Gene That Determines Gender Reportedly Discovered : Science: Work by British geneticists could eventually lead to insights on how to treat cancer and other diseases.

For the second time in three years, geneticists say they have found the single gene that causes a developing fetus to become a male.

This time they may be correct.

In the absence of this gene, an embryo develops into a female. When the gene is present, however, it triggers the formation of testes, which in turn initiate a complex hormonal chain reaction that eventually completes the development of a male.

Researchers hope the discovery of the gene will lead to new insights about how, starting in the seventh week of gestation, unspecialized tissues in the embryo grow into the highly specialized genitals. By studying the gene, they also expect to learn how other cells grow into specialized organs such as the heart, muscles and brain.

In addition, the discovery promises new information about the processes by which key genes in the body are turned on and off at appropriate times. Such insight could be extremely valuable in treating cancer and other diseases in which genes are turned on, or activated, when they should not be, as well as others, such as anemias, in which genes are not turned on when they should be.

“This discovery is likely to be a landmark that will be remembered for a long time in the development of science,” said John Maddox, editor of the journal Nature, which will publish the report today by geneticist Peter N. Goodfellow and his colleagues at the Imperial Cancer Research Fund in London.

Human cells contain 46 chromosomes--23 pairs--that contain all the genetic information necessary to construct a human. Two of those chromosomes, called X and Y, are sex chromosomes.

At conception, each embryo gets an X chromosome from its mother and either an X or a Y chromosome from its father. In 1959, scientists discovered that the Y chromosome controls sexual development: XX embryos are female, XY are male.

But exceptions occur. Geneticists have found a small number of XY women and XX men. These otherwise normal individuals share one common trait--they are infertile.

Unraveling the origin of these unusual individuals provided the pathway by which the male gene was ultimately discovered.

In the mid-1980s, geneticist David C. Page of the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology discovered that during the production of sperm, occasionally a small segment of the Y chromosome containing the male-determining gene would accidentally be inserted into an X chromosome.

The infant who received that X chromosome would thus be a male, even though he was XX instead of the normal XY. Similarly, an infant who received the other portion of the Y chromosome from which the gene had been deleted would be female, even though she was XY instead of the normal XX.

Studying blood and skin cells from more than 100 men and women identified by fertility clinics as being XX males and XY females, Page found the specific fragment of the Y chromosome that must contain the male gene.

The discovery triggered a trans-Atlantic race, with Page and Goodfellow, among others, frantically searching along the fragment for the gene. Because of the way they were conducting their respective searches, Page started at one end of the fragment and Goodfellow at the other.

In December, 1987, Page announced to much fanfare that he had a candidate for the gene. The most important evidence supporting its candidacy was that the gene was “turned on” only in testes and that a comparable gene was present on the Y chromosome of every animal species Page tested.

The discovery quickly found its way into textbooks as established fact and Goodfellow suspended his own search to study Page’s gene, which became known as ZFY.

But then contradictory evidence began to appear. Efforts by Page and others to transplant ZFY into female embryos inexplicably did not produce males. Even more disturbing, studies of marsupial animals, such as the kangaroo, showed that their counterpart of ZFY was not located on the sex chromosome, but on an ordinary chromosome.

The killing blow came in December when Goodfellow and his colleagues reported the discovery of two new XX males who did not carry the ZFY gene at all, indicating that some other gene must determine maleness.

Study of these XX males allowed Goodfellow to discover the male-determining gene. Ironically, the gene was located right next to the spot where Goodfellow had been searching when Page made his erroneous announcement. Had he kept searching, he would have found the new gene, which he calls SRY (for sex-determining region Y) almost immediately.

Page conceded that SRY is a good candidate, but he noted that the two XX males had only partially masculine characteristics. He now believes, he said, that both ZFY and SRY are required to make a male and that the interaction may be more complex than previously believed.

In any case, the British group is being circumspect. “We’re not actually saying it is the correct one, but it is by far the best candidate that’s come along,” geneticist Andrew H. Sinclair of the Imperial Fund said in a telephone interview.

Other observers are more confident, however. Molecular biologist Robin Lovell-Badge of the National Institute for Medical Research in London reports in the same issue of Nature that the SRY gene is turned on in mice at exactly the time when male and female development begins following separate paths.

“I’d bet on it (being the correct gene),” said geneticist Anne McLaren of University College in London.

The finding has no immediate practical application, such as for parents wishing to select the sex of an offspring or to learn the sex of a fetus. Better ways to determine the sex of a fetus are already available, scientists say, and the prospects for altering genes in humans lie in the far-distant future.

But because researchers know that this gene does turn on the genes that control testis formation, they hope that studying it will enable them to learn how to turn other genes on and off. That would make a major contribution toward therapy of many diseases.