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DAVE鈥橲 reasons for seeking his first hair transplant were typical. The 26-year-old Internet consultant in Los Angeles wanted to feel confident dating, wanted to feel at the top of his game in a competitive workplace. Unfortunately his receding hairline had gotten worse lately-so bad he鈥檇 taken to wearing a baseball cap much of the time, and when he did take it off, people were surprised that he suddenly looked 10 years older.

Nine years later, Dave has had eight hair transplants at a total cost of $11,000. But instead of rejuvenating his pate, the trauma of repeated surgery killed many of the hair follicles. Now Dave just wishes he could hide the evidence that he ever had those operations.

鈥淚 don鈥檛 even have the option of shaving my head because of the scars,鈥� he says. 鈥淚 look like I was in a bad car accident.鈥�

Dave鈥檚 experience is far from unique (see 鈥淭ransplants unplugged,鈥�). In the quest for a full head of hair, each year hundreds of thousands of otherwise level-headed men subject themselves to costly procedures that at best can offer a little extra coverage, and at worst end in disappointment and disfigurement.

So what鈥檚 the answer? Hiding under a baseball cap forever? To date, science hasn鈥檛 exactly distinguished itself in the search for anything better. Neither of the two anti-baldness drugs currently approved by the US Food and Drug Administration will transform a comb-over into a mop. The best, finasteride, offers 50 per cent chance of a few extra hairs after one year of use, while it鈥檚 a mystery why minoxidil, originally sold as a treatment for blood pressure, works at all. So when scientists researching hair loss start talking optimistically about a new assault on baldness, about high-tech treatments ranging from gene creams to 鈥渃loned鈥� hair follicles, about making bald pates as outmoded as toothless gums and hearing trumpets, it鈥檚 hard not to be just a teeny bit sceptical. Nevertheless, this is what the experts are now saying. And this time there might even be something in it.

What鈥檚 changed is the unprecedented level of understanding that scientists are now acquiring about the causes of baldness. The new assault will be waged not with dubious tonics or hit-and-miss surgery but with drugs and therapies that target the actual genes, proteins and hormones that conspire to turn some men into slapheads.

鈥淥ver the next 10 years, we鈥檙e going to see a different approach to therapy,鈥� predicts Rodney Sinclair, a University of Melbourne dermatologist who is gearing up to run one of the largest ever efforts to track down genes that predispose men to baldness. 鈥淲e鈥檙e going to start seeing more gene-based treatments that will last longer and be more specific.鈥�

Multimillion-dollar research programmes committed to unraveling the mysteries of hair loss? The might of gene technology unleashed on a superficial problem like balding? Hair loss research, it seems, has transmogrified into a deadly serious business up there with curing cancer. Is it worth all the effort? The would-be patients certainly think it is.

鈥淚t鈥檚 amazing how important this is to many people,鈥� says Ron Crystal, director of the Institute of Genetic Medicine at Weill Cornell Medical College in New York City. 鈥淚 get two or three e-mails a week from men around the world, people who are really devastated by baldness, pleading for us to do something about it. People send me scanned pictures of their heads.鈥� Crystal is best known for his efforts to develop gene therapies for cancer and heart disease, but as a sideline he has also discovered a gene that makes hair grow-at least in mice.

About 15 per cent of men, like Dave, have lost an obvious amount of hair by 30, and 50 per cent have by 45. Usually it鈥檚 the classic male pattern baldness, which begins at the temples or crown and advances until all but the back of the head is bare. But what鈥檚 classic for human males is decidedly rare in the rest of the animal kingdom, with stump-tailed macaques being the only other primates to routinely suffer receding hairlines. Women also suffer age-related hair loss, but it is usually diffuse and far less dramatic than the male version.

As for the rest of the human body, it might look bare compared with most other mammals bar the naked mole rat, but in fact its whole surface is remarkably hirsute: five million hairs in total coat everything except the palms of our hands and feet. Like the peach fuzz on the tip of your nose, it鈥檚 mostly fine and very short hair, whereas the 100,000 hairs on your scalp are thicker, longer and darker- at least for the first few decades of life.

