About one in 4,500 babies show ambiguous genitalia at birth, such as a clitoris that looks like a penis, or vice versa. For the Insights story, "Going Beyond X and Y," appearing in the June 2007 issue of Scientific American, Sally Lehrman talked with noted geneticist Eric Vilain of the University of California, Los Angeles, about the biology of sex determination, gender identity and the psychology and politics behind both. Here is an expanded interview.

When did you first discover your interest in intersex individuals and the biology of sex development?

I started in Paris as a medical student, and my first assignment was to a unit of pediatric endocrinology in a Paris hospital, and it was the center of reference for all of France for babies born with ambiguous genitals. And I was actually literally shocked by the way decisions were made on these patients. I felt it didn't rely on solid scientific evidence. I mean, I'm a scientist, I'm a big believer of you can't just do things without being supported by evidence. In this case it was more like people would say it was just common sense—if the clitoris sticks out this much, you have to fix it. Or if the penis is really too small, it has to be bigger. Otherwise what life is this child going to have? And you know, I was never convinced by common sense. I kept asking, "How do you know?" There was no good answer to that.

There were a lot of patients and it was always the same discussions. And it was mainly about clitoral reduction.

So there were sexual politics there, too?

Yes. I was reading at the time this book by Michel Foucault. He has book that's called Herculine Barbin. He basically tells the story of this girl who clearly has a large clitoris. She goes and gets sexually aroused as she sleeps in the bed of other girls, as it was normal for girls to do. She goes to this religious institution for girls until eventually someone finds out, and then it's a big scandal. She becomes a pariah, and she ends up committing suicide. I was reading that, I was pretty young, I was like 18.

Defining normality has always been an obsession of mine. How do you define what's abnormal versus normal? I guess it's the philosophical roots of the French educational system.

But why choose to study intersex questions for the rest of your career?

My scientific inclination was excited by this because not only was it understanding a rare condition that makes people different, all of these social aspects, but also it has scientific implications in the basic biology of developing male or female. Always in biology, you want to look at the exception to understand the general. So understanding intersex individuals makes us understand how typical males and typical females do develop.

So what has your research overall been able to say about sex development?

We've identified new molecular mechanisms of sex determination. In particular we've discovered genes, such as WNT4, that's female-specific and not present in males, and that's sort of shifted the paradigm of making a male as just activation of a bunch of male genes. In fact it's probably more complicated. What we've shown is that making a male, yes, is activating some male genes, but it's also inhibiting some antimale genes. It's a much more complex network, a delicate dance between pro-male and antimale molecules. And these antimale molecules may be pro-female, though that's harder to prove.

It sounds as if you are describing a shift from the prevailing view that female development is a default molecular pathway to active pro-male and antimale pathways. Are there also pro-female and antifemale pathways?

Modern sex determination started at the end of the 1940s—1947—when the French physiologist Alfred Jost said it's the testis that is determining sex. Having a testis determines maleness, not having a testis determines femaleness. The ovary is not sex-determining. It will not influence the development of the external genitalia. Now in 1959 when the karyotype of Klinefelter [a male who is XXY] and Turner [a female who has one X] syndromes was discovered, it became clear that in humans it was the presence or the absence of the Y chromosome that's sex determining. Because all Klinefelters that have a Y are male, whereas Turners, who have no Y, are females. So it's not a dosage or the number of X's, it's really the presence or absence of the Y.

So if you combine those two paradigms, you end up having a molecular basis that's likely to be a factor, a gene, that's a testis-determining factor, and that's the sex-determining gene. So the field based on that is really oriented towards findingtestis-determining factors. What we discovered, though, was not just pro-testis determining factors. There are a number of factors that are there, like WNT4, like DAX1, whose function is to counterbalance the male pathway.

Why are genes such as WNT4 and others necessary for sex development?

I don't know why it's necessary, but if they're doing this then probably they're here to do some fine-tuning at the molecular level. But these antimale genes may be responsible for the development of the ovary. And WNT4 is likely to be such a factor. It's an ovarian marker now, we know. But if you have an excess of WNT4, too much WNT4 in an XY, you're going to feminize the XY individual.

Is the conceptual framework for sex determination changing, then, because of these discoveries?

