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  Home arrow Inhalt arrow Wissenschaft arrow Interview mit Eric Vilain
Interview mit Eric Vilain

In folgenden ein Interview mit Eric Vilain, Wissenschaftler der UCLA, welches gut aufzeigt, welche Fehler bei der Geschlechtsbestimmung eines Menschen zu machen sind. Insbesondere im Zusammenhang mit dem Geburtseintrag ist damit anzumerken, dass die wahre Geschlechtsidentität das Wissen über sein Selbst (Bewusstsein) ist, und somit auch gesagt werden kann, dass Frauen mit Penis geboren werden können und Männer mit Gebärmutter. Selbst die Chromosomenbetrachtung lässt aus heutiger Sicht nur folgenden Schluss zu: Das einzige anwendbare Kriterium, welchen Geschlechts ein Mensch von Geburt an angehört, ist das Wissen des Menschen über sich selbst.

 
Quelle des Interviews (in Englisch):

http://www.learner.org/channel/courses/biology/units/gender/experts/vilain.html
 
Interview with Eric Vilain, MD, PhD Vilain is an assistant professor of Human Genetics at UCLA. His laboratory is exploring the genetics of development of the reproductive axis using the analysis of patients with disorders of sexual development, and the study of animal and cellular models. He is also testing the hypothesis that there may be genetic influences on behavioral differences between males and females, in addition to the direct influence of sex steroids.

Why is this field so well studied?

Sex determination is appealing to everyone because [it is] really the fundamental of what we are. One of the first characteristics of a human being at birth is a boy or girl. By understanding the basic biology of that, we really attempt to decipher [the] fundamental biological mechanisms of who we are.

The field of sex determination is very poorly understood. We don't know very much about it. We know a handful of genes that makes boys become boys and girls to become girls but we know that we're missing a very, very large piece of this puzzle.

What do you find interesting about this field?


I was drawn into the field of sex determination when I was a resident in a Paris hospital in France that was specializing [in] seeing patients born intersex. I became immediately fascinated by this intermediary state and I've always been extremely curious in discovering why, a number of babies would be born intersex. This is something fascinating both on the social level, but also at the basic biology level.

What do we understand in this field and also what do we not understand?

What we understand is how the sex determination pathway is triggered. We know what will start pushing the sex determination pathway into the male direction rather than the female direction. What we don't know is the detailed mechanisms of it. We know a handful of genes. We don't know how they interact with each other. We don't know how they work to make the gonad become either a testes or an ovary.

What we know even less is how our brain becomes either more of the masculinized brain or more of the feminized brain. That is a big mystery and that is really the goal of a number of scientific studies including my laboratory.

What do you mean by a masculinized brain?

Masculinized brain is probably is a wrong way of putting it. It's what society perceives as masculinized vs. feminized. There are a number of behaviors that are stereotypic for males and some others [that are] stereotypic for females, which we call "gender role behavior."

When I refer to masculinized brain, I mean a brain that is able to give the orders to the body to perform those stereotypic gender role behaviors that we usually perceive as masculine vs. feminine.

The Olympic Committee has abolished sex testing for the 2000 Olympics. Can you talk about how sex testing in the Olympics came about and how it evolved?

Until 1968, there was a "gender police" in the Olympics and basically every athlete had to go to a doctor who would do a physical examination of his or her genitalia. And this was considered degrading and humiliating by lots of athletes.

In 1968 the International Olympic Committee decided not do any physical examinations anymore but to leap into modern science and use a genetic approach to decide who was a male athlete and who was a female athlete. They started looking at chromosomes and it was decided that XX athletes were female and XY athletes were males.

In 1992 after the discovery of the SRY gene, which is the trigger for male sex determination, it was decided to look at the presence or the absence of SRY in athletes and the presence of SRY would deem an athlete a male and an absence of SRY would deem the athlete female.

This was abandoned in 1996, because the science behind this choice of looking at the genetic makeup of athletes to determine what the gender is, is absolutely poor and in fact untrue. There are so many ways to define what male and what female is and looking at the genetic makeup is very restrictive way of making such a definition of male and female.

