In a groundbreaking shift within the scientific community, researchers are increasingly challenging traditional notions of sex and gender in preclinical studies, advocating for a more nuanced and inclusive understanding that transcends binary classifications. While historically, the terms “sex” and “gender” have often been used interchangeably, contemporary science distinguishes sex as a biological construct, rooted in genetics, anatomy, and physiology, whereas gender encompasses the socially constructed roles, behaviors, and identities that vary across cultures and individuals. This distinction is particularly critical in research aiming to unravel the complexities of biological variation and its implications for health and disease.
The assertion that sex is a binary—that individuals are strictly categorized as male or female based on reproductive anatomy—has dominated both scientific discourse and societal norms. However, emerging evidence refutes this simplistic dichotomy. In nature, sex emerges as a multifaceted spectrum, with numerous biological traits including chromosomal patterns, hormonal profiles, and anatomical features that often do not align neatly into male or female categories. For example, hermaphroditism, where individuals possess both male and female reproductive organs, is estimated to occur in approximately 5-6% of animal species, highlighting a pervasive biological diversity that challenges binary assumptions.
Within preclinical research, the limitation lies in the accessibility of data related to gender—since gender involves social constructs that are inherently human and culturally variable, they remain largely intangible when studying other organisms. Consequently, preclinical models have traditionally focused on sex as a measurable biological variable. However, this focus demands a critical reassessment of what is meant by sex. It is no longer scientifically tenable to treat sex as a fixed, binary variable without acknowledging its inherent variability and dynamic nature. Biological sex should instead be operationalized through concrete, quantifiable metrics such as chromosomal analysis, hormone concentrations, and morphological assessments, rather than relying on broad, undefined labels.
Such operationalization serves a dual purpose: it enhances reproducibility of research findings and opens avenues to study species and systems that do not conform to the conventional binary framework. This paradigm shift encourages moving away from categorical sex classifications towards a multivariate and non-binary framework. By embracing this perspective, researchers can account for the rich biological variation observed both within and across species, fostering discoveries that better reflect the complexity of life.
Crucially, this approach extends beyond preclinical research into the interpretation and communication of scientific findings. There is a growing concern about overstating sex differences, which risks reinforcing harmful stereotypes that depict males and females as fundamentally and irreconcilably distinct. Simplistic binary treatments of sex in analyses often mislead by implying that sex itself is the causal agent behind observed differences. Instead, it is specific biological mechanisms—such as differential gene expression, hormonal milieu, or cellular responses—that drive variation. Therefore, future research must hone in on these underlying mechanisms rather than relying solely on sex as a categorical variable.
This nuanced understanding informs the design and analysis of experiments. Scientists are encouraged to select and report concrete, measurable sex-related variables that plausibly explain observed differences. Such methodological rigor enhances the precision and clinical relevance of research, reducing the risk of drawing erroneous conclusions about sex-based causality. By focusing on the mechanistic drivers of variation rather than the labels themselves, researchers can illuminate pathways that might be therapeutically targeted or that explain differential disease susceptibility.
The language used to describe sex-related phenomena is equally important. Terms such as “sexual dimorphism” and “sex-specific” are prevalent in scientific literature but often convey an exaggerated perception of dichotomy. Dimorphism traditionally denotes two distinct phenotypic forms, implying a clear and immutable divide, whereas “sex-specific” suggests characteristics or effects present exclusively in one sex. However, in reality, many phenotypes exist on a continuum, with overlapping ranges between sexes, and manifestations that cannot be cleanly partitioned. Choosing terminology that accurately reflects this complexity helps prevent misconceptions and fosters a more inclusive science narrative.
In addition to semantics and methodology, this expanding framework holds profound implications for the broader landscape of biomedical research. Disease models, drug development, and therapeutic interventions have historically been biased toward male organisms, largely extrapolating findings to females without sufficient consideration of sex-based biological differences. Recognizing and integrating the full spectrum of sex variation could rectify these biases, improving the translation of preclinical findings to clinical settings and ultimately enhancing health outcomes for all individuals irrespective of sex or gender identity.
This evolving paradigm also challenges regulatory and funding bodies to adapt their frameworks to better accommodate sex-inclusive research. Mandates that require sex-based analyses must go hand in hand with guidelines that encourage specificity, context, and mechanistic insight. Without this nuance, there is a risk of superficial compliance that does not truly address underlying biological complexity or the societal dimensions of gender diversity.
At the interface of biology and culture, it is vital to acknowledge that gender, though intangible in animal models, profoundly shapes human health. Socially constructed roles, behaviors, and identities contribute to health disparities and influence disease presentation, healthcare access, and adherence to treatment. While preclinical research may be limited in modeling gender per se, awareness of these factors is indispensable when translating findings from bench to bedside.
This comprehensive re-evaluation of sex and gender within research underscores the necessity of context-sensitive approaches. Researchers must be vigilant not only in the design and execution of studies but also in their dissemination. By providing detailed contextualization of how sex is defined and measured, scientists enable others to critically assess findings and build on them with greater fidelity.
Additionally, recognizing that sex differences often manifest as variations in effect size rather than categorical distinctions encourages a more subtle interpretation of data. It is more typical for an intervention to produce differing magnitudes of response in females versus males, rather than fully divergent effects. Appreciating this gradient avoids overemphasizing differences and supports a more integrative understanding of biology.
The thrust toward a sex-inclusive research framework promises to revolutionize our grasp of biology, medicine, and health disparities. It demands interdisciplinary collaboration, drawing from genetics, endocrinology, anatomy, sociology, and ethics, blending technical rigor with cultural competence. As this field advances, so too does the potential to develop personalized medical interventions that consider sex and gender in all their complexity.
Ultimately, scientific inquiry into sex and gender must balance appreciation of biological variation with sensitivity to sociocultural constructs, all while maintaining clarity and precision. The future of preclinical research hinges on embracing these complexities to produce science that is not only more accurate but also more equitable and translatable.
This ongoing transformation in research methodology is not a mere academic refinement but a critical step toward dismantling entrenched biases and fostering a more inclusive scientific enterprise. As the evidence mounts and perspectives broaden, the binary view of sex and the conflation with gender steadily give way to a vision of biology that celebrates diversity and complexity as foundational features rather than exceptions.
Subject of Research:
Sex and gender variability in preclinical biomedical research and the development of an inclusive research framework to address sex bias.
Article Title:
The Sex Inclusive Research Framework to Address Sex Bias in Preclinical Research Proposals.
Article References:
Karp, N.A., Berdoy, M., Gray, K. et al. The Sex Inclusive Research Framework to address sex bias in preclinical research proposals.
Nat Commun 16, 3763 (2025). https://doi.org/10.1038/s41467-025-58560-5
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