JANUARY 22, 2001 VOL. 157 NO. 3

DNA Microarrays
The workhorse of genomic medicine
By UNMESH KHER

ALSO The Future of Drugs Now that our DNA has been decoded, the search for better, faster and more effective medications begins in earnest • Inside the Brave New Pharmacy: At a leading genomics firm, the star of the show is a robot • DNA Microarrays: The workhorse of genomic medicine • Bioinformatics: How to design a molecule • The Search for Cures: The fight against aids, cancer, mental illness, obesity, Alzheimer's

ALSO IN TIME COVER: The Future of Drugs Now that our DNA has been decoded, the search for better, faster and more effective medications begins in earnest • Inside the Brave New Pharmacy: At a leading genomics firm, the star of the show is a robot • DNA Microarrays: The workhorse of genomic medicine • Bioinformatics: How to design a molecule • The Search for Cures: The fight against aids, cancer, mental illness, obesity, Alzheimer's NORTH KOREA: Out of the Bag A German doctor's close encounters with the Hermetic Kingdom shed light on the miserable living conditions in one of the world's last Stalinist states. Plus, excerpts from his diary THAILAND: The New No. 1 The numbers are lining up for Prime Minister-elect Thaksin JAPAN: Murder on the Wards Fears that a killer nurse has been on the loose lead to calls for a more open medical system THE PHILIPPINES: A Load of Rubbish The streets of Manila are overflowing with uncollected trash HONG KONG: Surprise Farewell A top civil servant's resignation puzzles the territory MEDIA: A Guy on the Move Hong Kong mogul Jimmy Lai starts anew in Taipei RELIGION: Muslim Rebellion Japanese food-additive maker Ajinomoto comes under fire in Indonesia for an odd way of making MSG TRAVEL WATCH: Bear Necessities in Ancient, Spicy Chengdu

Nowhere has Silicon Valley had a more direct impact on biology than in the invention of the miniature laboratory bench known as the DNA microarray. Microarrays detect active genes by exploiting the fact that when the two strands of a gene in the double-stranded DNA molecule are separated, each can readily pick its partner out of a crowd of similar molecules. In a typical microarray, thousands of single-stranded gene fragments are fastened to a platform —usually a silicon or glass wafer but sometimes a nylon sheet. The finished assemblage can be as small as a postage stamp. Its purpose is to answer, as comprehensively as possible, what it is that makes one cell different from any other.

Although nearly every cell in the body contains a full complement of genes, only a small fraction of those genes are active in any one cell. A cell on the tongue, for instance, may express genes encoding proteins required for taste sensation, while an immune cell battling infection churns out proteins lethal to bugs.

The overall patterns of gene expression in cells interest drug designers because they provide a molecular lineup of potential drug targets. But scientists trying to identify those targets have long been limited to probing active genes one at a time. No longer. Microarray kits, like those made by Affymetrix, based in Santa Clara, U.S., allow scientists to scan up to 60,000 gene sequences in a single step.

To probe cellular gene activity en masse, scientists first isolate the molecules that translate genes into proteins. They then copy these molecules into their corresponding DNA sequences, tag those sequences with fluorescent markers and pour the tagged sequences over the microarray. Active genes in this biochemical stew stick like Velcro to their single-stranded partners on the chip, creating patterns of fluorescent dots that reveal which genes are turned on. "This technology has fundamentally altered how we explore biology," says Dr. Olli Kallioniemi of the NIH, who studies gene expression in cancers.

It has also created something of a microarray gold rush. Several firms—from pioneering Affymetrix to the upstart Incyte Genomics, based in Palo Alto, U.S.—help pharmaceutical companies identify drug targets found exclusively in diseased cells. Others, like Phase-1 Molecular Toxicology of Santa Fe, U.S., sell chips that test how chemicals affect gene expression, allowing pharmaceutical firms to quickly reject candidate drugs too toxic to be worth pursuing.

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