 Well, thanks, Sarge. Well, I really also want to echo what Anne Foster-Sterling said about Art Arnold. He was very helpful to me in my progress toward writing that book on the sex chromosomes, very open-minded, and helped me make sure the science was right in the final version. I really wanted to take this opportunity to engage with the question of the conference, this notion of it being a critical moment and an opening to discussions around plasticity in the biology of sex and gender. So what I'm going to do is put on my historian and philosopher of science hat and go really hard at the concept of sex that we're using in our combined research efforts. Let me start with two widely divergent views. Here's Charlotte Perkins Gilman, the feminist intellectual philosopher who was writing in an era of the late 19th century, when the distinction between primary and secondary sexual characters was clearer than now and also in which sex was a much quesier topic of investigation. And she's known for her quips. And she said, in one of them, the brain is not an organ of sex, might as well speak of a female liver. Well, today, people are speaking of female livers. So here's a very, very, very different view from Janine Clayton of the Office for Research on Women's Health. Every cell has a sex. She says, each cell is either male or female, and that genetic difference results in different biochemical processes within those cells. And she would certainly say, a liver has a sex. So we're entering into a really transformative moment in the biology of sex and in the historical sweep of things as art already began to relate. We're moving out of an era in which we focused very much on a hormone-centered concept of sex, differentiation, and development into a more genomic-centered one. We're now molecular, and it's become more normalized to see sex everywhere at the molecular level. Cells have sexes, genomes have sexes, livers have sexes. But I really want to ask some questions, some provocative questions about this emerging model. Whether the concept of sex that it embodies is one that we truly want to accept. So I want to interrogate the concept of sex in contemporary biological explanation. And I want to suggest that the prevailing view that in the sciences of sex, we are going to eventually apprehend and discover sex itself in nature is actually a naive one. And the overarching goal of my talk is to encourage a kind of reflection on the oddity of sex as an explanatory category in the life sciences. So my intellectual trajectory is through looking at the history of the genome and attempts to locate sex in the genome. And this started with the discovery of the sex chromosomes at the turn of the 20th century, which instigated a historically novel understanding of the biology of sex differences rooted in this visually compelling binary of the X and Y chromosomes. So there was this notion as art related that the essential male and female processes would be determined and controlled by genes on the X and Y chromosomes. So the X came to be, as I document in my book, Sex Itself, the X came to be referred to as the female chromosome and the Y as the male chromosome. And they were even attributed with masculine and feminine traits. And this led to all sorts of funny business in our reasoning about sex differences in the 20th century. And as art said, this 20th century model is now beginning to be challenged. This notion that the X, X and X, Y gene complement are only relevant in this early moment of sex determination and then then on come the hormones. Instead, we have a more whole genome notion of sex determination in which these genes are also interacting dynamically with hormones. So for example, you have a lot of genes implicated in important sex determining processes that are not located on the X and Y chromosomes. So rather than this picture, we need something a little bit more like this. Okay, so if we're embracing the idea that there is a whole genome, there's a sexome as art has said, then do we wanna say something like a genome has a sex? And this is something that in the initial heady days of thinking about whole genome sexes, some really provocative claims came out about differences between male and female genomes and I won't play this clip from a TED talk by Y chromosome researcher, David Page, but he is among those who has made very strong claims that there are different male and female genomes, that we have a problem with the notion of a single human genome that is provoked by findings of sex differences in the genome. He has even suggested that males and females are as different as just a clip from that same TED talk as humans and chimpanzees. So has Huntington Willard at Duke University. In this moment, he claimed human males and females differ by quote 2%, kind of quantitative notion of sex genomic sex differences, greater than the hereditary gap between humankind and its closest relative, the chimpanzee, and that there is not one human genome, but two male and female. Well, this led me to make all sorts of charts and go through in a bit of detail. Why? Why? That's just a very foolish way of thinking that you're actually comparing apples and oranges there. So, and if you're interested in my larger argument about why males and females are not like humans and species, take a look at this paper where I work through that somewhat silly argument. But, you know, my argument there are rested on an older notion of the genome. Rested on a notion of the genome is nearly made up of sequence so that what you can't do is just count up sequence differences and make species or sex differences. But that notion of the genome as art related, I'm really glad my talk follows on his, is changing itself. So, today we're undergoing a major shift in the way that sex is conceptualized in the human genome away from these more essentialist and reductive approaches. Over the past decade, basic research on sex, gender, and sexuality has increasingly moved toward examining how hormones and genes interact dynamically and throughout the life course to regulate sex differentiating processes. And Art Arnold has called this notion the sexome. And I just wanna, I can follow