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Whole-genome technique may aid drug development A technique devised by researchers in the Seattle area promises to reveal the entire spectrum of a potential drug's cellular ac tivities—including unwanted side ef fects—without having to put it through expensive preclinical or clinical trials. The method employs robotically cre ated microarrays of DNA fragments that together represent the entire yeast ge nome. These DNA "chips" are used to analyze effects of drugs on gene expres sion in living yeast cells. The technique was developed by Stephen H. Friend, founder and chief scientific officer of Rosetta Inpharmatics, Kirkland, Wash.; Leland H. Hartwell, president and director of the Fred Hutchinson Cancer Research Center, Seattle; and coworkers [Nat. Med, 4, 1293(1998)]. "The reason we worked on this," Friend tells C&EN, "is the difficulty of identifying unsuspected toxicities or side effects of drugs during the stage in drug discovery when you're looking at leads. A drug lead may be doing what you want, but you don't have any idea what's going to happen when you put it into an animal or human in terms of unexpected or unwanted side effects. Nine out of 10 compounds fail in the process of going from a lead through finishing up clinical trials." The whole-genome expression technique developed by Friend's group aims to minimize this problem by moni toring not just a drug's effects on its di rect target, but on an entire cell. "If you can go into systems or cells where you can disrupt the primary target of a drug," Friend explains, "then that al lows you to monitor the drug's unwant ed activities much more cleanly, because in a cell where the primary target is miss ing, you can imagine that the changes you see have to be coming from unsus pected or unwanted [effects] that the drug is having on the cell." Hence, in the Nature Medicine study, Friend and coworkers created yeast "knockouts"—yeast engineered to elimi nate the primary target receptors for the immunosuppressants FK506 and cyclo sporin A (CsA). When the yeast knock outs were exposed to FK506 and CsA, the drugs still caused changes in the or ganisms' gene-expression patterns. By us ing DNA chips to analyze the altered ex pression levels of some 6,000 genes, the 14
NOVEMBER 9, 1998 C&EN
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Rosetta Inpharmatics group was able to analyze the ancillary effects of the drugs in great detail. Such observed secondary effects may be indicative of additional useful drug ac tivities or of potentially undesirable side effects—or they may be irrelevant, notes David J. Lockhart, vice president of geno mics research at Affymetrix, Santa Clara, Calif., in a Nature Medicine commen tary. He writes that gene-expression anal ysis of drug-treated cells "has gained the attention of the genomics and pharma ceutical communities because of its tre mendous potential to decrease the time and expense of developing drugs" by al
lowing earlier focus on a smaller set of at least partly validated candidates. But Lockhart points out that FK506 and CsA have fairly specific actions and do not interfere with essential cell pro cesses in yeast, and that gene-expres sion effects may not be as easily inter preted for drugs that do not share those characteristics. And he believes that the success of the whole-genome expressionanalysis strategy "will depend on corre lating the effects of drugs on yeast cells with their effects on humans, necessitat ing .. . yeast-human drug response asso ciation studies." Stu Borman
National Chemistry Week celebrates world of color
winning students will receive computers for classroom use. National Chemistry Week 1998 also marks the beginning of the long-planned International Chemistry Celebration (ICC). Already, 28 local sections and 10 foreign countries have indicated their intent to participate in at least one special activity. That activity is the "Global Salute to Poly mers," an international series of public events to recognize the positive impact of polymers, both natural and synthetic, on everyday life and to mark the sites of poly mer achievements worldwide. In addition•, Thompson says, students
National Chemistry Week (NCW)—the American Chemical Society's annual cel ebration of chemistry—kicked off on Nov. 1 with the theme "A World of Col or." The unifying event for the NCW cele bration—which ran through Nov. 7—was a national poster contest for elementary school students. All 188 ACS local sections are expect ed to participate in this year's celebration, says Kathleen M. § Thompson, NCW coordinator at | ACS headquarters in Washing- ? ton, D.C. And they were en- ^ couraged in their efforts by a t letter to ACS members from | President Clinton that stated: "I commend the members of the American Chemical Society for setting aside this special week to teach us more about chemis try and its contributions to our quality of life." For the poster contest, stu Fourth- and fifth-grade students participate in dents were asked to create an National Chemistry Week at ACS headquarters. 8Vz- x 11-inch poster using colorchanging markers. More than 8,000 pack from around the world will be able to ages of color-changing markers had been participate in a search for natural dyes by distributed to local sections upon request using an activity book called "A World of for use during NCW. Winning posters Color" to be distributed by ACS early from the national and local sections will next year and available in a number of be displayed at the ACS national meeting languages. in March 1999 in Anaheim, Calif. One na As always, NCW boiled down to a tional winner and one honorable mention whole lot of fun—the result of a whole lot will be selected in each of three grade cat of work that is a labor of love from the egories (K-2, 3-5, and 6-8). Winners will scores and scores of ACS local section vol receive a $1,000 savings bond or a com unteers who each year make NCW cele puter, and each honorable mention will brations possible. bring a $500 savings bond. Teachers of William Schulz
