When Eric Vilain began his medical school rotation two decades ago, he was assigned to France's reference center for babies with ambiguous genitalia. He watched as doctors at the Paris hospital would check an infant's endowment and quickly decide: boy or girl. Their own discomfort and social beliefs seemed to drive the choice, the young Vilain observed with shock. "I kept asking, 'How do you know?' " he recalls. After all, a baby's genitals might not match the reproductive organs inside.

By coincidence, Vilain was also reading the journals of Herculine Barbin, a 19th-century hermaphrodite. Her story of love and woe, edited by famed social constructionist Michel Foucault, sharpened his questions. He set on a path to find out what sexual "normality" really meant--and to find answers to the basic biology of sex differences.

Today the 40-year-old French native is one of a handful of geneticists on whom parents and doctors rely to explain how and why sex determination in an infant may have taken an unusual route. In his genetics laboratory at the University of California, Los Angeles, Vilain's findings have pushed the field toward not only improved technical understanding but more thoughtful treatment as well. "What really matters is what people feel they are in terms of gender, not what their family or doctors think they should be," Vilain says. Genital ambiguity occurs in an estimated one in 4,500 births, and problems such as undescended testes happen in one in 100. Altogether, hospitals across the U.S. perform about five sex-assignment surgeries every day.

Some of Vilain's work has helped topple ancient ideas about sex determination that lingered until very recently. Students have long learned in developmental biology that the male path of sex development is "active," driven by the presence of a Y chromosome. In contrast, the female pathway is passive, a default route. French physiologist Alfred Jost seemed to prove this idea in experiments done in the 1940s, in which castrated rabbit embryos developed into females.

 


Terms such as "hermaphrodite" and "intersex" are vague and hurtful Vilain says.


 

In 1990, while at the University of Cambridge, Peter Goodfellow discovered SRY, a gene on the Y chromosome hailed as the "master switch." Just one base pair change in this sequence would produce a female instead of a male. And when researchers integrated SRY into a mouse that was otherwise chromosomally female, an XX fetus developed as a male.

But studies by Vilain and others have shaped a more complex picture. Instead of turning on male development directly, SRY works by blocking an "antitestis" gene, he proposes. For one, males who have SRY but two female chromosomes range in characteristics from normal male to an ambiguous mix. In addition, test-tube studies have found that SRY can repress gene transcription, indicating that it operates through interference. Finally, in 1994, Vilain's group showed that a male could develop without the gene. Vilain offers a model in which sex emerges out of a delicate dance between a variety of promale, antimale, and possibly profemale genes.

Because researchers have long viewed the development of females as a default pathway, the study of profemale genes has taken a backseat. Over the past few years, though, geneticists have uncovered evidence for active female determination. DAX1, on the X chromosome, seems to start up the female pathway while inhibiting testis formation--unless the gene has already been blocked by SRY. With too much DAX1, a person with the XY complement is born a female. Vilain's group found that another gene, WNT4, operates in a similar way to promote the formation of a female. The researchers discovered that these two work together against SRY and other promale factors. "Ovary formation may be just as coordinated as testis determination, consistent with the existence of an ovarian switch,' " report geneticist David Schlessinger and his collaborators in a 2006 review in the journal Bioessays.

Lately Vilain has been exploring molecular determinants of sex within the brain and whether they may be linked to gender identity. Despite classic dogma, he is certain that sex hormones do not drive neural development and behavioral differences on their own. SRY is expressed in the brain, he points out, suggesting that genes influence brain sexual differentiation directly. His lab has identified in mice 50 new gene candidates on multiple chromosomes for differential sex expression. Seven of them begin operating differently in the brain before gonads form. Vilain's group is testing these findings using mice and is collaborating with a clinic in Australia to study expression patterns of the sex-specific genes in transsexual people.

This work, like much of Vilain's efforts, treads on fairly touchy ground. He copes by sticking to his findings conservatively. "You also have to be aware of the social sensibilities," he explains. Accordingly, he has come to agree with some gender activists that it is time to revamp the vocabulary used to describe ambiguously sexed babies.

At the 2005 Intersex Consensus Meeting in Chicago, he stood before a group of 50 geneticists, surgeons, psychologists and other specialists and argued that terms such as "hermaphrodite," male or female "pseudohermaphrodite" and "intersex" were vague and hurtful. Instead of focusing on a newborn's confusing mix of genitals and gonads, he urged his colleagues to let the explosion of new genetic findings point toward a more scientific approach. Rather than using "hermaphrodite," for instance, he recommended referring to a "disorder of sexual development" (DSD) and applying the more precise term of "ovatesticular DSD."

Although the attendees eventually concurred, not everyone likes the new terminology. Some who prefer "intersex" feel that a "disorder" is demeaning. Milton Diamond, who studies sex identity at the University of Hawaii, complains that it stigmatizes people who have nothing wrong with their bodies.

But the decision to change nomenclature realizes a 15-year dream for Cheryl Chase, executive director of the Intersex Society of North America (ISNA). Chase has fought for years against secret, rushed surgeries intended to comfort parents and adjust anatomy to match an assigned social gender. Recalling how a doctor once called her "formerly intersex," she hopes physicians will begin to see mixed sex characteristics as a lifelong medical condition instead of a problem to be quickly fixed. "Now that we've accomplished the name change, culture can accomplish a little magic for us," she predicts.

For her, Vilain has been a valued ally in the process as a member of ISNA's medical advisory board. The job, he admits, forces him to listen to patients, a practice he considers unusual for the field. He expects the new, medicalized terminology for DSD to have what he describes wryly as "an interesting side effect," in which "medical science should apply" to clinical decisions about ambiguous sex.

Indeed, the new consensus statement on managing intersex disorders encourages physicians to see beyond a patient's sex organs, agrees conference co-organizer Peter A. Lee. The statement, released last fall, recommends speedy gender assignment but a more cautious approach to surgery. The family should participate in decision making, along with a multidisciplinary team of caregivers in specialties that include psychology and ethics. But Lee, a pediatric endocrinologist at the Penn State College of Medicine, cautions that much more work lies ahead to fill in data gaps. For instance, physicians have not measured how their choices affect patients over a lifetime.

On one Friday afternoon Vilain's white coat and stethoscope lay tossed amid the papers on his desk, a reminder that his discoveries have more than philosophical meaning. He sees six to eight patients in the U.C.L.A. intersex clinic every month, and in his on-call capacity, he receives two calls about babies in the hospital within the space of a couple of hours. Even while immersed in the workings of DNA transcription, Vilain stays grounded in what his findings mean for people's lives.