GOVERNMENT & POLICY
ENVIRONMENT
OF GENES AND CHEMICAL TESTING EPAs new top scientist is steering research program into new terrain of computational toxicology CHERYL HOGUE, C&EN WASHINGTON
T
ALK OF GENE CHIPS AND COM-
putational chemistry lights up J. Paul Gilman's eyes. Gilman, 49, is the new head of the Environmental Protection Agency's Office of Research & Development (ORD). He's fresh from three years at Cèlera Genomics, the Rockville, Md.-based company best known for decoding the human genome, where he was director of policy planning. Gilman is eager to lead EPA's research office onto new ground. Computational toxicology is a major focus for Gilman. This involves use of microarrays, also known as gene chips—small glass or plastic plates containing hundreds or thousands of D N A strands—to determine how exposure to a chemical affects gene function. And it uses computational techniques to extrapolate results from one chemical to compounds with similar structure. Toxicology is one of EPA's "core competencies," and the agency must advance the state of this science, according to Gilman, who serves on the National Research Council's Board on Environmental Studies & Toxicology 28
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"We knew when I got here that genomics would play a growing role in the toxicology activities of EPA, of companies, of other federal agencies," Gilman tells C&EN. He became EPA's assistant administrator for O R D on April 5. "WE HAVE BECOME more sophisticated in toxicology There was a time when we gave a substance to a mouse, and if the mouse died or got sick, we said, 'We think there's a problem,' " he says. "Today, we know a lot more about what goes on at the cellular level, the organ level, and we're learning more about what happens at the molecular level. That's really genomics. That's understanding how a toxicant affects a protein or affects the gene itself that makes that protein," says Gilman, who holds a doctorate in ecology and evolutionary biology fromJohns Hopkins University "Our vision is that we will ultimately be able to build a library of the different biological pathways in our body that are affected by toxicants," Gilman says. 'The genomics side of that is you can represent those pathways through gene chips. "You
can represent perhaps the entire library on a gene chip and know which pathway is being affected by a toxicant and exactly how " But there are resource limits on the use of this technique, he notes. 'Are you going to do this every time for every pathway for every toxicant? No. This is where the computational side comes in," Gilman says. Understanding structure-activity relationships involves computational tools— using calculations to help determine the relationship between a chemical's structure and its biological activity These tools help determine whether a substance that has not been tested for health effects may pose a risk because it contains a structure similar to a substance of known toxicity With computational techniques, researchers can "take different compounds and try and make a prediction based on their structure as to how they might affect these different biological pathways," he says. Computational toxicology tools are not restricted to determining whether and how chemicals affect human health, Gilman notes. These techniques can also be applied to ecological effects ofpollutants. By determining the biological pathways of the plants and animals that are critical to the functioning of ecosystems, scientists can eventually use computational toxicology tools to extrapolate results to other organisms, he says. He sees researchers using genomics and computational chemistry tools to understand "the toxicology of ecosystems." In its pilot use of computational toxicology, EPA is developing and using techniques for a congressionally mandated program on chemicals suspected of disrupting the endocrine system. iC We have a requirement to come up with some screening techniques for endocrinelike substances," Gilman says. "We're going to use that mission to refine a strategy for applying both genomics tools and computational tools to the task at hand." As EPA develops its computational toxicology program, the agency will work with the National Institute of Environmental Health Sciences, which is coordinating an international research effort to develop the field of toxicogenomics. This field uses microarrays to study chemicals' toxicity Gilman says EPA is going a step further than NIEHS's basic research effort by applying toxicogenomic techniques in the endocrine-disrupter program. The results of computational toxicology studies, whether for screening endocrine-disrupting compounds or for other purposes, will likely affect the regulation of chemicals. Therefore, Gilman says, deHTTP://PUBS.ACS.ORG/CEN
velopment of these new tools "needs to be done hand in hand with the regulated public so they can have confidence in the tests." That means working with industry as the agency interprets results of tests exposing microarrays of genes to chemicals. In toxicogenomic tests, genes are tagged with two fluorescent nucleotides: red for genetic materialfromtreated samples and green for controls. Fluorescence indicates gene expression. Resulting color patterns of gene arrays can indicate toxicity "One of the raps that gene chips get is, yeah, some things go red, some things go green, but what the heck does it all mean?" Gilman says. "%u have to develop these
