoids don't maintain stable sex chromosome identity. So they're not going to be useful, by and large, for sex differences.

Florence Ashley
One thing people often forget is, like, we're using XY chromosome most of the time. But while admittedly it is rare, the sry gene is not actually only on the Y chromosome. And that's really most of the time what people talk about when they say Y chromosome, but it's not 100% guaranteed that it's on the Y chromosome in the first place.

Stacey Ritz
And how they discovered it, that's how they discovered it was the sex determining region of the Y chromosome. It was. They found it on some autosomes. Absolutely.

Stacey Ritz
And it turns out there's a paper that came out a couple of years ago that was talking about the loss of the Y chromosome in slothosomatic cells in humans and whole animals, that the Y chromosome is often lost cells just under normal conditions.

Stacey Ritz
And to make it even more complicated, you know, the inactivated X chromosome can become activated under certain conditions at certain times. So even the sex chromosomes, you're right, are not a perfect category. I mean, you know, talk about sex being fluid. You can see that that's evidence right there that it can be fluid on a cell by cell basis. So. But it's biology, right? And that's biology. It's always got lots and lots of variance. There's so many ways problems get solved in biology. That's why it's so fun to study.

Lucy Odling-Smee
Some of this you've touched on before. But, Stacey, can you tell us a bit more about the kinds of concerns you have about how studies on sex and gender are being carried out today?

Stacey Ritz
When we're thinking about sex and gender, scientists themselves are embedded in a cultural matrix of all kinds of beliefs about sex and gender and about men and women.

And our science isn't impervious to that. All of those beliefs that we bring with us and those biases and stereotypes do find their way into the science, and we see that in the literature in lots of ways. And so I think it's really valuable and important for people to interrogate their own beliefs very critically.

I think the other piece that I am especially concerned about these days is about the ways that understanding how sex and gender related factors can influence health gets framed into a strong binary framing, even when the data shows a lot of overlap between the two categories. So if, you know, if you're doing a study where you're comparing male and female animals, and you find a statistically significant difference between the means for those two groups, and then the language we start to use to talk about that is males are like this and females are like this, and suddenly that becomes a sort of harkening back to John Gray's famous books from the nineties about men are from Mars and women are from Venus, as if we're so different that we're from different planets. But when you actually look at the data and you look at the distributions of the data, they're very rarely that dimorphic. Sometimes they are, absolutely. Sometimes they are. And it's very valuable when that's the case. But it's rare. Most of the time, the distributions overlap to a greater or lesser extent. And. And that nuance tends to get lost in a lot of the ways that the data is interpreted and analyzed and talked about in the literature.

Lucy Odling-Smee
So, Florence, much of your work focuses on bioethics. So what else would you say we should be considering here, especially when it comes to the relationship between science and society?

Florence Ashley
I think the biggest thing for me in LTL research is just how much trans people are excluded. And oftentimes people aren't thinking about that. There's this idea of like, oh, well, you know, trans people are just going to kind of mess up our data.

But the reality is then the result of that is that we don't know shit about regular healthcare needs of trans people because it's not studied, because we're constantly excluded from those studies, and there's not enough funding to do each of those studies specifically on trans people. Again. And so we know so little about the healthcare realities and needs of trans people in just kind of regular medicine. It's a problem. And frankly, I think they should take to including more. And yes, you're going to have studies that are underpowered, and you're not going to be able to reach, you know, your 0.05 alpha and things like that. But a lot of times, the information is still going to be better than nothing, even if it's slightly underpowered. Hopefully, science is moving a little bit away from being overly rigid about the significance threshold.

There's been a lot of calls, especially within statistics, to stop overly focusing on this, on exactly where you fall around the line, because sometimes more information is better than none. And that's something I think we really need to start having in medicine. And healthcare research is like, stop excluding trans people just because you think you're going to mess up your data. Trans people are in the general population. They have healthcare needs. We need to know how those differences apply to trans people, because otherwise, you're going to have much worse healthcare outcomes.

