Abstract
Incorporating sex into biomedical research is envisioned as key to addressing inequalities in health. However, feminist research suggests that it is a complicated task. This is, we argue, especially the case with research that seeks to mobilise sex across different scales involving bodies, samples and populations to provide a basis for personalised biomedical prevention and treatment. Through case studies from stem cell research, cancer medicine and vaccine safety research, we analyse how sex is enacted, foregrounded and sidelined at different stages of research. We argue that sex becomes suspended between individual bodies, samples and population groups, and that this postpones biomedical analysis of sex differences in health. Yet, research on sex differences in complex embodied processes, such as drug metabolism or immunity, appears as a future potentiality. This potentiality shapes research practices that may open biomedicine towards multi-disciplinary study settings that bring together physiological and social dimensions of bodily difference.
Introduction
The ethos of conducting biomedical research is changing. To become more accurate, efficient and encompassing, biomedicine is expected to develop increasingly personalised forms of diagnosis and treatment (Erikainen and Chan, 2019; Hoeyer, 2019; Prainsack, 2017). As part of these changes, questions have arisen as to how to incorporate patients’ gendered backgrounds and how to investigate sex-related biological variables in illness and treatment outcomes. Over several decades, policies and guidelines have been introduced that require or recommend using samples from both female and male bodies in biomedical research. Already in 1993, the National Institutes of Health (NIH) in the United States mandated that all NIH-funded clinical trials must include both women and men. More recently, the SABV (sex as a biological variable) guidelines from 2015 extended the consideration of sex to preclinical cell and animal-based research (Clayton and Collins, 2014; Richardson, 2022). The European Commission and the Canadian Institutes of Health Research have likewise tried to influence researchers to integrate samples from male and female bodies (Lee, 2018; Richardson et al., 2015). Incorporating sex into biomedical research is understood widely as a necessary step in addressing gendered inequalities in health (European Commission, 2020; Heidari et al., 2016).
Sex differences are a widely debated topic also in discussions about drug safety and efficacy. In 2013, the US Food and Drug Administration (FDA) lowered women’s recommended dosage of sleeping drugs using zolpidem based on suspected side effects among women. The decision was praised widely as marking the beginning of sex-conscious licencing and, in the future, sex-conscious pharmaceutical development. Indeed, the case of zolpidem informed the SABV guidelines. However, Zhao and colleagues (2023) argue that the decision did not consider other variables, such as the impact of body weight, and ‘sex-difference’ became established as a fact without material evidence of sex difference. This example points to the difficulty of separating sex from other factors affecting embodied processes such as drug metabolism. While sex is often a matter of measuring height, weight, age and other factors, it is, we suggest in this article, more than a proxy for embodied variance or a set of calculable factors. We maintain that sex is processual in that it brings together scales and temporalities in research design. Furthermore, as biomedical research from epigenetics to epidemiology is increasingly interested in the social (rather than just biological) conditions underlying variance between patients, the idea of sex is becoming ever more complicated.
Reflecting the interest in variance in health outcomes, a field known as ‘gender medicine’ has emerged to highlight the need to study possible reasons behind gendered statistical health differences. It builds on the observation that while clinicians often recognise the importance of gendered differences in health, medical research and practice rarely attend to the complex reasons behind statistical differences, for example, in the symptoms and treatment outcomes of cardiovascular diseases (Regitz-Zagrosek, 2012; The EUGenMed Cardiovascular Clinical Study Group et al., 2016). Gender medicine research acknowledges the need to account both for biological and social differences, including the ways they are intertwined. Gender medicine, then, requires developing increasingly multi-disciplinary approaches to consider what sex and gender can mean in distinct research projects (Oertelt-Prigione, 2020; Shai et al., 2021).
The difficulties of approaching sex and gender in biomedicine have been noted by many feminist scholars. They have questioned the idea that including samples from female bodies would automatically address the connection between sex and disease mechanisms. Incorporating sex into biomedical research is not a simple issue of redesigning studies as male–female comparisons (Pape et al., 2020; Ritz, 2017; Ritz et al., 2014). Many have problematised what sex means in practice when biological materials are placed and cultured in the Petri dish (Pape, 2021; Richardson et al., 2015; Ritz, 2017). A cancerous tissue or an immortal cell line is largely a laboratory construct and cannot as such represent sex. Scholars have also maintained that biological processes – for example, high blood pressure, onset of illness, responses to medication – cannot be separated neatly into ‘culture’ and ‘biology’ (e.g. Fausto-Sterling, 2005). Social structures and gendered expectations shape how and where we live, eat, work and exercise, and ‘culture’ thus engenders differences between bodies in, for example, bone density or the presence of environmental toxins in blood (Fausto-Sterling, 2005; Valdez, 2018).