In an effort to solve the mystery of where it goes, hair loss researchers track individual follicles on the heads of balding men with all the single-mindedness of field biologists tracking endangered gorillas. Once a month, they photograph the same square centimetre of scalp and its hundred or so hair follicles, shave it, and then re-photograph it two days later.

Their research makes it quite clear that, contrary to expectations, baldness is not about having no hair-it is about having the wrong sort of hair. Each hair grows independently of the others. What鈥檚 more, its growth is far from constant. On average, a hair follicle on a non-balding head spends about 18 months growing, with the hair lengthening by about 0.4 millimetres per day. The hair-producing cells then die off and the follicle goes dormant for around six months, before eventually shedding its hair, sprouting a fresh one and entering a whole new growth phase. When a man goes bald, the fresh hairs become progressively finer and less coloured until they鈥檙e practically invisible, at which point the scalp looks bare.

But the man still has as many follicles as a hairy man, it鈥檚 just that the hairs have been miniaturised. There鈥檚 clearly something about certain follicles that make this happen. And now, with the help of some detailed computer modelling, Bruno Bernard, a biochemist at the L鈥橭real Hair Biology Research Group in Clichy, France, thinks he knows what it is.

In his view, each follicle is 鈥減rogrammed鈥� to go through a finite number of normal cycles, after which they run low on hair-producing cells and are able to produce only miniature hairs. But this alone doesn鈥檛 explain why some men go bald and others don鈥檛. So what does? The follicles of bald men go through just as many cycles as those of their richly maned counterparts, says Bernard. The problem, he suspects, is that they go through them much faster.

Sure enough, when Bernard looked at men鈥檚 scalps he found follicles in balding areas chewing rapidly through cycles, spending only six months actually growing. And the computer modelling cemented things. Teaming up with Albert Goldbeter, a mathematician at the Free University of Brussels, Bernard developed a set of equations that describe individual hairs going through a limited number of growth cycles at speeds typical of different parts of the head. The two researchers then applied their mathematical model to a theoretical head of 10,000 hairs and aged it by 25 years.

The model head lost hair on the crown, just as in a real man. The results, published last year, suggest Bernard鈥檚 hunch was correct: a variation in cycle speed can easily account for the classic pattern of male balding. But what shortens the hair cycle in the first place?

Hippocrates was probably on the right track 2400 years ago when he noted that eunuchs didn鈥檛 go bald. It turns out that hair loss usually only occurs if the scalp has a steady supply of the male hormone dihydrotestosterone or DHT. Castration removes a man鈥檚 main supply of this hormone. What鈥檚 more, although levels of DHT in the blood of balding men are the same as in hairy men, DHT levels in the follicles tend to be much higher in parts of the scalp that are going bald. This is because follicles in these areas have higher levels of the enzymes that manufacture DHT from testosterone.

It was against this backdrop that geneticists Stephen Harrap and Justine Ellis of the University of Melbourne went trawling for genes that cause baldness, hoping to find an entr茅e into the multibillion-dollar hair loss market. At first their nets came up empty-the genes for the enzymes that make DHT turned out to be innocent, as did several other long-suspected culprits.

Then, earlier this year, the two researchers discovered that baldies-almost to a man-have a particular version of a protein that carries DHT鈥檚 signal into the nucleus, compared with about three-quarters of the non-balding men. This suggests that you can鈥檛 go bald without this version of the carrier protein, but it clearly isn鈥檛 the sole cause, because so many hairy men have it too.

