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.

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