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of Sc ience & Medic ine

A Genetics Lab in the Palm of Your Hand

History

DNA Chips

M o d e r n B i o l o g y f o r H i g h S c h o o l C l a s s r o o m s

Molecular Biology Meets the Microchip

DNA Dragnets:How Much Testing Is Too Much?

Archana Nair:DNA Microarrays on an Industrial Scale

NIH Office of Science Education • Office of Research on Women’s Health

Volume 1, Number 2

Ethics

People

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of Sc ience & Medic ineSNAPSHOTS

RESEARCH IN THE NEWS

PEOPLE DOING SCIENCE

STORIES OF DISCOVERY

SOCIAL IMPACT

Gene Chips: A Genetics Labin the Palm of Your hand

Molecular BiologyMeets the Microchip

Archana Nair:DNA Microarrays on an Industrial Scale

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12DNA Dragnets: How Much Testing Is Too Much?

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DNA Chips: Summary Guide

From the Editor

Tools that speed access to information canbe revolutionary. For example, computermodems have been sending data down

telephone lines since 1962. But the wild, writhingmass we call the Internet couldn’t really take offuntil computer modems could send text, pic-tures, and sound fast enough to keep the averageJoe from falling asleep waiting. Who would surfthe Web if each page took 20 minutes to load?

The DNA chip is a fast, new tool for acquiringinformation, and it promises to do for molecularbiology what fast modems did for the Internet—namely, transform it from top to bottom. DNAchips, also known as DNA microarrays, are toolsthat will help scientists make sense of the hugemass of data flowing out of the human genomeproject and quickly get answers to questionsthey could only dream about a few years ago.You’ll likely see them showing up in everydaylife, too—in the doctor’s office, for example,where they’ll tell caregivers the specifics abouteach patient’s genes, or in a police detective’sstandard toolkit, where they’ll help convict theguilty and clear the innocent.

This issue of Snapshots, our second, tells you allyou need to know about this powerful technol-ogy. Research in the News gives you an over-view. The Story of Discovery tells you howDNA-chip technology developed. PeopleDoing Science profiles a young scientist who’sdeveloping the commercial potential of micro-arrays at Genometrix, a Texas biotech company.Social Impact presents a fictional—but verypossible—scenario from the world of crimefighting and asks you to think through how thistechnology should or should not be used. Asalways, we treasure your feedback. E-mail us [email protected], or hit the “ContactUs” button on the Web site.

Robert Taylor, Ph.D.Editor, Snapshots of Science & Medicine

CONTENTS

DEPARTMENTS

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Once you get past kindergarten,the alphabet is pretty muchold hat. Yet we use this little

set of symbols to express lifetimes ofthoughts, jokes, dreams, and joys.Shakespeare’s plays, Sweet Valley Highnovels, the U.S. Constitution, comicbooks—all written with the same setof squiggly lines. Pretty amazing. Butunless you know how letters worktogether to form words, sentences,and ideas, Shakespeare looks a lot likeSweet Valley—just gobbledygook.

Living things have a language, too,coded in the order of the nucleotideletters A, C, T, and G in their genes.One of the great scientific quests ofthe past—that’s the 20th—centurywas to understand this “language oflife.” First, scientists learned that cellsstore their instructions for living intheir DNA. Then, researchers figuredout how cells convert the nucleotidesequences in DNA into the sequencesof amino acids that make up proteins.Now, scientists are busy reading outcomplete DNA sequences for wholeorganisms. They already have a roughdraft of virtually the entire humangenome, all 3 billion nucleotides of it.

Unfortunately, a genome’s worth ofraw sequence data is about as com-prehensible as a shredded encyclo-pedia. You might pick out individualwords, or even a few paragraphs, butyou still can’t readily understand howthe whole thing fits together.

In the 1990s, scientists developed anew tool for deciphering DNA called

a “DNA chip,” also known as a “DNAmicroarray.” It allows one scientist tocollect more information about DNAsequences in an afternoon than anarmy of scientists could collect in sev-eral years using earlier techniques.

DNA chips promise to carry the sci-ence of understanding genomes to awhole new level, and to bring toolsfor getting DNA-sequence informationout of research labs into doctors’offices, the better to tailor-fit medicaltreatments to an individual’s particulargenetic makeup.

In fact, says Leroy Hood, a molecularbiologist at the University of Wash-ington in Seattle, DNA-chip technolo-gy will be key to meeting one of thebiggest scientific challenges of thecoming century—the analysis of howall the genes in an organism worktogether as a very complex system.

The brain has about a trillion neurons,and about a quadrillion interconnec-tions, says Hood. What we call “con-sciousness” somehow “emerges” fromhow all these neurons interact. “Wecould study an individual neuron for50 years, and that wouldn’t tell us oneiota more about the brain’s emergentproperties, because they arise fromthe network, not a single cell,” saysHood. “If we were to study each genein isolation, we’d never know how thegenome functions as a whole. DNAchips are the prototype global tech-nology for genetics, because they letus look at the behavior of thousandsof genes at once.”

How Chips Work

DNA chips come in many varieties.Some are “homemade” in scientists’laboratories, with glass microscopeslides and a robot arm wielding ahigh-tech fountain pen. Private com-panies are developing other tech-niques for mass production. But DNAchips all depend on the same basicprinciple: Complementary DNA standsstick together.