porting regulations, but that is a very vital part of what we do," he says. Gilman also praises Henry L. Longest II, an EPA career employee who was acting assistant administrator for ORD between the tenures of Huggett and Noonan and those ofNoonan and Gilman. In the weeks before Gilman assumed his post at EPA, the Bush Administration came under fire by lawmakers and scientific societies for eliminating a popular graduate and postgraduate fellowship run by ORD (C&EN, April 29, page regulatory programs—including the of- 22). On April 23, the House Science Comfices of air; water; waste; and prevention, mittee called Gilman to discuss the issue, pesticides, and toxic substances—appre- even though he was not officially head of ciate the work of EPA researchers. And ORD when the budget decision was made. they want more of what the researchers At the hearing, he said that although the produce. This situation "is really very grat- $ 10 million fellowship program did not get ifying," he says. transferred to the National Science Foundation, NSF's budget is increasing and can "I'M VERY LUCKY. I start with a good pick up the slack caused by elimination of foundation," he says, tipping his hat to his the EPAfellowship program. Improving the most recent predecessors at the helm of competitiveness of federal fellowship proORD. One is Robert J. Huggett, who grams for graduate students is "overall, good launched a major reorganization of the re- for the life sciences," Gilman explained. He search program during his 1994-97 tenure. declines to discuss the issue further. After years of criticism by Congress and Meanwhile, EPA Administrator Chrisoutside experts, Huggett changed the way tine Todd Whitman named Gilman as her EPAlabs relate to each other. He refocused science adviser on May 24. This mantle of EPA research around the elements of risk responsibility, he says, provides his biggest assessment—exposure evaluation, hazard challenge at EPA."She wants my vision to identification, dose response, andriskchar- be a little broader than ORD and more acterization—andriskmanagement, such agencywide as it comes to that notion of the as pollution control technology. And use of science in EPA," Gilman says." That's Huggett strengthened peer review. my challenge—to work with the different Nowadays, peer review isfirmlyincor- regulatory programs on not just the doing porated into EPA operations. "That's an of research but in the using of science." infusion of the scientific approach to the Whitman is making key changes in how regulatory process," Gilman says. science is used at the agency She wants EPA scientists to be involved in the earliest stages Gilman commends the work of Norine E. Noonan, who between 1998 and 2001 of regulating, long before the agency issues completed the reorganization Huggett be- a new environmental standard, Gilman says. gan and pushed ORD to become "a very This work will include the planning of recustomer-oriented organization" by sup- search that can help regulators set policy plying data needed by agency regulators, and implement pollution controls. Gilman says. "Our research isn't just for supWithin ORD, Gilman oversees research that runs the gamut from ecological field studies to tests using human volunteers in ORD AT A GLANCE: high-tech laboratories to development of pollution control technology About half Employees (full-time equivalents): 1P9A3 of the work within ORD is basic research, Fiscal 2002 budget: $591,9 million while the other half is applied. Research grants awarded, 2002: $94 million Some efforts, like computational toxicology, involve both basic and applied reFacilities: 13 search, Gilman notes. "On one hand, we're Ada, Okla.; Athens, Ga.; Cincinnati; trying to understand the basic science. And Corvallis, Ore.; Duluth, Minn.; Edison, on the other, we're engaged in trying to N.J.; Grosse lie, Mich.; Gulf Breeze, build a very practical applied screening Fia.; Las Vegas; Narragansett, R.I.; methodology" Newport, Ore.; Research Triangle Park, N.C.; and Washington, D.C. He adds, 'That's what makes the research program here very, very interesting." • Council's Commission on Life Science and NRCs Board on Agriculture. Since he's arrived at EPA, Gilman says he has found that the heads of the agency's
"Our vision is that we will ultimately be able to build a library of the different biological pathways in our body that are affected by toxicants."
things to the point where you understand what they mean and how to interpret them." ORD plans outreach to the chemical and pharmaceutical industry on the use of computational toxicology, Gilman says. Pharmaceutical makers are particularly important because these companies already use computational chemistry in drug development, he adds. Though Gilman comes to EPA from private industry, he has long been part of the government scene in Washington, D.C. He worked for 13 years on Capitol Hill as a Senate aide, starting as an American Association for the Advancement of Science congressional science fellow. During the Administration of former president George H. W Bush, Gilman served in the Energy Department and was associate director for natural resources, energy, and science at the Office of Management & Budget. From 1993 until he joined Cèlera in 1998, Gilman was concurrently executive director ofboth the National Research HTTP://PUBS.ACS.ORG/CEN
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