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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?
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 --
First of all, XX and XY cells do their business differently,
at the level of cells and all the higher levels of organization that follow.
So, we need to take account,
as researchers across the world,
that there are, in fact, fundamental differences,
not just in the reproductive tract,
but throughout the body,
between XX and XY cells.
We need to discover what those differences are.
Already, in my laboratory at Whitehead Institute,
we are pursuing this question,
and already, we've discovered
that XX and XY cells go about the business,
for example, of making proteins, in slightly different ways.
Second, we need to build a better toolkit
for the scientists and the clinicians
who are pursuing cures and treatments for disease.
We need to build a toolkit that is XX and XY informed,
rather than the present unisex toolkit.
We need a toolkit that takes full recognition
of the fundamental differences
between XX and XY cells, tissues, organs and bodies.
And I believe that if we do this,
and I believe that we can,
that we will arrive at a fundamentally new paradigm
for understanding and treating human disease,
so that, in the future, if you go to seek
the help of a health care professional,
that it will in fact matter,
if you're a male or a female --
the treatment that you receive,
and not just, if you're going to see
your gynecologist or your urologist.
So, in the future, this will transform
the way we encounter the health care system,
and I think that it will -- for you, and for me,
and for our children, and our grandchildren,
transform the experience of healthcare.
Thank you very much. (Applause)


【TEDx】為什麼「性別」真的很重要? (Why Sex Really Matters: David Page at TEDxBeaconStreet)

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阿多賓 發佈於 2017 年 7 月 17 日    板板 翻譯    Colleen Jao 審核
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