It's A Boy, and Here's Why

By MICHAEL D. LEMONICK

Ever since the time of Aristotle, scientists have been puzzled by exactly what determines whether a baby is a boy or a girl. Last week the ancient mystery appeared to have been unlocked. A nine-member team led by a geneticist at the Whitehead Institute for Biomedical Research in Cambridge, Mass., announced that an infant's sex seems to be fixed by a single gene called testis determining factor, or TDF. The discovery, declared Whitehead's director, Nobel Laureate David Baltimore, was the result of a "landmark set of experiments."

In the seventh week of embryonic growth, reported Chief Researcher David Page, the presence of the TDF gene appears to launch a process that leads to male sexual development; without it, the fetus will be female. The scientists, whose findings appear in the Dec. 24 issue of the journal Cell, caution that the evidence is still circumstantial, and the discovery will have no immediate application. Even so, says UCLA Geneticist Larry Shapiro, "they have begun to unravel one of the most complex mysteries of biology. We have a long way to go, but this is certainly a major step along the way."

Aristotle theorized that the father's degree of arousal during intercourse determined the offspring's sex; great excitement, he reasoned, produced a boy. In the 1920s, scientists confirmed the existence of human sex chromosomes, two of the 46 chromosomes people normally carry. Ordinarily, women have two X chromosomes, whereas men have an X and a Y. In 1959 the sex determining factor was traced to the Y chromosome. But it was still unclear whether the "switch" consisted of one gene or many.

To find out how sexual differentiation works, Page and his team decided in 1981 to study the sex chromosomes of people who are genetically abnormal: men with two X chromosomes and women with an X and a Y. Despite the genetic reversal, the XX men and XY women, although infertile, appeared normal. The scientists showed that one X chromosome in these men always had a tiny bit of Y attached, while the women's Y chromosomes always lacked that same tiny bit. The TDF gene, they figured, must be contained in that fragment, which sometimes breaks off from the Y.

Finding the suspect gene took 18 months of painstaking analysis. It was, Page says, "like seeing a brick wall and piecing it together brick by brick." After pinpointing the TDF gene, Page used computer analysis to hypothesize how it works. The suspicion is that TDF triggers the production of a protein that signals other genes to induce maleness.

"Perhaps the most important result of this research," says Peter Goodfellow, of London's Imperial Cancer Research Fund, whose lab had predicted the gene's location, "is that it could provide a model system for development in general." Explains UCLA's Shapiro: "It's not just a question of triggering the growth of gonads. It's how a cell decides whether it becomes a muscle cell or a skin cell."

To confirm their findings, the researchers must see whether inserting the TDF gene in a fertilized mouse egg will transform a female embryo into a male. If so, Goodfellow says, this knowledge may eventually enable researchers to predict and "program" sex ratios in livestock. But for now, talk about future applications pales next to the excitement of the discovery.

With reporting by Andrea Dorfman/New York and Dick Thompson/Washington