I think the frame has slightly changed in the sense that even though it's still considered that the ovary is the default pathway, it's not seen as the passive pathway. It's still "default" in the sense that if you don't have the Y chromosome, if you don't haveSRY, the ovary will develop. [SRY, or sex-determining region Y, encodes the so-called testis determining factor.] That's probably the new thing in the past 10 years, that there are genes that are essential to make a functioning ovary. That really has changed, and WNT4 is one of the reasons for it.

What do you feel are your group's most important contributions to the sex biology field so far?

The two things that we contributed was, one, to find the genes that are antimale, and reframing the view of the female pathway from passive to active. And the second thing is in the brain. We're the first ones to show that there were genes involved in brain sexual differentiation, making the brain either male or female, that were active completely independently from hormones. Those were probably our two main contributions.

Do you think this difference in gene expression in the brain explains anything about gender identity?

About identity, it says nothing [yet]. It might say something. So those genes are differentially expressed between males and females early during development. They're certainly good candidates to look at to be influencing gender identity, but they're just goodcandidates.

At a recent international meeting to discuss management of people with genital and gonadal abnormalities, you successfully pushed for a change in nomenclature. Instead of using terms such as "hermaphrodite" or even "intersex," you recommended that the field use specific diagnoses under the term, "disorders of sex development." Why did you and other geneticists feel a nomenclature change was necessary?

For the past 15 to 16 years now, there really has been an explosion in the genetic knowledge of sex determination. And the question being, how can we translate this genetic knowledge into clinical practice? So we said maybe we should have a fresh approach to this.

The initial agenda was to have a nomenclature that was robust but flexible enough to incorporate new genetic knowledge. Then we realized there were other problems that were in fact not really genetic, but that genetics could actually answer them. Ultimately individuals who are intersex will each have their diagnosis with a genetic name. It's not going to be some big, all-encompassing category, like "male hermaphrodites." And that's much more scientific, it's much more individualized, if you will. It's much more medical.

How did the conference participants respond to the proposal?

The majority of health care professionals were very happy with it. There were some, there was a conservative side that said, "Why change something that was working?" There was significant minority dissent that was saying, "Why do we care?" Because it was working, for us it's an intellectual frame that has worked. So it required a little bit of education, saying, you know, it's important not only because it's more precise and it's more scientific, but also the patients would benefit from it by removing the word "hermaphrodite" and so forth. About the change to disorders of sex development, there was no issue at all in the group.

Why is the medical emphasis of this new term problematic for some?

The one piece in the nomenclature that remains highly controversial is the replacement of "intersex" with "disorders of sex development." And I'll say a few things about that. One is that intersex was big. Sometimes we wouldn't know who to include and who not to include.

"Intersex" was vague and "disorders of sex development" at least is a very medical definition, so we know exactly what we're talking about. For instance, if there are chromosomal abnormalities, if you have a patient who is missing one X chromosome—Turner syndrome—or having an extra X—Klinefelter's syndrome—both those, now wedo include them in "disorders of sexual development." They're not ambiguous. They do belong in this large category of people with "medical problems," quote-unquote, of the reproductive system. So intersex was vague, DSD is not vague.

What were some of the social issues you were trying to address?

There was another issue with the old nomenclature, which was the actual word, "hermaphrodite." "Hermaphrodite" was perceived by adult intersex individuals as demeaning. It also had some sexual connotation that would attract a flurry of people who have all sorts of fetishes, and so the intersex community really wanted to get rid of the term.

Cheryl Chase, executive director of the Intersex Society of North America (ISNA), said she has been promoting a nomenclature change for some time. Why?

People like Cheryl would say intersex issues are not issues of gender identity, they are just issues of quality of life—whether early genital surgery was performed appropriately or not, and that's really what has impaired our quality of life. She and others at ISNA do support the change because of an interesting side effect—because it becomes a very medicalized definition, the medical science should apply. It should apply strongly. That means it's not as if now we're talking about something that's not a disorder, that is just a normal variant, a condition. If it's just a condition that's a normal condition, then there is no need for medical attention.

So basically my point of view is really, let's separate the political from the medical, the science. There's a whole psychology to this, you know, the surgeons often are under the impression that there is this tiny, vocal minority of activists who just want to destroy their work.