First, recall that a double-stranded

A Genetics Lab in the Palm of Your Handby Ivan Amato


A hand-held DNA chip and sample-handler,made by Nanogen, Inc. The sample ports are atthe top, and the chip is the blue diamond in thecenter.

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DNA molecule can unzip into twocomplementary strands. Each of thesecan zip back together with its com-plementary sequence. That could beeither its old partner, or a new partnerwith the same sequence. The trick thatmakes DNA chips work is that you cantether a “new partner” to a flat surface.

Imagine a standard checkerboard, 8squares on a side, 64 squares total. Ineach square, you tie down a differentsnippet of single-stranded DNA justthree nucleotides long. You writedown the sequence in each square.(You can make 64 different sequencevariations from three nucleotides—ACG, CGT, GTA, TAC, AAA, and soon—so there’s just enough room forall the possibilities.)

Now imagine you have an unknownsequence, also three nucleotides long.To find out what this unknown is, set itloose on the array so that it wandersfrom square to square. When yourunknown sequence finds its comple-ment, it sticks. To figure out your un-known sequence, all you have to dois find which square your unknownDNA stuck to. Because you know thesequence of the DNA you tied downto that square, you know that theunknown sequence is the comple-ment. (See illustration below.)

Using Chips

What gives DNA chips their power inthe real world is their flexibility, com-pact size, speed, and low cost.Scientists can put not just a hundredbut hundreds of thousands of distinctDNA sequences on a microscopicgrid a few centimeters across. Then,using fluorescent molecular tags thatlight up when a complementary strandbinds to a particular spot, a person(or a robot) can read out whichsequences on the chip find their com-plement in an unknown sample.

DNA chips can gather an incrediblevariety of data very quickly. And be-cause chips can be mass-produced,they will likely be very inexpensive inthe near future. That will allow easycollection of genetic information frommany, many individuals, opening upall kinds of opportunities to help doc-tors diagnose and treat their patients.

Expression Analysis

One way DNA chips allow scientiststo observe genes working together iscalled “expression analysis.” (Remem-ber that to “express” a gene as a pro-tein, cells first transcribe the gene’sDNA sequence into a complementarymRNA copy. Then a ribosome trans-lates the mRNA sequence into the

string of amino acids that makes upthe protein. Cells constantly switchgenes on or off as conditions change.To understand a cell’s behavior in res-ponse to a stimulus—the presence ofa hormone, say, or a toxin, or someenvironmental signal—it would behandy to have a minute-to-minutereading of which genes are turned on.

DNA chips are just about perfect fortracking this kind of minute-to-minutechange in gene expression. For exam-ple, Patrick Brown and his colleaguesat Stanford University wanted to findout the details of how yeast cellsmake spores. Other scientists hadalready determined the DNA sequence

Cellular DNA is double-stranded. Chromo-somes in a cell’s nucleus contain double-stranded DNA. The bases in the two strandsare complementary—A is opposite T, C isopposite G.

Using a single probe. In the 1970s, scientistslearned to use DNA probes to find specifictarget sequences in solution. First, they radio-actively label a known DNA sequence, thenthey put it into a mix of unknown sequences.If the probe’s complement is there, it willbind.

Look for the label. Next, separate the doublestranded DNA from the single stranded. If theprobe found its target, the radioactive labelwill be in the double stranded fraction.

“We could study anindividual neuron for50 years, and thatwouldn’t tell us oneiota more about thebrain’s emergentproperties, becausethey arise from thenetwork, not a singlecell,” says Hood.

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of every possible mRNA a yeast cellmakes. So, Brown and his colleaguesput the complements of each of thesepossible mRNA sequences onto achip. Then, they ground up a bunchof resting yeast cells, which of coursecontained an mRNA corresponding toeach gene that was active the momentthe cells hit the blender. Next, theresearchers spread this mixture overthe surface of the chip. Only the spotscorresponding to genes that wereactively churning out their mRNA litup, because these were the onlyspots on the chip that had found theircomplementary sequence.

This first experiment gave Brown andhis colleagues a baseline. Next, theystimulated the yeast to form spores(by taking away their food) andrepeated their chip analysis six timesover the next 12 hours. By looking atwhich genes turned on, and when,Brown and his colleagues got manynew insights into how yeast cellsgenetically shift gears to make spores.

But the significance of Brown andcompany’s work goes way beyondyeast physiology—it paved the wayfor using DNA chips to see howdozens of genes work in concert tochange a cell’s behavior.

Expression analysis has medical appli-cations, too. For example, a team led

by Eric Lander, director of theWhitehead Institute at the Massachu-setts Institute of Technology, an-nounced last October that they usedexpression analysis—made possibleby a DNA chip—to develop a test toclassify different types of leukemia.(To choose the best treatment, doc-tors need to know exactly what typeof cancer a patient has.) These re-searchers looked at samples fromabout 50 patients already known tohave one of two different kinds ofleukemia. Then, using the patterns ofgene expression they found in thetwo groups, they correctly predictedwhich type of leukemia severalpatients had. In the near future, doc-tors may be able to use this test todecide which is the best treatment fora new leukemia patient. Researchersalso plan to develop similar tests tomatch treatments to patients for otherkinds of cancer, too.

