Nothing reminds a man of his mortality more than a retreating hairline or the peach-fuzz feel of his thinning crown. For men entering middle age, effective ways to avoid hair loss can’t come soon enough. But balding has long proved a slippery foe for scientists. Despite decades of research, the fundamental biological mechanisms underlying it are not well understood. The question is whether there are any signs that this will change.

“For a long time there was a hiatus in term of coming up with new ideas,” says Angela Christiano of Columbia University in New York. “But right now is a really exciting time for the field.”

We have been pondering the causes of male-pattern baldness, also known as androgenetic alopecia, for centuries. The Greek philosopher Aristotle noticed that eunuchs don’t go bald. We now know this is because a by-product of the hormone testosterone – produced in the testicles – called DHT gradually shrinks hair follicles in the scalp, reducing the length and thickness of the fibers produced until they no longer breach the surface of the skin. Unfortunately, we don’t know much more than that.

There are hair loss treatments that have been approved by the US Food and Drug Administration, such as finasteride (Propecia) and minoxidil (Rogaine), which can prevent or slow hair loss in some men. Their virtues were discovered serendipitously, as side effects of drugs developed for other ailments. But right now there are no drugs that can reverse hair loss. To do that you need a hair transplant, an expensive and gorily invasive procedure in which fully functional follicles from the back of the scalp are relocated to desolate patches elsewhere.

The biology behind baldess may be complex, but the last few years has seen what could be described as hair-raising progress. In 2012, Luis Garza of Johns Hopkins University in Baltimore and colleagues discovered that a lipid compound called Prostaglandin D2 (PGD2) plays a key role in squeezing the life out of follicles. Gene expression analysis showed that PGD2 and the enzyme that makes it were far more abundant in balding than non-balding scalps. Most importantly, when the researchers added PGD2 to human follicles in a petri dish, hair growth was dramatically reduced.

The team also pinpointed the receptor on follicle cells to which PGD2 attaches to do its dastardly deed. In mice without the receptor, known as GPR44, PGD2 did not restrain hair growth. If the same is true in humans and we can figure out how to interrupt this mechanism – by either blocking the receptor or disabling the enzyme that makes PGD2 – we could put the brakes on hair loss. “We now have a very good target,” says Garza.

Drug promise

Conveniently enough, pharmaceutical companies are already testing drugs designed to block GPR44, as this has been implicated in allergic conditions such as asthma. That’s a great place to start, says Garza. But even if an existing compound blocks the version of the receptor on follicle cells and stops hair loss in lab-cultured follicles, the path to human trials is long and expensive.

What’s more, the PGD2 receptor may not be working alone. Instead, it may be just one of several agents that trigger follicle regression and it’s possible that it plays only a minor role. We won’t know how central PGD2’s role is until a treatment based on it is tested properly in humans because there are no animal models of male pattern baldness. “It’s got to be worth trying,” says Garza, “because a treatment for baldness that really worked would be an enormous blockbuster.”

It remains to be seen if restraining PGD2 can reverse balding and induce the growth of new hair in bald skin. If not, it won’t be much help to people who have already lost their hair. That’s why some scientists are trying to figure out how to make new hair follicles – a process known as follicular neogenesis.

One way to do that is to extract dermal papillae – skin cells that usually instruct surrounding cells to generate follicles – from a healthy patch of scalp, grow and multiply them in a dish, and then implant them into bald skin. The technique works a treat in rodents. But unfortunately when dermal papillae taken from humans are cultured in the lab, they quickly lose the ability to induce new follicles.

Perhaps the problem was the way they were grown. Earlier this year, a team led by Christiano found that in cells cultivated on a flat surface, the normal expression of almost 4,000 key genes was disrupted. However, she discovered that cultured dermal papillae maintain their ability to induce follicles if you grow them in hanging droplets of liquid nutrients instead.

Next the researchers implanted the cells into hairless human skin that had been grafted onto rats. Six weeks later, dermal papillae from five of seven donors had generated new follicles. In two cases, the follicles had begun to produce hairs.

This method restored the functioning of 22% of genes to normal. However to ensure the production of robust hairs, the researchers need to figure out how to restore the functioning of a greater proportion. Christiano’s team is now working on a chemical concoction that would do just that.

If they can reactivate even half of the genes, there is a good chance that the new follicles would make robust hairs and, crucially, have a normal growth-cycle – which means they would continue to produce hair after it naturally falls out. To avoid patients resembling crazed Barbie dolls, researchers must also develop an implant device that ensures follicles sprout hairs at an angle of 30-45 degrees to the scalp. 

End of transplants

Meanwhile, in an attempt to eliminate the need for transplants altogether, some groups are trying to trick skin cells into generating new follicles on the head. In 2007, George Cotsarelis of the University of Pennsylvania found that in mice, the wound-healing process reprograms skin cells to an embryonic state, providing a short window of time in which they can be enticed to become follicles. His team also identified a key chemical signalling mechanism behind the process. Blocking these signals in mice reduced the number of new follicles, whereas enhancing the signals increased follicle numbers.

Boston-based company called Follica has come up a treatment based on this discovery. It is tight-lipped on the details, but the basic idea is to use a proprietary device that removes the top layer of skin to turn the clock back on skin cells, before applying a cocktail of chemicals. Follica claims its tests show the process has been shown to consistently create new follicles in humans, however the research is unpublished.

Then, last year, Cotsarelis revealed that a protein called FGF9 plays an important role in persuading skin cells to transform into follicles in wounded mice, apparently by amplifying the molecular signals that kick-start the process. If it has the same effect in humans, the protein could make Follica’s therapy even more effective. “The nice thing about the FGF9 story is that it sets off a cascade of events that lead to hair follicle formation,” says Cotsarelis.

Balding is perhaps top of the list of the triggers for the infamous mid-life crisis – when men are said to try to recapture their youth by splashing out on Ferraris and ill-advised tattoos. Recent insights do offer new shoots of hope for more effective future treatments. For now however, the biology of hair loss and development remains mysterious. Luxury car dealerships and tattoo parlours that rely on a steady stream of men thinning on top need not fear for their incomes, for the next few years at least.

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