Stacey Ritz
And if I can expand on that, I mean, I think there's also an additional argument to be made, not only in terms of justice and health equity for trans folks, non gender agender folks, that sort of thing, but also when we studied trans folks, and when we study intersex folks, we learn all kinds of important things that shed light on biological processes more generally that are valuable knowledge that improve health for everybody. In the course I teach on sex, gender and health, we've read papers in the last couple of years that highlighted how studying trans people, for example, in a study about the immune system and about pain, actually helped to shed light on the. The relative roles of gender norms and expectations versus hormones and exogenous hormones and those kinds of things, that by studying trans people, it shed better light on how this functions for everybody. So not only does it address the health equity question for trans folks themselves, but I think it has broader benefits that are often under recognized.

Stacey Ritz
I'll just riff on that a little bit further, that there's, first of all, there's sort of a similar but different argument to be made for including people who are pregnant and studies. They are systematically excluded and therefore possibly deprived of important medications or treatments. But then also sort of to your point, Florence, about parsing out the groups. I can't tell you how many studies I've seen in humans that involve, say, fMRI of the brain, and they might compare men and women. And the women will range in age from 18 to 65.

Those two women are not the same. You know, it's like. It's. Nor is an 18 and a 65 year old man, but there's a clear demarcation in terms of their hormonal profile, and it's never incorporated into the data or things like people who are taking contraceptive medicine. What kind of contraception are you taking? It's like there's so much complexity out there in the data that's never. It's never gleaned because of exactly as you said, it's just binary. It's males versus females. So I think that these are really important arguments across so many categories that we should be including all of humans complexity, but then looking at that complexity and Florence, I'd like your opinion about. You talked about wanting to include trans individuals in ongoing clinical studies. What about clinical studies that are just specific to the trans population?

I feel like particularly in the states, we do not give enough resources to study the health of transgendered people. Whereas if you go to Europe, you go anywhere in Denmark and the Netherlands, et cetera, they have an unbelievable richness of information because they actually collect data, whereas we sort of ignore it and shove it aside and have a tiny, tiny little office inside the NIH that's dedicated to sort of non traditional gender.

Florence Ashley
Yeah, I'm not sure I agreed up about Europe being particularly good for trans health research, or found that the data that comes out of it actually tends to be worse.

You know, there's part. Yes, it is true that there's perhaps a bit more funding. I think a lot of it is centralized care that ends up a happy, captured population again, makes it easier to, well, frankly, coerce people into research, which is a huge problem. A lot of time, the quality of the data is quite poor precisely because there's so much kind of control and domination that is going on in the research team and in the clinical relationships that then get fed into research program. So it's been kind of a big issue, but there's just not enough resource dedicated to trans health at all. And it's quite unfortunate that so much of the resources that do exist tend to be arguably wasted, as in put towards research projects are not necessarily adapted to the needs of trans people, or end up just redoing the same study over and over and over again. Basically, there are two studies in trans well, three studies in Transhalla. One, does gender affirming care improve trans well being? And all the studies report, yes, but somehow we keep running the same study, two trans people are really suicidal, which tends to be cross sectional studies. They're just looking at kind of demographics and reported suicidality. And the third one is, are trans people different from cis people? And that's usually, like, brain studies and things like that. And I'm like, okay, can we move on? Like, I'm not saying those are bad studies to have, but, like, we do more than three studies.

Lucy Odling-Smee
So, peg, in your opinion piece, you talk about how important it is not to abandon comparisons of males and females, especially because this kind of work has just got started.

So what is your answer to people who say, but hang on, if you only do a binary comparison, you're excluding people who sex and or gender doesn't fall into a binary categorization scheme?

Stacey Ritz
Yeah, our animals don't come in as many of the rich varieties as humans do.

Stacey Ritz
Right.

Stacey Ritz
But they do have some. We have, you know, there are x y animals that are androgen insensitive that we can do to, say, study about what that means to have a one sex chromosome complement versus a different hormonal responsive profile. We do do experiments where my particular model is to often take newborn female rat pups and give them testosterone and see then how that impacts the way their brain develops. That might have relevance to transgender individuals in not necessarily immediately evident ways. I find that this idea that there is legislation that is being used to harm and marginalize trans people based on identifying gender as gamete size is absolutely abhorrent. I mean, one of the big sea changes that's come in the acceptance of homosexuality is the acceptance that it is just a biological variant. You know, it's not a deviance. Right. It's not an aberration. It's a biological variant. And some of our work on how hormones impact the way the brain develops in the context of different chromosome complements could speak to biological origins or variances of transgenderism. And therefore, passing legislation that is in defiance of that says that a person's gender is based on their gamete size. We could reveal the lie that there's no reason to think that a person's gender identity is tied to their gamete size.