Mapping Our Differences

Pick any two people in the world, andyou would find their DNA is 99.9 per-cent identical. The remaining 0.1 per-cent is the genetic basis of all ofhumanity’s differences, from the shapeof our faces to the way some patientsrespond to a certain drug while othersdon’t. Scientists are now starting touse DNA chips to map out tiny one-letter variations in the 3-billion-

nucleotide human genome. These pin-point differences are called “singlenucleotide polymorphisms,” or SNPs.Identifying them will help researchersunderstand the basis for human variation.

But to map SNPs, you need a differentkind of chip. For expression analysis,you use a chip containing all possiblegenes. For SNP work, you make a chipwith many, many possible variationsof one gene. Then you take a DNAsample from the person you want totest, use PCR to make multiple copiesof the gene you’re interested in, andput this “amplified” sample on thechip. The spot that lights up will cor-respond to the particular sequencevariant the person has. Because thetest is quick and not too expensive,you can do many of them. Then, youcorrelate different outcomes—response to a certain drug, for exam-ple, or the probability of getting heartdisease—with the different geneticvariations.

Francis Collins, director of the NationalHuman Genome Research Institute inBethesda, Maryland, is enthusiasticabout SNP analysis. “There are onlyabout 200,000 functionally importantvariants [SNPs] in the human genomethat have reasonable frequencies,” hesays. “Nearly all of the genetic contri-butions to diabetes and heart disease

DNA Chips: Thousands of Probes at Once.DNA chips allow scientist to use thousandsof probes all at once. First, they spot the dif-ferent probes on a flat surface, often glass.They keep a record of the sequence theyput at each spot.

Let the Targets Loose. With chips, scientistslabel the targets in solution and put the solu-tion on the chip. Any targets that find theircomplementary probes will stick to the sur-face.

Look for the Label. Next, they gently washthe surface, and look for the labeled spots.Because they know the sequences of all theprobes, researchers can easily deduce thesequences present in the solution.

continued on page 9

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STORIES OF DISCOVERY

Molecular Biology Meets the Microchipby Karen Hopkin, Ph.D.

It’s the spring of 2020, and yourgrades have taken a nose dive. Youjust can’t seem to concentrate on

the books—at home, your kid sister isdriving you nuts, and at school, you’rehaving serious daydreams about yourlab partner. So when your momthrows a fit about your “poor academ-ic performance,” she drags you downto the doctor for a DNA check. Onedrop of blood, and five minutes later,the results are in: Your door-slamming,eye-rolling, class-cutting, and body-piercing genes are all turned on; youryessir-ing, exam-acing, supper-table-clearing, and get-to-bed-by-8:30genes are completely shut down.Diagnosis: puberty.

Okay, so that’s a bit far-fetched—body piercing is probably controlledby a whole bunch of genes. But theidea that you can learn everythingabout anybody’s genetic makeupquickly and easily is fast becoming areality, thanks to DNA chips.

These chips, also known as DNAmicroarrays, are made of a silicon orglass plate studded with DNA frag-ments. Smaller than a postage stamp,DNA chips will someday make it pos-sible to identify and analyze everyone of your genes in an afternoon. Atrip to the doctor’s office, for exam-

ple, may involve a quick check of afew critical genes to determinewhether you’ll react well or poorly toa drug, which kind of bug you’vecaught, or whether you’re likely todevelop heart disease, cancer, orAlzheimer’s.

These powerful gene screens springfrom the marriage of two technolo-gies: techniques for slicing, dicing,and sequencing DNAand the miniaturiza-tion that reduced 30-ton mainframe com-puters to somethingyou can carry in onehand. DNA chipscome in a variety offlavors, with differentsubstrates, differentDNAs, different meth-ods of preparation.But they all exploit the fact that everysingle strand of DNA will bind tightlyto its perfect partner, its complemen-tary strand. So DNA fragments an-chored to a chip will latch onto theirpartners if the partners are present in asolution sloshed over the chip sur-face. Because you know the sequenceof DNA stuck to the chip at each par-ticular spot, you know that thesequence that will stick to that spot(see Research in the News for details).

In some sense, we are our genes. Byoffering a way to examine ourgenes—and the genes of other organ-isms—DNA chips stand to help usunderstand, at the most fundamentallevel, how cells work. And what it isthat makes you, well, you. Which isremarkable, considering that 50 yearsago, scientists had no idea what DNA

even looked like, much less how itworked.

To follow the twisty, turny pathwaythat led to DNA chips, wind your waythrough this timeline.

1865 Gregor Mendel, a curiousAustrian monk, publishes a studyshowing how living things—he wasworking with pea plants at the time—

inherit physical characteristicsfrom their parents and passthem along to their offspring.Cross short plants with shortplants, for example, and theresulting crop will be (youguessed it) short. By crunch-ing the numbers from many,many plant matings, Mendelrealizes that individual traitsare inherited separately—a

tall plant can have green peasor yellow peas, just as a tall personcan have brown eyes or blue.Incidentally, scientists believe thatBrother Gregor—though he really didunravel the laws of inheritance—mayhave fudged his data a bit to make thepattern he found “cleaner.” In real life,data never come out that good.