In fact we know that there are individuals who are XX males, who according to this definition of the Olympic Committee could have competed as females, because they have two X chromosomes, but yet they would have all the attributes of a male including two testicles and one penis. Yet they would have been admitted as females, which would have been completely outrageous.

So, after lots of discussions it was abandoned by the Olympic Committee who is now deciding to just do gender testing on a case-by-case basis when there is a suspicion that one athlete may compete in the "wrong category."

What did the Olympic Committee misunderstand?

The Olympic Committee did not fully appreciate that there is more than a genetic definition of sex. In fact, there [are] many ways to define sex and each one of them [is] just as equally important as the other; genetic sex being one important one and that's whether you're XX or XY.

But you can look at [it] with a different perspective which is the makeup of the gonads, whether they're testes or ovaries and that's a completely different perspective on it. We know there are individuals who have ovaries yet they can be XY and conversely you can have testes and be XX. So they're two independent primaries.

There is a third way of looking at this, which is what we call the "phenotypic sex" and that is probably the most common sense definition of sex and that's the appearance of the external genitalia. Penis, you're male. Vagina, you're a female. Again this definition may be discordant with the genetic makeup and the endocrine or gonad makeup.

And finally, another way of looking at it is gender identity. It's one's own perception of one's sex and that's how people feel like the way they are, either male or female. This can be completely discordant with the rest. You can have individuals who are fully masculinized, have a penis, have two testicles, they're XY, they have levels of testosterone of the majority of males, yet they feel like they belong to the [female] body and in their mind they are female. These four perspectives are very important as a whole to define what sex is.

I should add that there is a fifth perspective which is the legal perspective and that's what's decided at birth, in the birth certificate. You're either male or female and this can be also discordant with the rest of the other perspectives.

In the Olympic story there was a failure to appreciate the various parameters that make one individual male or female. This is a basically a mix of a number of perspectives on sex and so just looking at the genetic was certainly not enough.

Can you dispel the myth that if you have XX you're a female and XY a male?


When the sex chromosomes were discovered, it was immediately obvious that males and females were different at the chromosomal level. Females were XX; males were XY. Then the immediate question was: Well, what makes a male a male and a female a female? And there are two options.

One is it's the number of X chromosomes that makes you either male or female and females have two X chromosomes; males have only one. This mechanism is probably the most frequent in the animal kingdom. The dosage of one particular chromosome-in this case the X chromosome-is sex determining. If you have two, you're going to be a female. If you have one you're going to be a male.

But the other option is that it's the presence of the other chromosome that makes the male or female, and we know now that it is the second mechanism that is the correct one in mammals and in humans in particular. If one individual has a Y chromosome, one would be a male. If one does not have the Y chromosome, one would be a female.

Could you explain Androgen Insensitivities Syndrome?

Androgen Insensitivities Syndrome is the inability for androgens-that is essentially testosterone-to bind to their receptor. In the Androgen Insensitivities Syndromes, the individuals are typically XY. They have a Y chromosome. They typically have two normally functioning testicles which do produce male hormones, in particular high levels of testosterone, but the testosterone cannot bind to its receptor.

The inability for testosterone to bind to its receptor makes the external appearance of these individuals to be fully female. They do not have penis. They do have what appears to be a normal vagina and they look [like a] normal female at birth.

The fact that their levels of testosterone are high does not help them in terms of muscle mass, as the Olympic Committee could be afraid, because these high levels of testosterone have no effect. They do not increase the muscle mass. This is a relatively frequent situation caused by a mutation in the androgen receptor, which is located on the X chromosome.

What did people used to believe about sex determination?

There have been since the antique times this idea that was initially touted by Aristotle that it's the male that is active and that heat will actually trigger male sex determination: depending on how warm or hot the male semen was the baby would be either masculine or feminine. It was a view that was very centered on maleness being the active force driving the whole sex determination. If there was enough male activity, there would be a male baby eventually.

Interestingly this concept has made its made its way even throughout modern science and until recently it was thought that only the presence of a Y chromosome would be able to generate a male fetus. If there was no Y chromosome, there could never be any masculinized fetus born. And we know it's not true.

We know that, there are a number of babies born who are male-they have two testes and penis-and yet they do not have a Y chromosome. We started to decipher the molecular mechanisms that lead to this situation and we now know that there [are] a few other genes that can sometimes mimic the action of the genes in the Y chromosome. So the Y chromosome is not this single force that pushes the whole male sex determination pathway.

