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OUTLOOKGOOO Thegene hunters Unlocking the secrets of DNA to cure disease,slow aging

BY LESLIE ROBERTS

O ne by one, new colors appear on

the computer screen-red, blue, green, yellow-ticking off the pre- viously unknown code of human DNA. Each color is one chemical base-one "letter" in the 3 billion-plus letter script of the human . Soon the screen ":; " is awash in colors, a pointillist painting :..f!£:'. that holds the secrets of human heredity. :: Color by color, base by base, that scene is being played out in a handful of labo- ratories in the United States and England as scientists race to finish the Human Project:'-the most audacious endeavor undertaken in biology. When they are done, perhaps as early as the end of 2000, they will have accomplished what many said was impossible just 10 years ago: uncovering the complete genetic instructions of a human being. This revolution will bring changes no less sweeping than those wrought by the microchip in the 1990s. As with infomla- tion technology, imaginations and busi- ness energies will be fixed on biotech breakthroughs that promise to unfold in the 21st century. The consumer will keenly feel the ef- fects: simple blood tests, for instance, that reveal one's risk of developing cancer or Alzheimer's, or custom-made drugs that work without side effects. Genetic knowl- edge may be harnessed to cure diseases or even slow the aging process. Exploringthe unknown. Scientists got a peek of what's to come in December, when the first human chromosome was decoded. , who directs the project from the National Institutes of Health, confessed that he got chills when he glimpsed the "landscape of a complete human chromo- some," likening it to seeing the surface of another planet for the first time. Equally thrilling, said Collins, were the implications: that "this most ambitious of human en- deavors, a journey into the human genet- ic instruction book," will succeed. This vast project is designed to unlock the secrets in a genome-an organism's complete genetic code, which determines whether a fertilized egg develops int~ a Born:1Jct.14,1946, . Education:Ph.D., University of -SanDiego. mouse, a fly, a human, or some other hv- . . - . . . . ing species (gatefold, Page 39). A simple Proudestachievement: winning the Atlantic CupChallenge sailing race. Favoritebook: misspelling in a gene can wreak havoc- Consi/ienceby E.O. Wilson. True confession: "I almost flunked out of high school."

34 U.S.NEWS& WORLDREPORT, JANUARY 3/ JANUARY10, 2000 PHOTOGRAPHSBYDONALD GRAHAM FOR USN&WR i

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OUTLOOK8o00

turning a normal cancerous, for in- stance. To some as yet unknown degree, genesalso influence our personalities and behavior. Having the full human instruc- tion manual in hand-promises profound changesin ,medicine-and evenin our understanding of ourselves. The instruction manual will give sci- entists glimpsesinto the molecular changes that underlie a host of diseases,from can- cer to diabetes to mental disorders. But. such benefits do not come without a cost. Will insurers and employers have access to an individual's genetic profile? Will the medical benefits go to the rich and not to the poor? Will genesbe manipulated to design smarter kids? "The consequences .';:,,:~:~,,::;~:<;~c~;: are sofar-reaching as to touch everyas- ' ,," ~",~:::".-;~.;..:,.:;;::~.%., pect 0f society,". saysEnc Land er, a math - ematician turned geneticist who runs one of the biggestsequencing labs, at the Mass- achusetts Institute of Technology. Biology'smoonshot. Aside from the elec- tronic whirrings from row upon row of boxy PE3700 sequencingmachines, Lan- der's lab is eerily quiet. Hour after hour, the machines toil, deciphering DNA at a rate of millions of bases a day. If the genomeproject is biology'smoonshot, then the MIT megalaband four others like it are the Cape Canaverals, albeit ones where there is little work for humans, save for tending the machines.Like the race to the moon, the scramble to decipher the genomeunderscores man's drive to explore the unknown. With the stakesso high, the race has also seen its share of acrimony and egosas outsized as the endeavor. One of the first mavericks was Walter Gilbert, a brilliant and irreverent at Harvard who championedthe ide\i-the "Holy Grail" as he called it-15 years ago. He was soonjoined by another giant in the field: JamesWatson, codiscoverer of the structure of DNA.The two touted the idea, .".. ..,.. :..' but most were not impressed. z.:.. .' At the time,the biggest organism that had :..'.., ": been deciphered was a minuscule virus, Born: April 6, 1928, Chicago.Education: Ph.D., zoology, Indiana University. Proudest ;;::;",;.;::~:~~L~':;" just 240,000 baseslong-and that took achievement:writing TheDouble Helix. Role model: early in his career,chemist Linus several researchersyears to complete. At Pauling.Goal: stopping cancer. Favoritebook: TheGreat Gatsby. 3 billion bases,the human genomewould consumethousands of scientistsfor count- lessyears. And with its $3 billion price tag, cist Shirley Tilghman of Princeton Uni- worm, and a fruit fly, that carried the day. it would divert funds from other biologi- versity, aswell as Gilbert and Watson.They Most geneticists had cut their teeth work- cal studies. "It endangersus all," warned compromised on a phased approach that ing on these creatures, which share many MIT geneticist David Botstein in 1986. would begin not with sequencing but by of their geneswith humans. Biologists had Even NIH, the nation's major funder of constructing "maps" of the genome. Not no chance of understanding the human biomedical research,wanted no part of it, only were maps relatively simple to con- genome without insights from these or- leaving the U.S. Department of Energy struct, but they would greatly speed the ganisms, Tilghman argued. to lobby Congressfor the project. search for diseasegenes. As for sequenc- As the gained congres- But the audacious idea prevailed. The ing, the panel recommendedthat it be post- sional funding, NIH wrested control of the turning point was a 1988 National Re- poneduntil newtechnologies made it faster project away from DOE.NIH setup a spe- search Council (NRC)report, which unan- and cheaper. It was the panel's recom- cial genome office and, in a coup that imously endorsedthe project-a surprise, mendation that the project also map and brought instant credibility, nabbed Wat- as the NRC panel contained tough crit- sequence the of simple organ- son to head it. "My name was good," re- ics, including Botstein and mouse geneti- isms, such as yeast,a bacterium, a round- calls Watson. He set a deliberate plan: The