1909 Danish biologist WilhelmJohannsen names the “units of inheri-tance” described by Mendel’s genes.Nobody yet knows what these so-called genes are made of.

1944 Oswald Avery, Colin Mac-Leod, and Maclyn McCarty ofRockefeller University in New York Cityprove that genes are made of DNAand that DNA carries and transmitsgenetic information from cell to cell,generation to generation.

Gregor Mendel

DNA chips stand tohelp us understand,at the most funda-mental level, howcells work.


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1953 James Watsonand Francis Crick determinethe molecular structure ofDNA. Two strands of DNAwind around one another ina double helix. The nucleo-tide bases—A, T, G, and C—run down the center of thehelix, the A from one strandalways pairing with a T onthe other; the Gs pairingwith Cs. This arrangement—the pairingof complementary bases—allowsDNA to be copied. It also allows thepairing of matching sequences onDNA chips. In 1962, Watson and Cricktake home a Nobel prize for theirefforts.

1959 In the seemingly unrelatedworld of computer electronics, RobertNoyce and Jack Kilby first use a pro-cess called photolithography to buildintegrated circuits—tiny transistors,capacitors, resistors, and diodes—onto silicon chips. These miniature cir-cuits allowed computers to shrink insize. Decades later, molecular biolo-gists adopt this technique for buildingnucleotide arrays onto DNA chips.

1960 Molecular biologist JuliusMarmur and others realize that a littleheat causes double-stranded DNA tomelt into two strands, which recon-nect with their partners when cooledback down.

1965 Scientists first propose thatwhen fishing for DNA matches, attach-ing the bait to a solid support shouldmake it easier to detect complemen-tary sequences.

1975 Biologist Ed Southern popu-larizes a method for cutting DNA intomanageable bits, arranging these frag-ments in size order and securing themto a piece of filter paper. In this method,called Southern blotting, radioactivelylabeled pieces of DNA are washed

over this DNA-coatedfilter, and fragments withcomplementary sequen-ces stick to their part-ners on the paper.Exposing the filter to X-ray film (to locate theradioactive labels) allowsresearchers to identifywhich sequences match.Molecular biologists use

a similar technique for identifyingmatching RNA sequences. As a pun,they call the method “Northern” blot-ting. The name sticks.

1977 Molecular biologists FredSanger and Walter Gilbert come upwith related methods for chemicallysequencing DNA—reading thenucleotide bases that make up genesone letter at a time. The techniquesare used today for scanning the genet-ic blueprints of life. In 1980, they wina Nobel prize for their work.

1979 Researchers develop ashortcut to Southern blotting. Insteadof separating DNA by size, biologistssimply plop mixtures of DNA onto fil-ter paper in big dots. These “dotblots,” like their Southern cousins, arethen probed for matches with radio-actively labeled DNA fragments. (Dotblots that contain DNA samples takenfrom different organisms are affection-ately dubbed “zoo blots.”) DNA chipsare essentially dot blots in which sam-ples are spotted onto glass slidesrather than filter paper.

1985 Kary Mullis describes thepolymerase chain reaction, or PCR—atechnique that allows researchers tomake millions of copies of any pieceof DNA they wish to study. Themethod is used for generating theDNA fragments for chips and hasproven indispensable for almost allthe genetic studies done today, inclu-ding large-scale DNA sequencing of

organisms from yeast to humans. Mullis,who claims that the idea for PCR cameto him while he was cruising in hisHonda Civic along the California coast,is awarded a Nobel prize in 1993.

Around the same time, researcherscome up with a means of taggingDNA nucleotide bases with a fluores-cent dye. The trick makes sequencingDNA simpler and paves the way forusing fluorescently tagged DNA todetect complementary sequences ongene chips.

1989 Congress launches the Hu-man Genome Project, awarding $3 bil-lion in funds for a 15-year effort todetermine the exact sequence of the 3 billion DNA bases that make ushuman. And to compare the humangenome with the DNA sequences ofmice, yeast, fruit flies, and othermodel organisms. A decade later,researchers around the world cele-brate sequencing the one-billionthbase of human DNA.

1991 Scientists at the California-based biotech company Affymax pro-duce the first DNA chips. Affymaxtakes advantage of photolithographictechniques similar to those used toetch circuits onto computer chips tobuild their DNA probes, base by base,onto a silicon wafer or glass slide. Byselectively covering and exposing thegrowing stacks of nucleotide bases,

James Watson

Kary Mullis says his Nobel prize-winning idea

for PCR came to him while driving along the

California coast.

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the scientists can control what se-quences they lay down on the array.Researchers then flood this chip withfluorescently tagged DNA—isolatedfrom a bacterium or from your blood,for example—and look to see whichsequences stick. Because they knowthe exact sequences of the DNAprobes on the grid, the researchersautomatically know the sequences ofthe fluorescent fragments bound tothem. DNA that doesn’t find its matchon the chip is simply washed away.