Inspired by this feminist scholarship, we address the question of integrating sex in biomedicine in the context of complex, evolving biomedical research projects. Such projects reflect the changing ethos of biomedicine described above, connecting different scales such as the clinic, the lab and the population while striving towards future treatment that is tailored for specific individuals or population groups. The processuality of sex is intertwined with mobilisations of personalised medicine that focus on stratifying patient groups to gain insight into molecular characteristics of diseases (Erikainen and Chan, 2019; Maggioni et al., 2023).
We trace processes of enacting sex across different stages of research practice, from basic research to preclinical studies to clinical research. Our analysis has been inspired by Richardson’s (2022) argument on ‘sex contextualism’. Richardson proposes that sex is a flexible category that is operationalised in relational and situated ways. Focusing on preclinical settings and various laboratory model systems, such as cell lines, C. elegans and mice, Richardson draws attention to the pragmatic and material dynamics underlying why sex is operationalised in particular ways in particular research contexts (see also Karkazis, 2019). Our study investigates the complex logics of inserting sex in biomedical research settings beyond preclinical research. Furthermore, we argue that when traced across various stages of research, sex becomes two things in particular. First, it becomes a time-related issue, a potentiality for future studies. Second, it becomes an object suspended between bodies, samples and populations. This implies that the contextuality of sex is a matter of time and scale when striving towards increasingly personalised forms of diagnosis and treatment. We explore how sex appears, disappears and reappears as researchers move between patients’ bodies, individual samples, reference datasets, digital health data archives, population-level statistics and information about individual patients. Importantly, instances of enacting sex that we identify do not involve only ideas about sex differences in sourced patient materials or targeted biological variables but also moments when sex as an issue is sidelined despite attempts to incorporate it. Thus, we look at the complexities of redesigning current research settings as well as future study conditions.
Our focus on redesigning research settings has led us to analyse instances where biomedicine turns towards studying social aspects of health differences between people. For example, preclinical research orients towards clinical implementation and population-based research aims to consider complex, statistical differences among people. Even if research focuses on particular biological units, such as chromosomes or hormones, the redesigning of studies can involve considerations that extend beyond these biological parameters. In such instances, biomedicine extends its focus from calculable factors associated with sex towards considering social conditions of health-related differences understood to fall under the category of ‘gender’.
We analyse the processes of enacting sex at three sites. Two of the sites – basic stem cell research and cancer medicine – provide cases where the issue of sex is mostly absent in daily research practices but is perceived by many researchers within the field as a meaningful direction for future research. Our analysis underscores that inserting sex remains often unclear in preclinical and clinical experiments. The third site – biomedical knowledge production around the side effects of one of the Covid vaccines – provides a different viewpoint. While vaccine safety reports suggested a possible connection between a group marked by sex (young and middle-aged women) and a life-threatening adverse event, the link between sex and embodied processes appeared evasive when samples from patients were analysed. While representing three distinct fields of biomedicine, our cases all attest to how vibrant biological processes within bodies are mobilised to develop pharmaceutical treatment and prevention (see also Meskus and Oikkonen, 2020). Read in relation to one another, the cases make visible a series of practical difficulties and uncertainties in pinning down sex to bodily responses to new pharmaceuticals as research moves through basic, preclinical and clinical stages.
In what follows, we first introduce our analytical approach, which draws on feminist science and technology studies (STS). The subsequent sections build on our case studies showing how sex is framed as a future potentiality and how it operates as a shifting point of reference as research projects move across different scales.
