MENTION dance competitions to Kristy Bain, a 26-year-old advertising executive living in Sydney, Australia, and it brings back some bad memories. As a 10-year-old she regularly attended jazz ballet classes. Before her troupe took part in a major national contest, her teacher had the bright idea of buying some tanning pills and feeding them to the whole class, thinking they would look tanned and healthy in their leotards.
The effect, however, was anything but attractive. “Everything went orange – even the palms of our hands,” recalls Bain. “Our knees were bright orange, like one of those safety jackets. We stuck out like sore thumbs.”
Fortunately for Bain and her friends, the pills had no lasting effect. But they were never going to produce a real tan. The pills would have contained carotenoids, the family of chemicals that make carrots orange and tomatoes red. These compounds have no effect on skin cells, but at high enough doses they are stored in fat layers beneath the skin, turning it not golden brown, but orange.
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Carotenoid supplements are not the only products to have been sold as tanning drugs over the years, but the others either don’t work, or worse, present serious health hazards. Of course, there are fake-tan lotions that stain the skin brown, but these can be messy and time-consuming to use, and some people feel the effect looks unnatural.
But if pale and interesting doesn’t cut it for you, don’t give up hope just yet. The past decade has seen a slow blossoming of serious research into new ways to pharmacologically stimulate the biological processes involved in tanning, and to block the collateral damage that is part and parcel of exposure to the sun.
On the face of it researchers have worthier aims than pandering to people’s vanity. Their products could help people with a genuine medical need for the protection afforded by a suntan. For example, they could cut the risk of skin cancer for fair-skinned people in places like Australia, which would be good news for those who work outdoors, as well as beach bunnies. The products could also be a boon for people with medical conditions that make them susceptible to skin cancer, such as organ transplant recipients.
But just as Botox was originally launched as a medical therapy and then became hugely popular as a beauty treatment, any genuine tanning drug could explode onto the cosmetic market. The products still have several years of clinical trials ahead of them, but if they pass these tests, we should finally have that elusive natural tan in a bottle.
So why has it taken so long to develop tanning drugs that might actually work? The natural tanning process results from our skin’s love-hate relationship with sunlight. We need a certain level of UV radiation to allow keratinocytes, the main type of skin cells, to manufacture vitamin D, essential for healthy bones. But too much UV causes DNA mutations, which can lead to skin cancer.
To balance these conflicting requirements, evolution has come up with a natural sunscreen called melanin. This is a light-absorbing pigment that is manufactured from the amino acid tyrosine in cells called melanocytes, in response to a substance called melanocyte-stimulating hormone, or MSH (see Diagram). The cells release melanin from their long “tentacles”, and it disperses into surrounding keratinocytes.
Darker-skinned people, whose ancestors lived in sunnier climes, have melanocytes that work harder, producing more melanin. To fine-tune the process further, most people’s melanocytes make extra melanin in response to sunlight – producing a tan.
Perhaps surprisingly, it was only relatively recently that scientists discovered how melanocytes detect that you have been in the sun. When UV rays damage the DNA in skin cells, repair enzymes excise short snippets of damaged DNA. In 1994 a team led by Barbara Gilchrest, a dermatologist at Boston University, showed that these DNA snippets seem to make melanocytes more responsive to MSH, so they release more melanin. Her studies also suggested that the snippets trigger an array of protective systems against sun damage. “Every time we look we find more protective pathways,” says Gilchrest.
When our ancestors spent much of the day outside, this system meant that their tans built up gradually as summer approached, ensuring they received the right amount of sunlight with minimal damage. But foreign holidays, sunbeds and emigration have put a spanner in evolution’s good works. Take Australia. It is as sunny as southern Africa and its people enjoy an outdoor lifestyle, yet most of them are fair-skinned Caucasians. And in Europe and the US, people put themselves at risk by excessive sunbathing and using sunbeds.
Now, two out of three Australians who live to 75 will develop some type of skin cancer. The incidence of the disease has also soared in the UK and US in recent decades. Most cases are readily curable cancers of keratinocytes, but a small proportion are the more deadly melanomas, cancer of the melanocytes.
