Ernst Strüngmann Forum

Sex and Gender: Transforming Scientific Practice

L. Zachary DuBois and Anelis Kaiser Trujillo, Chairs

Research into gender and sex has recently gotten heightened levels of attention, driven partly by institutional mandates to consider sex as a biological variable (SABV) as well as the rising profile of gender-focused clinical research and practice. Yet science exists within society, not apart from it, and must therefore contend with societal discussions and polarizing debates, where the meaning of sex, gender, and their entanglement is anything but straightforward. The use of binary conceptualizations, the interaction between gender experience and sex-linked biology, and the very nature of these categories are currently under intense scrutiny across a range of disciplines and communities.

To some degree, binary categories of sex and gender organize human society, and these categories are widely applied in myriad ways in research, science, and policy. The term “sex” is typically used to refer to the categorization of bodies into male and female based on a suite of characteristics linked to reproductive biology, whereas “gender” is often used to refer to a culturally embedded suite of socially recognized categories reflecting group and individual-level power dynamics, identities, norms, and experiences that are recognized today as fluid, complex, and diverse. Remarkable contextual variation exists, however, in how these binary categories are defined and operationalized. The initial impetus for the conceptual differentiation of sex and gender was to decouple practices, roles, social expectations, etc. from biology and challenge essentialist claims upon which discrimination is frequently based. “Sex” then became primarily the category for biological sciences and “gender” was anchored into the social sciences and humanities, reflecting the old and problematic division of realms in academic cultures. However important, this systematic separation of the two concepts now shapes what is (and is not) possible to study within different disciplines. Moreover, the partitioning of gender from sex blurs their entanglement and insufficiently captures the breadth of human variation and biological and social/cultural coevolution. The combined terms “sex/gender” and “gender/sex” have been proposed but are currently deployed in only a very small sector of science or policy work, and not at all reflected in public discourse. Although significant theoretical developments have been made in certain disciplines, the necessity of revisiting these concepts and their entanglement remains unrecognized in others. Often-contested new policies and funding streams for the study of sex and gender indicate the need for further integration of theory, practice, and policy.

This Forum is being convened to identify areas where sex, gender, and their entanglement remain insufficiently or divergently theorized. By advancing dialogue between scholars from diverse disciplines, it aims to advance conceptualizations of gender and sex, to align dialogue across disciplines, and to promote sound application in research, policy, medicine, and public health.

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Metabolic Neuropsychiatry

Dost Öngür and Judith Ford, Chairs

Energy metabolism and related processes play a critical role in supporting and regulating brain function. Much of the energy generated in the brain is used to support action potential generation and synaptic transmission—the basic mechanisms of nerve cell communication. This realization has led to renewed interest in the role that energy metabolism plays in both healthy brain function and in the emergence of brain disorders, with the hope that improving energy metabolism may lead to treatments for brain conditions for which existing treatments are unsatisfactory.

Several lines of research provide converging evidence that neuropsychiatric disorders (schizophrenia, neurodegenerative disorders, and autism) are characterized by abnormal brain bioenergetics—evidence from GWAS of neuropsychiatric disorders, abnormal energy metabolism in patient-derived samples, reduced expression of mitochondrial markers in patient-derived postmortem brain tissue, and in vivo neuroimaging studies indicating reduction in the synthesis and utilization of ATP coupled with a shift from high-efficiency oxidative phosphorylation to inefficient glycolysis for energy production. These bioenergetic abnormalities are best conceptualized as part of a set of interconnected biochemical processes, including abnormal redox biology and neuroinflammation, which together impair brain function in various ways. Although the exact mechanisms linking abnormal brain bioenergetics to neuropsychiatric dysfunction are not well delineated, spatial and temporal aberrations in availability of energy supply may lead to abnormal neural signaling. Depending on the details of bioenergetic dysfunction in subcellular location, affected cell-types, and available compensatory mechanisms, this basic theme may manifest itself in deviation from expected developmental trajectories in early life, abnormal information processing in midlife, and accelerated neurodegeneration in late life.

Abnormal brain bioenergetics is receiving increased attention because of the potential for developing new treatment interventions. A large body of research in diabetes and other metabolic disorders has led to a deep understanding of energy metabolism and to effective diet/exercise and medication treatments to correct metabolic abnormalities, but until now has not been studied systematically in neuropsychiatry.

Reports of clinical improvement in response to the ketogenic diet in individuals with severe mental illnesses become relevant in this context. The ketogenic diet is an FDA-approved treatment for childhood epilepsy in the U.S., and several reports have linked it with positive outcomes in other brain disorders. Several large-scale studies are currently underway to test the effect of this diet and various other metabolic interventions in neuropsychiatric disorders, and more are expected. These developments provide hope that it may be possible to leverage metabolic interventions to improve outcomes in neuropsychiatric disorders. Greater focus on brain metabolism may also lead to the development of new treatments that are easier to administer, more efficacious, and associated with fewer adverse effects.

Are metabolic abnormalities seen in neuropsychiatric disorders restricted to the brain or are they systemic? Most evidence would suggest the latter, a point further highlighted by the well-known propensity of patients with neuropsychiatric disorders to develop metabolic syndrome. Since the same factors that contribute to the emergence of abnormal brain function may also contribute to a higher burden of medical conditions such as diabetes, obesity, and hypertension, this is an important area of focus in neuropsychiatric disorders not only to improve psychiatric outcomes but also to prevent medical morbidity and mortality.

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