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  • 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 under way,

  • 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.

  • I'll 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's that 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,

  • 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 --

  • (Laughter) 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 -- (Laughter)

  • In the face of innumerable insults to its character and its future prospect.

  • 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, maybe 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 is 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.

  • 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 -- (Laughter)

  • So, it turns out that Bill is as genetically similar to Hillary,

  • as he is to a male chimpanzee. (Laughter)

  • 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 man 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 is 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.

  • 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 --

  • Whenever 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 could 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 [suffering from] 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 Lups 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.

  • 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.

  • But how serious is the problem? Am I making this up?

  • Is the research enterprise really unaware of this reality?

  • Well, if I go to visit my research colleagues around the world

  • working in universities, in medical centers, in pharmaceutical companies --

  • If I got to ask colleagues around the world

  • who are studying human cells, as shown here --

  • If I ask them, "Are you studying XX cells or XY cells?"

  • The answer I get, almost always is -- "I don't know."

  • Well, if you don't know whether if you're studying XX or XY cells --

  • How could you possibly be taking account of this most fundamental difference

  • between male and female cells, tissues, organs and bodies?

  • And so -- it is the case that a great deal of the researchs being conducted today

  • with an eye towards understanding the cause of disease,

  • and identifying possible cures and treatments for disease,

  • is failing to account for this most fundamental difference

  • between men and women.

  • And it is for this reason that I said, somewhat provocatively,

  • at the beginning of this talk with you,

  • that the study of disease is flawed.

  • Well -- what to do? What can be done?

  • How can we think about this differently?

  • How can we think about reconnecting and reconsidering

  • the link between sex and disease?

  • Well, here is what I think --