Intersex individuals are really distinct from, for instance, the gay and lesbian community that does not have any a priori medical issue, there is no difference in the development of any of the organs, or they don't need to see a doctor when they're a newborn. I think it's quite different. Sure, some intersex are gay or lesbians, but not all are.

Why was it necessary for intersex individuals to take an activist stance at one time?

Because otherwise nothing would have changed in the practice. Otherwise this consensus conference would just not have happened. It was really in response to activism. They put the problem on the table and it required, it really forced the medical community to address an issue that was rare enough not to be addressed.

Some have called the new term a political setback, because it pathologizes what could be seen as normal human variation.

First of all, we can call normal variants everything; we can call cancer a normal variant. Of course, it kills you in the end, but it is a normal variant. We can play with words like that, but for practical purposes these "normal variants" have a lot of health risks that require lots of visits to the doctor for a bunch of issues that intersex patients have: fertility issues, cancer issues (the testis inside the body can increase the risk of cancer), sexual health issues. So if you're to start going to the doctor a lot for your condition, you can call it a normal variant, but that's not really useful. You're calling it a normal variant for political purposes. I'm calling it a disorder because I want all the rules and the wisdom of modern medical practices to be applied to the intersex field. I don't want intersex to be an exception: To say, "Um, you know, it's not really a disease," so therefore [physicians] can do whatever they want. That's what has been driving this field, people saying, well, you know, we can experiment, it's a normal variant.

There has been considerable controversy over whether surgeons should immediately make a decision about an infant's sex and quickly correct ambiguous genitalia. The consensus statement seems to promote a more cautious approach to surgery, while still assigning gender rapidly. What is your view?

I'm saying intervene [with surgery] only if you've proven that intervention is actually of benefit to the patient. Not of benefit to the parent. Because you know that surgery is used a lot to help the parent psychologically. It's a quick fix, if you will. The child looks different, it's very distressing for everyone, and one way to make it go away is just to make the kid look like everyone else. And that's really psychological help for the parents. But that should not be a parameter for surgery. We're talking about psychological distress to the parents, and that should be treated appropriately by a psychologist or psychiatrist, but not by surgery of the child.

Do you think this consensus statement will change the common practice of performing sex-assignment surgery early on?

(laughing) Well, yes. See, the consensus statement is a house of cards. You build it once, and there's no one that really inhabits it; it can be destroyed. They're not guidelines. I think it will change, but it will require some additional work. One of the things I think should happen next is to have a few leading clinics actually apply all the consensus recommendations and then do studies showing whether they actually impact the health and the well-being of the patient. It's not easy to do, because some of the recommendations require money. Like saying, "We need a psychologist"—that's easier said than done. There's no funding for having a psychologist in all these clinics. So I think it will influence some things. For instance, the nomenclature will change. I get a lot of phone calls and e-mails from authors of major textbooks, they're going to change. Also from editors of journals who publish articles about intersex, so that's going to change. But will that change the general outcome of patients? I don't know. I hope so. I think it's a step in the right direction.

Many physicians and geneticists look at intersex simply as a medical condition that should be addressed. You seem to take patients' social and political concerns very seriously, too. Why?

I've always been interested in the fact that medicine is very normative, and reductionist—it reduces people to their pathologies….'' Medicine should be in the business of making people as a whole better, rather than just curing the disease. And anyway, I'm not the only one saying that. Actually, I always use cancer as an example. A lot of cancer doctors are very well aware of this. They're offering options that sometimes do not include treatment just because they're aware of the fact that the treatment would ruin the quality of life so much that it's just not worth it.

How do you handle working in a field that is so volatile socially and politically? Everything that you do, people jump on and make claims about sexuality or gender.

I interpret everything conservatively. You have to not make the mistake of overinterpreting anything. That's my way of trying to navigate that. You also have to be aware of the social sensibilities. You can't just have an autistic approach to it and say, I'm just going to ignore it completely. If you're aware of the social sensibilities, and if you don't overinterpret your data, you're in good shape.

How do you stay aware and informed?

Being part of ISNA is one way [as a member of its medical advisory board]. It forces me to listen to what the patients have to say, which is really not part of the medical culture, at least in this field. The way to assess the well-being of a patient is to really listen to what the patient has to say.