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Laboratories at the Institute for Systems Biology sport magnificent views across the sailboat-cluttered waters of Lake Union, with the hilly downtown of Seattle as a backdrop. On this unusually sunny and warm June day, graced by an endless turquoise sky, the large windows provide an entrancing, even romantic, view. And it well suits the young institute, which has built itself around one of the grandest of biological visions.

Systems biology, one of the hottest fields to spring from the Human Genome Project, defies a simple description. It promises nothing less than to reshape the way that scientists think about how the human body works, providing clues to unraveling the complexities of illness and ultimately leading to new medicines to prevent and treat disease. But even the Institute for Systems Biology’s Web site prominently raises the question “What is systems biology?”, then offers an answer that fills six full screens of a computer monitor.

As the site struggles to explain, systems biology aspires to connect the dots of all of the body’s RNA, DNA, genes, proteins, cells, and tissues, elucidating how they interact with each other to create a breathing, blood-pumping, disease-fighting, food-processing, problem-solving human. “Systems biology is a holistic view of what’s going on,” says Alan Aderem, cofounder and director of the institute. It looks beyond the individual actors and tries to discover the script they are following, and that marks a radical shift for biology. “The focus for the last century has been on individual molecules,” says Marvin Cassman, executive director of the California Institute for Quantitative Biomedical Research, a fledgling systems biology program that joins researchers from the University of California schools at Berkeley, San Francisco, and Santa Cruz. “What’s been missing is an understanding of the way individual molecules operate together.”

Using this new approach, researchers have begun to address some of medicine’s most basic questions: Why do some people become gravely ill from an infectious agent that only causes mild disease in most? Will a clearer picture of how immune-system cells interact with each other guide the development of new vaccines? If scientists identify a defective gene, or an aberrant protein, can they correct it without doing harm somewhere else?

Scientists have dreamed about doing systems biology for decades, but explaining the workings of even a single cell has proved too daunting. Now a confluence of developments has fundamentally altered biology. An explosion of blazingly fast, highly automated machines has enabled the analysis of biological molecules in a fraction of the time it took a mere five years ago. Similarly, the torrent of new information from the Human Genome Project and related projects that comprehensively examine entire families of such molecules has presented scientists with dizzying new “parts lists” for humans. Add in the ever increasing computational muscle of today’s computers, and the systems biology approach that once seemed implausible becomes not only possible but also necessary to make sense of it all.

The formation of the Institute for Systems Biology four years ago fanned the flames, with a dozen universities and biotech firms subsequently announcing new interdisciplinary programs with a systems biology bent (see table “Other Systems-Biology Hubs). But the Seattle institute remains the highest-profile player, in part because of its founders’ combination of scientific expertise and machine-making prowess. It helps, too, that one of the cofounders, Leroy Hood, has something akin to celebrity status.

In the mid-1980s, Hood became famous in the biotech community when his lab at Caltech developed the automated DNA sequencer, a machine that made the Human Genome Project possible and helped to reconfigure biology. With support from Microsoft’s Bill Gates, Hood in 1992 came to the University of Washington and started an interdisciplinary molecular biotechnology program. The program planted the seeds of systems biology, but by 1999, Hood had become frustrated with the limitations of academia, and he decided with two other researchers at the school, Aderem and Ruedi Aebersold, to start the Institute for Systems Biology. “In the end, we decided we needed more freedom, and that’s why we took this pretty drastic step,” says Hood. Aderem came to systems biology through a less obvious route and with a more pragmatic motivation. A pioneering immunologist, he had earned a sterling scientific reputation for his work on a single family of proteins. Still, he says, “At the end of 10 years, I was tired and realized I wouldn’t live long enough to get any real understanding of a system if I was going to do it one by one.”

Despite the excitement it inspires, systems biology remains very much in its infancy. The institute has so far churned out papers that begin to establish the virtues of the approach with arcane biological systems like yeast and sea urchins. But at the institute’s core are far more ambitious programs in cancer, heart disease, infectious diseases, autoimmunity, and inflammation. And as they make the leap from relatively simple models to critical human problems, Aderem and his colleagues believe that their work will move medicine toward an era in which our life spans increase by 10 to 30 years. That’s a terrifically bold claim. But a closer look at what Aderem and others at the institute have begun to explore shows it may be more than just a daydream inspired by the splendid view.

Other Systems-Biology Hubs Institution/Company Strategy Beyond Genomics (Waltham, MA) Startup will use proprietary informatics technology to research new medicines for heart disease, central-nervous-system problems, and cancer California Institute for Quantitative Biomedical Research (University of California at Berkeley, San Francisco, and Santa Cruz) A cross-campus effort will link biology, computer science, and engineering in a multidisciplinary systems approach Computational and Systems Biology Initiative (MIT, Cambridge, MA) About 40 researchers from 10 disciplines will collaborate on cell death, toxicology, biochemical networks, models, tissues on a chip, and synthetic biology Department of Systems Biology
(Harvard Medical School, Boston, MA) More than 20 faculty from biology, physics, computer science, and engineering will study networks of cells and organs to identify new approaches to treatment Ingenuity Systems (Mountain View, CA) Startup will use its proprietary “pathways analysis” software and database to speed drug R&D Lewis-Sigler Institute for Integrative Genomics (Princeton University, Princeton, NJ) Up to 15 interdisciplinary research groups will conduct basic research on the systems that control cell growth, neural circuits, synthesis of carbohydrates, and protein-protein interactions Life Sciences Institute (University of Michigan, Ann Arbor, MI) Up to 30 research teams will collaborate on projects that emphasize the networks that genes and proteins in a cell use to sense and adapt to stimuli Merrimack Pharmaceuticals
(Cambridge, MA) Biotech firm will exploit “network biology” to find new drugs for cancer and autoimmune diseases Okinawa Institute of Science and Technology (Onna Village, Okinawa, Japan) New graduate university now being planned will emphasize integrative research in biosystems


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