Analytical Framework
The article builds on the view central to STS that technologies are productive. That is, instead of being uncomplicated tools of discovery, technologies enact phenomena (Barad, 2007). In biomedicine, human and non-human bodies such as the bodies of patients and laboratory animals emerge and are shaped by technologies that enact the ontological status of these bodies. In other words, bodies are enacted through technological modification conducted in the laboratory, the randomised controlled trial, public health policy measures and health care markets (Birke, 2012; Michael and Rosengarten, 2012). This entails that a disease in the body may be a different entity when diagnosed in the outpatient clinic, treated in the operating room, and analysed in the pathology lab, as these sites rely on different diagnostic and medical techniques and technologies (Mol, 2002). In our study, sex is not only understood in multiple, context-specific ways but also enacted as a different entity in different research settings. Likewise, material tools used in the bioscientific lab, such as cultured tissues, affect the shape of the phenomena studied by scientists. For instance, the material conditions of culturing cells mould the qualities of the cultured cells (Helosvuori and Homanen, 2022; Landecker, 2009; Meskus, 2018). In this article, we trace how the material-technological conditions of biomedical research, such as biological samples and digital data, shape how ‘sex’ can be operationalised as research moves towards clinical research.
Our approach is informed by STS analyses that show how ways of defining population groups and assumptions made about their differences structure what kinds of comparisons between stratified groups appear as scientifically meaningful. For example, STS researchers working on genomics have shown that the way samples are selected and grouped affects what connections can be established across the data (M’charek, 2005; Oikkonen, 2020; Tupasela and Tamminen, 2015). Drawing on this literature, we explore how research designs that bring together different scales and types of data produce particular constellations of sex differences.
We also pay attention to how sex is enacted as absent. In recent years, rich research literature has shown that assumptions of racialised differences shape research even when race is not explicitly mentioned (e.g. M’charek, 2005; Weasel, 2004; Williams, 2021). Race operates as a ‘ghost variable’ that resides in the relations that constitute assumptions of embodied differences (Karkazis and Jordan-Young, 2020). However, there is less research on how ideas of sex are mobilised across multiple scales of biomedical knowledge production. While we view the issue of sex (like race) as relational, we draw from Richardson’s (2022) idea of ‘sex contextualism’. Richardson shows that sex is contextual in experimental research and its model systems. To understand the enactment of sex also beyond experimental model systems, we follow sex to other sites of future-oriented biomedical research. This allows us to ask how the seeming absence of sex shapes what sex can be when research moves towards increasingly personalised applications.
Finally, we build on research that demonstrates the pragmatic and cumulative aspects of biomedical research. Scholars have shown that choices of material arise from practical concerns such as the availability of samples or technologies (Kent, 2012; M’charek, 2005; Waldby and Carroll, 2012). Furthermore, technologies and materials available at one point often continue to shape future research even when more advanced technologies or more suitable materials become available (M’charek, 2014). From this viewpoint, exploring sex as contextual means understanding context as having a temporal dimension, as past ways of collecting data and conceptualising and quantifying sex differences shape what sex can be as a biomedically meaningful category.
The Three Empirical Cases: Materials and Methods
Our analysis uses data collected within our respective research projects. The first case study consists of ethnographic data collected by Meskus in various European biomedical research groups and laboratories between 2010 and 2016 on cellular reprogramming. The data includes 33 in-depth interviews with stem cell scientists, clinical doctors and regulatory authorities conducted in Finland, Sweden, the United Kingdom, and Italy, as well as fieldwork over 10 months at a university-based stem cell laboratory in Finland. Basic biomedical research has become widely dependent on so-called induced pluripotent stem (iPS) cells that are mostly derived from patient-donors’ skin biopsies (Meskus, 2018). The first decade of pluripotent stem cell research beginning at the end of the 1990s involved sourcing biological material: stem cells from women’s egg cells and human embryos. Reproductive tissue donated by women was the key biological material in stem cell science and commercial biotechnological innovation (Cooper and Waldby, 2014; Kent, 2008; Pfeffer, 2008). The discovery of iPS cell technology, however, has sidelined reproductive tissues and cells as the primary source material. Research material can now be derived from any suitable, consenting person and from tissues not linked to reproduction. The case of stem cell research demonstrates how sex appears and vanishes in experimental biomedicine at various stages.