In the quest for a blockbuster anti-balding pill that wouldn鈥檛 have mattered if only the protein鈥檚 vital functions had been limited to the hair follicle. In fact the carrier protein is vital in many other parts of the body, ranging from muscles to vocal cords. 鈥淚f you interfere with it,鈥� says Sinclair, 鈥渢here鈥檚 a risk that you鈥檒l interfere with all male hormone functions in the body. It would be like creating a eunuch.鈥�

Still, Harrap and Ellis鈥檚 find looks set to put the search for baldness genes on track after years of floundering. Their gene resides on the X chromosome. That corroborates the old wives鈥� tale that men inherit their baldness from their mothers, but can鈥檛 explain the clinical studies that clearly show that in some families it鈥檚 bald fathers who sire bald sons. In other words, the new gene clearly shows that baldness can be inherited from your mother or your father-a revelation that gives researchers like Sinclair new leverage. Past efforts to find the genes may have got hopelessly muddled because the researchers unwittingly included men who inherited the two different types of baldness in the same study.

鈥淲e鈥檙e going back and looking for men who inherited it from their mother鈥檚 side, to give ourselves a better chance of finding the [other genes],鈥� says Sinclair. He is preparing to search for baldness genes among no fewer than 40,000 Australian men and women. And besides tracking down other DHT-related genes, he鈥檚 also going to look at a dozen or so 鈥減atterning鈥� genes.

As their name suggests, these give us our basic anatomy, ensuring for instance that an embryonic mouse or human grows the correct number of limbs in the correct places. They do this by ensuring that cells go down particular developmental pathways according to their position in the embryo. Genes that are associated with embryonic development may seem like strange candidates for underpinning a condition that usually hits in middle age, until you take into account a string of curious observations.

Firstly, infants (both girls and boys) born with a full head of hair often temporarily lose it in the classic male pattern soon after birth. Secondly, follicles on the back of an adult man鈥檚 head don鈥檛 miniaturise when they are moved to balding areas-the rationale behind hair transplants. In other words, there鈥檚 something about the original position of a follicle on the scalp that determines its growth pattern, and that鈥檚 determined by patterning genes very early in life.

But perhaps the best evidence for the role of patterning genes in baldness comes from studies of a gene called sonic hedgehog. It ensures that your developing brain divides into two hemispheres, and that you get two eyes and two front teeth rather than one, but it is also vital for the development of normal follicles. Mice that are genetically engineered to lack the gene die at birth, and they have follicles that are strangely distorted and lack some of the key cells needed to make a hair.

What鈥檚 more, sonic hedgehog also continues to play its 鈥渆mbryonic鈥� role throughout adult life. That鈥檚 probably because hair follicles are one of the few tissues-the lining of the uterus being another-that constantly die off, only to regenerate again and again. And as Crystal discovered in 1999, sonic hedgehog can kick-start hair growth even in adult mice. When he injected the gene into the skin of mice, the mice sprouted new hairs.

While sonic hedgehog seems like an obvious choice for gene therapy for baldness, you鈥檝e got to be careful, warns Crystal: too much of it causes tumours. Crystal knows how to attach the gene to a virus that could be used to deliver meagre doses every few months, thereby reducing that risk, but since he has bigger fish to fry-such as developing gene therapy against killer cancers-for now he鈥檚 leaving that for others to try.

And there are plenty of others positively salivating at how accessible hair follicles-unlike most organs-are to gene creams that could be slapped on like sunscreen. One researcher who鈥檚 keen to show that such an approach might work is Christopher Wraight, a biochemist at the Royal Children鈥檚 Hospital in Melbourne. He鈥檚 developing a gene cream for another skin disorder, psoriasis, in which cells proliferate madly. For now he鈥檚 shown that injecting the skin of mice with 鈥渁ntisense鈥� molecules-pieces of DNA that block gene signals-stops the out-of-control cell division, and he鈥檚 about to test an antisense cream. Wraight envisions the same approach being used for hair loss: an antisense cream that鈥檚 rubbed on daily could, for example, be used to block a gene that transmits DHT鈥檚 harmful signals to the cell nucleus without turning anyone into a eunuch.