U.S.NF.ws &:WORLD REPORT,JANUARY 3/ JANUARY 10, 2000 35 . r

OUTLOOK.OOO

goal was to build a set of power tools-the map and the sequence-akin to the par- ticle-smashingaccelerators that had trans- formed physics.And he relentlesslypushed the project's first tangible goal: the maps that would speedthe searchfor genetic de- fectsthat causedevastating hereditary dis- eases.Knowing full well that Congressdid not have the patience to wait 15 years for results, Watson staked his reputation on getting the maps done in five. Once the maps were complete, geneswould fallout in short order-including the putative Alzheimer's gene, which Watson joked should be a high priority, given the age of most congressmen. Map building entails looking for dis- tinctive pieces of DNA and using them as landmarks along the chromosomes. The , more landmarks, the better the map. But _:'...~c.'. first scientistshad to find those landmarks, a task that entailed scouring through base after base of DNA. Slowly, researchers found landmarks and placed them on the map. Even before they were done, the landmarks proved invaluable, enabling I investigatorsto find the cystic fibrosis gene I in 1989. Genesfor other diseases,includ- ing neurofibromatosis and Huntington's, quickly followed, years earlier than would have been possible without the maps. At the same time, biologists and engi- neerswere trying to speedthe sequencing process.Until the mid-1980s, the task con- sistedof breaking DNA into fragments, tag- ging them with radioactivity, and then plac- ing them in a slab of clear semi-solid gel, sandwiched between two pieces of glass. The gel was zapped with an electric cur- rent, which pulled the fragments along at different speeds,depending upon their size.Finally, technicians photographedthe gel and "read"the sequence-which looked like a seriesof gray blobs. With these tech- niques, a skilled worker could sequence a mere 15,000 bases a year, but by 1986, Caltech biologist and col-. . - . leagueshad found a way to up the speed Born: April 14, 1950, Staunton,Va. Education:Ph.D., Yale; M.D.,Umv. of North Carolina. to 15,000 basesa day-thanks to the first Proudestachievement: finding the cystic fibrosis gene. Rolemodels: the Alberts- automated sequencing machine. Schweitzerand Einstein.Hobby: riding his motorcycle. favorite book: Mere Christianity. Enter Venter. Meanwhile, other scien- tists wereworking out the kinks in the new machinesby testing them on the genomes and then sequenceda small bit of it. The rector Bernadine Healy, who sided with of yeastand worms. Although the hurdles partial sequenceserved as a "tag" to iden- Venter. At issue was whether scientists remainedhigh, the project was on course- tify the gene. Thumbing his nose at the could stake a claim on a gene, or a par- until it was challenged by a relatively un- genome establishment, Venter asserted tial gene, without even knowing what it -: known NIH biologist, J. . that he could find most of the 100,000 did. If they could, that claim could dis- In 1991,Venter came forward with an human geneswithin a few years. courage other researchers from laboring iconoclastic idea: Rather than painstak- Watson dismissed Venter's cream- long and hard to understand that geneand ingly decipher eachand everybase of DNA, skimming plan, but Venter pursued it any- develop it into a product, say,a diagnostic why not concentrate first on sequencing way, and NIH began filing patent appli- test. The fight cost Watson his job. the genes?What's more, Venter boasted cations on Venter's partial genesat a rate After Watson's abrupt departure, NIH that he had a clever way to find the genes, ofl,OOOeach month. When Watson found picked Francis Collins, a genehunter ex- which he touted as a shortcut to the out, he erupted, denouncingthe patenting traordinaire at the University of Michigan, genome project. Venter simply looked in scheme as "sheer lunacy." He went to to take the helm. Dedicatedand ambitious, DNAfor the telltale signs of an active gene war with both Venter and then NIH Di- Collins was fresh off the heady successes