The second case study is based on data collected by Temmes at a research institute focusing on molecular medicine in Finland. The ethnographic data consist of personal observational notes collected during a 4-month visit at the institute and 83 interviews with biomedical researchers (representing different academic stages, some also working as clinicians), technicians and other personnel collected mostly in 2014 with some follow-up interviews in 2017. The analysis presented in this article focuses on the cancer systems medicine research at the institute, which offers insights on how sex remains an elusive and future-oriented category even when basic research moves towards a clinical understanding of differences between patients. At the institute, cancer cells derived from patients were used to test drug compounds to design new treatments and to identify differences in how patients’ bodies respond to treatment. Most of the interviewed researchers worked with cell samples or computational models to form a systems approach to cancer disease mechanisms, analysing how a particular cancer functioned in different bodies. Temmes asked researchers whether they considered differences between genders in their research. This confounded most interviewees. However, the prospect of developing clinical applications offered framing for them to explain why categories such as sex or gender were not relevant for their research while suggesting that such categories might be useful in future studies. These moments in the interviews offer a basis for examining the processual nature of sex.
Our third case study consists of biomedical research publications and public health and drug safety organisations’ statements on a possible connection between an adenovirus-vector Covid vaccine and vaccine-induced immune thrombotic thrombocytopenia (VITT). The condition is characterised by a low platelet count and blood clotting at unusual sites. These data were collected by Oikkonen as part of a research project on public debates about vaccines in Europe. The case illustrates what happens when sex becomes an object of biomedical lab-based research after population-level clinical trials. It shows how the connection between sex and embodied biological processes – the mechanisms of a possible vaccine adverse event – is evasive when sex is turned from a statistical category into an investigated factor in lab-based analysis of a small set of samples.
To analyse the processes of enacting sex, we read the materials collected in each case study in relation to the other two case studies (Rule and John, 2015). We identified continuities and discontinuities across the case studies to understand when and how sex is mobilised in complex biomedical research designs that link biological samples to clinical trials and population-level studies. We traced both direct and indirect mobilisations of sex across time and scale in the materials. This developed into an examination of the circumstances in which sex emerges as biomedically meaningful or disaggregates into a subordinate variable.
Sex as a Future Orientation
Ideas of sex figure in the transition from basic research to clinical use in ambiguous ways. This ambiguity arises from two patterns. The first pattern concerns future-orientation in discussions on how sex should be incorporated into lab-based research. In early-stage biomedical studies, as in our first two cases, the future relevance of sex is approached through studies of drug effects as a site where differences between individuals could be addressed. Since basic and preclinical research often focuses on modelling diseases with patient-specific cells, processes of enacting sex take place at the level of the Petri dish.
We begin with the stem cell research case. The everyday use of iPS cell lines is focused on creating disease- and patient-specific cell lines to study and model disease mechanisms. When basic research is focused on biological mechanisms such as how genes can be manipulated under chosen experimental conditions, cells are often treated as members of clones of a named cell line. These cell lines represent disease conditions. This means that the donors of skin or blood cells are present mostly through the disease that they ‘provide’ for research. The primary focus is on genetic mutations while other factors are subordinate to this interest. In Meskus’ study, patient-specific heart disease cell lines were derived from one interlocutor’s consenting patients. This interlocutor, a head of research laboratory and a university hospital physician, explained:
In principle, all these cells that I have in my cell colonies have the same genome as the patient from whom I took it [the skin biopsy]. So, if I generate heart cells from these, they have the same genetic defect as the patient. I can then investigate how these patient-derived heart cells behave, do they beat well, and are they sensitive to some drug compounds. Can I induce a cardiac arrhythmia with some drug? Before, we have not been able to do this [derive patient-specific cell lines].
The quotation exemplifies the disease-in-a-dish model: gene defects and related disease mechanisms are created and studied in a cell culture dish. Stem cell researchers participating in this study constantly noted that the created cardiac cell lines were appropriate only for basic research. If stem cell-derived heart cells were to be transferred from basic science laboratories into preclinical research, in addition to genetic mechanisms, the issue of sex could come into focus.
Stem cell technology is seen to enable more effective drug screening when transformed stem cells can represent person-specific genetic defects in different organs. However, much of the research effort is focused on getting the ‘tool’, that is, the cell lines, to work in aspired ways. At this stage, the connection between sex and the cellular material is usually not important. The situation reflects the existing sourcing of materials in basic biomedical research, where the ‘sex’ of the cells remains elusive: in major commercial cell vendors’ product catalogues, around 16% of human cell lines have been sold without sex identification (Lee, 2018; Park et al., 2015). For animal cell lines, most primary cells and stem cells were sold without mention of whether the cells came from the body of a male or female animal (Lee, 2018; Park et al., 2015). A recent survey on biomaterials research shows that sex goes largely unreported for both purchased and isolated primary cell lines (James et al., 2021). As commercial vendors do not disclose information about cell line sex, and many journals have still little to no requirements for reporting cell line characteristics, researchers do not communicate this information in their publications.