very quickly on what he already laid out for us. But look at some of the key terms here. Complex intersecting causal pathways, gene networks pulsating with activity, dynamic nets of interactions, the totality of sex bias factors in the network comprising the sexome. So this, and here's a nice image. This concept of the sexome suggests the presence that is of sex specific processes and pathways throughout the genome, not restricted to genes or chromosomes conventionally linked to classic reproductive traits. So we're back to livers having sexes. And epigenetics is a key element of this sexome model. So here in this model, X and Y chromosomal genes and hormones and other cofactors are visualized as producing long lasting and sex specific epigenetic modifications during early developmental stages which results in gender A and gender B. All right. So let me give an example of an exciting finding in this field from this year. A recent study from Margaret McCarthy's lab, Brain Feminization Requires Act of Repression of Masculinization via DNA methylation. McCarthy and colleagues examined the epigenetics of gonadal steroid action in the sexually differentiated pre-optic area of the brain. The study, the conclusions of which are summarized in this figure, found reduced activity of DNA methyltransferase enzymes in the male rat pre-optic area, suggesting that the quote unquote masculine phenotype of the pre-optic area is produced by demethylation or releasing masculinizing genes from epigenetic repression. And then the study also showed that inhibiting these DNA methyltransferase enzymes with a drug or knocking out these methyltransferase created a masculinizing effect in adult female rats. OK, here's what you need to know about the provocative findings of this study. It can be read as challenging received understandings of sexual dimorphism in the brain at several levels. First, in contrast to a view of male and female brains, as organized and hardwired during early development, the study authors conceptualized this epigenetic finding is showing that the neuronal DNA methylation methylome is highly modifiable with rapid demethylation and de novo methylation occurring in response to changes in excitability, particularly in genes associated with neural plasticity. Second, rather than viewing the female condition as the passive default in the absence of masculinizing factors that overlay or repress feminization, the authors flip the script. They interpret the experimental manipulability of male or female phenotype via alteration of methylation as confirming that feminization is an active and ongoing repression of masculinization and thus reversible. So without methylation, a masculine phenotype can emerge in female rats even in adulthood. Hence, they conclude that feminization is the active process of suppressing masculinization by a DNA methylation. And further, that this finding is, quote, evidence for the duality of the brain with some arguing for the simultaneous presence of male and female circuits or phenotypes. Third, the authors suggest that methylation is on balance a means of preventing far greater sex differences in the brain. So only 70 genes of all those that they screened showed sex differences with 34 of those more highly expressed in females and 36 in males. Methylation assured equal levels of gene expression in the 381 other genes, which the authors called convergence genes. OK. Now I want to step back and talk about this moment in terms of the theme of the conference around plasticity. So of course, feminist science studies scholars, such as myself, are keenly interested in models of how gender, the social norms, and expectations associated with masculinity and femininity is corporealized in the biological sexed body. With its emphasis on the reactivity and responsiveness of the body to social and environmental influences, epigenetics offers a potentially rich and provocative theoretical frame for understanding sex and gender at the level of the body. Feminist intellectual traditions have long conceptualized gendered minds and bodies as deeply conditioned by their historical and social context. Charlotte Perkin Gilman's again in that 1898 text famously argued that the social conditions of subjugation had created, quote, rudimentary female creatures weak in body and servile in mind. Gilman contended that sexual inequality between the sexes was produced and maintained by social factors working in interaction with body and biology. And she argued that with greater equality, women would grow physically larger, stronger, and more agile. Three quarters of a century later in the genetic age, Joanna Russ, in her famous feminist science fiction classic The Female Man, followed this with an elaborate feminist parable, making very much the same point. The book features a meeting between four women with identical genomes and from different time periods brought together in a time traveling scientific experiment. And it shows them interacting with each other and having different stances and postures and ways of being in the world conditioned by the different gender environments in which they find themselves. And most recently, the BBC America science fiction series or Fin Black, any fans in the room, praised for its scientific acumen and feminist vibe, features a single actress who plays eight different versions of a contemporary woman with identical genomes. So the television show is a gender-bending phantasmagoria showing the clones living wildly different lives from my favorite, the Brainiac scientist, Cosima, to the uptight, straight-laced soccer mom, Allison. So the show's writers actually regularly include epigenetics as a kind of explanation for the kinds of differences between these women. I raise this because these compelling visions of gender plasticity form an imaginary that has historically animated feminist intrigue with plasticity affirming biological theories of all sorts. And attending to the materiality of gender plasticity in the body, it is thought, might ultimately help to promote greater social tolerance and acceptance of marginalized forms of gender expression. Now that said, I think we have to be realistic about