"Life on earth evolved in the presence of UVR irradiation from terrestrial sunlight and essentially all organisms developed photoprotective mechanisms to limit the resulting damage. In the case of human skin, two photoprotective mechanisms have been recognized.
- (1) Melanin pigmentation, both constitutive (baseline) and facultative (inducible), is the major recognized form of protection against UV-induced damage. Photoprotection is attributable to the fact that the melanin polymer can directly absorb UV photons, dissipating the otherwise injurious energy as heat, and can further absorb free radical species generated by interaction of UV photons with cellular lipids and other molecules that otherwise cause oxidative damage.
- (2) Scattering and reflection of UV photons by proteins in the statum cornenum is known to thicken following UV radiation, particularly in poorly melanized skin.
"Mammalian skin responds to UV irradiation by increased production of the pigment melanin in melanocytes with subsequent distribution to surrounding keratinocytes in a manner shown to be photoprotective. Also, recent data indicates that mammalian cells, like bacterial cells, have a UV-inducible DNA repair capacity that further protects the tissue from subsequent UV exposure. The combined effect of UV-induced melanogenesis and enhanced DNA repair capacity as well as possibly other as yet poorly elucidated inducible responses, is to render the skin far more resistant to subsequent UV injury. Such responses can reasonably be presumed important in protecting skin from acute and chronic UV damage including the development of skin cancer. In addition, sun induced tanning is known to be photoprotective, with a sun protection factor (SPF) of approximately three to five, depending on the individuals genetically determined ability to tan."
The words above were not written by me, although they could have been because they substantiate my "science of tanning" rationale for the benefits of sensible, moderate and responsible exposure to UVR. Rather, they were written by Barbara A. Gilchrest, M.D. and Mark S. Eller, M.D., of the Department of Dermatology at the Boston University School of Medicine for an article published in the September 1999 issue of the Symposium Proceedings (1999) of the Journal of Investigative Dermatology.
What Does This Article Mean?
I believe this article is just the first of many that will, perhaps without meaning to, support the benefits of sensible, moderate and responsible exposure to UVR. This especially is true since this article was written by respected members of the dermatology community and published by a prestigious dermatology magazine. If they primarily are concerned about their patient's welfare it is counterproductive for the American Academy of Dermatology to continue ignoring evidence proving that the benefits of tanning far outweigh the minimal and manageable risks involved.
"We would be extremely pleased if someone wanted to commercialize our idea," asserts Barbara Gilchrest, professor and chairwoman of dermatology at Boston University. Gilchrest's group is working on a sunless tanning method that she says several "major pharmaceutical and cosmetic companies" have contacted them about. However, she notes, "in the U.S., such a product would be called a drug and would be subject to the process at the FDA [Food and Drug Administration] for drug development and approval." If a new technology were classified as a drug, it would require vigorous and costly testing under FDA guidelines.
Gilchrest fears that products containing new cosmeceutical ingredients will be withheld from the market because they would be prohibitively expensive to test as a drug. FDA needs to establish an intermediate category between cosmetics and drugs to encompass products that carry defined benefits and low risks for normal skin, she wrote in a recent article. The regulatory process for this new category, she argued, should not be as time-consuming as it is for new drugs yet should scientifically verify safety and efficacy for consumers (B.J. Vermeer, B.A. Gilchrest, Archives of Dermatology, 132:337-40, 1996). FDA has no plans to initiate a review category for cosmeceuticals, according to John Bailey, director of the agency's Office of Cosmetics in Washington, D.C.
Rather than let another company commercialize his sun-related research, molecular biologist Yarosh formed his own company, Applied Genetics. But this entrepreneurial effort stands virtually alone in the industry, he notes: "I don't see new companies starting up." Instead, large cosmetic and drug companies want to incorporate his and others' research into their products. "We survive because of cosmeceuticals," he says.
Yarosh founded Applied Genetics in 1985, following a research career in molecular biology and DNA repair at Brookhaven National Laboratory on Long Island, N.Y., and the National Cancer Institute. The focus at Applied Genetics is on the development and commercialization of products for genoprotection-that is, restoring and repairing DNA damaged by sun, aging, and diseases. Yarosh bases his products on a molecular understanding of how the sun's UV energy damages skin cells. When the sun's UV rays strike the skin's DNA, the body recruits DNA excision repair enzymes to mend the destruction. The enzymes recognize damaged DNA, remove the damaged strand, and use the healthy DNA strand as a template to rebuild a matching piece. But mending is never complete, and skin cancer develops as wounded cells accumulate.