Can you talk about the SRY gene?

The story of the discovery of SRY started in 1959. In 1959 the chromosomal constitution of two genetic syndromes was discovered. One is called "Klinefelter's Syndrome" and these patients have an extra X chromosome. Instead of having 46 chromosomes, they have 47 XXY and they're males. This immediately told the scientific community that to be a male it was not the question of having a Y chromosome. We know now that there are exceptions to this but at the time, it was clear that the sex determination mechanism was to have one Y chromosome. And whatever the number of X chromosomes, individuals who were born with the Y chromosome are usually males.

In the same year, another syndrome called "Turner Syndrome" [was found] where one X chromosome is missing, so there are only 45X0, not 46 XX. These patients are born completely female. So again it's not the presence of only one X chromosome that makes you male. If you have only one X chromosome as long as there is no Y chromosome one would be a female.

So in 1959 we knew that what had to be a testes determining factor or TDF had to be on the Y chromosome. The question was where was it on the Y chromosome. It took about 30 years to discover where this testes determining factor was. It was mainly discovered because of the cooperation of a number of patients who were born with a complete discordance between their chromosomal constitution and their phenotype or the appearance of their external genitalia. [These people] are XX males and XY females.

It took 30 years because these patients were rare, first of all, and because the whole human genome was very poorly understood at the time and we did not have the tools to rapidly figure out which gene was responsible.

The idea [was to find] where the testes determining factor was by looking essentially at XX males and finding if there was a piece of the Y chromosome present-which there was in lots of them-and how much of this Y chromosome was present.

What we were looking for was the smallest possible piece of the Y chromosome that was necessary and sufficient to produce a male phenotype in an XX individual. In 1989, four XX males who had the smallest ever described portion of the Y chromosome (about 35 kilobases, 35,000 base pairs) that was translocated on one of their X chromosomes and that was sufficient to give them a male phenotype.

This was not visible under the microscope looking at the chromosomes. They looked like normal X chromosomes. But when you looked with molecular tools, molecular probes, you could see that there were pieces of the Y chromosome present.

Within these 35,000 base pairs, one gene named SRY was discovered in 1990 by the team of Peter Goodfellow in London. Rapidly after, a number of scientific teams including ours in Paris, showed that mutations or mistakes in the DNA of this SRY gene resulted in the reverse phenotype of XX males and that's an XY female. This was very strong genetic evidence that SRY was the testes determining factor. That was in 1990.

It sounds like intersex patients have been key to the study of sex determination genes.

Intersex patients were key in understanding the genes involved in sex determination because by identifying mutations in various genes that are part of this pathway, we were actually able to prove that they were part of this pathway. If we do not identify mutations in these genes in intersex patients, we are left with looking at the way these genes are expressed in their gonads. [These would be] very indirect arguments, whether these genes are indeed crucial for sex determination. If we do not have the mutation, we're never entirely sure.

Now one new way that is being developed is to look at animal models which we start doing in our laboratory and if we have a candidate gene that we think is important in sex determination, we can either mutate it or over express it. We create a genetically engineered mouse and then we look at the effect of tweaking the expression or the presence of a specific gene and then we look at the phenotype. We look at the external genitalia and the internal genitalia of these mice.

That's an alternative approach; however, sex determination is a very poorly conserved mechanism throughout evolution and what is true in the mouse may not necessarily be true in humans.

Is it understood specifically how the SRY gene works to determine the male?

For a long time we thought that SRY would activate a cascade of male genes. It turns out that the sex determination pathway is probably more complicated and SRY may in fact inhibit some anti-male genes.

The idea is in instead of having a simplistic mechanism by which you have pro-male genes going all the way to make a male, in fact there is a solid balance between pro-male genes and anti-male genes and if there is a little too much of anti-male genes, there may be a female born and if there is a little too much of pro-male genes then there will be a male born.

We [are] entering this new era in molecular biology of sex determination where it's a more subtle dosage of genes, some pro-males, some pro-females, some anti-males, some anti-females that all interplay with each other rather than a simple linear pathway of genes going one after the other which makes it very fascinating but very complicated to study.