what the science can do and what it has been able to do so far. Let's return to the paper that I just discussed by Margaret McCarthy's lab. Moving epigenetic processes, such as methylation, to the center of action, McCarthy at first appears to be proposing a thrilling and intellectually challenging rewriting of long-held paradigms of profound and fixed differences in the biology of sex and gender, right? But here, I guess I wanna say that the curiously, McCarthy and her colleagues do not presently fully embrace this vision. The public discussion that followed the publication of her study made this clear. The field received the study as showing how epigenetics works to over-determine and fix in place sex differences in the brain. So here's pure degrees quoted saying, our understanding in light of the study, our understanding that the female state of the brain is default still stands. What changes now because of the study is our thinking as to how that default state is preserved. Here's a new scientist article titled, Female Brain Maintained by Methylation, which framed the study as explaining how, quote, differences in male and female rodent sexual behavior are programmed during brain development and as showing that male hormones unleash the male program. So it says it concluded taken together these latest findings suggest that there may be more sex differences in the rodent brain than previously thought, quite in contrast to the narrative of marvelous fluidity and plasticity, flexibility of brain phenotype in response to methylation. Here, maleness and femaleness are proposed to be antagonistic and programmed processes. And the lead study author herself, Bridget Nugent, said of her paper, my hope is that these studies have taken us one step closer to fully understanding how and why males and females are so different. In this paper, we've shown a mechanism whereby hormones create sex differences in the developing brain by producing sex specific patterns of DNA methylation, maintenance of the DNA methylation patterns established during sexual differentiation of the brain appears to be necessary to sustain the brain's differentiated state. So what I wanna do is draw attention to the ironies, the way in which programming and plasticity are two sides of the same coin in this new science. And I want to draw out three themes, the canalization of maintenance of sex, the focus on plasticity, but plasticity that is sexually dimorphic and the argument that sex is ubiquitous in the molecular architecture of the body. So first, in this emerging systems network epigenetics based science of sex, plasticity and complexity is not opposed to programming, rather epigenetics is positioned as a powerful and over determining agent in the canalization and programming of sex differences, not despite, but because of its plasticity. Okay, so the central explanandum of epigenomic research remains to stabilize and over determine binary sexual dimorphism in the brain. Second, male and female epigenetic plasticity in response to the environment itself is theorized to be sexually dimorphic. That is inquiry is focused on epigenetics as a source for the elucidation of the biology of sex specific responses to the environment. Okay, so there are sex, there are male responses and female responses to the environment, right? Not on how, what it might be, which is how environmental exposures create variation in sex stereotype behavior in males and females. It might be, it might go there one day, but it is not empirically there right now. Third, in explanatory models in the biology of sex that invoke epigenetics, sex and gender become ubiquitous processes not localized to gross regions of sexual dimorphism. So epigenetics does not merely mediate sex specific processes at the interface of sex steroids and the genome in early development and possibly throughout the lifespan, but it postulates sex as much more broadly part of the substructure of the gene environment interrelation. So in this model, rather than epigenetics or the environment becoming a resource to explain sexual variation, sex differences become an expanded explanatory resource for explaining biological variation. So in the epigenetics paradigm, every gene network, cell and organ is seen as having a sex in the sense that is mediated by sex epigenetic processes. Let me draw this out a little bit more because I think it's relevant to some really core contested issues at this moment. So what I've shown so far is that on the one hand, this sex home framework represents a significant reformulation in the conceptualizing core processes of sex determination and development and it renders the genome as a dynamic product of its milieu and problematizes an essential understanding of sex. It looks like from this perspective, sexual processes can vary, they can be mosaic like and over time from cell to cell and from body to body in ways that might deviate from talking in those old ways about a male genome and a female genome. At the same time, in the sex home model, the whole body is imbued with networked processes that are sexed. So conceptualizing any process that involves genes and hormones as sex, this model greatly multiplies what I call the signs and signifiers of biological sex at the molecular level. So for these reasons, the movement of epigenetics to the center of sex difference research in the brain presently appears as poised to reiterate and even amplify essentialist and thoroughgoing notions of biological sex differences as to complicate and soften them. So why does this matter? I think there's a relationship between the growth of this model, which I'm calling the omnirelevant concept of sex, the notion that it's everywhere in every cell in every organ organ and the recent drive for more basic preclinical molecular sex research. Most of you will be familiar with this major 2001 report, which is part of an effort to bring to the fore a history of androcentrism in research and to encourage looking at more sex variables in basic preclinical research. The Society for Women's Health Research again has been a major mover in this area. And of course, just last year and into this year has been the development of