The recent decision of the National Institutes of Health to require the inclusion of both sexes in animal research is encouraging. Nevertheless, in spite of constant urging from those of us interested in gender-specific medicine, it is disappointing that we had to wait for it almost three decades after the NIH recommended the inclusion of women in clinical trials in 1986. That first mandate clearly was the result of an imperative from the public, and not from the scientific community: the great wars of the first half of the 20th century had provided women with access to positions and opportunities never before available to them. The feminist movement was an inevitable consequence of those experiences. By the end of the century, women had prevailed on the Public Health Service to issue a report on what medical practitioners and biomedical investigators actually knew about women. The answer was astonishing and incontrovertible: we knew nothing about their unique physiology except for breast and reproductive physiology-a bikini view of women that has taken decades to overcome.
The 1985 Public Health Service Report began a crescendo of attention to women’s unique physiology and the experience of disease that has produced an amazing harvest of data about the scope and significance of the differences between the sexes. Our expanding understanding of those differences is completely changing the way we prevent, diagnose and treat illness in men and women. What began as an interest in women’s health almost immediately expanded into new questions: What’s different beside reproductive biology between the sexes? How do those differences affect normal function and how illness impairs health? We know now that thousands of identical genes make slightly different proteins in brain, heart, muscle and adipose tissue depending on the sex of the animal. The very stuff of which our organs are made varies as a function of biological sex. Whether an organism has the XX chromosomal pair of the female or the XY of the male turns out to be colossally important. They have important roles in impacting the structure of the proteins our genes produce in a sex-specific way.
The unexpected cornucopia of data about gender differences in human beings seems finally to have captured the public imagination: television specials, the internet and printed articles are all discussing the apparently revolutionary idea that there are actual, profoundly important, unexpectedly abundant differences between the sexes. Actually, we’ve known about many of them for over two decades, but in spite of our best efforts, the first findings created very little excitement. Virtually everyone agrees that men and women are different. Just how different is astonishing. The concept of gender-specific medicine, which takes those differences into account in the prevention, detection and treatment of disease, was one of the most important medical developments of the 20th century.
The present century began with another profoundly important achievement. The White House announced in June of 2000 that a world-wide consortium of scientists, collaborating in what is called The Human Genome Project, had spelled out the sequence of chemicals on our DNA that make us what we are. The accomplishment generated an explosive exploration of the structure and function of the 46 chromosomes that make up our genome. We are learning to modify or eliminate selected genes on those chromosomes entirely and insert others, prolonging and improving the quality of human life. But the most important consequence of the Human Genome Project’s achievement was what one of its leaders, Dr. Craig Venter, founder of Celera Genomics, famously said: once we could describe a naturally occurring chromosome, we could create one-a chromosome of which the parent was not a living organism, but the computer. Scientists have done just that: designed completely novel chromosomes which, when injected into host cells, successfully seize the machinery of the cell and makes it function to order. We are squarely in the new era of what is called synthetic biology. The age of Darwin, where randomly occurring changes in genes produce new varieties of species, is over: for the first time in the history of the planet, we are able to manipulate the genome deliberately to produce completely new forms of life.
These apparently different phenomena: our growing awareness of the impact of the sex chromosomes on the function of others in the genome and the new discipline of synthetic biology are in fact fundamentally related and pose one of the most underappreciated issues in contemporary biology. We are now at the beginning of a different era of evolution, in which man plays an unprecented and powerful role. The achievements of synthetic biologists are astonishing: Dr. Denis Malyshev’s group at the Scripps Research Institute recently reported that they have created a new functioning chromosome that includes two new structural elements in addition to the four that form the backbone of naturally occurring DNA. It’s dismaying that Malyshev’s group called the new components X and Y; that unfortunate choice of nomenclature may well cause a great deal of confusion as we go forward.
Those of us who have grown up with gender-specific medicine wonder if in fact future, computer generated genomes will include the sex chromosomes and if so, if the sex chromosomes themselves can/will be altered in some fundamental way to modify how the genome works. Certainly there is no reference to that idea in the new literature of synthetic biology. In fact, as yet there is no assurance that biologists have an accurate and reasonably complete understanding of the importance of the XX and XY chromosomes in modifying genomic function.
It has taken a very long time to focus the attention of the public and of the biomedical community on the absolutely essential role of the sex chromosomes in function on all levels of organisms from cells in culture to humans. We should capitalize on this interest and urge that as we go forward to create new forms of life that we consider how the XX and XY chromosomes will modify a finished, artificially produced genomic product. Ultimately and inevitably, we will have to consider what might be the consequences of modifying the sex chromosomes themselves and/or of eliminating them altogether as this new era of biological research expands. It’s essential to use the public interest to create a research agenda that will include looking at these fundamentally important questions as the power of synthetic biology expands. Hopefully it won’t take another 30 years to focus on this aspect of what it means to be male or female.
Marianne J. Legato, M.D.,F.A.C.P.
Emerita Professor of Clinical Medicine, Columbia University
Founder and Director, Foundation for Gender-Specific Medicine, Inc.
Author/editor, Principles of Gender-Specific Medicine