Despite a growing awareness of the dangers of sun exposure, many pale-skinned people cannot resist the urge to tan. The sunbed industry claims its devices provide a safer way to build up a tan with less risk of burning, but many doctors dispute this, and anyway, users are still exposed to damaging UV rays. “The problem is getting brown skin if you have white skin,” says Stuart Humphrey of EpiTan, one of the firms trying to develop a genuine tanning drug. “The only option is to go out in the sun or a solarium and damage your DNA.”
“At the moment the only way to get brown skin if you have white skin is to damage your DNA”
Certainly none of the pills and potions currently touted on the internet or in health-food shops is likely to help. There are no products approved by drug regulatory agencies for use as tanning agents, but that does not stop some firms selling their products as such, without any good evidence they work, or, in some cases, despite serious safety concerns.
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The commonest carotenoid, canthaxanthin, for example, is banned for sale as a tanning agent in the US because it can cause problems ranging from liver damage to crystals building up in the eye. Another widely sold class of tanning pills contain the amino acid tyrosine, on the premise that this will boost melanin production. But most people already have enough tyrosine for the job, and more makes no difference. The only people with a shortage are either severely malnourished or have a rare genetic disorder called phenylketonuria.
A class of drugs known as psoralens do actually promote tanning, by binding to cells’ DNA and making the skin supersensitive to the sun. In 1959 John Howard Griffith used them to experience life as a black man in the southern US. But psoralens have numerous side effects, including suppressing the immune system, so now they are only used to treat serious medical conditions such as severe psoriasis.
Despite the field’s disreputable status, serious research into the biology of tanning has continued. And our improved understanding of the mechanisms behind skin damage has prompted work on a variety of protective approaches. For example, a company called Applied Genetics Inc. Dermatics based in Freeport, New York, is developing a lotion called Dimericine, which contains a DNA repair enzyme designed to reduce UV-induced skin cancer. Although it is initially being targeted at vulnerable patient groups, it could one day be more widely used by sun worshippers.
The firm plans to apply for US regulatory approval to use the drug in patients with xeroderma pigmentosum, a rare genetic disease that cuts people’s ability to repair DNA damage from UV light, and so leads to multiple skin cancers. In a 30-patient trial, Dimericine reduced by one-third the incidence of a type of skin cancer called basal cell carcinoma.
AGI Dermatics is also testing Dimericine in kidney transplant recipients. People who have had organ transplants have a higher risk of cancer – about a hundredfold greater in the case of skin cancer, and even higher in sunny places such as Australia. This is most probably because the immunosuppressive drugs that patients take to stop them rejecting their new organ reduce their immune system’s ability to kill cancer cells.
Gilchrest’s discovery of the mechanism by which melanocytes respond to sunshine could also help fight cancer. Her team is developing a lotion containing DNA snippets designed to harmlessly mimic UV damage in skin and thus pre-emptively boost repair mechanisms. Last year her team showed that swabbing the backs of mice with preparations containing the snippets reduced the incidence of skin cancer after subsequent UV exposure (Proceedings of the National Academy of Sciences, vol 101, p 3933). The DNA fragments also stimulate human melanocytes in the lab to produce melanin, so Gilchrest hopes the product can eventually be developed as a tanning drug. “Tanning is what skin does to prevent UV damage,” she says. The DNA treatment “could give us that protection without the requirement for the damage”.
Another obvious way for a potential tanning drug to work is by encouraging melanocytes to convert more tyrosine into melanin. Contrary to what the marketers of tyrosine supplements would have us believe, the rate-limiting step in this process is not the availability of tyrosine – it is the levels of an enzyme called tyrosinase that catalyses the conversion process.
A team led by Seth Orlow, a dermatologist at New York University, is investigating ways to boost production of tyrosinase in melanocytes. In a paper due to be published soon in Chemistry and Biology, Orlow’s team say they have found a class of chemicals that do just this. “We have identified a number of small molecules that promote pigmentation in human melanocytes,” he says. Clinical trials are still some way off, however.
