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funding. But for the research that does get support, the paper claims, NIH’s investment has a significantly high rate of return to society in terms of saving and extending lives. According to the paper, the aging population of the U.S. makes the need for such investments even more critical. MEMBERS OF the government’s biomedi-
PREACHING CONVERGENCE Deeper integration of disciplines would benefit science, in particular BIOMEDICAL RESEARCH, MIT paper posits GREATER CROSS-DISCIPLINARY research efforts among the biological, physical, and engineering sciences are needed to accomplish the U.S.’s scientific and technological goals, according to a group of scientists from Massachusetts Institute of Technology. To move toward a “true disciplinary integration,” the group says it has developed a convergence model of research, which it defines as “the merging of distinct technologies, processing disciplines, or devices into a unified whole that creates a host of new pathways and opportunities.” The MIT scientists made their case for this new research model at a forum held by the American Association for the Advancement of Science (AAAS) early this month. They presented a white paper with ideas and recommendations on what it would require, in terms of federal and academic support, for this research model to be effective in biomedical science. Speakers at the forum discussed how this model would affect federal science and engineering research funding and policy decisions. Others argued that what the MIT scientists propose is already happening. “What we’re talking about is new concepts moving into the field of biology,” said Phillip A. Sharp, a professor of biology at MIT, who noted that the white paper cites biomedical research as the first area to benefit from the convergence of disciplines. “This includes the concepts of informa-
tion theory, dynamic stability, and noise control, all of which are concepts common to engineering disciplines that are moving into life sciences.” Other scientists in the group proposing the model gave examples of how convergence is being applied to biomedical research at MIT’s David H. Koch Institute for Integrative Cancer Research. Paula T. Hammond, a professor of chemical engineering, described the multidisciplinary efforts that went into the invention of a device to detect metastasizing cancer cells in human blood. Tyler Jacks, a professor of biology and director of the Koch Institute, spoke about the variety of convergence research projects in such areas as nanotechnology-based detection methods, new imaging agents for disease detection, and development of mathematical models to simplify complex biological phenomena. The MIT paper cites the need for higher and more consistent federal support for research. Most biomedical research is supported by the National Institutes of Health, which has seen below-inflation budget increases over the past few years. As a result, NIH’s grant success rate remains low, making it challenging for new work to receive
cal establishment who spoke at the forum were impressed with the progress MIT is making with increasing integration across research disciplines but took the view that convergence is already happening in some universities and federal agencies. They also noted some wrinkles in supporting cross-disciplinary work that still need to be ironed out, such as tenure, funding, and training, for the model to work. “We are certainly aware of the call for NIH to do more work across its institutes,” Alan Guttmacher, director of the National Institute of Child Health & Human Development, told the forum. NIH, he said, is already moving in that direction with its work in translational research and in programs such as the National Children’s Study, which will require collaboration from many different disciplines. Still, Guttmacher noted that universities, where most of this research is performed, have a problem finding ways to reward and advance scientists who participate in convergence research. Thomas Kalil, deputy director for policy at the White House Office of Science & Technology Policy, agreed that convergence-type research is important and told the forum that government policymakers should be considering the arguments made in the MIT paper when deciding how to fund research to meet the nation’s problems. Guttmacher also sees the lack of a mechanism for funding of convergence research as a stumbling block. “A lot of people are in favor of innovative funding models—as long as you continue to fund their research,” he said. “This is going to require taking stock of our funding process and having everyone step back from their own self-interest a bit.” Alan I. Leshner, chief executive officer of AAAS, said that the convergence model will “threaten the hell” out of the traditional Continued on page 33
“This is going to require ... having everyone step back from their own self-interest.”
