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As Green began distributing his programs by e-mail to sequencing centers around the world, genome sequencers found the software to be remarkably precise and powerful. "Quality is king with Phil, " says Haussler, who is director of the Center for Biomolecular Science and Engineering at the University of California, Santa Cruz, "and that comes out in his software."
In the 1990s, issues of quality became a major consideration for Green in another way. Despite his self-effacing manner, he found himself drawn into a rancorous debate over the best way to sequence the human genome. He argued that the method known as whole-shotgun sequencing, in which DNA is divided into small sequenced snippets that are then recombined by using computers, would lead to too many errors in published sequences. Other sequencers, including those at the private company Celera Genomics, vociferously countered that the shotgunning method would work. The argument sputtered out as elements of various approaches were combined. And the contretemps did not detract from Green’s contributions to the effort: The 400,000 contigs that the publicly sponsored Human Genome Project combined to produce the human sequence were the output of PHRAP. “The whole edifice for doing that was based on Phil’s work,” says Haussler.
In 1994, Green received an offer that he found too enticing to turn down. Immunologist and technology developer Leroy Hood had been putting together a new kind of genetics department at the University of Washington, one designed to foster interdisciplinary research by bringing together people with many different backgrounds. According to Waterston, who became head of the department after Hood left to form a nonprofit research institute, the department’s aim remains “to bring together the key disciplines that will be needed to make progress on the very hard problem of interpreting genomes.”
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At the University of Washington, Green devotes the bulk of his time to working on what he calls the “parts list”: a catalog of all the molecules involved in biological processes in human cells. The proteins encoded by DNA are an essential component of this list, which is one reason why biologists want to identify all the functional genes in DNA. Green is a member of several research teams at the University of Washington and elsewhere that are looking for genes, typically by comparing human DNA sequences with the sequences of other organisms. “You’re searching for stretches of sequence that look as if they are not evolving neutrally,” he says. “In other words, you’re looking for regions that have a slower rate of change, which is evidence that selection is acting on those regions.”
The parts list will help biologists build a “wiring diagram” for human cells: a schematic representation of all the interactions that occur among all the elements on the list. Constructing the wiring diagram is a much harder problem because any given molecule can have many functions in a cell. DNA is a prime example. DNA molecules contain not just the specifications for proteins but regulatory regions that control when a protein will be expressed and in what quantities. “The genome is not just an information repository,” says Green. “It is also an active part of the processes going on in the cell.”
Once biologists have a general sense of the wiring diagram of a human cell, they can move on to what Green sees as the third main objective of human genetics research: They can begin to reconstruct, both in computers and in the laboratory, synthetic systems that mimic those in the cell. They then can perturb these systems to get a sense of how biological molecules work together, which is the goal of the new field of systems biology. They may even be able to design novel biological systems to achieve desired outcomes—the goal of the even newer field of synthetic biology.
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