26 August 2005

The Race To Understand Skin Cancer

By Rusty Rockets

According to the findings of a Mayo Clinic study, published in the August 10 issue of The Journal of the American Medical Association, skin cancers among young adults have been steadily increasing over the past thirty years. This rise can be attributed to a number of factors, the popularity of tanning, better detection of skin cancers, and a depleted ozone layer that allows us to be exposed to an increased level of ultraviolet (UV) radiation. While researchers looking into skin cancer and UV know a great deal more than they once did, the relationship between UV's effects on DNA and the formation of skin cancers remains elusive. Ed Yong, Cancer Information Officer at Cancer Research UK, says: "Both genes and environmental factors influence a person's risk of cancer, and the interplay between the two can be quite complex. Environmental factors like UV radiation cause cancer by damaging genes. But inheriting a mutation in a key gene can also predispose a person to developing certain cancers." So questions remain as to the complex relationship between inherited genetic traits that cause some people to be more prone to skin cancers, and the environmental factors responsible for irreparably damaging DNA structures.

For humans to have survived as a species thus far would require that we do have some natural protection from UV radiation. In 2000, Bern Kohler, assistant professor of chemistry at Ohio State University, found that "DNA functions somewhat like its own sunscreen." Kohler's observations revealed that the light-absorbing parts of DNA convert UV radiation from the sun into heat in a blindingly fast one-trillionth of a second. It is the speed of this process that is the key to DNA's natural ability to protect itself from the sun's radiation. Kohler explains that without this process taking place, UV photons can cause DNA to mutate and cause conditions that include skin cancer and premature aging. "For the first time, we've been able to see just how fast DNA dissipates UV energy, and that will help us better understand how light damages DNA," he added.

Kohler's experiment involved taking portions of the DNA molecule called nucleosides, placing them in water, and bombarding them with an ultra-short pulse of UV light from a laser. The pulse deposits energy in the electrons of the nucleosides much as sunlight would, putting the nucleosides into an excited state. Because the laser pulses were so short, the researchers were able to study the extremely rapid process by which DNA changes the energy from UV radiation into heat. In a trillionth of a second, the UV energy was transformed into increased vibrational motion of the nucleoside's atoms.

During the transfer, the nucleoside's temperature jumped to more than 1,300 degrees Celsius, but it quickly cooled by transferring energy to the much cooler water molecules that surrounded it. As you might imagine, the cooling process is so brief that we don't even notice the extreme temperatures that our DNA reaches. Kohler speculated that: "The longer the excited state energy remains localized in DNA, the greater the chance for permanent damage." It is findings like this that may help researchers design better sunscreens for people and photostabilizers (compounds that protect paint, plastics and other materials from damage by UV light) for paints. But while the experiment was by all expectations a success, Kohler cautioned that: "We had to look at a component of DNA to start, but eventually it will be important for us to look at the whole DNA molecule." And look they did.

In a more recent study, published in the August 25 issue of Nature, Kohler observed that full DNA behaved very differently compared with the single bases that he had used five years previously. "It turns out that you can't extrapolate the results of base pairs to whole strands of DNA," Kohler said. While the UV energy still changed to heat when Kohler and his colleagues turned their laser on whole strands of DNA, this time the energy dissipated a thousand times more slowly. "Eventually, the energy does turn into heat, but the important point is that the energy is retained within the molecule for much longer times. This can cause all kinds of photochemical havoc," added Kohler. But despite the reduced speed, there was no evidence that the UV photons affected the chemical bonds between the base pairs, as was previously expected. "Prior to our study, there was a belief that UV energy could possibly induce mutations by acting on paired bases," said Kohler. The team deduced that the UV energy must have been leaving the molecule via the edges instead. It's possible that when base pairs are aligned in their natural state in a DNA strand, the electronic interactions along the stack provide an easier way for DNA to rid itself of UV energy, compared to passing the energy back and forth between the two bases in a base pair, as scientists had previously thought.

"So much attention has been paid to base pairing that this other interaction, base stacking, has been neglected," Kohler said. Kohler believes that the reason that base stacking has been overlooked is because of the analogies that we use to describe DNA structure. A "ladder" implies that there are "rungs", or spaces, in between successive bases. This is misleading, says Kohler, and a better analogy would be to think of the bases as a stack of coins.