In 1989, Yarosh cloned T4 endonuclease V, the first enzyme that sets off the repair process, and encapsulated it into a product his company calls T4N5 liposomes. When rubbed on the skin, T4N5 liposomes augment the body's repair mechanism like "a second shift working," says Yarosh. T4N5 liposomes are under investigation in Phase III trials as a treatment for the rare genetic disease xeroderma pigmentosum (XP). Patients with XP are extremely sun-sensitive and develop skin cancer early because they lack the DNA repair mechanism. T4N5 liposomes prevent sunburn and speed up DNA repair with no side effects. Applied Genetics plans to sell T4N5 liposomes first as a prescription drug for XP, then later as a possible ingredient in sunscreens.
"The economics of putting T4N5 in over-the-counter sunscreens is difficult to do because the price point of sunscreens is low, " notes Yarosh. " It's hard to compete in that market with expensive ingredients. It would be difficult to add this bioengineered product just now and compete." Yarosh also formulated a new type of nonprescription sunscreen, sold under the trade name Ocean Secret. The product uses Photosomes, the company's trademarked name for the bulk ingredients-special liposomes that incorporate enzymes from marine plankton. "Plankton float in the ocean where there's a tremendous amount of ultraviolet light, and they developed a mechanism to protect themselves," says Yarosh. Plants, fish, and frogs have the same protective mechanism, but not people. Photosomes absorb UV, then enzymatically convert the energy to repair damage caused by UV. Trade secrets prevent Yarosh from giving a more detailed scientific description.
The company sells Photosomes in bulk to other cosmetic companies, which use them in various products. Another company product, called Oxysomes, consists of special liposomes that deliver antioxidants to the skin.
Dinucleotide Tanning Sunless tanning products account for 20 percent of the sun-care market and are the fastest growing segment. The main ingredient in products used today is dihydroxyacetone, a dye that imparts a sightly orange, uneven coloration to the skin. A possible way to obtain a safe, natural-looking sunless tan grew out of work to understand what causes tanning. When UV strikes the skin, pieces of DNA weld together to form pyrimidine dimers, which are snipped by excision repair enzymes. This repair process triggers melanocytes to synthesize melanin, the pigment that tans skin naturally.
Pyrimidine dimers containing pTpT (dithymidylic acid) segments preferentially accumulate during the repair process. When Mark Eller, a research assistant professor in Gilchrest's department at Boston University, treated cultured mouse melanoma cells with pTpT, they produced seven times more melanin than control cells did.
Then Eller added pTpT to a lotion and spread it on shaved guinea pigs, whose skin structure is similar to humans. The animals produced a tan within 10 days that lasted up to two months. Histological examination revealed an increase in melanin where the epidermis was treated with pTpT that was identical to skin tanned by sunlight (M. Eller et al., Nature, 372:413-4, 1994; M.S. Eller et al., Proceedings of the National Academy of Sciences, 93:1087-92, 1996). A topical lotion containing pTpT could bypass DNA damage to provide a safe tan that increases protection from the sun. "Companies have contacted us, but it's still in the exploratory state," says Gilchrest.
Morning-After Cream
Other researchers dream of a gene-replacing, morning-after sunburn treatment, designed to prevent a sunburn from turning lethal. The treatment targets squamous cell carcinoma, which involves the tumor-suppressor gene p53. Although not as deadly as melanoma, squamous cell carcinoma disfigures and kills if not removed quickly.
Precancerous sunspots, called actinic keratosis, progress to squamous cell carcinoma. At Yale University School of Medicine, biophysicist Douglas Brash discovered that in actinic keratosis cells removed from patients, 75 percent contained mutations in p53.
By bombarding mouse skin with UV rays to simulate a scorching day at the beach, Brash learned that the p53 gene coordinated apoptosis (normal programmed cell death) to remove damaged cells, which appear as peeling, dry skin after a sunburn. But sometimes UV radiation zapped p53 itself, garbling apoptosis signals. Instead of sloughing off, cells with damaged DNA survived to become cancerous (A. Ziegler et al., Nature, 372:773-6, 1994). "Now that we know what the genetic injury is, we can develop a cream that contains a compound to reconstitute the p53 protein. Down the road it seems likely that we can prevent skin cancer in a morning-after approach," reports dermatologist David Leffell, a Yale colleague of Brash's. Such a product would not replace sunscreens, but rather would repair damage from imperfect sunscreens and human fallibility.
Are drug companies interested? "I wish," says Brash. Drug companies have called him about his p53 investigations, "but when they found out they would have to shell out money, they backed off." And with prior patents filed to use p53 to treat other types of tumors, companies fear legal complications.
Old Standbys
UV's suppressive effects on the immune system are gaining attention. Mice exposed chronically to UV radiation lose their ability to mount an immune response to skin cancer, owing to an induction of suppressor T lymphocytes. Mice, rats, guinea pigs, and humans exposed to UV show delayed-type hypersensitivity in response to various antigens. This UV-induced immunosuppression may be an additional risk factor for skin |