But there鈥檚 a catch. Using a gene cream every single day would break the bank of all but the wealthiest bald men. One solution would be to synchronise all your hair follicles so that they enter their growth cycles en masse, which is the only time the progenitor cells can take in new genes. Then you鈥檇 simply apply your gene cream once and enjoy the rush that goes with having a full head of hair for the 18-month duration of the cycle.

And a drug capable of synchronising hair cycles is already available, points out George Cotsarelis, director of the University of Pennsylvania Hair and Scalp Clinic in Philadelphia: retinoic acid, which regulates cell division and is prescribed for acne. Using that pharmaceutical ploy, Cotsarelis has taken a giant step towards making gene therapy for baldness a reality. He has used a lotion to introduce 鈥渕arker鈥� genes into progenitor cells of synchronised hair follicles taken from a man鈥檚 head and implanted on the back of a mouse. Targeting genes specifically into the progenitor cells of a follicle is a tricky task-but if you can do it with a marker gene, you should be able to do it with any gene. 鈥淚t鈥檚 very important. It shows you can put [genes] where you want to, and not all over the skin,鈥� says Angela Christiano, a geneticist at Columbia University in New York, who works on hair loss.

But solve one problem and another rears its ugly head. At the beginning of those synchronised cycles you鈥檇 lose every hair on your scalp-a big downside for a man so devastated by hair loss that he feels compelled to use a treatment as radical as gene therapy. What鈥檚 more, Cotsarelis still has to test different genes to find out which ones will do the job best, and satisfy rigorous safety requirements. So it will be some time before such a therapy becomes available.

Still, if Cotsarelis succeeds, he could end up the Rupert Murdoch of hair restoration. 鈥淭here are drugs that haven鈥檛 been enormously successful, and they are still doing $400 million a year,鈥� points out Sinclair, referring to the hair-growth drugs minoxidil and finasteride.

For now, hair transplants remain the most effective treatment going, despite the fact that they suffer from one major limitation: the procedure doesn鈥檛 add new follicles, it just rearranges them. Christiano and Colin Jahoda of Durham University think they can get round this. They鈥檝e found that certain cells harvested from human follicles grow into entire new follicles if they鈥檙e implanted on a bare patch of skin, in a process dubbed 鈥渇ollicle cloning鈥� by an enthusiastic lay public. Unfortunately, getting enough cells to grow one new follicle means destroying 20 donor follicles. But if the researchers can multiply the cells they harvest by growing them in a test tube, which they鈥檙e now trying to do, they could create many new follicles from a single donor follicle.

鈥淐ellular therapies like this will be the next wave,鈥� predicts Christiano. 鈥淚t will take a lot longer to figure out rational drug targets that really work. These cellular techniques shouldn鈥檛 take as long.鈥�

And Christiano has a very personal stake in getting such techniques to work. She used to study genetic skin blistering diseases, but six years ago she abruptly switched her research interest when her waist-length brown locks began falling out for no apparent reason, and she was diagnosed with alopecia areata (see 鈥淏ald for a day鈥�).

鈥淚t was one of the first times I鈥檇 really been a patient with anything,鈥� she says, 鈥渁nd not only do they not know what causes it, but they can鈥檛 tell you if it鈥檚 going to get worse, better or stay the same. It was frustrating.鈥�

Clearly Christiano is not alone in her frustration. The voicemail greeting at her lab informs callers that she鈥檚 not a physician and isn鈥檛 conducting clinical trials, but she still gets up to 10 e-mails, calls and letters a week, including clinical histories and photos of scalps. 鈥淚 get whole bags of hair,鈥� she says. 鈥淭hey collect the hair in their brush, and in their drain, and send it every month with a note that says, 鈥業 hope this can help.'鈥�

And perhaps it will, by acting as one more spur to the research efforts that are beginning to hold promise that in the future men will have the option of keeping hold of their hair even as they struggle to keep hold of their Zimmer frames.