Supercomputers to pursue diseases

       For over 10 years, Eric Schadt has been one of a handful of scientists blending mathematics, biology and supercomputers to pursue a new understanding of human biology, one that suggests that the mechanisms of human disease are far more complex than anticipated.
       The chief scientific officer for Pacific Biosystems in Menlo Park, California,Schadt,44, is known for finding unorthodox solutions to problems - and for wearing shorts, sandals and rumpled polo shirts, even in business meetings.
       When he and other scientists in his field began their work, biologists had long thought that common diseases such as cancer and heart disease could be characterised by identifying a single cause - perhaps an errant gene - and treated with a drug aimed at that gene,or, more likely, the protein the gene produced.
       Some of the drugs developed that way, including Herceptin for breast cancer and antiretroviral drugs to treat Aids,were great successes. But that method has faltered. For instance, of drugs that enter human clinical trials,89 percent fail, according to a 2004 study in Nature Reviews ,usually because of unanticipated side effects.
       The problem is no surprise to Schadt."It turns out that common diseases involve thousands of genes and proteins interacting on complex pathways," he said.
       In 2003, Schadt was first noticed as a co-author of a paper in Nature that articulated the need to move beyond the impact of individual genes on disease and to create computer models of diseases that included the interaction of genes and proteins.
       He went on to create some of those models in detail and to report on pilot projects for diabetes and heart disease that analysed in actual patients the complicated series of biochemical interactions that together form a metabolic pathway implicated in a disease. The results of his work offered new possibilities for developing drug treatments and diagnostic tests for predicting risk factors for disease.
       Schadt has helped energise the growing field of systems biology, developed and championed by researchers that include Lee Hood, founder and president of the Institute for Systems Biology in Seattle; George Church, a geneticist at the Harvard Medical School; and Steven Friend, a geneticist who is the director of the non-profit Sage Bionetworks in Seattle and who is also Schadt's longtime colleague and co-author on many important studies.
       "He has the ability to take what everyone knows and think about it in novel ways," Hood said."He is exceptional at thinking outside the box."
       Schadt is a warm, intense man whose casual wardrobe has become legendary in classrooms and boardrooms. He was raised in the small town of Stevensville,Michigan, in a working class family that he said had little interest in science or in a university education.
       After high school, he enlisted in the Air Force and was assigned to an elite rescue unit."I would never have known about biology or mathematics, except for an accident," he said.
       While rappelling down a cliff he badly dislocated his shoulder, which forced him to leave his unit. Because his scores in an aptitude and an intelligence test were off the charts, the Air Force sent him to the California Polytechnic State University in San Luis Obispo. He soon discovered mathematics and later genetics before earning a doctorate in biomathematics at the University of California, Los Angeles.
       "My non-conventional background makes me non-conventional," Schadt said."I don't like to be told that I have to do things certain ways."
       From 1999 until last month, Schadt worked as the head of genetics and bioin-ABOVE Dr Eric Schadt, chief scientific officer for Pacific Biosystems, in his lab in Menlo Park, California.SCIENCE TIMES formatics for Rosetta Inpharmatics, a company based in Seattle.
       Founded in 1996 by Hood, Friend and the biologist and Nobel Laureate Lee Hartwell, Rosetta was bought by the pharmaceutical giant Merck in 2001 for $620 million. At Merck, the Rosetta team was provided with resources beyond those usually available in academia,Schadt said.
       Rosetta built one of the fastest supercomputers in the drug industry,running 16 trillion calculations a second.Researchers also developed specialised chips to sequence and analyse tissues from throughout the body.
       "Merck dropped a hell of a lot of money into this," Schadt said.
       Peter Kim, president of Merck Research Laboratory, said,"The investment has paid off for us."
       The company now has in clinical trials eight drugs that emerged out of Rosetta's platform, Kim said, with more than a dozen others in preclinical trials. He declined to provide specifics about the costs of the candidate drugs.
       Kim said that Merck was developing some cancer drugs that would be directed at various subpopulations of patients rather than the one-size-fits-all approach that has been a hallmark of modern pharmaceutical companies."We're going to target specific networks and pathways," he said.
       Despite Schadt's success, Merck disbanded Rosetta this summer and is closing the Seattle research facility as part of a plan to cut $4.2 billion (143.3 billion baht) and 7,200 jobs. But Merck is donating data, research and hardware from Rosetta to Sage Bionetworks, a non-profit founded this summer by Schadt and Friend, the co-founder of Rosetta, who just stepped down as senior vice-president for cancer research at Merck.The new organisation has received a $5 million (170.6 million baht) anonymous donation as well.
       Friend, who is working full-time for Sage, wants to carry on Rosetta's work of modelling highly complex systems by adopting an open-source model such as the one used in software design, where thousands of people from around the world work together in a loose network.
       For biology, the idea is to link up scientists and huge databases on everything from genetic pathways to patient records."The complexity of human biology is simply too huge to work out in a single company," Friend said."We need a contributor approach, like Twitter,which sets up a platform and is run by a few people that maybe a billion people contribute to."
       Church, the Harvard geneticist, said,"The idea of Sage and open-source is fantastic, but losing Merck's resources may be a net loss to the science, at least in the short term."
       When Schadt left Merck last month,he took on two jobs - as the co-director of Sage with Friend, and as the chief technology officer of Pacific Biosystems,a company founded in 2004.
       He was attracted to the company's novel use of nanotechnology and lasers to sequence DNA and other molecules."It's like the best microscope in the world for accurate reads of DNA," said Schadt, who will head efforts to analyse data that is expected from Pacific Biosystems next year.
       "What Eric is doing has a controversial side," said Dr Eric Topol, a cardiologist and the director of the Scripps Translational Science Institute in San Diego."First, is it going to really work? Also, we may yet find that some of the single gene markers are actually powerful predictive indicators for disease."
       But Schadt said,"It's all about learning to connect the dots - lots and lots of dots."