While sex as a biological variable is often not incorporated into the preclinical research, sex differences could become a meaningful topic of study if basic research moved towards clinical research in which a more personalised approach to therapy is developed. This underscores the processuality of how sex is enacted through biotechnological tools and in relation to biological samples at different, anticipated stages of basic, preclinical and clinical research.
This processuality became clear in an interview with a research director at a European pharmaceutical company. The director explained that if a stem cell-derived, disease-specific cell line was to be systematically used for drug screening (as in the heart diseases he was specialising on) in preclinical and clinical trials, this would lead to increasingly personalised approaches to therapy: ‘We would first screen in in vitro circumstances, like patient-in-a-dish, the 17 possible drugs. We would not give you any medicine before we would have tested in vitro which ones work for you’. This could generate a growing interest in not only genetic variability but also in how individual, gendered bodies respond differently to drug compounds. Indeed, the interest in personalised or precision medicine has increased the prominence of sex differences as a potentially significant variable in future biomedical research (e.g. Miller et al., 2015).
In the shift from basic research towards clinical application, other factors besides genetic mutations may become increasingly salient both on an individual and on a population level. As a result, the sex of the body from which cells are collected may accrue significance it does not have in the preceding research phases characterised by the positioning of sex differences as potentialities to be looked at ‘later’. Pursuing the transition from a disease-in-a-dish model towards a patient-in-a-dish model may involve the enactment of sex through, for instance, the selection of clinical research participants. Instead of having a fixed status, then, sex has the potential of emerging in relation to other studied factors.
In our second case study, cancer medicine, research settings and phases likewise structure the enactments of sex. While sex differences were not actively studied at the institute when Temmes conducted her study, researchers working with drug screening were open to the possibility that clinical trials might show sex differences. For example, one researcher recounted how they had seen a presentation of a phase 3 clinical trial:
Suddenly you could see that there was a big difference in response between men and women, whatever marker they looked at, it was predictive for women but not for men. And in therapeutic response. [. . .] So I asked why they thought it was so and they didn’t know. But one possibility which is actually kind of a simple, boring, explanation was that they used a fixed dose, and women are smaller, so they ultimately get a higher dose and maybe that’s why. But they didn’t know. There could certainly be many other reasons but that was the only simple explanation they had.
This description shows how the issue of sex, when not factored into preclinical studies, might nevertheless emerge unexpectedly in later stages of research, undermining the trial in process – in the example above the studied drug did not pass the trial.
An interview with a cancer researcher who worked closely with clinicians gives further insight on how researchers could proceed if clinical trials showed sex differences:
Maybe if you want to understand the mechanism why would there be a difference between males and females, then it might require some in-depth basic research study where you’d have to set up, for example, mouse models and see if there’s difference between male and female mice when they are given these drugs and then you can dig deeper into what is it in either males or females that would cause that difference, hormonal difference. So that might involve some additional laboratory setup.
The researcher’s focus on hormones is not surprising as it is well established that hormones shape how drugs affect patients’ bodies (Spoletini et al., 2012: 92). Here, the assumption is that sex differences in clinical trials could be explained as differences in bodies’ hormonal status. Yet, affirming this would require a different research design. This implies that while differences between sexes are seen as a potential future area of study, the task of incorporating sex into research requires returning to the basic and preclinical phases, animal experimentation, and revising the original study setting.
Currently, however, basic and preclinical phases tend to erase sex from the setting. For example, the question of sex differences tends to disappear when data derived from patient samples is processed in computational modelling. As Temmes (2018) has previously argued, researchers need to purify all technical and biological variation between the samples that is not seen as relevant for the primary research aims. In studying cancer mechanisms, this meant that biological variation associated with sex and age was cleared from the data and the focus was instead on molecular similarities of patient subgroups.