36 U.S.NEWS& WORLD REPORT,JANUARY 3/ JANUARY10, 2000

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of finding several disease genes. While Watson had talked about building tools, Collins, a physician by training, talked about saving lives. Soon the early investInents began to pay off as maps were completed and genes were ;~;~:; discovered at breakneck speed. But the . "'" project'sgenome, ultimatewas lagging goal, behind.sequencing Collins, the

like Watson before him, had hoped for rad- ical new technologies that would make se- quencing a breeze. None had materialized. Investigators continued to fine-tune the ,;" machines so they could handle longer stretches of DNA. But finishing the job- piecing the fragments together like a giant jigsaw puzzle-was proving tough. Some ~::: :c pieces of DNA simply refused to be se- :: quenced, leaving troubling gaps. , Shot in the arm. Genome sequencing sorely needed a shot in the arm. It came from an unlikely quarter. In 1995, Venter, then head of the Institute for Genomic Re- search in Rockville, Md., published the entire DNA sequence of the microbe -the first se- quence of a free-living organism. The microbe was small-just 1.8 million bases- but the feat was stunning because Venter's crew blasted through it in just one year. More startling still, Venter did it using a new approach, whole genome shotgun se- quencing, that NIH researchers had in- sisted wouldn't work. Venter's technique involved chopping up the entire genome into small pieces, sequencing each piece, and then reassembling them in correct order. NIH-fundedscientists, on the other hand, were starting with one relatively small chunk of the genome and then break- ing it into pieces-an approach that left, them far fewer pieces to reassemble. NIH's approach was soon vindicated when a Stanford University team polished off the genome of baker's yeast, a milestone

,.," " ,. not only because of its size-15 million ',-: bases-but because of its complexity: Its . . . cell resembles those of humans. It provided Born: Sept. 17, 1946, Toronto. Education: Ph:D., Temple University. Role models: blo- stunning insights, as Tilghman predicted. chemist and cancer biologist . Favorite book: Vanity Fair. Buoyed by these successes, researchers Favorite movie: All About Eve. True confession: addicted to murder mysteries. were increasingly eager to plunge into the . In April 1996, Collins gave six labs the charge to sequence a long pany, Celera , that would sin- billion bases 9fthe human genome. ~",Jk" stretch of human DNA while simultane- gle-handedly sequence the human Although Collins maintained a polite ~~i;~: ously imp~oving the technology. If all went genome i.nj~st three yeax:s, and for a mere front, h: and other scientists in the public ';;~:": well, the SlXgrOUpS would complete 3 to 5 $300 mIllIon. The claIm was not far- consortium felt angry and threatened. If ;i;~~, percent of the human genome by 1999. fetched: Venter had several innovations Congress believed Venter's bravado, would "i~~'" Then the project would scale up, with com- to rely on and a hefty bankroll to fuel it pull the plug on the federal effort? In

1 :;( pletion in 2005, a daunting task since that them. He had 300 of the world's fastest public, and even more in private, scientists

'. entails sequencing the genome 10 times sequencing machines, the PE 3700, each denounced Venter's headline-grabbing over to ensure accuracy. capable of accurately processing 400,000 StYle and insisted the shotgun technique That cautious game plan was turned bases a day, and one of the fastest su- could not work on the human genome. on its head when Venter dropped a bomb- percomputers in existence. And he had They accused Venter of conspiring to lock shell. He announced in May 1998 that he the whole-genome shotgun approach that up the genome in patents and deny the had teamed up with Perkin-Elmer Corp. had worked so well on Haemophilus. But public the fruits of the genome project. of Norwalk, Conn., to create a new com- this time, Venter was going to shred all 3 But all the while, the publicly funded re-