Affymetrix, a spinoff company dedi-cated to gene-chip technology, isestablished in 1993. Today the com-pany offers a variety of gene chips,including human DNA arrays andchips for identifying HIV strains ordetecting mutations in cancer genes.The chips are dense, sporting up to400,000 different DNA probes in anarea the size of a thumbnail. But theirprice tag—up to $2,000 per single-usechip—puts these arrays out of thereach of many basic researchers.

1995 Researchers at StanfordUniversity, led by Pat Brown and RonDavis, work out a recipe for makingDNA chips right in the laboratory.Instead of building the probes onenucleotide at a time on a silicon sur-face, à la Affymetrix, these researchersspot whole DNA fragments onto aglass microscope slide. To make theirarrays, Brown and his colleagues builda robot that uses fountain pen–liketips to dot tiny droplets of a solutioncontaining the DNA probes—largepieces of genes copied by PCR—ontothe slide. These DNA chips are like thedot blots developed in the '70s, onlybetter: They’re more sensitive, theyrequire less sample DNA, they don’trely on radioactivity, and you can dotens of thousands of blots in a singlerun. Once a lab is geared for produc-tion, Brown estimates, chips will costabout $20 apiece. His Stanford Website offers complete instructions for

any lab interested in do-it-yourselfDNA chips, making the technologyaccessible to the scientific community.

1996 Researchers start puttingDNA chips to the test. In 1996, FrancisCollins of the National Human Gen-ome Research Institute in Bethesda,Maryland, uses an Affymetrix microar-ray to detect mutations in the breastcancer gene BRCA1 in women at riskfor the disease. Within a year, Brownand his colleagues synthesize the firstchip containing all 6,000 yeast genes.The chip enables researchers to trackwhich genes are switched on (or off)as yeast cells grow, divide, formspores, or defend themselves againstpoisons. For the first time, researchersare seeing global “gene-expressionpatterns,” with whole clusters ofgenes turning on and off together toorchestrate the activities of a livingorganism.

1998 Researchers begin to useDNA chips to identify and cataloguepolymorphisms—single-nucleotide-base changes that may affect whethera patient will respond to certain drugtreatments.

1999 DNA chips prove valuablefor classifying and studying cancers.Researchers at the Whitehead Instituteat the Massachusetts Institute of Tech-nology (MIT) and others at Stanfordfind that by examining gene-expres-sion profiles, they can differentiatebetween two different subgroups ofleukemia. Only one subtype offers agood chance of survival. These resultssuggest that gene-expression profilingwith DNA chips may be useful for dia-gnosing, and perhaps treating,leukemia.

In other labs, DNA chips allowresearchers to examine everythingfrom which genes make strawberriesripen to which genes make the Ebolavirus so deadly. In October, young sci-

entists anxious to take advantage ofDNA-chip technology pack a courseat Cold Spring Harbor Laboratory inNew York in the hopes of learninghow to build the robots they need tobreak into the chip biz. A handfulpony up $30,000 so they can take theequipment home after class.

Tomorrow Analysts estimate thatthe market for DNA microarrays will be$500 million to $1 billion per year, so,clearly, chips are in demand. In thefuture, advances in technology shouldmake DNA chips cheaper and easierto make. Several groups of researchers,for example, are developing methodsfor printing chips using devices similarto an ink-jet printer. Eventually, custom-order chips may be commerciallyavailable, just a mouse click away. Inthe meantime, molecular biologistshave teamed up with computer scien-tists and programmers to devise waysto make chips easier to read, and theresulting data easier to analyze. Soonscientists will have access to DNAchips containing every gene in mice orhumans. With chips in hand, we’ll bethat much closer to the dream ofunderstanding ourselves—down tothe very last base. •

• All the articles you see here, but inflashy color and optimized for theWeb.

• Audio versions of all our articles.Eyes tired? We’ll read to you.

• A Shockwave animation explain-ing how DNA chips work.

• Hands-on classroom activities,complete with good graphics and ateacher’s guide, to help studentsreally get a grip on the sciencebehind this technology.

• • A compendium of further Webresources about DNA chips.

• All the past issues of Snapshots.

•A feedback page. We really, trulywant to know what you think of ourpublication and any ideas you havefor making it better.

On the Web

If you only have the print version of Snapshots of Science & Medicine, you don’t have it all. Come to ourWeb site (http://science-education.nih.gov/snapshots) for more. For the DNA chips issue, we have


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Molecular Biology Meets the Microchipcontinued from page 5

and hypertension and all of the com-mon illnesses are found in those200,000 elements.” Moreover, saysCollins, once researchers know whichSNPs correlate with higher risk for dis-ease, people with these traits will beable to take extra steps to avoid get-ting sick. This might allow “medicine tomove from its present mode, wherewe spend most of our resources treat-ing people who are sick, to a preven-tive strategy, which is individualized,”says Collins.

Big Power, Big Responsibility

DNA chips will help scientists make

sense of genetic information. Medicalapplications are on most people’sminds, but the same technologies canbe used for everything from confirminglineages of racehorses to teasing outevolutionary relationships betweenclosely related species.

