The Concept of Relevance of Gender to Personalized Medicine
The Concept and Relevance of Gender to Personalized Medicine
Marianne J. Legato, M.D.
Those of us working in gender-specific medicine are asked repeatedly why the sex of the patient matters if we are able to characterize the individual genome. Put simply – will the advent of personalized medicine with its dependence on the genomic analysis of the patient make the consideration of gender irrelevant? Indeed, the genomes of different individuals differ by between 1 and 3%.
The answer is that in identifying the systems that operate to produce phenomic characteristics, it is clear that personalized medicine does not make biological sex irrelevant, but reinforces its essential role in shaping the phenotype. In defining the moral and ethical responsibilities of the physician/scientist, this is a crucially important concept. It is important to note that in interpreting genomic data which are necessarily sex-specific, fashioning gender-specific therapy to address those differences will inevitably follow. It is equally important for those involved in changing genomic structure to be cognizant of the fact that the consequences of their intervention might have significantly different consequences depending on the sex of the subject. This is a consideration rarely if ever commented on in reports of such interventions.
The profound alterations in the physician/scientist’s view of human physiology over the past two centuries of medical investigation have evolved in three sequential phases. Historically, we regarded humans, with the exception of reproductive biology, as essentially interchangeable. The medical research of the latter half of the 20th century introduced the realization that men and women are not, in fact, interchangeable but significantly different, establishing the relatively recent discipline of gender-specific medicine; the detailed study of the differences between men and women’s normal function and their experience of the same diseases. The new approach produced cornucopiae of data, the extent and significance of which were completely unanticipated.
Most recently, the stunning discovery of the structure of the human genome less than two decades ago created an entirely new paradigm: a detailed description of individual genomes has revealed the uniqueness of each person.
These sequential views of the human phenotype were a reflection and direct result of societal attitudes, mores and the cataclysmic events of human history that directed scientific research along the path at which we have arrived in the last two decades: personalized medicine. Pari passu, our sense of the rights and responsibilities of both the human subject of medical investigation and the scientist pursuing a more precise understanding of personal physiology have inevitably and fundamentally changed.
What is Personalized Medicine?
Broadly considered, genomic architecture is only one component of personalized medicine. In fact, personalized medicine is an example of systems biology, wherein genomes, transcriptomics, proteomics and metabolics are combined with data about the individual subject’s life style, cultural and social environmental factors and beliefs, disease profile, and a general phenotypic description., It is an encompassing, highly detailed and completely individualized approach to the patient. Moreover, it is not a fixed phenomenon but is changing constantly in response to the individual’s developmental stage, hormonal status and environment in sex-specific patterns. It is essentially driven by the same principles that have always been applied to the clinical care of the individual patient in the clinician’s consulting room, but which increasingly are amplified, focused and more accurate as a result of our increasing expertise in establishing the molecular biology of health and disease.
The current push to authenticate the concept of personalized medicine envisions a universe in which each individual can be completely characterized at a molecular level and the prevention, diagnosis and treatment of disease meticulously tailored to the unique features of that person’s physiology. To that end, we have constructed and made universally accessible enormous collections of genetic information based on the conviction that we will be able to delineate the precise genetic scaffolding that creates specific diseases and that accurately predicts responsiveness to therapeutic interventions. Siminoff et al. reported that reasonably current sources (1999, 2013) document more than 500 million biospecimens containing genetic material stored in public and private databanks.
Venter warns, however, “The generation of genomic data will have little value without corresponding phenotypic information about individuals’ observable characteristics and computational tools for linking the two”. He correctly warns that collecting, much less keeping confidential, adequately detailed data about each participant in the genome databases will be as complicated and challenging (not to mention perhaps much less accurate) as defining the molecular structure of the genome has been. Defining the connection between genomic biology and the enormous variability of population groups seems a virtually insurmountable obstacle to deciphering the relevance of genetic architecture to the physiology of all races and the subsets of race. Humans populate vastly different geophysical, societal and cultural environments. Some aspects of different cultural values and perspectives on the human condition (particularly with regard to the respective societal roles of and the widely different value placed on men and women), are virtually impossible to quantify but profoundly impact health and treatment modalities. For example, Jafarey and Moazam report one trenchant comment from a Pakistani student: “Gender ‘images’ are created by society…and ‘we spend our lives living up to those images’”.
As our exploration of genomic activity progresses, we continue to expand our information about how it is modified by the environment/experience, age/developmental physiology, hormones and perhaps most unexpectedly, by biological sex. In a trenchant discussion on the importance of sex in biological research documented among other authoritative voices by the authors of the Institute of Medicine Report, Virginia Miller writes: “One must wonder then, why is sex of experimental material so often ignored in an era of genomics and personalized medicine?” Investigators universally accept the fact that sexual dimorphism is significantly fashioned by gonadal hormones but all too often consider them the only force delineating the unique characteristics of the two sexes. In fact, the action of the sex chromosomes themselves is a separate and essential agent in shaping the phenotype. Furthermore, as Ober et al. point out, autosomal genes as well, heretofore assumed to be the same in both sexes, are in fact often the agent of differences between males and females:
“Although genes with sex-biased expression are enriched on the sex chromosomes, thousands of sex-biased genes are also found on the autosomes” … Although the DNA sequence, gene structure and frequency of polymorphisms on the autosome do not differ between males and females, the regulatory genome is sexually dimorphic.