Not so for another compound, first synthesised about 20 years ago by chemists at the University of Arizona in Tucson. Melanotan is a modified form of melanocyte-stimulating hormone (MSH), the chemical that directly stimulates melanocytes to make melanin. The changes make the hormone more active than its natural form, which is especially significant for people who tend not to tan easily, such as redheads. These people are relatively unresponsive to normal MSH, but not, it seems, to Melanotan.
As a protein molecule, Melanotan cannot be taken orally – sadly for those hankering after a tanning pill – so Melbourne-based-firm EpiTan has developed it as an injection. In a small placebo-controlled trial, 65 people of European descent received 30 injections over three months. By the end, those who got Melanotan were significantly more tanned, with roughly 50 per cent more melanin in their skin than those in the control group. The findings have not yet been published, but were presented last year at the Australasian Society for Dermatology Research conference in Sydney.
The tan lasted for at least three weeks after the last injections. What’s more, the fairest individuals had the biggest increase in melanin, with even the redheads developing a slight tan. “We’ve shown you can change the ability of people from northern Europe to make melanin,” says Stuart Humphrey of EpiTan. The resulting tan also seemed to protect against sun damage in the same way as a normal tan, hinting that Melanotan may indeed be able to prevent skin cancer. The researchers measured the number of cells that died after UV exposure to a small area of skin, and found that the tan reduced the death rate by half. “You are not just getting brown, you are getting protection,” Humphrey says.
Improved formulations
The tan came at price, however, with side effects such as nausea, vomiting and facial flushing severe enough to make about 1 in 6 of those who received Melanotan quit the trial. EpiTan is now developing two new formulations that it says should cut side effects by delivering a continuous low dose. And users may prefer them to frequent injections.
One is an implant that is inserted under the skin. In an as-yet unpublished trial on 30 patients, the implant produced a tan for eight to 12 weeks, with “much reduced” side effects, says the firm. The implant is being tested in patients with polymorphous light eruption, a condition in which even low levels of sunlight can cause painful red spots and blisters. The other formulation is a spray applied to a small patch of skin, where it is absorbed into the bloodstream.
Larger trials will be essential before drug regulators can approve Melanotan. It would take decades to measure any effect on cancer rates, so trials will instead assess whether Melanotan prevents the sort of tissue damage most likely to precede skin cancer, such as production of DNA snippets. “If you had your own built-in sunscreen that reduces your lifetime UV exposure by a factor of 2 to 4, it should theoretically reduce your skin cancer risk,” says Antony Young, a skin photobiologist at King’s College London.
But Young points out that the cancer protection afforded by a natural tan may be due to more than just colour. For example, Young’s studies suggest that skin that tans easily is better at repairing DNA damage, and is more resistant to immunosuppression caused by UV.
There are also safety issues to consider. Melanotan stimulates melanocytes, the very cells that can transform into the deadliest type of skin cancer. So could it somehow push the cells in that direction? “Until we have had decades of human use, there can’t be an answer,” says Humphrey. “But years of work in the lab using mice and human melanoma cells do not support the concept that Melanotan stimulates the growth of melanomas.”
“If you had your own built-in sunscreen it should theoretically reduce your skin cancer risk”
Designing a drug to protect against skin cancer also raises the issue of whether it would encourage sun worshippers to expose their flesh to the sun’s rays even more, and so increase their cancer risk rather than reducing it. And if any firm does get a tanning drug approved, it will have to think carefully how to market it. The existing carotenoid and tyrosine supplements have given tanning pills a bad name. If a company claims its new drug really does produce a “natural tan”, potential customers could take some convincing.
After her traumatic childhood experience, Kristy Bain comments: “I have an abject fear of even thinking about getting a fake tan now.” But on second thoughts, she relents. “If I really could look like I spent a month in Bali just by taking a pill, well, I’d give it a go.”
After all, a bit of colour in your cheeks can do wonders. The result in her team’s jazz ballet competition? They won first prize.