But as the power of chips and geneticscience grows, questions that societymust answer pop up right and left.Should employers use genetic informa-tion in hiring decisions? How aboutinsurers who may want to avoid insur-ing people at high risk for certain dis-eases? How about a zealous politicalgroup trying, say, to portray an oppos-ing candidate as having a high risk of

dying of a heart attack? Today, it’simpossible even to list all the ques-tions, let alone answer them. (Do theSocial Impact section, for insight intoone interesting question.) It will takelaws, regulations, restraint, and wisdomto ensure that the good consequencesof the genetic revolution outweigh thebad, say many researchers, includingLander. “I know of no other field that ismore exciting, or in which it is moreimportant for us all to imagine thefuture,” he says. •


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By her ownadmission,

Archana Nair is alittle bit impa-tient. “I’m always

eager to see results in final form,” shesays, “and I like to get things done.”Fortunately, this approach is exactlywhat she needs in her work at Geno-metrix Incorporated, a young biotechcompany near Houston, Texas. AtGenometrix, Archana is helping devel-op a powerful new technology, vari-ously known as DNA chips, DNAarrays, or DNA microarrays.

A fusion of computer science, bio-engineering, and genetics, DNAmicroarrays are small plates spottedwith hundreds to thousands of specif-ic DNA sequences from plant, animal,or human tissues (see Research In TheNews for details). Far superior toolder techniques that could studyonly one gene at a time, DNA arrayscan tell researchers about the activityand sequence of many genes in a testsample with a single, short procedure.

Archana’s path to Texas began on theother side of the globe. She was bornin Bombay, India, and raised in NewDelhi, where her father worked in theplastics industry and her mothertaught grade-school math and sci-ence. In high school, Archana foundshe had a real affinity for science—especially biology. “My first high-school biology teacher, Bimala Ghai,taught me the significance of under-standing the science, as opposed torote learning,” Archana recalls. “Shehelped me see that science is a cre-

ative activity, with so much still tolearn and explore. I was excited bythe sheer scope of the subject, by allthe ways that science touches every-thing we do.”

Her high-school science experienceinspired Archana to pursue biology asa career. After graduating with a B.S.

in Botany from Delhi University, shewent on to earn a master’s degree atthe Indian Institute of Technology, inKharagpur, specializing in moleculargenetics and biochemistry. She return-ed to New Delhi to begin her profes-sional life, taking a job with the TataEnergy Research Institute. There, shecarried out experiments aimed atdeveloping more-productive strainsof plants.

This job was something of a turningpoint, Archana says, because it intro-duced her to applied molecular

genetics, the science of manipulatingand copying genes. “I knew then thatmolecular genetics was the future ofbiology—and my future,” she says.

But that meant moving on. In India,“we didn’t have any schools where Icould get a degree in molecular biol-ogy that I could then apply right away,and I was in a hurry to work soonerrather than later,” Archana recalls.Moreover, she adds, “I was fortunate


Archana Nair: DNA Microarrays on an Industrial Scaleby Richard Currey

SNAPSHOTS

Archana Nair

“I was fortunateenough to learn a lot of the how inIndia, but I didn’tknow the why. Togrow and develop asa scientist, I neededthe why. And that’swhat brought me tothe United States.”

Just because you work hard doesn’t mean youdon’t get around. Archana sightseeing in Alaska.




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enough to learn a lot of thehow in India, but I didn’tknow the why. To grow anddevelop as a scientist, Ineeded the why. And that’swhat brought me to theUnited States.”

She found her way to theUniversity of Florida, whereshe earned a second master’sdegree, this time in molecularand cell biology. She thenworked with microarray tech-nology for three years atanother biotech companybefore joining Genometrix in 1999.Genometrix was founded in 1993 todevelop DNA-chip technology. Thecompany makes and analyzes cus-tomized DNA microarrays forresearchers in universities and thepharmaceutical industry, helpingspeed up drug discovery and basicbiological research.

When she first joined Genometrix,Archana helped set up the processesand procedures the company uses todeliver the information its customersneed. In her current position as agroup leader in the Process Engin-eering Team, she troubleshoots anyissues that come up on the produc-tion floor. That includes implementinglong-term improvements in automatedprocedures, as well as dealing with allthe little glitches that inevitably cropup. “This means I’malways interacting withthe different engineersand scientists who han-dle automation, bioin-formatics, and researchand development, aswell as those who oper-

ate the equipment and do the analy-ses,” says Archana.

The variety and hectic pace of hereveryday work always hold her inter-est, but she also likes being right on

the cutting edge ofbiotechnology.“Microarrays are thedoorway to futurebiological research—in preventive health,medical diagnostics,and the development

of new medicines, to nameonly a few applications,” shesays. “I like to think of the differ-ence between conventionalgene techniques and micro-arrays as analogous to the dif-ference between ground-based telescopes and theHubble space telescope. Theolder techniques work, but thenewer ones allow us to ‘see’better and farther.

“For me,” Archana continues,“the challenges and potential inmicroarray technology make a

thrilling blend of molecular geneticsand computer science. The wholefield of bioinformatics [using microar-rays to find patterns within large vol-umes of DNA data] is limited only byour imagination. Think about it: Wecan now simultaneously target multi-ple specific genes, and see how theyreact to or interact with other genes,or to external variables such as drugs,bacteria, or viruses. We can look forcorrelations, connections, or relation-ships—some of which will inevitablybe very surprising! This entire area ofresearch will grow by leaps andbounds. And I want to grow with it.”

