Biology of Sex and Gender

The Biology of Sex and Gender

An Interview with Eric Vilain, MD, PhD

This is an excerpt from the full interview which discusses advanced biology and how sex and brain differentiation in foetal development is not as straightforward as once thought. The full interview can be read at

What was the significance of the Joan/John case?

the biology of gender identity - 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?

the role of oestrogen in gender identityHormones 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.

An excerpt from an interview with Eric Vilain, MD, PhD
The full interview can be found at

1,434 total views, 1 views today

Leave a Reply

Your e-mail address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.