The “Biological Sex or Gender?” Debate

“Everything flows, nothing stands still. Nothing endures but change.” -Heraclitus1

As Heraclitus pointed out, everything in the world inexorably changes over time. Medical science and medical perspectives are no exceptions. Points of view about biological systems capture our imagination and then fade, to be replaced or modified by new ones. Depending on the persuasiveness of the investigator and the sturdiness of the data, we shape new views, hopefully (but not necessarily) more accurate than those to which we held with such conviction before. This applies to our view of the very nature of what we call gender-specific medicine.

The 1990s ushered in a stunning and completely unexpected new idea in academic medicine: that observations in males could not be applied to females without direct testing. To put it simply, we realized that men were not normative for the entire human population. As Mary-Lou Pardue, one of the editors of the invaluable monograph Exploring the Biological Contributions to Human Health. Does Sex Matter?, commented: “Sex does matter. It matters in ways that we did not expect. Undoubtedly, it also matters in ways that we have not begun to imagine.”2 The push to include American women in clinical research began a revolution that still has not completely trickled down to studies on animals or simpler systems involving isolated tissues or single cells. In general, the inclusion of both males and females in clinical investigation has been and continues to become ever more reasonably successful, principally because it was mandated by the National Institutes of Health in 1990, and over the decade that followed, bolstered by congressional legislation and a reversal of the FDA policy of excluding women from research protocols. Unfortunately, the mandate was restricted to human studies and thus a consideration of the impact of sex on data from animal, single cell, and, most recently, genetic studies has been much less common.

As we began to compare data obtained from the direct study of female patients with those we had gleaned from males, the new science of gender-specific medicine predictably (had we thought about it at the time) spawned a furious debate. Did chromosomal sex alone determine phenotype or did environment and experience have a profoundly significant impact on male and female function? Some argued that if societal conditions and attitudes were identical for men and women, the functional characteristics and attitudes of the two sexes would much more resemble one another. Were the male and female phenotypes biologically determined, hardwired, and essentially inescapable, or did the sequence of a lifetime’s experience play a vital role in what made the two sexes different? During the mid-90s, board meetings of the Advisors to the Office of Women’s Health Research at the National Institutes of Health were laced with fiery confrontations over whether people understood the difference between the two concepts of biological sex and the broader and more complex notion of gender.* In general, the group was divided into biological researchers who were intrigued with the idea that an individual organism was hardwired by its DNA to behave in inevitable and sex-specific ways and the behavioral scholars, who thought we were underestimating the profound impact of experience on pheno- type. We did not yet understand the intricate mechanisms by which the environment modified genetic expression; we were definitely discussing what we believed were two quite separate concepts. The announcement in 2000 that we had defined the human genome3,4 immediately intensified our fascination with DNA and began a time of rapidly expanding information about how genes and the myriad of things that control their operation make us what we are, what we will become, and even for some, challenge the notion of free will. But when our debates first began, the behavioral scientists deplored what they believed was the biomedical community’s contempt for a detailed exploration of the impact of experience on phenotype. At one of the first international congresses in gender-specific medicine in Berlin in 2006, a group of social scientists made a formal statement challenging the attitude of the biomedical research community that they believed overemphasized the importance of what might be termed for want of a better word, chromosomal biology.5 There was a distinct feeling of hostility and alienation between the two sets of disciplines.

As the work on the impact of environment and experience on the way genes are expressed progresses, it becomes evident that biological sex and gender are not separate phenomena but ultimately have a final common path. They are actually two aspects of an enormously complex continuum: both experience and the environment in which an organism is placed profoundly impact the way genes function and, as a result, the very structure and composition of tissues and organs. How that happens, precisely, is the rivetingly interesting problem that faces us now. Biological sex is an essential factor in how tissues function: thousands of genes show sexual dimorphism in the liver, adipose, and muscle; hundreds of genes are sexually dimorphic in the brain.6 Not only the X and Y chromosomes, but autosomes are also enriched with sexually dimorphic genes in a sex-specific way. Just as important, incontrovertible evidence that experience modifies genetic expression in ways that determine behavior for a lifetime continues to mount. For example, there are measurable neural changes associated with environmental enrichment; these include an increase in brain size, cortical thickness, neuron size, dendritic branching, spine density, synapses per neuron, and glial numbers.7 Environmental factors act by mutating promoter and coding regions of genes; they modify CpG methylation at critically labile genomic regions.8

Thus, experience and the genome are inextricably woven together; the environments into which we are placed from the moment of conception work to make each phenotype unique and account for the enormous diversity of created life. Schlain puts it this way: “There is no gene-controlled inheritable trait that cannot be altered by the environment. . . . Humans enter the world as a work-in-progress . . . Nature/ nurture is not an either/or duality but, rather represents a both/and type of complementarity.”9

I had an opportunity this week to review the achievements of one of the government-sponsored institutes of health responsible for supporting gender-specific science in another country; again the question arose: what about the functioning organism is the consequence of sex-specific chromosomal composition, and what is the contribution of experience and the environment to the final manufacture of the chemicals that make us ourselves? To put the question in another way, if the social environment of a male and a female were absolutely identical, how many phenotypic differences would remain? To answer those questions and to explain precisely and completely how our genes and the environment interact is arguably the most important problem in biology today.

There is no question, then, that the old question about what about us is the consequence of biological sex and what is the result of our experience is slowly being refashioned. Instead of using two apparently quite separate terms, “biological sex” and “gender,” what is necessary, as one investigator put it recently, “is a new word that erases an apparent duality and separation between the two” (H. Macmillan, MD, MSc, FRCPC, personal communication, 2011). To my mind, gender-specific medicine is as good a term as when we first coined it. It is our view of what it means, precisely, that has changed dramatically. Our expanding understanding of how we get to be what we are makes it obvious that biomedical researchers need the expertise of scholars in other areas of science. We must form new teams that include not only geneticists but social scientists, historians, philosophers, and theologians as well. The enterprise is much more complex and difficult than we originally even imagined. It is also infinitely more exciting.

The author was a member of the Advisory Board to the Office of Research on Women’s Health at the National Institutes of Health from 1995 to 1998.
 

REFERENCES

  1. Heraclitus of Ephesus (c535 BC– 475 BC). Quoted by Plato in Cratylus and by Diogenes Laertius in Lives of the Philosphers, Book IX, section 8. http://en.wikiquote.org/wiki/Heraclitus. Accessed March 3, 2011.
  2. Pardue M. Preface. In: Committee on Understanding the Biology of Sex and Gender Differences, Board on Health Sciences Policy, Wizemann TM, Pardue M-L, eds. Exploring the Biological Contributions to Human Health. Does Sex Matter? Washington, DC: National Academy Press; 2001.
  3. Lander ES, Linton M, Birren B, et al. International Human Genome Sequencing Consortium. Initial sequencing of the human genome. Nature. 2001;409:860 –921.
  4. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science 2001; 291:1304 –1351.
  5. The 1st World Congress on Gender-Specific Medicine. Men, Women and Medicine: A new view of the biology of sex/gender differences and aging. Berlin, Germany, 2006. www.gendermedicine.com. Accessed March 3, 2011.
  6. Yang X, Schadt EE, Wang S, et al.Tissue-specific expression and regulation of sexually dimorphic genes in mice.
  7. Kolb B, Whishaw IQ. Brain plasticity and behavior. Annu Rev Psychol. 1998;49:43– 64.
  8. Waterland RA, Jirtle RI. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition. 2004;20:63– 68.
  9. Schlain L. Sex, Time, and Power: How Women’s Sexuality Shaped Human Evolution. New York: Penguin Books, 2004.