With the coin analogy in mind, Kohler and his team suspect that as sunlight warms our skin, UV photons are absorbed by the bases, causing their electrons to vibrate. "We were able to look with high enough time-resolution to actually see where the energy goes. We found that it rapidly becomes trapped in vertically stacked bases, and does not act on base pairs," said Kohler. These high-energy vibrations nudge the atoms in the bases around, but only along one edge of the DNA ladder at a time. "This insight offers an explanation for the known patterns of DNA photo-damage: almost all lesions show up between stacked bases. That is, fundamental properties of DNA direct energy to one strand at a time. This offers a possible explanation for why most damage occurs to just one strand at a time," explains Kohler. The fact that DNA is usually only damaged on one strand can be recognized as yet another safety mechanism to protect the integrity of the entire DNA structure.

"The beauty of this is that double-helical DNA contains two strands, and either strand can be predicted exactly from the other one since A always pairs with T, and G always pairs with C. Nucleotide excision repair works by identifying damaged bases on one strand, and then replacing those bases with newly synthesized ones. The enzyme that carries out this repair simply reads off what is needed from the second, undamaged strand," explains Kohler. UV induced damage is always occurring at the DNA level, but with these processes, the body is able to repair the damaged DNA. However, by the same token, if both strands of DNA were damaged, the template would effectively be missing. Kohler notes that occasionally some lesions just go un-repaired which can lead to mutations that can turn into cancer. However, says Kohler, "the steps leading from lesions to cancer are very poorly understood."

Other researchers are tackling skin cancer from the other end of the spectrum: in patients who have already developed cancer. Researchers at the Dana-Farber Cancer Institute, writing in the July 2005 edition of Nature, have identified a genetic error responsible for melanoma tumor growth. The research team, led by Dr Levi Garraway, made the discovery by identifying DNA errors in tissue samples taken from patients with malignant melanoma and comparing these to healthy tissue samples. The team spotted a specific genetic error that appeared important to tumor growth, most notably in some of the most aggressive and metastasized (cancer that has spread beyond its primary site) cancers.

The team identified the error as an abnormal replication of a gene called MITF, with some tumors having as many as 13 extra copies of MITF. The discovery of MITF also uncovered other related mutations, such as the silencing of a gene called CDKN2A (also known as p16), which prevents cells from dividing too quickly or indefinitely. Ed Yong said that: "Mutations in this gene increase the risk of developing cancer because cells are less able to repair DNA damage [such as that caused by UV radiation] and are more likely to grow indefinitely." A scenario that is analogous to a computer virus programmed to disable your anti-virus software in order for it to exist and spread without your computer detecting its presence. "By pinpointing the abnormally multiplied MITF oncogene, we may be able to develop better diagnostic and prognostic tools as well as provide a target for highly specific therapies for metastatic melanoma patients who have this over copied gene," said co-researcher Dr William Sellers.

But questions remain as to the relationship between heritable gene mutations that make a person more susceptible to skin cancers, and mutations in the DNA structure caused by sun damage. Douglas Brash, Yale professor of therapeutic radiology, genetics and dermatology, completed a study in February of this year that suggests the type of pigment an animal has, in addition to skin transparency, plays a large role in who gets sunburnt. It was previously believed that those who had fair skin, with blonde or red hair, were most at risk. However Brash's study shows that this is only partially correct. He found that those who have dark hair and fair skin are not subject to the same risks as those with fair skin and red hair. Brash said that the type of melanin that causes blonde and red hair actually increases the risk for cell death as seen in sunburn. Blondes and redheads have what is called pheomelanin. People with darker hair have eumelanin. Melanin usually filters UV radiation, but counter-intuitively, it can have the effect of increasing UV exposure. So unfortunately, the pheomelanin found in people with light hair or skin acts with the sun's UV rays to increase sun damage. "What this tells us is that melanin is not only good for you, it also can be bad," said Brash. "It depends on the color of your particular melanin. Even red melanin can vary widely, depending on whether your ancestors were Irish, Swedish or Dutch, and some of these variations are known to be associated with greater risk for skin cancer," he added.

Are the different types of melanin a type of evolutionary variation, much like the variations of blood groups that make it more difficult for viruses to kill off the whole human species? Could they be environmentally caused mutations, passed down from one generation to the next, making subsequent generations' DNA even more sensitive to UV photons? In Kohler's first experiments that discovered DNA "sunscreen", he stated that: "Today, ozone in the stratosphere protects us from most UV radiation, so scientists have wondered how life could have withstood that early onslaught. The fact that DNA functions very much like its own sunscreen may have been a critical factor in the evolution of life." Perhaps the relatively recent increase in skin cancers amongst young adults is an indicator that UV radiation is increasing faster than the human body can adapt.

While Garraway and Kohler's research could lay the groundwork for new treatments for skin cancer, their research may also uncover even more fundamental insights into our bodies. Kohler reminds us that basic research, like that of Crick and Watson's description of DNA, "has led to countless advances in medicine and related fields virtually none of which could have been anticipated at the time."