June 3, 2005

Marnett’s research garners MERIT Award

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Lawrence Marnett, Ph.D.

Marnett’s research garners MERIT Award

Lawrence J. Marnett, Ph.D., has received a MERIT (Method to Extend Research In Time) Award from the National Cancer Institute in support of his research on DNA mutation and carcinogenesis.

Less than 5 percent of National Institutes of Health-funded investigators are selected to receive MERIT awards, which recognize superior competence and outstanding productivity. A key feature of the awards is the opportunity for investigators to gain up to 10 years of grant support without competitive review.

“I was very pleased and surprised to receive this MERIT award,” said Marnett, director of the Vanderbilt Institute of Chemical Biology. “It is a tribute to our group's efforts and productivity over the years. It will give us some flexibility and the opportunity to try out riskier ideas, to ask bigger questions.”

Marnett, who is also Mary Geddes Stahlman Professor of Cancer Research and professor of Biochemistry and Chemistry, joins 14 Vanderbilt University Medical Center investigators with current MERIT awards, and he is the only Vanderbilt investigator to be honored by the NCI.

“Larry Marnett is precisely the kind of faculty member the MERIT award program was designed to support,” said Jeffrey R. Balser, M.D., Ph.D., associate vice chancellor for Research. “His contributions to science are so high-impact, and so consistent, that providing long-range funding that frees his hands to focus on science is in the best interest of Vanderbilt, the NIH and the patients we all serve.

“It is great to see our most productive scientists recognized and rewarded by the NIH in a way that not only honors them, but also invests in their high likelihood of making future contributions.”

The $2.2 million grant will support Marnett's efforts to track DNA damage and mutagenesis caused by compounds made by the body, so-called “endogenous” compounds.

The compounds that Marnett studies are produced during inflammation. Chronic inflammation is a major risk factor for many different cancers, he said, and there is great interest in discovering how the DNA damage that arises during chronic inflammation contributes to carcinogenesis.

“We know that mutated genes cause cancer, but we don't know what's causing the mutations in many cases. If we know that, we can limit exposure, which is a major component of prevention,” Marnett said.

Marnett's current line of research goes back to his earliest days as an assistant professor at Wayne State University.

It was the late 1970s, and Marnett was interested in a small molecule called malondialdehyde, which was the only metabolite of arachidonic acid — a fatty molecule in the cell membrane that serves as the starting material for prostaglandins and other signaling molecules — that no one knew anything about.

At about the same time Marnett and his colleagues discovered that the metabolism of malondialdehyde was “pretty boring,” there was a report in the literature suggesting that the compound was mutagenic and carcinogenic.

“I didn't know anything about mutagenesis or carcinogenesis at the time, but it was intriguing to me that this molecule that we make ourselves might damage DNA and cause cancer,” he recalled. Most investigators in the late 1970s favored the idea that foreign compounds — like cigarette smoke and things we eat — were responsible for DNA damage and cancer, Marnett said.

The team proposed that malondialdehyde behaves like other carcinogens, reacting with DNA and binding to it to form “adducts,” which cause DNA mutations. With continuous NIH funding since 1980, Marnett and his colleagues have tested this hypothesis.

The investigators have identified all of the products formed when malondialdehyde reacts with DNA.

They have studied the biological activity of these adducts — whether they cause mutations, how effectively they cause mutations, and how they are repaired. The group has also developed methodology to detect the presence of malondialdehyde-DNA adducts in people, publishing the first report of this type of DNA damage in the journal Science in 1994.

A number of groups have since demonstrated the presence of DNA adducts formed from other endogenous compounds.

“There's a whole family of adducts generated from lipid oxidation products,” Marnett said. “There's DNA damage going on all the time — some from environmental chemicals, some from endogenous chemicals. The real challenge to the field is to discover how those things interact to push a cell over the limit and cause mutations in critical genes.”

In the current studies, Marnett and colleagues including Carmelo J. Rizzo, Ph.D., associate professor of Chemistry, will carefully examine the relationship between the structure of the DNA adducts and the kinds of mutations they cause. Rizzo, a synthetic organic chemist, has successfully developed synthetic routes to make forms of DNA damage not previously available for laboratory study.

The adducts are on “A” residues in DNA, and appear to induce a type of mutation that is very common in human cancer, Marnett said. The team is also working to develop analytical methods for detecting and monitoring DNA adducts in urine. Such methods might provide a convenient, non-invasive way to monitor DNA damage resulting from inflammation for use in studies of different human populations, Marnett said.