Can you discuss why some people say that the female is the "default" sex in development?

We used to think that females were the result of a default passive sex determining pathway and we now know that is not true. We now know that there must be genes that actively trigger a female pathway. Although we don't know what they are, we know that they must be there.

We also know that the female pathway is not necessarily the default pathway because there have been a few cases where you can observe masculinization of a fetus, becoming a male newborn without the presence of a Y chromosome or without the presence of the SRY gene, which means that one can become male without a Y chromosome.

What role do you play at UCLA at the medical clinic when intersex babies are born?

At UCLA I do essentially two things. One of my roles at UCLA is to be part of a medical team, who is always on call when there is a baby born intersex. What we do is immediately go to see the baby, talk to the parents, and try to help them understand what is happening. [We] try to make a precise diagnosis; because of the research that we do in the laboratory, we have many more tools-in particular molecular tools-for rapid diagnosis of these babies.

With all this information coming in rapidly, we're able to very quickly give the parents a good idea of what is happening and then help them in the decision-making process.

What lead to the discovery of the DAX1 gene?

After the discovery of SRY, we found out that SRY could explain only about 15% to 20% of XY females. In the other cases, SRY had no mutations, which meant that there had to be other genes.

And, quite rapidly it was found that a number of XY females who did not have a mutation in SRY had a duplication, a double dose, of a portion of their X chromosome. Again, what was looked at was the smallest possible portion of a duplicated region of the X chromosome that could lead to an XY female phenotype.

The smallest possible region was found by a consortium of investigators. There was a gene named DAX1 that was found to be responsible for XY sex reversal when in double dose. DAX1 is what we call an orphan nuclear hormone receptor so it it's a very bizarre molecule. It's bizarre because it has structure that's very novel but it's also bizarre because although it looks like a receptor we call it "orphan" because maybe there is no ligand, so it's a receptor with no hormones. Yet it looks like a receptor.

What it does precisely has been the topic of intense investigation. It is thought to bind DNA, but it can also bind RNA and although we know some of its biochemical properties, we don't really know its target.

We know that DAX1 seems to antagonize the action of SRY so we see it as more of an anti-male gene, whereas SRY is more as a pro-male gene. If you have too much of DAX1 in an XY individual-that's what happened in these duplications of the X chromosome-despite the presence of a normal SRY, the XY fetus will become female and not male.

[There] is a balance between pro-male factors and anti-male factors, and SRY is the typical example of a pro-male factor. DAX1 is a typical example of an anti-male factor. If you have too much of it, you're going to be a female, even if you have a normal Y chromosome.

Can you talk about WNT4, another gene that is involved in female development?

We recently identified in humans a gene named WNT4, which seems to have the same function as DAX1. That is if you have too much of WNT4 in an XY individual, this XY individual will become female. It seems that again WNT4 is another example of an anti-male factor. We actually showed that WNT4 and DAX1 interact with each other at the molecular level so they're part of this anti-male and possibly pro-female pathway, both antagonizing the effect of pro-male genes such as SRY.

How do the many factors lead to male or female?

The pathway is made of a complex network of genes that interact with each other at the molecular level and these interactions depend highly on the dose of each of these genes. So the end result is a subtle balance between a number of genes, most of them still unknown unfortunately that lead to either the making of a male or the making of a female.

What are the mysteries that still remain in human sex determination?

We know a number of things in sex determination. We know a handful of genes. We know a little bit how they work. We unfortunately don't know how to explain the majority of our patients, who are either intersex or with a complete sex reversal. We can understand what's happening in the molecular level in only about 30% of the cases and that's not very much.

There is a majority of our patients for which we don't understand what happened while they were developing as a fetus and this keeps us busy in the laboratory. We continue to need the cooperation of patients and their families to help us fully understand the mysteries that effect sex determination.

How much further along are we from the 1950s?

We know some of the important triggers. We just don't know the details in terms of molecular mechanisms. Back in the '50s, we had no idea that even one gene was involved. Now we have a framework of a few genes and it's easier for us to work with those and find out genes that interact with those already known genes, so it gives us a springboard to look at other genes. But as usual in science every new gene unravels more complexity so the story never seem to end, but we're working on that.