new NIH policy following on EU policies, Canadian policies, and so on, encouraging even in some cases, mandating consideration of sex as a variable in preclinical research, meaning tissues, cells, animal models, okay. Does every cell have a sex? Let's return to this question. That is, is sex omnipresent? So as we engage the hypothesis of omnipresence, it's worthwhile, I think, to revisit some of our core conceptual resources in this field. Foucault's admonition, for example, that the signs of sex do not speak for themselves as matters of fact, outside of history and discourse. So that sex does not refer just to the act of sex itself, but also to the biological and anatomical signs, symbols, and markings on the body that signify its sexuality, and that this concept of sex has tended to create an artificial unity in order to give more force to notions of sex differences within politically formed moments. If you're not one for critical theory, how about the analytic philosopher Sally Haslanger, who's a social oncologist and gives us some tools for approaching this question from another perspective? She says, you know, if we want to know about a concept and what it's doing for us, we want to define it, extensionally make lists of what it might be, but we also want to know what we might want it to be. That is, considering the pragmatics of why we want this concept and what scenarios explanatory and otherwise a political that we might want to think in this omnirelevant way about sex or not. With limited time, let me just toss out some possible candidates for how we might think about sex biologically. With no presumption that we all have to agree on one, but just to drive the point that we don't always know what we're talking about when we say sex, and we might implicitly have different conceptions, and this can lead to misunderstandings. One, very narrow conception of sex, but very successful conception of sex if you want an essentialist definition would be a gametic definition of sex. All those things that have the larger gamete are females and all those things that have the smaller gamete are males. But most people are going to reject that definition because it does not do the explanatory work that they want. Looking just at gametes to understand sex would not get at the kind of functional explanations whether they're evolutionary or physiological that most workers in the sciences want. And that is to define those things as sex that are functionally related in a coherent way to reproductive differences between individuals. Note that this kind of concept of, a functionalist concept of sex need not reify male-female sex differences because if we take very seriously reproduction, then we could have many sexes based on different reproductive life histories. For example, we could have pregnant persons, lactating persons, menstruating persons, infertile persons, and so on. And then we might have this more omni-presentist concept of sex. And that is an attributional conception of sex in which we reason synagogically so that all parts of the whole also have the sex of the whole. So that if a cell is in a male body, it is a male cell. And that is the kind of very broad conception of sex that I see emerging in this moment. So Sally Haslinger poses some questions to us. When we're doing this kind of conceptual work, we have to think about what the point of having these concepts is. She says, is this an effective tool to accomplish our legitimate purposes? And it's not just a question of descriptively finding out what everyone thinks sex is, but also she says a stimulative element to these kinds of projects. We need to say this is the phenomenon that we need to be thinking about. In other words, we're in a plural space where we can make choices about the words we use and the concepts we use and the end that we invest in. Now there are some good reasons that we might want to say that every cell has a sex. We might want to bring awareness to sex-related variables so as to expose androcentrism in science and thereby counter it. We might want to capture the full range of biological diversity. I think these two are probably pretty good reasons. The next two, I think are less good reasons to mobilize gender justice discourses to compel or direct resources in a competitive research environment or to address women's health disparities. And on number four, I have a forthcoming piece in PNAS laying out my reasons for thinking that's not a good approach to health disparities. But so I guess I want to say that I, my own view is that the claim that a cell has a sex represents an extreme instance of cynically ascribing sex to the factors and parts of the body. It contributes to a notion of sex as a ubiquitous or pervasive sign or signifier and to a conception of bodies as divided in a thoroughgoing way into maleness and femaleness. So hence, I think there are ethical and political and social dimensions to our decisions about how to operationalize sex in the current research environment. But I also think that it's empirically under-determined and conceptually unsophisticated and hence likely to lead to conceptual confusion and muddle. So what I've tried to do in this talk is to encourage reflection on the ethics of our ontologies of instantiating sex at a molecular level. I've suggested that this is a critical or contested moment as the concept of the genome itself is transforming to magnify the signs and signifiers of sex. And as new discourses of plasticity emerge, I've also suggested that we need to remain critical and analytic. Plasticity and programming are not necessarily opposites but two sides of the same coin. Our conception of sex is not determined by our empirical findings. It is also shaped by our pragmatic and explanatory aims, including biomedical platform building, social justice goals, and opening funding avenues. We should be aware of the overuse or expansive use of the category of sex and be aware that it's part of our social ontology as well as our biological ontology. We should use the concept critically, conditionally, and reflexively and work to innovate terminology to leave open the possibility of a totally different ontology. Thank you.