By David N. Leff

The first gene ever implicated in human baldness has just been discovered, with inputs from 78 Pakistani villagers, living and dead, plus numberless hairless mice.

Research dermatologist and geneticist Angela Christiano told a press conference Thursday at Columbia-Presbyterian Medical Center, in New York, "The discovery of this new gene gives us endless possibilities that may allow us to effectively treat hair loss, and possibly baldness, within the next five years."

Christiano is senior author of a paper in today's Science, dated Jan. 30, 1998, titled: "Alopecia universalis associated with a mutation in the human hairless gene."

Alopecia, of course, means baldness, a nonlethal but aggravating human disorder that comes in a spectrum of configurations:

* Alopecia universalis means what it says: total absence of head and body hair, not sparing eyebrows and eyelashes. Fortunately, it's a relatively rare syndrome.

* Androgenic alopecia, better known as male pattern baldness, is far from rare. It's believed to afflict 80 percent of the population, and has a hormonal (testosterone) etiology.

* Female pattern alopecia is a less-familiar subset of the androgenic hair dysfunction, usually reflected in thinning, rather than outright loss, of a woman's hair.

* A. areata is a patchy hair fallout from areas of the scalp, eyebrows and beard, often beginning in childhood. Some 2.5 million Americans have this trait, suspected to be caused by autoimmunity or stress.

Columbia's Christiano and her co-authors looked at the whole-body, billiard-ball baldness of A. universalis and reasoned that pinning down its genetic underpinning might well throw light on the other, less drastic forms of human hair loss. "It could be the trigger that turns on the entire human hair cycle," she suggested.

It Took A Village

Biologists at the Quald-l-Azam University, in Islamabad, Pakistan, came up with a village in which A. universalis had a far-from-rare prevalence. A single extended family of 78 members counted seven affected females and three males in six generations.

Genomic linkage analysis of the seven living affected members of this kindred and their close relatives revealed a likely gene locus on the short arm of chromosome 8.

To find the A. universalis gene sequence lurking inside this genomic hot spot, the team turned to a strain of extremely bald mice called hairless, and compared its gene with human chromosomes. Using PCR technology, the researchers cloned the entire construed coding sequence of human hairless from this murine model. The human hairless gene product consists of 1,189 amino acids, of which 80 percent are identical in both mammalian species, Homo sapiens and Mus musculus.

"With the hairless gene," Christiano told the media conference, "the real basis of hair loss can begin to be understood. We can now look at the cause -- the genes themselves -- with the understanding that hormones are important but not primary."

In mouse and human, hairless is expressed in the skin fibroblast cells from which hair follicles arise. But, the Science paper noted, the human gene is "most highly expressed in brain, where its importance remains unknown."

Having located and described the normal hair gene product, the Columbia-led team went on to track down its baldness-wreaking mutation.

Direct sequence analysis of a 1,039-amino-acid stretch of the protein revealed an adenine-to-thymine switch in the gene. This mutation occurred in all of the affected Pakistani villagers, showing they had inherited it from both parents. That is, they were homozygous for the mutant gene. It didn't show up at all in unaffected family members, but some relatives in between did carry the alteration, acquired from only one parent -- i.e., they were heterozygous -- with no signs of baldness.

Scientist Foresees A Hairier Future

As men in particular know too well, current remedies for lost hair run from disappointing to dismal. "Treatment for male pattern baldness," Christiano observed, "traditionally has focused on hormonal regulation of the hair follicle for regrowth of hair, yet none of these approaches has provided any relief without significant side effects.

"Hair follicles," she explained, "like all cells, have growth cycles. Our hairless gene finding is the first indication that we may be able to regulate that cycle, triggering the growth of new hair. It is now within our reach to design ways to grow hair, remove hair, even dye hair genetically and -- best yet -- this can all be accomplished topically, reducing possible side effects." She concluded: "It may be possible, for instance, to treat hair loss through gene therapy administered topically via the hair follicles."

Meanwhile, consumers in the U.S. alone spend $7 billion annually on products to treat their alopecia. These remedies run from prescription drugs to over-the-counter compounds to surgical implants to hair replacement to wigs.

Among the Science paper's 17 co-authors were two from Research Genetics Inc., of Huntsville, Ala., and one from FibroGen Inc., of South San Francisco. Both companies contributed, under contract, to the linkage analysis and sequencing work. *