Can you talk about how our distant ancestors didn't have sex chromosomes?

Sex chromosomes are a relatively recent invention. Our ancestors in the tree of evolution did not have two sex chromosomes that are fully differentiated the way we know them with an X and a Y chromosomes. Sex chromosomes look pretty much alike and it's only relatively recently that one of these chromosomes which was to become the Y chromosome started shrinking and became highly specialized in male sex determination.

What was the significance of the Joan/John case?

What happened was that the idea of nurture being always able to overcome nature became prevalent in the scientific and medical world. And until we knew the outcome of this famous John/Joan case, this idea was the norm.

After it was clear that John was very unhappy in his gender reassignment as a female, this hypothesis that nurture could always overcome nature started to be challenged in many circles. We now know that it's much more complicated than that and that there's so many factors influencing gender that are not only limited to the environment but also are triggered by hormones, by genetic factors, and maybe by a number of unknown factors that we can't even imagine at this point.

How did Joan know that he was a boy?

Knowing that you're a boy or you're a girl is something that's unique to humans. This is what we call "gender identity" and we don't know how this happens. We don't know why suddenly at a certain age, and rather early actually, about 3, 4, 5 years of age, we just know that we're either boys or girls. And it's not just that we know. It's that we feel good about one gender vs. another one. And Joan just knew that she, because she had been assigned as a girl, was feeling very unhappy as a girl. Even though she probably could not put this into words at first, it was clear that something was terribly wrong in her being. And, after a number of years, she realized that she probably would feel better as a boy.

How did this happen? How did she know? How do we know the best way to feel as boys or girls? I have no idea. I don't think anyone has any idea. I would love to know. We're trying to work on some biological determinance of gender, to try to understand what happens in our brain, that makes us feel good about one gender vs. another. But that probably will not even tell us how we know at the time we knew it.

What do you think is interesting about that case?

What's interesting is that it shows the failure of the single-minded hypothesis of nurture always overcoming nature. It shows that gender identity mechanisms are very complicated and should not be restricted to just environmental factors. It demonstrates that environment is far from being enough in determining gender.

How do you study gender?

Studying gender is complicated: first because there is no animal model for it. You have to study humans. One way to study gender is by looking at individuals who don't feel right in their own gender. They have what we call "Gender Dysphoria." They're unhappy about their gender. Some of them may become transsexuals. They actually perform surgery because they're so intensely unhappy about the gender that was attributed to them that they feel the need to change using surgical tools.

Some of these Gender Dysphoria individuals cluster in families. There is more than one case in one family so we can start looking, using genetic tools, at those families and see if we can find some genetic factors that would be different in these individuals who are unhappy with their genders compared to other members of their family, for instance. So that's one way to look at gender factors.

Another approach is an indirect approach still using animal models, although they're not ideal, but they're easy to manipulate. We look at brain sexual dimorphisms, which means the difference between male and female brains in terms of their structure, in terms of number of neurons in specific structures, density of neurons, and there are subtle differences between male and female brains.

So using animal models we can try to understand which factors, whether they're hormonal or genetic, influence these subtle differences between male and female brain structures. Once we know the biological factors underlying those sexual differences between male and female brains, then we can in the future go back to humans, with gender dysphoria and see if those factors also are implicated in these individuals and why they feel this way.

What role do hormones play in gender identity?

Hormones have always been thought as the unique or major factor influencing the development of a male or female brain. We now know that hormones cannot explain everything in the making of a brain, whether it's masculine or a feminine brain. But we don't know really what the other factors are.

We suppose that some of these factors may be genetic. Maybe pieces of the Y chromosome are important at some level in the brain sexual differentiation. Maybe some environmental factors are also important: there are compounds in the environment that are hormone-like, they're estrogen-like for instance, that might play a role in this. These are purely speculative arguments, but those are the kind of things that we are trying to decipher.

To give you an example, we found that SRY, the main gene triggering male differentiation, is also expressed in the brain. We don't know why it's expressed in the brain but it is. We are wondering what it does and to study this we are creating animal models such as a mouse that would have a piece of a Y chromosome in her brain. If it's a female mouse, we would look at her behavior and look at her brain structure to see if somehow this mouse brain has been masculinized. This would show that there is a direct role of the Y chromosome on brain sexual differentiation independently from hormones.