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based on 22 selection criteria, calculates inflammation, pain, and hypertension. an index value that represents how much Administering sEH inhibitors and a compound’s measured behavior profile COX-2 inhibitors together decreases the deviates from the target product profile. production of prostaglandins, thereby Lapatinib has unusual kinetic behavior, causing both inflammation and pain to Williams reportdiminish, Hammock said. The hope is that F3C ed. Its off-rate— integrating such O O which is a meainhibitors N N N sure of how quickly in a single N S NH2 H H a compound dissociates compound from its target once bound—is will result O somewhere between the value expected in an anti-inflamfor a covalent inhibitor and that matory effect with expected for a compound with fewer of the cardiovasDual COX-2/sEH inhibitor cular side effects that are fast off-rate kinetics. They used X-ray crystallography to investioften seen when COX-2 gate whether this behavior is a property of inhibitors are administered by themselves. the compound or of its effect on EGFR. Sung Hee Hwang, a postdoctoral reSome of the unusual behavior could be searcher in Hammock’s group, used celeexplained by the crystal structure, Wilcoxib as a starting point for finding dual liams said. When his team solved a crystal COX-2/sEH inhibitors. He found a dual structure of lapatinib with EGFR, they inhibitor that overlaps with celecoxib in observed that lapatinib triggers conformamodels of COX-2 binding and also fits in tional changes in the enzyme that extend the catalytic site of sEH, Hammock said. In beyond the ATP-binding site. The drug’s diabetic rats, the dual COX-2/sEH inhibitor large headgroup pushes up into a pocket, reduces neuropathic pain to a greater exnudging a methionine out of the way. In tent than the individual inhibitors adminthis more compact, closed structure, the istered alone or together, Hammock said. inactive enzyme collapses around the inhibitor in a closed, inert form. Movement IN ADDITION TO assisting the discovery of a helix in the enzyme pushes catalytic of new drugs, polypharmacology can help residues out of register. All of these things find new uses for old drugs or CH3 happen without the compound covalently explain troublesome side effects, N binding to the kinase. Kroeze said. “Many well-known The project team concluded that the drugs are highly promiscuous,” he N unusual kinetic behavior was due to both said. For example, the schizoN the molecule and its effect on the phrenia drug clozapine affects Cl enzyme. “The conformational 28 of the 71 targets Kroeze and change and the unusual kinetic his coworkers assayed it against, N H behavior was a direct consequence of a number probably limited only lapatinib’s large headgroup,” Williams Clozapine by the number of assays. “Adsaid. And it was the compound’s large headgroup that made lapatinib a good dual Continued from page 29 inhibitor. “The compounds that had the academic disciplinary structure and fundbest dual-kinase and pan-kinase profiles all ing mechanisms with which scientists are had large headgroups,” he said. The kinetic familiar. findings are true for ErbB-2 as well, but One part of the funding structure that structures of that enzyme are harder to obneeds to change to support convergence is tain, Williams said. peer review. The MIT white paper is critical of NIH proposal reviews as becoming inYET ANOTHER USE of polypharmacology creasingly conservative and more selective. approaches could involve the design of new The present system discourages innovation multitarget drugs that mitigate the side efand novel ideas in favor of just incremental fects of existing drugs. Hammock’s group progress in science, the paper states. Anis working on compounds that inhibit both other problem with peer review of convercyclooxygenase-2 (COX-2) and soluble gence research is finding reviewers with the epoxide hydrolase (sEH) as a way to treat necessary expertise. inflammatory and neuropathic pain. Both To address these problems, the white of these enzymes are involved in the arapaper recommends reforming the peer rechidonic acid cascade, which plays a role in WWW.CEN-ONLINE.ORG
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ditional O targets O Cl are likely O to reveal Fenofibrate additional hits,” he said. Roth’s lab is gathering polypharmacology information into a database of known receptor-psychoactive drug pairs, Kroeze said. Users of the database, found online at pdsp.med.unc.edu, can mine the resource to learn what drugs hit a specific receptor or what receptors a drug interacts with. They intend to uncover such information for every target in the central nervous system, in part through their role of running the National Institute of Mental Health Drug Screening Program. Understanding how drugs work in this new multitarget paradigm requires taking a systems-level approach to drug discovery, said Tatiana V. Khasanova, a scientist at Encinitas, Calif.-based GeneGo, which is now a Thomson Reuter company. She described how the company’s “knowledge base” of pharmacological interactions allows researchers to identify the various targets of a drug. The analysis can go in either direction, starting with a compound and finding targets or vice versa. For example, GeneGo’s application uncovered 268 indirect targets for the anticholesterol drug fenofibrate, which helps explain why the drug has anti-inflammatory activity and may explain its many side effects. The days of the “magic bullet” are quickly disappearing, and researchers need to come to grips with the magic shotgun. With polypharmacology, maybe they’ll be able to sharpen the aim of their ammunition. ■ view process. For example, the authors say NIH needs more diversity in its peer review teams, which would increase “both the cutting-edge disciplinary depth and the array of disciplines represented.” This would make approval of convergence proposals more likely, the MIT researchers contend. Other recommendations in the white paper include establishing a formal mechanism for building connections across stovepiped science-mission agencies within the government to establish a “convergence ecosystem” and encouraging universities to start teaching the next generation of convergence researchers through new curricula, apprenticeships, and training programs.—DAVID HANSON
