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New Gene Research Grows Hair in Mice

Wig makers, tremble! Purveyors of hair restorer, whether F.D.A.-approved or purest snake-oil, brush up on bankruptcy law! Messrs. Michael Milken, Ted Danson, Marv Albert and all hairpiece wearers; Governor Ventura and the proudly bald, and all those about to become so — listen carefully, for a sudden ray of hope is playing upon all your shining pates!

The new herald of hirsuteness is no mere cream or chemical but a gene with the strange and potent name of Sonic hedgehog. Known to gene jockeys by its acronym SHH, it is not unworthy of silent awe. SHH is a master sculptor of the human body. In the growing embryo it divides the brain into segments. Too little SHH can cause cyclopia, an undivided brain with a single central eye, a condition named after the terrible cyclops who imprisoned Odysseus and devoured his men.

After its demiurgic role in the fetus, Sonic hedgehog plays a sort of retirement role in the adult body, that of shepherding the hair follicles through their cycles of growth, regression and rest. In the bald, the 100,000 hair follicles with which everyone is born are not dead but merely stuck in rest phase or producing a patchy lawn of much thinner hairs.

So there is much reason for interest in a feat by gene therapists at the Weill Medical College of Cornell University in New York, led by Ronald G. Crystal. In the latest issue of The Journal of Clinical Investigation, they report that they have forced resting hair follicles of mice into their growth phase by exposing the cells to the activity of the Sonic hedgehog gene.

Although no experiments have yet been done in people, there seems a reasonable chance that Sonic hedgehog, or related genes, might jump-start the resting human hair follicles on bald pates from their regrettable and inexplicable torpor.

“I would say it would be very exciting to try this in humans,” said Dr. Anthony E. Oro, a dermatologist at Stanford University.

Dr. Ervin Epstein, a dermatologist at the University of California at San Francisco, said of the Sonic hedgehog treatment, “There is reasonable hope it would drive hairs that are resting into active phase earlier than otherwise.”

The effect might or might not be cosmetically useful, Dr. Epstein said, but Sonic hedgehog certainly seems to be one of the factors that trigger hair to start growing. “So my guess is that maybe someday we will be using Sonic hedgehog as part of a cocktail of growth factors to make hair grow,” Dr. Epstein said.

Dr. Crystal and his colleagues Noboru Sato and Philip L. Leopold used an adenovirus, one of the viruses that cause the common cold, to insert the Sonic hedgehog gene into the mouse’s follicle cells. Because viruses can penetrate a cell and force it to make the products of the genes they carry, these infectious agents are useful vehicles for the genes of interest to gene therapists. Dr. Crystal’s team stripped out the genes that allow the virus to replicate and replaced them with a copy of Sonic hedgehog.

The virus was injected into young mice whose hair follicles had just entered their resting phase. To distinguish any unusual hair growth that the gene might cause, Dr. Crystal acquired an unusual scientific reagent, Clairol blond hair dye, from a nearby beauty parlor and bleached the mice blond. A few days later, vigorous tufts of black hair — the mice’s natural color — started to sprout around the sites where the virus had been injected.

Analysis of the follicle cells showed the Sonic hedgehog gene was active in the injected areas of the skin but not elsewhere.

Dr. Crystal’s experiment seems to show that the cells infected with Sonic hedgehog were forced into their growth phase ahead of the surrounding follicle cells, which remained in the resting state.

If the therapy works in humans too, a person would presumably need to have multiple injections over the scalp. Sonic hedgehog, and whatever other genes might be required, would have to induce thick enough hairs to be cosmetically significant.

But the injections would probably not need to be repeated until the follicles’ next cycle.

Human hair follicles take roughly four years to pass through one turn of the growth-regression-rest phases, although the cycles shorten with age, which is why teen-agers can grow very long hair more easily than older people. But unlike in mice, whose hair follicles cycle all in lockstep, the cycles of human follicles are unsynchronized, which could in some cases complicate treatment.

Many problems remain to be solved, however, before any clinical trial could be contemplated. Dr. Epstein has shown that over activity of Sonic hedgehog is the cause of basal cell carcinoma, a common though treatable human skin cancer. Although Dr. Crystal’s treatment gives a very small dose of Sonic hedgehog, and he saw no sign of basal cell carcinoma, the safety of the technique remains to be established.

A question mark, maybe momentary, has also arisen over adenovirus after the death last month of a patient who received a high dose of the virus in a gene therapy trial at the University of Pennsylvania. Other viruses, however, could easily be developed to insert the Sonic hedgehog gene, Dr. Crystal said.

It would be strange if gene therapy, a heavy-duty technique being developed to treat cancer and other difficult diseases, should lead to something as cosmetic as hair restoration among its first major applications.

Dr. Crystal, himself a gene therapist who works on cystic fibrosis and heart disease, is diffident about the hair restoration question. He stresses the interest of his finding for understanding the basic biology of the hair follicle, and says its possible practical value should first be explored for treating patients who have lost their hair from chemotherapy.

Dr. Crystal was trained as a nuclear physicist but developed an interest in the physiology of the heart and switched into medical school. He is a pioneer of gene therapy, having worked in the field since 1985.

He became interested in hair follicle growth as a way of making a virtue out of necessity. Corrective genes carried into the body by adenovirus enjoy only a brief spurt of activity before their host cells are zapped by the body’s immune system, which can detect the adenovirus lurking within. Dr. Crystal found he could insert the correct gene to treat cystic fibrosis, but it was active in patients for too short a time to be clinically effective.

So he began looking for therapeutic genes so powerful that clinically useful doses might be delivered during adenovirus’s brief lifetime in the body, a quest that led him to Sonic hedgehog.

The gene was first discovered by biologists who noticed that fruit-fly embryos lacking the gene would fail to form proper segments and assumed a scrunched-up, hedgehog-like appearance. Mammalian counterparts of the hedgehog gene were quickly found, one of which was named Sonic, after Sonic the Hedgehog, a hero of a Sega video game.

The Sonic hedgehog gene has been patented by others, but Cornell University has applied for a use patent, covering the gene’s possible role in treating hair loss.



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