That's just a false connection. And we can use our animal research as ways to make those arguments against that. But I also recognize here there's always a danger, and this was really true in the early days of studying the biological origins of partner preference, that if you find out a cellular mechanism, you might be able to create a cure. Right? And that's the reason you're doing the science is to create a cure I would just use in the United States anyway. The overwhelming now, you know, the legalization of same sex marriage and the cultural acceptance of it was happened stunningly fast, and it happened around the same times that we were revealing research about the biological origins. And I would love to see the same thing happen in terms of transgendered individuals, that we have the same kind of come to the realization that this is just another naturally occurring human variant that we don't need to try to cure and we don't need to legislate against in any way.

Florence Ashley
Well, the thing about same sex marriage is it's likely to be overturned at the Supreme Court level soon enough, unfortunately, so very temporary advances. I mean, as somebody who's done a lot of work around conversion practices, I do have quite a lot of concerns around a potential development of high tech conversion practices. Partly because even if it's often based on a misunderstanding of science and a misrepresentation of new science, it just gets misused by people who already want to offer conversion practices. But it kind of adds to a toolbox that is quite abusive. But to me, the problem, and as somebody who's quite embedded in trans research circles, I rarely see people as saying we shouldn't study sex. A lot of more concerns is about how we do it, what language we use, how are we being sensitive to trans people, and how much we're incorporating trans expertise in doing that. Now, I have been known to be a little bit of an opponent of constant transgene, or fMRI studies for trans people.

But a lot of it is not just based on the risk of it, but also because a lot of time it's been done poorly, it's been done kind of lazily. And that's what bugs me much more than the very idea of doing that research in first place. But also when it comes to specifically studying trans people, I just think that there, given how few resources are dedicated to trans health, I would like to see those resources redirected to something that's more useful. But otherwise, I think we should fully study sex, gender and continue doing that.

What I want to see is not less research of that. I want to see more. I just want to see us do it more accurately and better and more sensitively.

Stacey Ritz
If I can just expand on that too, I would say I don't have any objection to female comparisons as a tool for trying to understand the influences of sex and gender. My ethos is that it's one of many tools and that I think there's an extent to which some people have become over reliant on that tool and failing to recognize that there are other tools in the toolbox, at least in human studies.

Lucy Odling-Smee
It seems like a lot of difficulties arise because people aren't yet collecting the data that would help provide a clearer and more inclusive picture.

The reality is scientists are just beginning to be persuaded to factor in sex and haven't really got their heads around gender at this point. So, Stacey, would you say there's still some kind of shift in mindset that needs to happen amongst researchers?

Stacey Ritz
Oh, absolutely, for sure. For one thing, depending on the pockets of scholarship that you're talking about, there's a greater or lesser resistance to the idea in the first place. There are people whose research focuses is trying to understand the influence of sex and gender on whatever the phenomenon is. They're interested in those people. Obviously, they don't need to be won over, but there's a huge number of, probably the majority of scientists who are doing work where their priority of their question is not principally about sex and gender, but where they ought to be doing a better job of bringing at least an awareness to the sex and gender considerations that are relevant for their work.

Stacey Ritz
But, Stacey, it's the practicality that becomes the problem. Right? The devil's in the details. So. And particularly people who are resistant to begin with, to then say, well, now you have to. You can't just sort by, you know, male or female mice. You have to look at hormones. I mean, can you give some, like, practical examples of what you mean?

Stacey Ritz
In some ways, it speaks to the way that you were fleshing it out earlier, Peg, is that, you know, we can't expect, we shouldn't expect that every scientist is going to interrogate sex and gender as the core focus and everything that in itself is a whole career's worth of work that is not something you just do is like. And now the mandate requires me to do that changes the focus of the work. So I think it is that kind of iterative process where you say, what are the most relevant things here right now? In some cases, that may simply be a matter of people becoming better acquainted with what's already known about how sex and gender influence the phenomenon they're interested in. There's a huge gap there already where a lot of people who are doing different forms of research haven't even really spent much time looking at what we already know about sex and gender, why it is relevant. That in itself would be a huge step forward for people to invest more energy into thinking about what might be relevant here. So that then, as they build their experiments, as they generate their hypotheses, as they analyze their data, they can bring those insights with them. Even if they didn't put it in the experiment, they can bring that insight with them to help interpret, because there.

