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Presentation to IGM 10th Annual Meeting
- 1. Marianne J. Legato, M.D., Ph.D. Columbia University
- 2. The Evolving Concept of Gender Specific Medicine Marianne J. Legato, M.D., Ph.D. (hon.c.) Emerita Professor of Clinical Medicine Columbia University Adjunct Professor of Medicine, Johns Hopkins
- 3. We build in a great longitudinal continuity of scholarship on the ideas that have gone before until the modified thought is perfected for our own current environment. 3
- 4. Foundation for Gender- Specific Medicine (USA) 1997 We began as clinicians, tabulating a compendium of differences between two strictly defined categories (male and female) at the level of tissues and organs. International Society for Gender Medicine 2006 Interest in differences between men and women spreads internationally led by Marek Glezerman in Israel, Jeanette Strametz-Juranek in Austria, Vera Regitz- Zagrosek in Germany and Karen Schenck-Gustafson in Sweden. Israel Society for Gender and Sex Conscious Medicine (Israel) 2009 The relative roles of nature versus nurture in shaping the human phenome becomes a central point of Glezerman’s leadership, eventually culminating in the postgenomic surge of interest in the emerging science of epigenetics. What’s in a Name: How a Label Reflects a Concept
- 5. Our Evolving View of Human Physiology in the 21st Century: What are Our Most Important New Perspectives? • The ascendancy of epigenetic science: transition from the 20th century view of the gene as the prime mover and sole source of human physiology to the current wider concept of the genome: a complex system of sex-specific gene regulation that adapts through epigenetic manipulation to environmental experience. • Reconceptualization of how sex is established and maintained in the human genome. • Rethinking our concept of the sex chromosomes: the impact of feminism on our search for the origin of sex in the chromosomal complement. • The rejection of two rigid categories of biological sex: male and female. The emerging biology of variations in human sexuality. • Personalized medicine: the child of the postgenomic era. promises and pitfalls.
- 6. 1. Transition from the 20th century view of the gene as the prime mover and sole source of human physiology to the current wider concept of the genome: a complex system of gene regulation that adapts through epigenetic manipulation to environmental experience.
- 7. “Hard Heredity” The 20th Century was the Century of the Gene • The gene is regarded as the sole architect of the phenotype and is sequestered from social influences. Meloni M.The Sociological Review Monographs 64:1 61078 2016 7
- 8. “Soft Heredity”: The 21st Century: The Post Genomic Era and Epigenetics • Chromatin is a signal integration and storage platform in which the environmental signal has the potential to be entered into transcriptional memory to set the template for the future. (Landecker 2016) • Soft heredity describes an unceasing exchange of the biological and the social. • The previous generation’s experiences and environments are embedded in the biology of the next one. 8
- 9. “Once the outside world is seen as transduced and thus physically present deep inside the molecular biology of the cell, social “things” can be concretized and conceptualized in new ways as constitutive elements of biochemical templates…the signal shapes the dimensions according to which social problems are defined as biological ones and vice versa.” * *Landecker H. Sociological Review Monographs 64:1.79-99.2016 9
- 10. • 2. How is biological sex established and maintained throughout the life span? • Challenging the view of the X and Y chromosome • Accommodating transitional forms of human sexual identity and behavior
- 11. • All our concepts and perceptions are molded by our culture and experience. Our view of biology is no exception. • The view of how biological sex is determined and maintained is being reconceptualized by feminist geneticists.
- 12. How Is Sex Established? What is the Role of the “Sex Chrocmosomes?” • The traditional view: the genetic sources for male and female reside in the X and Y: The Y chromosome makes an active switch to establish and control the male pathway. In the absence of the introduction of Y, female sex develops as the “default mechanism”: (Anne Fausto Sterling: Male presence, female absence). • Has our view of X and Y’s role been significantly distorted and limited by social and cultural views of maleness and femaleness? (Sarah Richardson: “the persistent gendering of biological phenomena and the ways in which male processes are valued over female ones reflected in the SRY model of sex determination.”) • Have we unconsciously imbued the X chromosome as the genesis of all aspects of “femininity” and the Y for all traits associated with masculinity? • Is the establishment of biological sex in fact, multifactorial?
- 13. Sarah Richardson Jennifer Graves Anne Fausto-Sterling
- 14. Global models or scientific hypotheses may draw on cultural gender conceptions to shape and motivate research programs. “ Gender ideology distorts our biological view of sex. “The history of sex chromosome science is not a chronology of ….complete and accurate facts.”