The possibility to incorporate sex differences into future research was nevertheless a topic of discussion. When the definitions of ‘sex’ and ‘gender’ were addressed by our research participants, ‘sex’ was mostly considered as a biological variable and ‘gender’ as signifying the social and environmental aspects of differences. Yet, the distinction between the two became rather obscure when envisioning concrete directions for future research. The following interview with two cancer researchers illustrates this. The interview took place after Researcher B had participated in a workshop discussing ‘sex and gender dimensions in research’. After Temmes asked how their work implemented these dimensions in research, the interview turned into a dialogue indicating the challenges of pinning down embodied differences:
Did it come up as to why they refer to this as ‘gender dimension’ in research? Because it is clearly only sex that they are talking about. So, I’m so confused when people talk like ‘the gender’ of their cells – it makes absolutely no sense.
My understanding is that sex is the actual biology, so the cell biology. So, you know, chromosomes of your cells. And [when] talked about gender then it’s the behaviour and it’s the. . . overall baggage.
That would make sense for social sciences, to talk about gender dimension in research, but then in these kinds of sciences, I don’t see any sense in talking about ‘gender dimension’ in research. I see a sense in talking about sex dimension in research.
I mean, yes. But you have the gender, you know, for the population studies for example, for genetics. Because then you still talk about gender.
But that’s still sex, though.
It is still the sex, yes. But there might be behavioural differences between the genders that might impact on your . . .
That’s true, there might be, yes. [Impact on] your gene expression.
The end of this discussion underscores the point we are making here: attempts to mobilise sex (and gender) in biomedicine are processual, constantly emerging and disappearing. Sex (and gender) becomes a question of the future – of some novel, not-yet-realised mode of conducting research. This possibility of a new kind of future research is present in a comment by Researcher A: ‘I think it’s multidisciplinary kind of research that we should be moving towards and not just [by] looking at one and the other but how we can bring behavioural [scientists] – sociologists, psychologists – into working with our cell biologists’. Implementing different types of data thus requires new research designs that challenge the clear distinction between cell and population-level research. Simultaneously, ‘sex’ and ‘gender’ gain specific, situated meanings in different biomedical contexts – here described as a difference between chromosomes and behaviour – along the lines suggested by Richardson’s (2022) sex contextualism. The comment also suggests that in the future, if cell biologists, sociologists and psychologists collaborate in biomedical studies, the ‘context’ of sex can expand across disciplinary boundaries, highlighting the shifting enactments of sex.
Furthermore, the future-oriented discussion about the inclusion of sex into biomedical research is always embedded in the realities of past and present research settings, including original collections of tissue samples. Data-collecting practices reflect social biases (Pot et al., 2019), and types of data collected have implications as to what kind of questions can be asked and answered in the future. Existing laboratory methods introduce material and epistemological constraints, as when the laboratory surroundings of cell culture and the mixing of human and non-human materials with different genomic and chromosomal constitutions fundamentally challenge attempts to mobilise sex (Landecker, 2009, 2016; Richardson, 2022). Furthermore, the focus on drug screening in biomedical research narrows down variation to bodies’ responses to a biomedical compound, structuring what biomedically meaningful differences can be if the question of sex differences gained priority. Our cases nevertheless illustrate that investigating sex through sex-conscious sourcing of biological materials and by factoring in sex differences into study settings constitute a future potentiality for research. This makes sex a placeholder that indicates that further studies are needed to explain, for example, differences in drug effects. Yet, we show in the next section, when research focus is directed from statistical sex differences back to individuals, sex may lose its value as an explanatory frame.
Enacting Sex between Samples, Patients and Populations
The ambiguous ways in which sex figures in the transition from basic research to clinical use can be summarised, as we propose above, in terms of a tension between an apparent absence in the present and a future approach that reaches across not only sex-related biological variables but also gendered, socially grounded differences in health. This intersects with a second pattern we have identified: the tension between sex as a characteristic of an individual and enactment of sex as a group-level process. Our cases all point to a crucial contradiction: although samples are inevitably linked with sex in the sense that they come from an individual body, sex as an analytical category tends to disappear when the research moves between statistical observations and biological samples, that is, when the reference point shifts. In all our cases, sex may be mentioned as patients’ background information (the ‘sex’ of the cells or samples) but is seldom analysed further, for example, in terms of how it affects a body’s response to a treatment. In our third example, the Covid vaccine case, biomedical research tried to identify disease mechanisms – a link between a vaccine and a type of thrombosis – through individual gendered bodies. In this case as well, when attention moves to embodied processes, it becomes difficult to pinpoint where sex differences are located in the biological sample and whether they shape a person’s reaction to immunisation.
