THEMAGIC

OF MICROARRAYS
Research tools known as DNA microarrays are alrea y clari!yin" the molec#lar roots o! health an isease an s$ee in" r#" isco%ery& They co#l also hasten the ay when c#stom'tailore treatment $lans re$lace a one'si(e'!its'all a$$roach to health care
DOT )ATTERNS EMERGE

+Y STE)H EN H& FRIEN D AND RO,AN D +& STO-G HTON

when DNA microarray s analy(e tiss#e sam$les& In i%i #al i!!erences in those $atterns co#l one ay hel$ octors match treatments to the #ni*#e nee s o! each $atient&

44
SCIENTIFIC AMERICAN

Copyright 2002 Scientific American, Inc.

MOST )EO),E STRIC.EN

with a cancer called diffuse large B cell lym-phoma initially respond well to standard therapy. Yet in more than half of cases, the cancer soon roars back lethally. Physicians have long assumed that the reason some individuals succumb quickly while others do well is that the disease actually comes in different forms caused by distinct molecular abnormalities. But until two years ago, investigators had no way to spot the patients who had the most viru-lent version and thus needed to consider the riskiest, most intensive treatment. Then a remarkable tool known as a !" microarray, or !" chip, broke the impasse. #t enabled a team of researchers from the !ational #nstitutes of $ealth, %tanford &niversity and elsewhere to distinguish between known long- and shortterm survivors based on differences in the overall pattern of activity e'hibited by

Copyright 2002 Scientific American, Inc.

hundreds of genes in their malignant cells at the time of diagnosis. That achievement should lead to a diagnostic test able to identify the patients in greatest danger. !" microarrays, first introduced commercially in ())*, are now mainstays of drug discovery research, and more than +, companies sell them or the instruments or software needed to interpret the information they provide. The devices are also beginning to revolutioni-e how scientists e'plore the operation of normal cells in the body and the molecular aber-rations that underlie medical disorders. The tools promise as well to pave the way for faster, more accurate diagnoses of many conditions and to help doctors per-sonali-e medical care.that is, tailor ther-apies to the e'act form of disease in each person and select the drugs likely to work best, with the mildest side effects, in those individuals.

Tiny Troupers
T $ / " 0 0 " Y % 1 2 3 / # ! several

varieties, but all assess the composition of genetic material in a tissue sample, and all consist of a lawn of single-stranded !" molecules 4probes5 that are tethered to a wafer often no bigger than a thumbprint. These chips also capitali-e on a very handy property of !"6 complementary base pairing. !" is the material that forms the more than 7,,,,, genes in human cells . the sequences of code that constitute the blueprints for proteins. #t is built from four building blocks, usually referred to by the first letter of their distinguishing

chemical bases6 ", 1, 8 and T. The base " in one strand of !" will pair only with T 4"9s complement5 on another strand, and 1 will pair only with 8. $ence, if a !" molecule from a tissue sample binds to a probe having the sequence "T1881, an observer will be able to infer that the molecule from the sample has the complementary sequence6 T"8118. 0!", which is !"9s chemical cousin, also follows a strict basepair-ing rule when binding to !", so the se-quence of any 0!" strand that pairs up with !" on a microarray can be in-ferred as well. 1omplementary base-pairing reactions have been integral to many biological tests for years. But ama-ingly, !" microarrays can track tens of thousands of those reactions in parallel on a single chip. %uch tracking is possible because each kind of probe.be it a gene or a shorter sequence of code.sits at an assigned spot within a checkerboardlike grid on the chip and because the !" or 0!" molecules that get poured over the array carry a fluorescent tag or other label that can be detected by a scanner. 2nce a chip has been scanned, a computer converts the raw data into a color-coded readout.
%cientists rely on !" microarrays for two very different purposes. %o-called genotype applications compare the !" on a chip with !" in a tissue sample to determine which genes are in the sample or to decipher the order of code letters in as yet unsequenced strings of !". :requently, however, investigators these days

use the devices to assess not merely the presence or sequence of genes in a sample but the e'pression, or activity level, of those genes. " gene is said to be e'pressed when it is transcribed into messenger 0!" 4m0!"5 and translated into pro-tein. 3essenger 0!" molecules are the mobile transcripts of genes and serve as the templates for protein synthesis.

Gene Hunters
have employed the genotype approach to compare the genes in different organisms 4to find clues to the evolutionary history of the organ-isms, for e'ample5 and to compare the genes in tumors with those in normal tissues 4to uncover subtle differences in gene composition or number5. 2ne day gene comparisons performed on !" chips could prove valuable in medical practice as well.
0/%/"01$/0%

1arefully designed arrays could, for instance, announce the precise cause of infection in a patient whose flulike symptoms 4such as aches, high fever and breathing difficulty5 do not point to one clear culprit. " surface could be arrayed with !" representing genes that occur only in selected disease-causing agents, and a medical laboratory could e'tract and label !" from a sample of infect-ed tissue 4perhaps drawn from the per-son9s nasal passages5. Binding of the pa-tient9s !" to some gene sequence on the chip would indicate which of the agents was at fault. %imilarly, chips now being developed could signal that bioterrorists have released specific types of anthra' or other e'otic germs into a community.

O % e r%ie

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s$ eci! ic "e ne s or to me as #re "e ne acti %ity in tiss #e sa m$ les&

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