- 15. Sarah Richardson: Simplistic Thinking About the the X and Y: How social and cultural phenomena influence human knowledge • “The notion of the Y as the “chromosome for maleness” is evidence of the abiding appeal of the idea of a simple gender binary, writ molecular in the human genome.”
- 16. “The X has been overburdened with explaining female biology and sex differences.” The conviction that the X chromosome underlies female biology femaleness and femininity as complex, contradictory and challengable remain palpable influences in contemporary biomedical research on women’s health.”
- 17. Arnold’s Sexome: The aggregate of all sex-biasing influences. • “(cells and tissues are) composed of highly interconnected networks of molecules, pulsating with activity, in which individual components increase or decrease the activity of each other to produce emergent phenotypes of the system…Some (networks) are affected by sex differences which reach into the pulsating networks…pushing them one way or another, raising or lowering their activity, creating differences in the networks in XX v. XY cells. The aggregate of all sex-biasing influences can be conceptualized as the “sexome”.
- 18. Arnold incorporates epigenetics into the sexome • “The inherent nature of multiple independent mechanisms that are inherently sex-biased and that interact with each other does not imply that they are not modifiable. • Rather, outside circumstances..can gate, inhibit, or enhance the sex differences in physiology…depending on life stage, disease status, environmental conditions and many other variables.”
- 19. The Regulatory Gene Cascade: Explaining Variations in Sexual Development. • The authors propose a gene, “Z”, which opposes male sex determination. In males, SRY represses or negatively regulates Z which allows for male determination. • Gradations in the functionality of the Z gene determine variations in sexual development. McElreavey K, Eric Vilain et al. Proc. Natol. Acad. Sci.90:3368-3372.1993
- 20. 3. Personalized Medicine: Promise and Reality • 2000-2003: An early concept: If we knew the correlation between genetic architecture and human function we could eliminate any consideration of the impact of biological sex on individual patient physiology. This a 20th century concept of the “hard genome” in which the gene is the direct driver of physiology. • This turns out not to be the case; the epigenetic modification of gene expression is dynamic and sex specific. It occurs in real time over the course of an individual life • Personalized medicine must encompasses not only genome structure but life style, environmental factors, socio-economic exposure.
- 21. “If the news in the genome era was that the genome would be the secret of life and would cure cancer, the news in this postgenomic era is that we don’t know how it will do this. The value of knowing the sequence of the human genome turned out to be far from obvious….rather than reveal meaningful knowledge about life itself, Genomics instead has given life to a deluge of data. How to make anything of value out of this data is now, quite literally, the million dollar question.”* Jenny Reardon.The Postgenomic Condition University of Chicago Press. 2017 pp319
- 22. What Should Be the Path For Future Investigation? National Science Foundation Statement:* • Converging technologies for improving human performance Concept of NBIC: Nano-Bio-Info- Cogno) provinces of science and technology • Urges a “new Renaissance” in science, in which separated independently developing disciplines unite in a coordinated effort to collaborate. Roco MC and Bainbridge WS. J. Nanoparticle Res.4:281-295. 2002 National Science Foundation.
Editor's Notes
- Good morning. I’m sending you this presentation in lieu of being with you in person.
- My purpose today is to trace how the concept of gender-specific medicine was established in the last two decades of the 20th century, and how it has evolved into a broader, more accurate view of human physiology.
- Nowhere is this observation more pertinent than when we consider the transformation of our understanding of human biology over the past 200 years.
- The first effort to compare the physiology of the two sexes divided humans into two simple dyads: male and female. Shaped by clinicians, the science it concentrated on the sexual dimorphism of tissue and organ function. It was a reasonable beginning. The concept spread internationally, spurred by leadership from Israel, Austria, Germany and Sweden. Led by Marek Glezerman, the community of scholars concentrated on the respective roles of biological sex and the response of the individual to the environment, the latter characterized by epigenetic modification of gene expression.
- These are the three areas in which our concept of the individual’s physiology as a unique amalgam of genetic information which is modified by the response to the environment, both internal and external, over the course of a lifetime. The second major change in our thinking is to expand the concept of a rigid binary of male and female to describe the human population. We now conceptualize human sexual identity as a continuum, incorporating variations as legitimately defined entities deserving of inclusion at all levels of research. This includes a rexamination of how the cultural and social perceptions of the time impacted our sense of how research was planned and the results interpreted. The third major trajectory of investigation is to define the concept of personalized medicine, fueled by our ability to decode each individual’s genome. Personalized medicine promised to predict not only the risk for disease but enabled the physician to plan an indivualized response to preventive and therapeutic intervention.