As DNA microarrays accelerate thepace of discovery, Archana foreseesnew breakthroughs in scientificresearch that will prompt fundamentalrevisions in the prevailing theories oflife, heredity, health, and disease.And—in character—she’s in a hurry toget there. “I’d love to leap forward 50years and see the changes wrought bymicroarray technology,” Archana says.“I guarantee those changes will beremarkable.” •

Archana vacationing in Yosemite National Park.

Archana as a young student inIndia.

“For me, the challenges andpotential in micro-array technologymake a thrillingblend of moleculargenetics and computer science.”


12


SOCIAL IMPACT

SNAPSHOTS

The Social Impact section is your opportunity to workthrough an ethical, legal, or social question that theresearch we’re reporting on has raised. Many times,these questions are so new, it’s difficult to pose themclearly, much less answer them easily. For this issue ofSnapshots, the question is, How broadly should policebe allowed to cast a “DNA dragnet” while investigatinga crime? As the cost of doing DNA-identification analy-sis comes down and the speed increases, interest inusing this technology to sift through large groups ofpeople in a search for suspects will surely grow.

First, students should read the scenario below. Then,they should pick a question from the list and workthrough the Decision Form on the next page. The formis designed to mimic the kind of back-and-forth discus-sion the society at large will go through as peopleattempt to reach consensus on this and other ques-tions that biomedical research raises.

Scenario*

September 9, 2003. Peyton County Police Detective JohnFranklin has a very hard case on his hands. Two women,Mary Adams, age 24, and her sister Gloria Adams, age 17,were brutally murdered while camping near YorktownSprings, a small town in his jurisdiction. The crime occurredat night in Big River State Park, during a heavy rain. Franklincan find no witnesses, no footprints, no murder weapon,no tire tracks, and no fingerprints. He has only one goodlead—bits of skin under the fingernails of Gloria Adams,almost certainly from the killer. A DNA match to this tissuewould conclusively link a suspect to the crime.

But where should Detective Franklin start? He has no sus-pects. However, just last week a company called GeneIdentification Systems sent him a brochure about a newproduct. It uses a device called a DNA microarray to doDNA-identification analysis very quickly and for relatively lit-tle money.

Because Yorktown Springs is so small, Franklin thinks hecould use the new technology to carry out a “DNA drag-net.” He could ask all 2,143 adult residents to give a DNAsample—just a Q-tip rubbed gently inside the cheek—andtest them all. With Gene Identification’s microarray technol-ogy, he could do all the testing for less than $20,000, andget the results in just 3 days. DNA dragnets have been usedfrequently in Great Britain, and they sometimes get results.

Franklin decides to try. He makes a list of all the people inthe county over age 17. He contacts them all, and asks eachto provide a sample voluntarily.

Questions

1. Imagine you live in Yorktown Springs and Franklinasks you for a sample. What would you do?

2. After Detective Franklin sends out a letter to alladults in the area, he begins testing. The 238th person on the list, a man named Irving Tomston,doesn’t respond to letters or phone calls. Whatshould Franklin do?

3. After processing samples from all Yorktown Springsresidents over 17 years of age, Franklin doesn’t finda match. What should he do?

4. A match is found in the samples taken in the drag-net. At trial, the defense argues that the evidenceshould not be admitted. What should the judge do?

5. After the testing, Franklin announces that hisdepartment will put all the DNA profiles collected inthe dragnet into a computer database for futureinvestigations. Should he be allowed to do this?

DNA Dragnets: How Much Testing is Too Much?by Ronnie Yashon, Ph.D., J.D.

* NOTE: This scenario is fiction. Any resemblance to real people, events,or places is purely coincidental.

Policemen conduct aDNA dragnet in thetown of Wee Waa, inNew South Wales,Australia. (See “A FewFast Facts About DNADragnets,” page 14.)


13

Which question on page 12 will you or your group address? _______

List three possible answers to this question.

1.

2.

3.

Come to a decision about which of these answers is best, and circle that number. List three reasons why this is the best answer.

1.

2.

3.

List three reasons other people might not agree with your best answer.

1.

2.

3.

With those counter arguments in mind, why is your answer still the best?

Identify at least three people or groups with a stake in the question, and state how they would be affected by your solution.

1.

2.

3.

Give two possible outcomes for the country if your solution was put into practice.

1.

2.

Decision FormStudent’s names

SOCIAL IMPACT


14



“A banana a day keeps the doctoraway.” Researchers at the BoyceThompson Institute (BTI) are busyadding bits of bacterial and viral DNAto bananas, potatoes, and other foodplants to create “edible vaccines.” Byserving up the antigens that the insert-ed DNA sequences encode, theresearchers hope to give people long-lasting immunity. If it works, the fruitscould provide a powerful and rela-tively inexpensive way to fight dis-ease—especially in poor countries,where a single dose of a standardvaccine can cost many times the aver-age amount a person there spends ina year for all health-care needs com-bined.

The idea of making an edible vaccineis the result of blending two fieldsthat you might not think would everbelong together—namely, humanimmunology and plant biotechnology.Find out how these two differentparts of science grew up and, even-tually, grew together.

