SCIENCE / MEDICINE : Sex Determinant: Hypothesis That Went Wrong : Genetics: Theory on what makes boys or girls was so good that it was taken as fact by many until further research found too many loopholes.
On the corner of Dr. David Page’s desk rests a foot-high stack of newly published genetics textbooks. They matter-of-factly describe the location of the sex-determining factor, the single gene that settles the question of whether a fertilized egg will be a boy or a girl.
The gene was Page’s discovery. Its rapid rise to the status of accepted wisdom is hardly a surprise, for when he revealed it at a news conference, the announcement was a major event in the world of genetics.
Isolating the gene was a milestone in basic biology, the prize in an exhausting race and the kind of achievement on which distinguished careers are built, clearly a breakthrough in a field that uses the word sparingly.
Or so it seemed.
The story was simple: One tiny bit of genetic code rules gender. If we have it at the moment we are conceived, we will be male. If not, we’ll be female.
Just two years after Page’s announcement, the precise location of the sex-determining factor is a mystery again. The gene he found, while interesting and probably important, is almost certainly not it.
The case illustrates the skittish and often whimsical way science moves. Rather than flowing forward in a neat, sane way, facts--and theories cobbled together to fit them--emerge in a jerky tango of discovery and setback. A new set of lab results can turn breathtaking insight to smoke.
Page is a staff scientist at the Whitehead Institute, an elite center for genetics research across the street from Massachusetts Institute of Technology. While still in training at MIT, he used to smile at a cartoon on a biology professor’s door: “Theory, like mist on eyeglasses, obscures vision.”
Page’s theory, accepted by many, is now in a shambles. But it is not the first time people have been wrong about the location of the sex-determining factor. A decade ago, many believed it was a gene called H-Y, and some textbooks still state this unequivocally.
Page’s quest to find the sex switch began in 1982. Like others, he tried to track it down by a process of elimination.
Everyone is born with 46 strings of genes called chromosomes. Two of these, called X and Y, are the sex chromosomes. Women have two Xs, while men have an X and a Y. Scientists reason that the gene that makes men different from women must be located someplace on the Y.
Page and others have concentrated on apparent exceptions to the rule, so-called XX males. To all outward appearances, these people are physically normal men. But their cells contain the double Xs of women. Through a genetic mix-up, one of their Xs contains a tiny fragment of Y, enough to make them men.
Among those he studied was an XX man with just half of 1% of a Y chromosome. Within this bit of DNA he found a gene that was shared by other XX males. He postulated this was TDF, testis-determining factor--the sex switch.
His description of the gene and his idea of what it did were published in December, 1987, in the journal Cell. It was a depressing moment for Dr. Peter N. Goodfellow at the Imperial Cancer Research Fund in London, whose team was just a few months from making the same discovery.
Page was almost certain he had correctly identified TDF but remembers feeling uneasy when colleagues flashed slides during lectures that confidently called it that. “You try as hard as you can to say that something is a working hypothesis, and it gets boiled down, even in a textbook, to established fact.”
To be on the safe side, he named his gene ZFY, or Y-linked zinc finger protein, a reference to the kind of chemical structure it makes. Then he and other scientists searched for evidence that ZFY is TDF. But when new pieces of the puzzle emerged, they did not quite fit.
“If you get something that is right, more and more things start clicking into place,” Goodfellow said. “What happened with the ZFY story is that it didn’t get stronger and stronger.”
Among the conflicting details:
--Page knew from the start that there was a related gene on the X chromosome. But when its structure was decoded, it was disquietingly like ZFY. If ZFY is uniquely male, why would females have a very similar gene?
* All mammals have their own version of ZFY. But among the marsupials, such as kangaroo, the gene is not on the Y chromosome at all; it lies on one of the non-sex chromosomes that presumably has nothing to do with sex determination.
* Other XX males turned up who did not carry ZFY.
* In mouse embryos, the gene did not seem to be doing anything at the time when sex is determined.
* Efforts to transplant ZFY into female embryos did not produce male mice.
Alone, any of these tidbits could be explained away. Maybe the male mouse embryos were not producing the ZFY protein because scientists were looking for it after the gene had already turned itself on and off. Maybe marsupials and their distant relatives among placental mammals have simply evolved different means of sex determination. Together, though, the tidbits raised doubts.
“As the data accumulated, it seemed to be more and more puzzling how it could be the sex-determining gene,” said Benjamin Lewin, editor of Cell.
The breaking point for Page’s model came with a paper in December in the journal Nature. Goodfellow had found four XX males who carried a bit of the Y chromosome, but not the part with ZFY on it. He argued that somewhere in the fragment they shared was the true sex-determining factor.
While Page was unmoved by the earlier skepticism over ZFY, Goodfellow’s discovery was a shock. “It hit me, sure, in part because I did not know this was coming until it was published.” He could dismiss the other evidence as circumstantial, but Goodfellow had used precisely the same line of reasoning to attack ZFY’s role as Page had used to support it.
“This makes it clear that ZFY is not the only sex-determining function on the Y,” Page said. “It’s possible that ZFY has little, if anything, to do with sex determination.”
Goodfellow is not gloating. If he had found ZFY first, he said, he would have written the paper Page wrote.
