Hutch News

From asbestos to tobacco

Nov. 15, 2001

The Hutch, in collaboration with the University of Washington, has been selected to participate in a federally funded, $37 million research consortium to study how individual genetic makeup affects one's response to environmental agents ranging from asbestos to tobacco smoke.

Such research will help answer puzzling questions such as why some people who have never smoked a cigarette develop lung cancer, while others who have smoked heavily for years never show signs of the disease.

The Hutchinson Center/UW Toxicogenomics Consortium, part of a research collective involving a handful of academic institutions nationwide, will receive more than $7 million in funding over five years from the National Institute of Environmental Health Sciences (NIEHS), headquartered in Research Triangle Park, N.C.

Dr. Helmut Zarbl, an investigator in the Human Biology and Public Health Sciences divisions, will serve as principal investigator, and Dr. David Eaton, director of the UW Center for Ecogenetics and Environmental Health, is co-principal investigator.

"The ultimate goal is to predict an individual's risk of cancer based on his or her genetic profile and environmental exposures," said Zarbl, also an associate professor of pathology and toxicology at UW.

Tools of genomics

Each member of the NIEHS Toxicogenomics Research Consortium brings its own area of expertise. But collectively the group will use the tools of genomics to obtain a fundamental understanding, on a genome-wide scale, of the mechanisms of environmentally induced disease processes.

Researchers will attempt to better understand how disease occurs, how to identify potential environmental hazards, how to predict potential disease, how to identify exposed individuals and how to prevent disease.

The goal of the Hutch/UW partnership is to shed light on genetic differences that make some people more sensitive than others to various environmental exposures.

The Seattle-based consortium will exploit the combined strengths of the Hutch and UW in DNA-microarray technology - the use of so called "gene chips" to monitor the expression of thousands of genes at once - and the UW's long expertise in toxicology and environmental-health sciences.

Zarbl's work focuses on using DNA-array technology to determine whether particular genes are sensitive to the actions of chemical toxicants and how these genes are involved in cancer development. Genes sensitive to a toxic substance can be identified by an increase or decrease in their expression level after exposure.

"If people carry a combination of genes that puts them at higher risk with a particular environmental exposure, then we may be able to develop methods of intervention such as dietary modifications, chemopreventive agents or drugs to counter the effects of exposure," he said.

"Or, among individuals we identify as highly susceptible, we may give them information on the types of occupations they should avoid, for example, or the types of exposures to which they may be particularly sensitive."

Many other chronic diseases - such as most cancers, Parkinson's disease and Alzheimer's disease - also are caused by complex interactions between genetics and the exposures to factors in our environment.

The consortium's four lab-based projects will focus on the effects of toxic substances on breast-cancer development, how exposures to certain pesticides may affect behavior in children, environmental factors that may harm the developing nervous system, and the development of laboratory tests that can replace animal testing.

Each research project is supported by an infrastructure of technology cores that will provide a range of materials and services.

Technology cores

A tissue-acquisition core, directed by UW pathology professor Dr. Peter Rabinovitch, will provide access to genetically defined tissues and cell cultures. A DNA-expression array core, led by Zarbl and Dr. Jeff Delrow, manager of the Hutch facility, will compare the molecular fingerprints of cells exposed to different doses of environmental agents.

Another important strength of the consortium is the combined Hutch/UW expertise in bioinformatics and statistics, which will be key in analyzing data that ultimately will contribute to a national microarray gene-expression database.

The consortium's bioinformatics core will be co-directed by Dr. Steven Self, a PHS investigator; and Dr. Roger Bumgarner, director of the UW Center for Expression Arrays and research assistant professor in the Department of Microbiology.

A toxicology core, directed by Dr. Terry Kavanagh, associate professor of environmental health at UW, will coordinate the development of standardized methodologies in expression-array analysis to be used across the national consortium's participating universities as well as the NIEHS.

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