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Yuanli Liu
Heather Nelson
Stephen Buka
Barbara Burleigh
Eric Rimm
Karen Kuntz

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As a kid growing up in Fargo, North Dakota, Heather Nelson tagged along on visits to the greenhouses where her agronomist dad, a statistician and classically trained geneticist, bred plants for disease resistance. "I'd run along the rows looking for diseased specimens," she remembers.

While nurturing an artsy side and dancing semi-professionally, Nelson "fought science-ness growing up." But in college, she gave in to her analytical bent. Fired up about ozone depletion and other assaults on the environment and the public's health, she found an outlet for her activism in HSPH's Ph.D. program in the biological sciences. There she became intrigued with the way genes and environment conspire to raise cancer risk.

The link between smoking and lung cancer was well known, but Nelson wanted to explore how tobacco exposures touched off the disease at the genetic level. A notorious mutation in some lung tumors called k-ras became the focus of her thesis. How tight is the link between the k-ras mutation and smoking?, she wondered. Does having the k-ras flaw predict how well or badly a patient will do? The answers were startling: the k-ras mutation occurred only in current and past smokers. In patients whose tumors were identified by standard tests as early-stage and non-spreading, it quadrupled the risk of eventual death, suggesting that cancer cells had flown under the tests' radar to far-flung areas of the body. And k-ras affected women three times more often than men, helping explain the epidemic of lung cancers in women.

The practical implications were that patients could be one day screened for the k-ras flaw and, if they had it, opt for aggressive treatments to try to beat their disease. Today, with researchers at Brigham and Women's Hospital, Nelson is gearing up to search for receptor molecules for the hormone estrogen on lung tumors with k-ras gene mutations, suspecting that estrogen compounds lung cancer risk in women with the mutation.

Nelson's lab is also wrestling with another big public health problem--non-melanoma skin cancers. Though rarely fatal, basal and squamous-cell cancers affect more than 1.2 million Americans each year, and the associated costs are enormous. "There are two types of genetic changes we're interested in," Nelson explains. "First, there are polymorphisms--common, naturally occurring genetic variations we're all walking around with, which can interact with environmental exposures to increase or decrease our cancer risk. Then there are mutations you get from environmental exposures, like ultraviolet light."

UV sunlight wreaks havoc on DNA and is to blame for the explosion in non-melanoma skin cancers. Nelson suspects people's susceptibility to these malignancies differs owing to natural variations in genes whose role is to repair DNA. Subtle differences in these genes would help explain why some people get environmentally induced cancers, including certain leukemias or lung and bladder cancers, while others don't.

When it comes to choosing a research problem, Nelson says she's opportunistic: "I can get excited as long as it's good scientifically and I can make a difference." Little wonder, then, that she jumped at the chance to work with her Brigham and Women's colleagues in a study of mesothelioma, a lethal cancer linked to asbestos. "Given that we've been phasing out asbestos for years, one might think mesotheliomas would be disappearing, but that's not so," she says. She will see whether hospital patients' past exposures to environ-mental hazards correlate with genetic changes in their tumors. The researchers will also examine tumors for evidence of infection by the SV40 virus, to test a controversial theory that some mesotheliomas stem from contamination in the 1960s of the U.S. polio-vaccine supply.

As a molecular biologist working in environmental epidemiology, Nelson concedes she's "kind of rare." Long-time HSPH collaborator Karl Kelsey puts it this way: "Few people in the world have Heather's broad understanding of both biology and population science. Most lab scientists don't know how to make sense out of a large database of information, do the statistical manipulations on a computer, and draw causal inferences," he says. "But Heather's not intimidated."

In Nelson's view, applying genetics to the study of exposure-induced diseases is inevitable, "the way the world is going.
"We need to find out which genetic variants make people more and less susceptible to harm," Nelson says. "And we need to make policy accordingly, setting exposure standards that protect the most vulnerable."

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Photo: Kent Dayton