n e w s of t h e
week
Stanford's Khosla wins NSF's Waterman Award Chaitan S. Khosla, a 34-year-old associate professor of chemical engineering and chemistry at Stanford University, will receive this year's Alan T. Waterman Award from the National Science Foundation. The award, which consists of a medal and $500,000 to support research or advanced study, is NSF's most prestigious prize for young researchers. Khosla "has been the moving force in this country in what people are calling combinatorial biosynthesis, which is the purposeful manipulation of genes that make polyketide natural products, including antibiotics, immunosuppressants, and other important therapeutic agents," says Christopher T. Walsh, professor of biological chemistry and molecular pharmacology at Harvard Medical School. In those manipulations, Khosla and others are creating libraries of new molecules, some of which may turn out to be important new drugs, Walsh adds. Khosla's "creativity, productivity, and intellect are defining the forefront of his field and opening a whole new opportunity at the interface of chemistry, biology, and chemical engineering," says Peter G. Schultz, professor of chemistry at the University of California, Berkeley, and himself a recipient of the Waterman Award in 1988. "It's always good for the community when chemists and chemical engineers get recognized" with awards such as this one, Khosla says. "Awards tend to put one person in the spotlight," he adds, "but in the kind of research that we do, we are embarrassingly dependent upon not just the commitment but also the creativity of the students and postdoctoral fellows we work with. So this is an award that they share in, too." A good example of the new directions Khosla and his students are exploring appears in work published last week in which he and his colleagues dissect and exploit intermodular communication in polyketide synthases, the modular megaenzymes that make polyketides [Science, 2 8 4 , 482 (1999)]. The new work "represents a significant shift in the way that we—and hopefully others—not just do, but think about our science," Khosla says. Until now, Khosla explains, the manip14 APRIL 19,1999 C&EN
ulations he and others have made to the enzymes that synthesize polyketides have each made relatively small changes in the resulting polyketide. The work is in many ways analogous to making point mutations in protein engineering, where each mutation replaces a specific amino acid in the resulting protein. Khosla now proposes that whole modules of the enzymes that synthesize polyketides can be shuffled around to produce the equivalent of chimeric natural products. "The question we wanted to ask," he says, Khosla "is can I take a portion of, say, erythromycin and fuse that to a portion of rapamycin and then fuse that combination to a portion of avermectin
and create a molecule that has structural features drawn from all three natural products?" The answer to that question seems to be yes, Khosla says. His group has half a dozen examples in which they have been able "to grossly rewire these multimodular systems." The key feature seems to be not the modules themselves or the chemistry they direct, but rather the short connecting segments between them. If the right connector is attached to a module, it can be linked to another module to form a chimera, allowing researchers "to take apart the functional properties of natural products by a very different approach," he says. Rebecca Rawls
Genome mapping effort gets more competitive A two-year, $45 million collaborative effort to map a small but important snippet of the human genome and make that mapping information freely available to the public was announced in Chicago last week. The SNP Consortium, named after the genetic markers known as single-nucleotide polymorphisms, is being funded by Wellcome Trust (the U.K-based medical research charity) and 10 American and European pharmaceutical companies: AstraZeneca, Bayer, Bristol-Myers Squibb, Hoechst Marion Roussel, Hoffmann-La Roche, Glaxo Wellcome, Novartis, Pfizer, Searle, and SmithKline Beecham. SNP Consortium's chairman and chief executive officer is Arthur Holden, former CEO of Celsis International, a U.K-based biotechnologyfirm.The consortium, a year in the making, is headquartered in Chicago. SNPs are DNA base pairs that differ from person to person. They account for about 0.1% of the roughly 3 billion nucleotides that make up the human genome. The consortium's goal is to identify up to 300,000 and map 150,000 SNPs. The consortium's founders believe that mapping these SNPs will help pinpoint the subtle genetic differences that predispose some people but not others to diseases such as arthritis, Alzheimer's, and diabetes. Such gene identification may in turn facilitate development of novel diagnostic tests and new treatments, which can be turned into profitable products (see page 59).
The actual identification and mapping will be done by Whitehead Institute, Cambridge, Mass.; Washington University School of Medicine, St. Louis; Wellcome Trust's Sager Centre, Hinxton Hall, England; and Stanford University's Human Genome Center. These research institutions will work with DNA samples from a representative group of anonymous volunteers and sequence information from the U.S. government's Human Genome Project and the U.K. Medical Research Council's Human Genome Mapping Project. The work of organizing, analyzing, managing, and distributing the resulting data will be handled by the bioinformatics program at Cold Spring Harbor Laboratory, in New York. Explaining the reason the consortium is undertaking this effort, Holder said in a statement that consortium members "believe that free and unrestricted access to this powerful tool will benefit scientific inquiry in industry, government, academic, and independent laboratories." Unmentioned are companies such as Celera Genomics, Rockville, Md., which plans to map the whole human genome by 2001 and charge for access to the databases it develops. Within the past few months Celera, a division of Perkin-Elmer, has signed two major subscribers—Amgen Inc. and Pharmacia & Upjohn. Janice Long