The discussion around the rare but life-threatening adverse event, VITT, focused initially on the AstraZeneca vaccine, which was approved conditionally for use in January 2021 in the European Union. The approval relied on randomised controlled trials of efficacy and safety in the United Kingdom, South Africa and Brazil, with interim results published in The Lancet in December 2020 (Voysey et al., 2021). The trials focused initially on 18- to 55-year-olds with few pre-existing health conditions and presumably robust immune reactions. Women were in majority among the participants. While sex is listed as a variable, it is not framed as an explicit object of research. The researchers mention the need for further analysis of results from subgroups marked, for example, by ethnicity and age, but this call comes after the initial population-level studies.
While a range of possible adverse events were reported in the clinical trial results (as would be expected in clinical trials on any new drug), no connection between sex and a specific type of adverse reaction was suspected (Voysey et al., 2021). This is not surprising since no adverse event emerged as statistically significant on the population level, that is, ‘there was no pattern of these events that provided a safety signal in the study’ (Voysey et al., 2021: 109).
However, in March 2021, sex emerged as a potentially meaningful variable with the first reports of suspected cases of VITT. This highlights the processual, shifting character of sex. As the early clinical data suggested that the condition may be more common among vaccinated women, drug safety organisations, such as the European Medicines Agency (EMA), and national and international public health organisations noted the possibility of a previously unknown connection between sex-linked variation and the specific type of vaccine injury (e.g. EMA, 2021a). This transformed sex from background information about vaccine trial participants to an object of biomedical research. It was mentioned that blood clotting had been previously associated with hormonal products and that the affected patients were in the age group where hormonal contraception and hormone replacement therapy were common (e.g. Tobaiqy et al., 2021). Yet, sex was not enacted in a consistent manner. Instead of revising vaccination policies by sex, many European countries discontinued the use of the AstraZeneca vaccine among all members of younger age groups by introducing a cut-off age at around 55–65 years (e.g. Prince, 2021).
Once the possibility of the vaccine-associated adverse event had been noted on a population level, the attention turned to potential mechanisms within individual bodies. Research publications documented the progression of VITT in a small number of patients as well as reviewed published case studies (Franchini et al., 2021; Greinacher et al., 2021; Wolf et al., 2021). In this framework, the mechanisms of vaccine injury were located in unique bodies characterised by individual, gendered health histories and combinations of attributes such as age and sex. These mechanisms were approached through blood samples and scans. Through these individual cases, researchers discussed the possibility that the immune reaction triggered by the vaccine had resulted in low platelet count and blood clotting. At the same time, population-level data suggested that VITT was not linked to sex in a straightforward manner, and the previously suggested connection between VITT and hormonal products was unclear (e.g. Pottegård et al., 2021). Reflecting these developments, the World Health Organization (WHO), the EMA and many national agencies no longer highlighted sex differences but instead referred to risk factors such as a person’s previous history of thrombocytopenia (e.g. EMA, 2021b).
In this movement from population to individual, the question of sex is present and yet falls out of focus. By drawing on individual patients’ clinical information and biological (blood) samples, biomedical studies of the mechanisms of injury relied on gendered bodies. However, although the patient’s gender is usually mentioned, once the focus moves to the disease mechanisms in specific bodies, sex differences receive relatively little attention. While the difficulty of pinning sex to immunological responses reflects the population-level statistical uncertainty as to whether there were sex differences in the first place, the biomedical tools of analysing individual samples are not designed to capture the complex effects of sex-related biological variation on immunological processes.
In the move from populations to individuals, sex thus disappears as a biomedically meaningful category. We suggest that this is at least partly because sex operates on a collective and relational level that makes it difficult to pin down sex to an individual bodily mechanism. When the point of reference is an individual patient or a sample, the potential connection between sex and disease mechanism becomes evasive. Statistical indications of possible sex differences do not translate easily into biomedically meaningful information. In all our case studies, sex remains an unfixed signifier to which different ideas of embodied differences, such as sex differences as hormonal, are attached and again removed.
