Transcript: David Page on Why Sex Really Matters at TEDxBeaconStreet Conference

So, it turns out that Bill is as genetically similar to Hillary, as he is to a male chimpanzee. But, human genome, we have a problem. In the human genome era in which we’re living, this fundamental difference between males and females has been overlooked. Instead, we have been operating with a unisex vision of the human genome. And so in fact, men and women are not equal in their genomes as I just explained, and, as I want to go on to explain now, men and women are also not equal in the face of disease.

Now, what do I mean by that? And what are its consequences and what are the implications for health care? I will cite a number of examples to illustrate what I have in mind.

We’ll take the case of Rheumatoid Arthritis. For every many with Rheumatoid Arthritis, there are 2 to 3 women who are affected with this disorder. Now, is Rheumatoid Arthritis a disease of the reproductive tract? No. Is there any obvious anatomic difference between men and women to account for this dramatic difference in the incidence of Rheumatoid Arthritis, its higher incidence in women? There is no simple, anatomic explanation to be had.

Let’s flip the tables now and consider Autism Spectrum Disorders. For every girl with an Autism Spectrum Disorder the most recent numbers suggest that there are about 5 boys with such a disorder. Why is that the case? Let’s flip the table yet again. Lupus, a long term, autoimmune disorder with devastating consequences that can result in death, for every man who is suffering from Lupus, there are 6 women who are suffering from this disorder. And so, for a whole host of disorders that occur outside the reproductive tract we see that the incidence or prevalence in men and women can differ dramatically. And even in the case when a disease occurs in both men and women, that disorder can be much more severe or have more severe consequences in one sex than the other.

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Let’s consider here the case of dilated cardiomyopathy. Dilated cardiomyopathy is a condition where the wall of the heart thins, and the heart balloons dangerously and sometimes, with devastating consequences.

What I’m going to show you here is the survival curve, the death curve, if you will, for women who have dilated cardiomyopathy due to a very specific genetic defect. It turns out that men can also get dilated cardiomyopathy as a result of this same specific genetic defect, but if they do, they tend to die at a much younger age. Why is this the case? Well, so I asked my colleagues. When I travel around, I ask my colleagues in biomedical research, why is it that for so many disorders, the incidence of disease or the severity of disease differs so dramatically between men and women? Why is this the case? And the answer that I almost invariably get is, “I don’t have a clue.”

Now, this is a big question — this is a big, big question. But as I press harder on my colleagues and say, what do you think might be going on? The answer that I receive, most frequently is, “Well, maybe it’s the sex hormones.” How can it be that we are in such a place in the research world, in this human genetics era, when the answers are so shallow?

Well, it turns out that the human genetics revolution has delivered us, has provided us with a set of tools with which we can ask the question: Why is one man at a higher or a lower risk than another man of suffering from a particular disease? Similarly, we have the tools with which to ask the question: Why is one woman at a higher or a lower risk than another woman of suffering from a particular disease?

But, as unbelievable as it may seem, we have no genetic toolkit to ask the question: Why are men, as a group, at a higher or lower risk of a particular disease, than women, as a group? This is a big, big question and to this point, we have had no answers, no systematic way of proceeding. But perhaps, just perhaps the answer has been staring at us in the face all along. Because, of course, the individuals who are prone to autism, and who tend to suffer more severely at an early age from dilated cardiomyopathy, those individuals are men and they are XY. And those individuals who disproportionately suffer from lupus and rheumatoid arthritis, and a host of other diseases, are women and they are XX. Of course, being XY versus XX is the most fundamental difference, between males and females.

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But, the whole biomedical research enterprise has been operating for decades under the assumption that the Y chromosome is operating only within the cells of the reproductive tract or, to frame it another way, that the Y chromosome matters only in our nether parts. And, as an extension, the notion has been held firm throughout the biomedical research enterprise for decades, that all the differences between the sexes outside the reproductive tract, including differences in disease susceptibility outside the reproductive tract, the notion has been that all such differences must stem from sex hormones that are produced by the reproductive organs.

But it turns out that in recent years, my laboratory at the Whitehead Institute has discovered that the Y chromosome is functioning not just in the reproductive organs but actually, throughout the body. So that all the cells of your body — the skin cells, the cells of your liver, and of your heart, and even of your ear, those cells know, at a fundamental molecular level, whether they are XX or XY.

And the question that I want to put before you is, “Does this matter?” Does it matter outside the reproductive tract? And I would like to suggest that it does matter, and it suggests a path forward towards a better health care.

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