Protecting oneself against the sun typically involves a lot of slatheringñfirst a sunblock or sunscreen, and if one forgets that, later, and painfully, a soothing cream to tame the fiery red skin of a sunburn. A new type of sun cream will soon be possible, with a biotech twistñincorporating natural DNA-repair enzymes to literally undo the sunís damage.
Youíd have to be living in a cave not to know that the suntans people often sought in times past are now on the hit list of formerly fun things to do that are now considered dangerous. A $2 billion global market in skin concoctions has emerged to address consumer concern over ultraviolet-radiation damage from the sun.
"Solar damage is the major cause of skin cancer," says Daniel Yarosh, PhD, president of Applied Genetics Inc., in Freeport, N.Y. The company will soon begin a phase-III clinical trial of a liposome-encased and delivered repair enzyme.
A cellís eye view of sunburn
Ultraviolet radiation zeroes in on the DNA double helix. DNA consists of four types of building blocksñthymine and cytosine (called pyrimidines), and adenine and guanine (purines). In places where two pyrimidines lie side-by-side in a gene, UV light causes an extra chemical bond to form between them, resulting in a "pyrimidine dimer," in the chemical lingo. The dimer produces a tiny flat stretch in the curving helix, a little like two adjacent escalator steps suddenly coalescing. When it comes time for the affected DNA to replicate, mistakes occur because of the misshapen area.
Fortunately, cells have contingents of repair enzymes that peruse DNA, detecting mistakes and snipping them out so the correct building block sequence can be inserted. The enzyme that initiates the removal of a pyrimidine dimer is called T4N5 endonuclease, and this is what Applied Genetics wraps into liposomes and has turned into a skin lotion. "The idea is to use liposomes as delivery vehicles for products to the upper skin layer," says Dr. Yarosh.
But some sun damage may be so severe that the cell throws in the towel, and, instead of repairing, peels off. A protein called p53 orchestrates the response to sun damage, deciding to either pause the cell from dividing so it can repair the damage, or trigger programmed cell death, thus sending the cell on its way rather than attempting to repair it. But the sun can damage p53 protein or the gene that encodes it, or a person can be born with an abnormal p53 gene, which provides an inborn cancer susceptibility. When p53 isnít working properly, sun-damaged cells go unrepaired. Eventually, they may grow into a squamous or basal-cell carcinoma (the two less serious types of skin cancer).
Tipping the scales
Adding T4N5 endonuclease to a sunburn scene seems to tip the scales in favor of repairing skin cells, rather than killing them. "The enzyme repairs damage and averts programmed cell death," says Dr. Yarosh. In mice given sunburns in a 30-week regimen of ultraviolet light exposures three times weekly, the enzyme-containing cream prevented p53-related skin cancers.
Researchers at Applied Genetics are less sure of the productís effects on melanoma because there are no test animals that can serve as models, as there are for the other two forms of the disease. However, melanocytes (melanin-producing cells) grown in the laboratory respond to the liposomes by repairing DNA, and they increase production of melaninñsuggesting that the lotion may not only protect against cancer, but may stimulate a tan too!
The first market for the T4N5 liposome lotion will be those who have the extremely rare inherited disorder called xeroderma pigmentosum. They lack the gene that encodes the repair enzyme, and, for them, the sun is deadly.
For one little girl from upstate New York who has this condition, the sun is a monster. Katie Maherís parents noticed early on her reaction to the sun. When she was only a month old, they put her under a tree in the backyard to enjoy a warm, early spring day. Within seconds, Katie was covered with spots. The spots quickly turned into painful blisters, and then scabs, some of which might one day develop into skin cancers. It happened again and again, even when a shaft of light entered the little girlís bedroom and hit her skin.
Hiding from the sun
To help their daughter live as long and cancer-free as possible, the Mahers have turned their world around. Katie and her three siblings play outdoors at night only, or indoors on a jungle gym in the garage, where all light except that from a low-ultraviolet incandescent bulb is blocked out. She is liberally smeared with sunblock eight times a day to protect against a stray ray. And trips to the doctor are taken at night.
If the T4N5 endonuclease in Applied Geneticsí lotion does well in its upcoming trials, Katieís world may broaden. She is one of only 250 people worldwide known to have the condition. "Then we will get to a larger market, to patients with skin cancer" or susceptibility to it, says Dr. Yarosh.
Researchers at Applied Genetics and academic researchers at Yale Universityís School of Medicine are working on a similar product and predict availability of a damage-correcting skin care lotion within five years, as a prescription drug. It could be used before, during or after sun exposure. With skin cancer on the rise since 1973, and our love of the sun never abating, it will be a most welcome addition to the ever-growing list of practical products spawned from biotechnology.
By Dr. Ricki Lewis
Contributing Editor
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