Florence Ashley
Are a time where they fully can do ask the question and incorporate it into their study, but they don't, because they haven't really sat down for an hour to ask themselves, what do I care about and what should I be looking at? And part of it is because it is disincentivized at the structural and the institutional level by the culture of publisher perish. We're in a situation where like, just like fast faction, we have fast science increasingly, you know, you have like all these Nobel Prize winners coming around and saying, like, I wouldn't get hired. I wouldn't even get into a PhD program today. Unfortunately, that's to the detriment of science, because people don't have the time to sit down and think, how do I consider sex, gender in my studies? And if they had the time, if we gave them the time, I think we could improve a lot of the studies without having to have more resources, without even expanding people's expertise that much. And so I think at some point, we will have to have a reckoning with the cultural science and the way that it's being incentivized in all the wrong directions because of, well, nobody's individual fault. And that's what makes it such a difficult problem.

Lucy Odling-Smee
So, one thing I realized in working on this series is that there really is a ton of confusion, because as we talked about at the beginning, people use the term sex and gender to mean different things.

And we know there's a lot of complexity to working with more variables, not to mention cost. But I do think there is quite an eagerness to do things better.

So perhaps we could sort of go around with each of you. But what do you think scientists should be doing? How do you start collecting better, more inclusive, clearer data? And how do you get people to start being on the same page, even with respect to the very meaning of these two words?

Stacey Ritz
Well, I think that Stacy's article with Donna Maney and Madeleine Pape and sell laid out a really nice set of guidelines for things about making sure that your statistical analysis is correct. So more rigor in our statistics writ large, although I also agree with getting away from the lock in a 0.05 p value, but to better analyze our data. Also, not just as like, rote statistics, we should do more aggression analysis, we should do more sort of model building and things of that sort to bring in sex as one of many variables. I think that the term from SABV, sex is a biological variable.

It's a really catchy term, but it carries an enormous amount of weight and it should be considered as one of, of many variables, unless it is the variable that you care the most about, which just happens to be in my case. I see people also more what Stacey was saying about understanding that sex and differences. I have people come to me so excited because they found a tiny, tiny little sex difference, and they're like, oh, this is so cool, this is so great. And I'm like, I don't know how to disappoint you, but this just doesn't look important.

So what is the difference in what's really biological, what matters, what sex differences are actually going to teach us something important about the biology that's going to have relevance ultimately to all of human health. And there, too, I think if we thought more about that, I think right now the literature is being sort of flooded with manuscripts that have the title sex differences in blah, blah, blah. And as Donna Mane's kind of team has done, they've analyzed that a lot of those are really very, very poorly, poorly done. So. And that's why we need to get to the journals. I was actually recently at a national Academy of Medicine's science and Engineering workshop on that. They're looking at how the NIH in the United States spends money relevant to women's health. And one of the things that they were complaining about is that they don't think that the journals are taking sex differences seriously and that they don't recognize them as a, important, and b, they don't seem to bothered want to try to bring any rigor to them. And Florence was absolutely right, with the biggest problem being the publishers and, sorry, nature. I know I'm talking to nature. The incentive to get a paper in nature is so high, it's career transforming. And this is kind of having an impact on what people view as important. And if nature doesn't publish papers that are rigorous and interesting analyses of sex differences, then people aren't going to pursue that as an important research topic. So despite the fact that the funding agencies might do specific calls, specific requests for applications around sex differences, if the journals, the high impact journals, aren't publishing it, then it's the final completion of the process, because that's what gets people's jobs.

It was gets them promoted, is what gets them the next grant. I mean, it is the absolute keystone to career success.

Florence Ashley
The tremendous benefit of being in a primary affiliation faculty that does not give a rat sauce about nature. Most of them don't even know what it is.

For better or worse, you know, what should scientists be doing?

They should be doing the thing that I just said they can't really do, which is sit down and think.

Sit down and think about how they can run their study, how they can do better, how can better designers study? There's so many studies that could have easily been just better designed and aren't, and there's no apparent reason for it other than they just didn't do it. And I suspect it's because they didn't have the time to do it.