The need for new ways to preventdisease, especially in poor countries,is clear. But the whole idea of geneti-cally modifying foods has caused aworldwide uproar. This section allowsyou to explore how these two issuestogether might play out when itcomes to genetically engineering fruitto prevent illness.

Joyce Van Eck spends much of hertime trying to make plants make mis-takes. Specifically, Van Eck, director ofthe Plant Transformation Facility at BTI,develops new ways to mass-producemutant plants. By looking at whatphysical and chemical changes themutations cause, researchers can bet-ter understand what each plant genedoes. Sarah Abend is a researchassistant who works with Van Eck.Abend earned a bachelor’s degree inplant science in 1997, and figuresthat’s enough formal schooling for her.She plans a career in industry, workingon applications of plant engineering.

Next Time in SNAPSHOTS...RESEARCH IN THE NEWS STORIES OF DISCOVERY

SOCIAL IMPACT


A Few Fast Facts about DNA Dragnets

SOCIAL IMPACT

• Although the scenario presented here is fictional, DNAdragnets have been employed in other countries, includ-ing the United Kingdom and Australia. For example, onJanuary 1, 1999, a 91-year-old woman was raped in herhome in Wee Waa, a small town in New South Wales,Australia. The police had no good leads. In April 2000,police asked all men between the ages of 18 and 45 liv-ing in and around the town to give a saliva sample fortesting. Stephen Boney, a 44-year-old laborer, was one ofover 600 men who gave a sample. Ten days later, beforehis sample was analyzed, Boney confessed to the crime.He pleaded guilty at his trial on July 11, 2000, and nowawaits sentencing.

• Taking DNA samples from many people in a specific areais called a mass DNA screening or a “DNA dragnet.” Asthe cost of doing DNA analysis comes down, interest inthis tactic will surely grow.

• Currently, DNA identification is labor intensive and costsabout $50 per sample. DNA microarrays could dramati-

cally reduce this cost, however, making it more practicalto test a lot of people quickly.

• DNA-identification analysis reveals nothing about anyphysical traits a person might have. It’s useful for identifi-cation only.

• To do DNA identification, labs analyze a set of DNAsequences called short tandem repeats (STRs). As theinvestigator analyzes more STRs, the chance of a randommatch goes down. The FBI has identified a standard set of13 STRs for DNA identification. The chance that two peo-ple are identical in each of these 13 STRs is virtually zero.

• DNA testing could conceivably reveal much about per-son’s physical characteristics. If the original sample is alsokept, not just the identification profile, an enormousamount of information about an individual’s genetic traitscould be acquired by performing other tests.


15


Here are some basic facts aboutDNA chips. Don’t memorize this

list, but read through it. After readingthis issue of Snapshots, you will (wehope) be able to say, “OK, I knew that,”about each point.

• DNA chip is slang for DNA microarray.

• DNA chips are a revolutionary tech-nology. They speed up research,helping scientists understand the pri-mary sequence of the human genome,now almost complete. They will alsoallow doctors to get important genet-ic information from individual pati-ents and, therefore, to choose thebest treatments.

• Each of the strands in a bit of dou-ble-stranded DNA is complementaryto the other. Adenine (A) is oppositethymine (T), cytosine (C) is oppositeguanine (G). So, the sequence CCATGA would be complementaryto GGTACT. Complementary DNAstrands separate on gentle heating.They bind again when cooled.

• A DNA chip is made of many differ-ent DNA sequences stuck to a flatsurface. Each spot on the surfacecontains a different sequence.

• You can use a single strand of DNA to“probe” a solution for that strand’scomplement: Put in the probe, sloshit around, pull it out. If the comple-ment is in there, it will bind onto theprobe.

• A DNA microarray allows you toprobe a solution for thousands of different sequences all at once. Stickeach different probe at a specificspot on a flat surface. Slosh a solu-tion containing the unknown single-stranded sequence over it. Rinse.Look for the spots where the probesfound their complements.

• Microarrays can have tens of thou-sands of spots. This means they canlook for tens of thousands of DNAsequences all at once.

• A sequencing array is made of manydifferent short DNA sequences.Researchers use these to find thesequence of an unknown bit of DNA.A researcher chops the unknownsequence into short bits, sees wherethe bits bind on the array, deducesthe sequences of all the short un-known bits, then reassembles theoverlapping sequences into one longsequence.

• An expression array is made up ofmany different long DNA sequences,each complementary to every mRNAsequence that a certain cell can make.Researchers use these to studymoment-to-moment changes inwhich genes are turned on or off. Aresearcher breaks a cell preparationopen, extracts all the mRNA sequen-ces it contains at that moment, andputs those on the expression array tosee which ones are there. This tellsthe researcher which genes in the cellwere turned on—being expressed,making mRNA—at the moment thecell broke open.

• Researchers love DNA chips becausethey give a huge amount of informa-tion, fast, at low cost.

• Doctors will soon learn to love thembecause there are many times when adoctor would like to know somethingabout a patient’s genes (such aswhether the patient is likely to res-pond well to a certain drug). Whenthe price comes down enough,microarrays will likely become routinetools in the doctor’s office.

Summary Guide: DNA Chips

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