It seems, then, that operationalising sex in biomedical research design requires bringing together different scales in ways that can account for both the uniqueness of individual samples and population-level differences. This is a complex task. While it is often assumed that an interdisciplinary research design would help address complicated issues such as links between sex-related variation and disease (e.g. Oertelt-Prigione, 2012: 13), our case studies suggest that a more complicated design may in fact be less, rather than more, capable of addressing bodily variation. When individual samples are made sense of in relation to population-level data, potential sex differences may be de-emphasised rather than addressed. The cancer medicine case illustrates how sex-related variation is difficult to address when individual samples are studied through computational models where ‘noise’ (i.e. too many variables) needs to be curtailed. Sex causes friction in the research design and is thereby easily sidelined.
Sex appears and disappears in situated practices in different phases of research depending on what is being compared and how it is compared. That is, sex is enacted through shifting points of reference and acts of comparison. Crucially, our case studies show that this may result in tensions within a research field or even within a project. Stem cell research and cancer medicine face a tension between a clinical framework that acknowledges unique gendered histories of illness and a molecular framework that approaches sex in terms of drug responses. This tension appears, for example, as hesitation among researchers as to how sex could be mobilised to understand biological processes in regenerative medicine and cancer treatment. These tensions around embodied differences have, we suggest, significant implications for sex-conscious, future-oriented biomedical research projects.
Conclusion
As biomedical research extends to new aspects of the body, it is crucial to understand how sex is enacted in these emerging fields. Our case studies in stem cell research, cancer medicine and vaccine safety research show that although the body is often assumed to be the location of sex differences, sex appears, disappears and reappears in basic, preclinical and clinical studies over time and in relation to research settings and data. While statistical sex differences are often explained in relation to calculable measures such as height or weight, ‘sex’ cannot be pinned down to these. This highlights that sex constitutes a processual and relational question in biomedical research. From the body with a gendered illness history to sex in the cell culture dish to statistical differences in clinical trials, sex is elusive. While sex-related variation is generally not regarded as relevant in cell culture-based studies, it may become an issue requiring specific attention in downstream instances of biomedical development. Yet, attention on sex differences may result in re-affirming the impossibility of adding sex as a variable or the irrelevance of the gendered body in biomedical intervention.
Feminist and STS research on sex in biomedicine needs to be attentive not only to the ways in which ‘sex’ is enacted in existing research settings but also how its role is visualised as a potential future direction in biomedical research. While sex in complex biomedical research settings appears as elusive, it is nevertheless present as constant potentiality of becoming relevant. The ways in which biomedical samples, databases, methods and technologies are brought together within preclinical and clinical research settings produce the relations through which enactments of sex take place and sex gains situated meanings. While the question of sex has the constant potential to become a meaningful dimension of biomedical research, it is nevertheless equally prominently disappearing and backgrounded.
We propose that identifying logics through which sex is enacted in biomedical research requires a comparative, processual, and open-ended approach to sex. Instead of viewing sex as a fixed, binary categorisation of male and female that is either included or excluded in biomedical research, we need to approach sex as enacted in evolving practices that bring together different scales. This allows addressing how constellations of sex arise from creating connections between datasets and forms of biomedical knowledge, and, conversely, how different ways of using data and methods result in different conceptualisations of sex differences. Focusing on enactments of sex makes visible differences between how sex is enacted in basic, preclinical and clinical stages of research. Methodologically, this requires tracing the logics through which the question of sex gains or loses meaningfulness. In future studies, it is important to trace enactments of sex also in relation to age, gender identity, sexuality and socioeconomic context to make visible the complex biases built into biomedical research.
Our analysis does not give direct answers as to how sex-conscious medicine could become more effective or prevalent. Yet, it seems clear to us that both challenges and opportunities lie in addressing the tensions arising from relations between individual samples, bodies and population-level data. How sex differences can be studied is also shaped by the movement between past, present and future research settings. Biomedical research on sex differences needs to start with an acknowledgement that assumptions about sex are already there, and that they are there in multiple, even incompatible forms. Developing more inclusive biomedical knowledge is not about adding sex as a category to where it seems to be missing, but about harnessing these underlying tensions and making visible the presence of assumptions about sex where they appear to be absent.
Footnotes
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The research was funded by the Research Council of Finland (grant numbers 326544, 339143, 326546) and the Kone Foundation.