Part of that is, I think there's a dire need to listen to trans scholars and engage with trans scholars and take trans scholars seriously in this discussion, because oftentimes, especially when it comes to human subject research and medical research, there's often just a disengagement with trans communities. And there's this idea of, like, trans communities are merely an objective study, but they're not subject. They're not. They don't themselves have anything important, kind of theoretically, to contribute. And so a lot of those conversations are happening without trans people. And so I think it's really important to incorporate trans scholars in that.

We think. I think we should also just kind of expand our conceptual vocabulary and inventory to include things that are beyond just kind of sex and gender as a categorization scheme. Like, we should think in terms of hormones, we should think in terms of a gender assigned at birth. And then in our piece for nature, we also talk about gender modality, which refers to the relationship between gender identity and gender assigned at birth. For people, most often is going to be cisgender or transgender, but is actually a broader category that allows us to incorporate a lot more nuance in our thinking. And, of course, when is that going to be something you're going to look at is going to depend on your study, and there's going to be a need for scientists to just, you know, think and decide for themselves.

But, you know, taking that time to sit down and think about what. What do I want to study? What actually matters is something I think would greatly, greatly improve the quality of research.

Stacey Ritz
I think a few things. One is building on Peg's point about statistical analysis and making sure you're doing the appropriate rigorous statistical analysis, but also thinking about practices like reporting effect sizes and measures of overlap. I think that is something that we see regularly in some fields, it's very common in psychology, as I understand it, to report effect sizes, but it's very uncommon in other fields, and I think it's a particularly valuable tool. I'd like to see people be very careful about the language that they use and reflect very thoughtfully about the way that they characterize the kinds of sex and gender related effects that they see.

When we look at the literature, it's very common for people to talk about having found a difference in means between male and female groups, and then the language that they use emphasizes, uses words like dimorphism and sex specific, which actually aren't even supported by their own data because they're actually, most of the time the distributions overlap, but those words imply a much more stark difference than the data actually warrants. So being very careful and thoughtful about language, be very, extremely careful about extrapolating from animal models to human condition.

And not only because animal models are not always perfect biological models for the human condition, but also the human condition always has so many additional layers around power, privilege, you know, the other layers of gendered experience that absolutely impact on those things. And finally, I think the biggest impact that we can have in this area is thinking about educating our next generation of scientists. They are coming into a field of science that is already requiring them from the start to think about sex and gender because of these mandates.

And I think making sure that our training programs equip trainees to bring these sensibilities with them right from the start of their careers is what's really going to be transformative.

Lucy Odling-Smee
Fantastic. Thank you so much. Incredibly fascinating conversation. I feel like we maybe should have commissioned another ten opinion pieces.

Stacey Ritz
Thanks so much, Stacey.

Stacey Ritz
Florence Peg, it's been super fun.

Florence Ashley
Yeah, thanks.

Stacey Ritz
Thank you for highlighting such an important topic.

Lucy Odling-Smee
This was a podcast extra from Nature, produced by me, Noah Baker, with editing help from Cara Tannenbaum, Brendan Marr, Richard Webb, and Lucy Odling. Smee. And a particularly big thank you to Lucy for working so tirelessly on this whole package. If you'd like to read more, including Stacey Pegg and Florence's opinion pieces, they'll all be added to a special collections page, along with a series of other pieces published now and over the coming weeks, all exploring the endless complexity of the human condition. I'll put a link in the show notes.

If you'd like to reach out to us about anything you've heard in this piece, we'd love to hear from you. You can reach us on email, podcastature.com or on xformally, Twitter at naturepodcast or look for nature on whichever social channels you prefer.

Thanks for listening.

Nature Podcast
Deep dive into the world of science with nature. Plus, from the vastness of the distant star systems to the intricacies of infectious diseases due to climate change, we've got you covered. Enjoy access to over 55 cutting edge journals, breaking scientific news, and over a thousand new articles every month. Whether you're a seasoned researcher or just curious, NaturePlus simplifies complex studies. Plus, it's all available right at your fingertips on nature.com.

Nature, the key to unlocking the world's most significant scientific advances. Subscribe today at Go dot nature.com.

Burrow
Plus, we all have smartphones, and we all know they're pretty amazing.

Stacey Ritz
But they can also be amazingly distracting, especially when we're around other people.

Burrow
So us cellular wants us to reset our relationship with our phones by putting down our phones for five.

Stacey Ritz
That's right, a company that sells phones wants us to put down our phones and see what we find. Learn more@uscellular.com builtforus that's uscellular.com builtforus.