News Column

Skin-cancer Clues Lead to Jungle

March 4, 2013

Tom Avril

The scientist and his companions puttered down winding waterways by boat, and bounced along dirt roads in a Ford Explorer. The longest of more than a dozen such trips into the Malaysian jungle took 10 hours.

Only then could the researcher from Penn State College of Medicine ask tribal leaders for the information he sought:

Surat warisan manusia. The letter of human inheritance.

That was Khai C. Ang's way of explaining the concept of DNA, and it was effective. Hundreds of villagers agreed to give blood samples, and now back in the Hershey, Pa., lab of Ang's supervisor, Keith Cheng, their DNA has begun to yield insight into a weighty trio of subjects: cancer, human migration, and race.

White people are prone to developing melanoma, as their pale skin is vulnerable to the sun's ultraviolet rays. Yet Asians, plenty of whom also have light skin, are relatively immune to the disease.

Cheng, director of experimental pathology at Penn State, thinks he can find out why. He chose to study DNA from the Malaysian jungle because its inhabitants have not intermingled with Europeans, for the most part, and because they have a range of skin colors -- like a living mosaic of evolution.

As a physician, Cheng fights cancer. But with genetic material like that at his disposal, he seems equally enthusiastic about anthropology, about the chance to describe a chapter of human history. "You'd have to be made of stone to not be curious how we got all these colors in humanity," Cheng said.

The story begins more than 50,000 years ago with Vitamin D. The body needs sunlight to make it, so when humans migrated out of Africa, they likely became vitamin-deficient. Blame the weaker northern sunlight, and the fact that in the colder climate, they had to cover more of their skin with clothing.

But people with lighter skin can more readily make Vitamin D. So those with that trait would have been healthier, likely explaining why they came to dominate the northern latitudes. One light-skinned group spread across Europe, the other across Asia.

Yet the mutations that gave rise to European skin were accompanied by about a 20-fold rise in melanoma. The skin of Asians, on the other hand, is somehow nearly as good as dark African skin at absorbing harmful ultraviolet radiation, keeping it away from the nucleus of skin cells.

On the advice of Oxford University scholar Stephen Oppenheimer, whose book The Real Eve describes human migration from Africa, Cheng sought answers in peninsular Malaysia. The region is home to three tribal groups that have been largely insulated from European influence: the Senoi, the Proto-Malay, and the Negrito.

At the national university near Kuala Lumpur, Cheng met Ang and quickly sold him on his idea to gather DNA in the jungle.

He explained how, once they had the genetic samples back at Penn State, they would test various genes by tamping them down in zebrafish, a popular creature in pet stores but also increasingly a valued lab tool. If a gene contributed to lighter skin color in humans, fish with that gene should follow suit.

But first, the team needed to get permission: from various Malaysian agencies, from the national university, from Penn State, and above all from the villagers. Among the concerns was that the tribe members grasp the goal of the research so they could give informed consent.

By June 2009, Ang was on his way, joined by health workers who handed out material on malaria, dengue, and other ills.

He spoke to the various tribes in his native Malay, which for them was a second language, carefully explaining the goals of the work. Besides collecting DNA, Ang also measured their skin color with a small device like a flash camera, which gauges the light reflected off a person's skin.

Sometimes, Ang had to wait a few days for a messenger to go out and summon hunters back to the village, so he showed movies to others in the meantime. It was also a way to alert the men that something was up in the village, as some were near enough to hear his sound system.

One movie was 1980's The Gods Must Be Crazy, about an African bushman's contact with modern society -- an apt choice. Others included Legally Blonde and one about the Monkey King, a character from Chinese folklore.

Race and skin pigment are sensitive issues across the world, Malaysia included. The fact that Ang was a native, coupled with his respectful demeanor, was a big help. "The idea that we were going to research people's skin color could've been a real no-no if handled in the wrong way," Oppenheimer said.

Ang brought back the precious vials of blood, keeping them cool by stopping at restaurants along the way to replenish his supply of ice.

Now at Penn State, he and Cheng seek to learn which genes make a difference, by testing them in the zebrafish.

In the lab, hundreds of the small, striped fish are zipping back and forth in tanks, some darker, some lighter, some in-between.

Scientists have used many animal "models" to study genetics -- mice, worms, fruit flies. Cheng is partial to the fish because like humans, they are vertebrates, yet they are quick to reproduce and their skin color is evident within two days of hatching.

Once they identify the mutation or mutations that are the key to Asian skin, it can be traced back to see when it originated, and how it matches archaeological evidence of human migration.

And then there is the question of skin cancer, and why Asians are not prone to it. The answer likely has to do with melanin, the pigment that protects the nucleus of skin cells. It comes in different forms, and its granules are distributed differently in people depending on skin color, said Murray Brilliant, director of the Center for Human Genetics at the Marshfield Clinic in Wisconsin, who has been following Cheng's work.

"It's a fantastic and important study," Brilliant said.

Cheng, a rare scientist who is equally at home in the lab and in explaining his work to the public, has drawn notice for his work on skin color before.

In 2005, he and colleagues discovered a single mutation that was responsible for a large part of the difference in skin color between black and white people. He found that a physical trait responsible for no small amount of historical prejudice and misunderstanding, in other words, was caused largely by the merest of genetic quirks -- a change in one DNA base pair out of three billion.

Brilliant invited Cheng to discuss the work in a public lecture at the University of Arizona. And Cheng, an accomplished pianist, chose to supplement his talk by performing selections from Bach's Goldberg Variations.

Drawing inspiration from his idol, famed pianist Glenn Gould, Cheng spoke of how the music was like science, with many threads merging into a melodious whole.

"It's trained me to parallel-process a lot more," Cheng says of his music. "You actually have to keep track of different voices at once."

And if the DNA from Malaysia reveal their secret, Cheng will shed light on the different voices, and colors, of humanity too.



Source: (c)2013 The Philadelphia Inquirer Distributed by MCT Information Services


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