- Our view of how DNA modifies physiology has evolved over the past two centuries. The 20th century view of the genome resurrected interest in and reemphasized the importance of Mendel’s notion of stable genetic material in what was termed the Modern Synthesis or Neo-Darwinism. Neo-Darwinism is actually a misnomer, as Darwin himself recognized other mechanisms in addition to natural selection which included the inheritance of acquired characteristics.
- In contrast to hard heredity, soft heredity and the machinery of epigenetics, have resurrected, transformed and expanded Lamarckism. In this view of how human physiology is molded and inherited by progeny, (read the slide points)
- Landecker sums up the new view of the relationship between the biological and the environmental components of human experience.
- A second and vitally important modification of our idea of male and female was to agree that there is a broader concept of human sexual identify.. The individual is more accurately placed on a continuum between the two categories rather than being confined to one of two immovable dyads.
- This important concept is the gift of prominent femninst geneticists, each of whom has challenged our view of the omnipotence of the sex chromosomes as the unique and omnipotent determination of sexual identity.
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- These are three of the most important feminist geneticist who have challenged the traditional description of the X and Y chromosomes’ roles in establishing not only biological sex, but as the repository of all the machinery that describes attributes and behavior commonly thought to represent maleness and femaleness. These geneticists made compelling arguments which corrected The lack of investigation into ovarian development; it was considered the “default condition” which as Fausto-Sterling put it, described men as presence, women as absence These thinkers all refuted the organization of sex as a clear-cut binary.—”Fausto sterling says this led researchers to ignore data which are better accounted for in approaches which accept the existence of intermediate states of sexuality.
- Richardson writes: “Active research models in the biolosciences are often openly debated. Competing hypotheses are posed by two or more groups of scientists. Is the Y chromosome degenerating, or is it in a holding pattern? Does the SRY gene control sex determination or is it better conceived of as one in a network of genes implicated in a convergent sex determining pathway?”
- Essentially, Richardson points out that the chromosomal disorders of Turner’s and Kleinfelter’s were described in strongly sexed and gender terms; she maintains that identifying maleness with the Y chromosome and femaleness with the X led to critical errors in the interpretation of sex chromosome variability. Turner women were described as sex reversed males rather than as a disorder of female sexual development and of development in general. It is not a masculinizing condition; physical deformities, heart trouble, hearing impairment, infertility and autoimmune disorders are the principal concerns for medical management. Klinefelter males were originally portrayed as feminine: investigators postulated that they were genetic females having two X chromosomes. Actually, they are phenotypic males and many men live out their lives never knowing about the extra X chromosome.
- She also criticizes the view of the X chromosome as the source of all feminine characteristics, including, for example, the theory that the female is a mosaic of X chromosomes, depending on their origin from the male or female parent, and that mosaicism accounts for the mysterious , even capricious behavior of women.
- The idea that sex influences can wax and wane over the course of a lifetime depending on external factors like age, disease and experience is a crucially important concept that may help to explain variations in human sexuality, sometimes within the same individual, at various states of life and development.
- There is an unwarranted accumulation of social and historical views of the sexes that has caused an unsubstantiated series of assumptions about the X and the Y being the sole source of all differences between the sexes. “The 2 gene hypothesis explains all known pathologies of human sex determination.”This suggests that many factors participate in pushing the balance of sex determination in favor of male or female, explaining the observed spectrum of intersex phenotypes. (XX who express male phenotypes or XX true hermaphrodites).
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- Whom does it benefit? The “emergent digerati”. The Technoloigcal elite?
- This program proposed a well integrated collaboration between four disciplines: Nanoscience and nanotechnology Biotechnology and biomedicine including genetic engineering Information technology including advanced computing and communication Cognitive science, including cognitive neuroscience. The proposal, now two decades old, would have involved extensive reconstruction of many elements: making the specialized expertise of individual disciplines intelligible to those in other disciplines and Collaborating with teams of diverse expertise rather than continuing to operate in silos. (The space field is the best example of converging disciplines.) It would also have required a reconstruction of educational and training centers so that converging technology rather than an emphasis on individual disciplines and effort would be emphasized. Unfortunately, there is very little evidence that there is effective institutional leadership to restructure not only the research environment, but the way science is taught. Overcoming the silos of individual expertise is a formidable task, and even the National Science Foundation agreed that their proposal might be wildly optimistic.