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

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David Page, Director of the Whitehead Institute, discusses “Why Sex Really Matters” at TEDxBeaconStreet conference. Here is the full transcript.

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David Page – Director of the Whitehead Institute and Professor of biology at MIT

I would like to talk with you about sex and disease, but perhaps not what you’re thinking.

So, now that I’ve gotten your attention, I’d like to tell you about something that’s really fundamental. I’d like to tell you about a connection between sex and disease that is very critical, but a connection between sex and disease that has gone largely unnoticed and unexplored even within the scientific community.

So, to get things underway, let me open with three observations that I think you may find a little surprising and startling.

First of all, human genome, we have a problem. Second, men and women are not equal. A pause there. And third, that the study of disease is flawed. So, let’s explore each of these in turn.

Across the course of time, scientists, no matter how brilliant they are, have gotten things wrong in a big way. For a long time, we thought that the Earth was flat, and we thought that the sun revolved around the Earth. Well, in this time of the human genome revolution, it turns out that we’re missing something that is of critical importance. And to understand what that’s all about, I need to ask you to return with me to the beginning where each of us began.

So, here it is, the moment of conception, egg meets sperm. All the cells of your body — your lung cells, your liver cells, your skin cells, all the cells of your body ultimately derived from this one founding cell, the fertilized egg. So, the fertilized egg divides to become two cells, those two divide to become four, and eight, and so on — until your entire body consisting of — on the order of 10 trillion cells has been assembled.

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And what is most amazing is that within the nucleus of each of those 10 trillion cells that make up your body, within each of those cells, you carry the same 23 pairs of chromosomes. And those 23 pairs of chromosomes carry all of the DNA, all of the hereditary material, all of the hereditary information with which your cells, and tissues, and organs in your body execute their functions.

So, let’s look at those 23 pairs of chromosomes in more detail. It turns out, that of the 23 pairs, 22 pairs are absolutely identical and shared between men and women. And here they’re shown — The differences arise in the 23rd pair, which in females is a beautifully matched pair of X chromosomes, but in males, that 23rd matched pair is replaced by a mismatched pair, an XY pair.

And let’s look in more detail at that mismatched XY pair. Here they are — to the left, the stately and grand X chromosome. Why do you laugh? To its right, the diminutive and demure Y chromosome, with its head down. Now, if truth be known, I’ve spent the entirety of my career at Whitehead Institute defending the honor of the Y chromosome – in the face of innumerable insults to its character and its future prospects. Even to this day, it is thought by physicians and most scientists around the world, that the function of the Y chromosome is restricted to the cells of the reproductive tract. And in fact, this idea that the cells of the reproductive tract are the only place where the Y functions, has led, in turn, to the notion that the genomes of men and women are, apart from the reproductive tract, functionally, may be even morally equivalent.

And so, in fact, it has been said many times that apart from the reproductive tract and even disregarding that for a moment, it has been said many times that our genomes are all 99.9% identical, from one person to the next. This idea that we’re 99.9% identical has gained great traction and for a number of reasons – it’s very appealing to say that we are all 99.9% identical – it’s so appealing that this idea was seized upon by President Bill Clinton in his 2000 State of the Union address — when he stated that, “This fall, at the White House… we had a distinguished scientist visiting, an expert in this work on the human genome, and he said that we are all, regardless of race, genetically 99.9% the same.” Wow! It turns out that this idea is even correct — as long as, the two individuals being compared are both men. It’s also correct, if the two individuals being compared are both women.

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However, if you compare the genome of a man with the genome of a woman, you’ll find that they are actually only 98.5% identical. In other words, the genetic difference between a man and a woman is 15 times the genetic difference between two men or between two women. Let us consider, for example, the case of Bill and Hillary.

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.”