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When the first draft of the human genome was completed in 2000, it was hailed as a revolution in health care. A complete understanding of the 30,000 genes in the body, the estimated 50,000 proteins they encode, and the tiny chemical variations that make each of us different suddenly seemed within reach. Medical prognosticators declared that within a few years, we would unlock the secrets of the world's worst ills and figure out how to eradicate them. Medicine would become personalized: We would go to the doctor, have our genes screened, and get customized drug regimens that would keep us healthy throughout our long lives.
This vision wasn't flawed so much as drastically premature. The fact is, we still don't understand how most genes operate. We know they encode proteins involved in complex biochemical pathways that underlie most diseases. But so little is known about those proteins that the drugs on the market today target just 10% of them. "The genome has given us a wonderful parts list, but it's only the beginning," says Dr. Leroy Hood, president of the Institute for Systems Biology, a Seattle research group.
Hood and other scientists are championing a research approach designed to close the knowledge gap. They believe that instead of examining one gene at a time, scientists should strive to discover how the body's many different biological systems interact in an illness and affect our individual responses to drugs. Only that knowledge will lead to the goal of switching off diseases while avoiding toxic side effects.
Decoding complete disease pathways could have tremendous implications for drug research and marketing. Roger M. Perlmutter, Amgen's executive vice-president for R&D, points to the company's rheumatoid arthritis drug, Kineret, as an example. There is a small subset of patients with the disease who don't respond to any of the commonly prescribed remedies, but they do get better on Kineret. "We don't know who those people are," Perlmutter says. If Amgen could figure out which genes trigger the positive response to Kineret, it might be able to develop a test to identify those patients. That would allow Amgen to market Kineret more precisely, thus lowering costs and boosting sales and profit margins.
Genentech has experience with this model. Its breast-cancer drug, Herceptin, helps 25% of patients with the illness -- those who have too much of a protein expressed by a gene called Her2. Doctors can use one of two tests to identify women with the problem, and administer Genentech's drug. Last year, sales of Herceptin jumped 11% to $385 million.
The ability to examine all the body's systems in concert is still far off. But it is already possible to extract tips from the behavior of groups of genes. Psychiatric Genomics Inc. in Gaithersburg, Md., is studying manic depression, schizophrenia, and autism -- disorders in which multiple genes are switched on or off by a variety of factors that aren't yet understood. The company is building biochemical models of mental illnesses using diseased brain tissue, and is also looking for patterns in drug effectiveness by studying medical records of deceased patients. The goal is a new model of drug development that involves finding all the genes that change in the course of the disease, then identifying a drug that can restore the most critical genes to a normal pattern.
Companies pursuing this new, systems-based approach to research are finding that it requires a paradigm shift. To build complete models of diseases, companies must foster constant collaboration among chemists, biologists, physicists, mathematicians, and computer engineers. "Everyone used to be in their own silos," says Psychiatric Genomics CEO Richard E. Chipkin. "That doesn't work anymore. Teamwork is critical." Adds J. Craig Venter, chairman of the Institute for Genomic Research and one of the pioneers of mapping the human genome: "We need to take a far more sophisticated approach and pool our resources to gain a full understanding of disease."