What about homosexuality?

Sexual orientation is an independent parameter from gender identity. Those are two different things.

What we know about the mechanisms of gender identity is extremely poor. What we know about the mechanisms of sexual orientation is a little better but it's not clearly understood. It probably is a mixture of a number of factors-social, environmental, genetic-and we don't know what they are.

What we know is there have been a few studies looking at genetic inheritance of some regions of the genome and in a few scientific articles there seems to be a statistic link between homosexuality in males and a specific region of the X chromosome, XQ28.

This work is still somewhat controversial because it's not reproducible by all the teams that have been working on this. But if one does a full statistical analysis of all the studies that have been made, it seems that the statistics still hold up and there seem to be a statistical link.

What does the statistical link between this genomic region of XQ28 and homosexual mean in terms of biology? We don't know. We don't know what the gene is or genes are in this XQ28 region. We don't know what they do. The only thing we know is the presence of a statistical link.

If it is true that there is a genetic difference, it will be just different and it will be interesting if we find the specific genetic factors, to look at variations. What I'm expecting is that it will not be a binary state. It will be a full range of genetic states and we will probably see that every one of us is somewhat a little gay. I really think that it's not going to be normal vs. abnormal. I really think that there will be a spectrum of variations at the genetic level.

Can you define intersex?

Intersex is an intermediate sexual phenotype. This means that this is a state of being in-between what's commonly accepted as male or female at all levels, that is an anatomical level, gonadal level, and brain level, and behavioral level.

What is a complete sex reversal?

Complete sex reversal corresponds to the extreme end of the intersex spectrum, where apparently there is no ambiguity of the genitalia at birth, but yet there is a intermediate state, at some level which is either the genetic level or the hormonal level or the brain level. But at birth sex reversal doesn't show. At birth phenotypically they look either male or female. It's only later on during their lives because they usually cannot go through normal puberty, that we find out that they had some intermediate state in terms of either their genetic makeup or their hormonal makeup.

What is your hope in this work?

The big dream for me and the big challenge in fact, is to understand the mechanisms of gender identity. This is really the big enigma and to me it's also the most important aspect of sex determination to understand because I believe out of all the definitions of sex, gender is the most important. In fact it's how people feel that is important, regardless of what they look like, of what their levels of hormones are, or what their face or genitalia look like. It's what they feel within themselves. That's what's important. And to understand what make gender identity happen at some point in a human life is absolutely fascinating and extremely complicated to study but that's certainly the next challenge in the research in sex determination.

What do you see in the future of sex and gender study?


The future will certainly consist of understanding much better the molecular mechanisms of sex determination and also being able to understand every single intersex individual.

Once all this is understood, again the next challenge is going to be to understand how everyone's gender is actually determined, regardless of how the physical attributes are determined.

Will we eventually know all the genes in the sex determination pathway?


With the continuing collaboration of our patients and of intersex individuals, we really hope to be able to identify all the genes involved in the sex determination pathway.

 

Wichtiger Hinweis: Der Begriff "Geschlechtsidentität" in älteren Artikeln auf dieser Website meint etwas völlig anderes, als das, was offiziell unter "gender identity" verstanden wird. "Geschlechtsidentität" meint auf mut23 das Wissen um seine eigene Geschlechtszugehörigkeit bzw. einfach nur Geschlecht. Da die Verwechslungsgefahr zu "gender identity" aber gross ist, kommt der Begriff "Geschlechtsidentität" in neueren Artikeln nicht mehr vor. Übrigens: Eine "gender identity" gibt es nicht. Die Vorstellung einer "gender identity" basiert auf Geschlechtsrollen-Klischees, der Vorstellung von Mann-Frau-"Verhaltensweisen" und gehört Geschlechtsstereotypen, die transphobe Gesellschaften dazu missbrauchen, transsexuellen Menschen ihr Recht auf ihr Geschlecht zu verwehren. Der Begriff "gender identity" wurde von John Money erfunden, und dient bis heute als Grundlage für geschlechtliche Zwangszuweisungen wie der Verstümmelung intersexueller Menschen und der Psychiatrisierung transsexueller Menschen.

 

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