Yang’s observations confirmed this. Her group reported that indeed, even at the molecular level, sex-specific genes are expressed in virtually every tissue of the body with small but significant differences in the proteins they produce. They comment: “Here we report surprisingly wide-spread sexually dimorphic gene expression…”. Thousands of genes showed dimorphism in muscle, fat and liver; hundreds in the brain. This striking sex-specific gene expression explains the multitude of differences in phenotype between male and female in spite of nearly identical genome sequences. Importantly, the sexually specific genes were highly tissue specific. Moreover, in addition to the X and Y chromosomes, Yang’s group also identified tissue specific sex specific autosomes.
The consequences of sexual dimorphism in gene expression result in sex-specific susceptibility to disease. That susceptibility, moreover, is often tightly related to developmental stage and thus by inference to hormonal profiles, that change significantly over the lifetime. The clinical profiles of asthma, coronary artery disease and autoimmune disease, for example, are sex-specific in timing and pathological mechanisms.
Over the last decade, our exploration of genomic science has eliminated the traditional conceptual division between the terms (biological) sex and gender. Historically, sex was considered the hard-wired biological characteristic of the organism, while “gender” encompasses all the environmental influences that shaped the phenotype, which is often in many respects fluid and profoundly impacted throughout the life span. The first years of seminars at the Office of Research on Women’s Health at the National Institutes were marred with striking confrontations between molecular biologists and experts in the social and anthropologic disciplines; the latter repeatedly criticized the biologist’s disregard for the role of environment, culture and experience in fashioning the human phenotype. In fact, it is now evident that the environmental sea in which the individual lives out his or her life modifies their molecular biology by impacting the genotype with powerful epigenetic modifications that change its expression.
In a very real sense, the genome is plastic, changing throughout the life span in response to the individual’s unique environment. Some of these changes are not only permanent but are passed on to at least two subsequent generations, often in a sex-specific manner. Thus, this new, expanded concept of personalized medicine provides us with a final common path for what were considered two quite separate modalities. It presents a compelling explanation of how we are not only able to adapt and compensate for what happens to us in the exterior world, but makes apparent the mechanisms by which we are also the heirs of the experiences of previous generations. Scott Gilbert offers a new construct called ecological developmental biology:
“This is a science where organisms and environments possess agency, and the genome is both passive and active…This is not an approach against genetics or big data. Rather, it demands a broadening of the scientific portfolio, so that other perspectives are also included in biological funding and as appropriate biological explanations. It argues that...the physical organism is critically important and that the environmental context plays a large role in gene expression”.
Springer and her colleagues offered this definition of the new framework:
“We are not arguing against any biologically based male-female differences. Rather we are arguing that the vast majority of male-female health differences are due to the effects of the irreducibly entangled phenomenon of “sex/gender” and therefore this entanglement should be theorized, modeled and assumed until proven otherwise”.
Not only our conceptual view of sex differences is changing in spectacular ways – so is our ability to generate the science to support those perspectives. The 8-year-old Common Fund’s Genotype-Tissue Expression (GTEx) Program is expanding our awareness of the significance – and mechanisms – regulating gene expression. It is dedicated to studying all the factors that govern gene expression and is a crucially important step to integrating the importance of sex in the regulation of gene activity. The GTEx consortium operates on the principle that although genome-wide association studies have identified thousands of loci for common diseases, the mechanisms of how those loci are related to disease remain unknown. A much more fruitful approach to solving the issue is to concentrate on the impact of regulatory regions in the genome, since most associated variants are not correlated with protein-coded changes. Essentially, it proposes a biobank containing samples of the major tissues of 1000 deceased adults. The complexities of recruitment and appropriate informed consent of donors and their families are challenging. For example, the responsibility of investigators who utilize donor tissue to return information that might not only interest but affect the health of donor relatives, must be defined. Most important, how well and for how long after death postmortem data would correlate with the physiology of living tissue still needs assessment.
One of the most elegant examples of how the GTEx can yield sex-specific information with an unprecedented degree of sophistication is the recent paper from Tukianinen’s group. The investigators established that incomplete inactivation of the X chromosome in female cells varies between individual cells and extends to populations levels across a wide range of tissues. They reported that at least 60 genes were sex-biased due to escape from XCI and hypothesize that “escape” elements are contributing to sex-specific differences in health and disease.
Collaboration between the Office of Research on Women’s Health and the Common Fund was highlighted in a joint 2017 workshop. The large databases built by the Common Fund contain a wide assortment of biomedical information on both sexes that is being mined and supported by supplemental grants to support research that considers sex an important variable in human physiology.
Remarkable and exponentially expanding new technologies to explore the molecular mechanisms that underlie the maintenance of health and the susceptibility to disease are reinforcing the importance of biological sex in shaping the unique features of males and females. It is worth reflecting on the account in Genesis of how Adam and Eve originated: God shaped Adam from a handful of dust; his intricate physiology an active, direct and original creation. Eve, in contrast, was fashioned out of one of his ribs – essentially a clone of her mate. It is interesting to think that we have spent the last ten decades establishing with greater and greater confidence how differently the expression of their nearly identical genes are uniquely regulated, producing unique versions of human physiology. We are in the midst of an astonishing series of discoveries about not only how extensive those differences are, but of how they are created and maintained in the extraordinary fluidity of genomic economy.
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 Personal observation during four years of my membership in the Advisory Council to the Office of Research on Women’s Health at the NIH.
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 https://commonfund.nih.gov/sexdifferences#GTEx_Sex Differences.