U.S.NEWS&; WORLD REPORT.JANUARY 3{ JANUARY 10, 2000 37 - - '- "f"~

OUTlOOKt)OOO -~ searcherswere placing orders to use genetic profiles to pre- for the PE 3700, and-more diet how individuals will re- important-Collins was re- spond to drugs. Further out is vampingthe program~.o try the prospect of "personalized to beat Venter. The publ1c medicine," in which drugs are consortium decided to con- tailor-made to a patient. centrate money in the five Some of the most profound fastest sequencing labs-at changes will emerge when MIT, Washington University scientists uncover the genes in Missouri, Baylor Collegeof that increase the risk of com- Medicine in Texas, DOE'S mon diseases-not just can- genome institute in Califor- cer, but diabetes, heart dis- nia, and the SangerCentre in ease,Alzheimer's, and mental England. Collinsvowed to fin- disorders. Even before new ish the sequenceby 2003, two drugs are ready, tests will re- years aheadof schedule.And, veal an individual's risk and in a major shift, he promised show ways, such as dietary ::~:;:'::: to produce a "rough draft" change, to prevent it. ;-,~ ',: of the genome by spring Stunning as the achieve- 2000, a year ahead ofVen- ment is, scientists no longer ter-a strategydesigned to un- call the sequence the "Holy dercut any'attempt by Celera Grail." "It's a parts list," Lan- to patent most of the genes. der says. "If I gave you the "Cxt"" Feats with DNA.The race parts list for the Boeing 777 .".'""',"~ ~, was on. First Venter said he and it had 100,000 parts, I had sequenced the fruit fly don't think you could screw it with Gerry Rubin at the Uni- together and you certainly versity of California- Berke- wouldn't understand why it ley. Next, Venter boastedthat flew." But with the parts in 1 billion basesof human DNA hand, scientists can begin to were done, a feat dismissed figure out what eachdoes and \~i byNIHbecausehedidnotre- how they build a human-a ~ leasethe data. SoonNIH pro- task that should keep biolo- ~ claimed that it, too, had se- ,- gists busy through the new quenced 1 billion bases and Born: Feb.23, 1957,New York. Education: Ph.D., mathematics, century. "This is absolutely put the data on the Internet. OxfordUniversity. Favorite books: Angela'sAshes, Charlotte's Web. the beginning," saysVenter, ~.7~ Venter countered at3 billion. Favoritemovies: Casablanca,Shakespeare in Love. "which is why we are in such a I, Just last month, the rivals hurry to get there." reached a detente and began In a lesstangible but equal- ~ talking of collaboration. By then itwas wafers containing samples of DNA, scien- lyprofound way, the genome project may clear that Venter wasunstoppable, the two tists can see which genes are switched changehow peopleview themselves.These-

..." approacheswere complementary,and Con- on in a cancer cell-which suggestsmyr- quence will provide tools to probe which gresswas not going to pull the plug on the iad newways of attackingthe disease.Lan- personality traits are hardwired in the public effort. der, for one, is convinced that cancer will genes,which are more amenable to envi- And surely there was enough in the sci- eventuallybe cured, though not in the next ronmental influences. The danger is that -..,., ,..' Already,entific future genetic to cover knowledgeboth entities is illuminat- in glory: is10 so or mykids'kids 20 years. "The will reason never I diedo ofthis cancer. work others-aspeople will nobegin more to thanseethemselves-and their genes. But ing the processesat work in many diseases. And that is a pretty darn good goal." as Collins notes, "free will will not go out By using new "DNA chips," dime-size Well before then, doctors should be able of style"once the project is done..

g~.~~~.~~.,.~,~.~.~,~,~,~ life insurance. That is partic- they deny coveragefor the - - ularly troubling because the child if she doesn't? Says Many benefits , many perils thenew~est.swillpr~dict~~lylikelIhood of Inhenting a GeorgeBostonUniversityeth~cist Annas: "The nght cientists mapping uninsured, and the ill and disease.Finding cures will not to know is going to be- S, human DNA ire rush- disabled often find it hard to lag behind. That's why fewer come as important as the ing us headlong into a get coverage.With genetic than 15percent of those at right to know." genome century, but the testing certain to become risk for deadly Huntington's Also worrisome: In a na- creaky American health care more common, people with a diseasehave sought the test- tion of health care haves system is unprepared. geneticpredisposition to dis- ing already available.And if and have-nots, gene-based A little geneticknowledge easessuch as breast cancer a prenatal test showsrisk, treatments may become an can be a dangerousthing. Al- or Alzheimer's could be vul- will insurers pressure a option only for the wealthy. ready, there are 44 million nerable to losing health or woman to abort a fetus? Can -Joseph P. Shapiro

38 U.S.NEWS" WORLD REPORT,JANUARY 3 / JANUARY 10,2000 -' - ;;\ cj!~t:::!1"': ~I .':~ -, Decodingthe Future! Thegoal of theHuman GenomeProject is to decipherthe genetic code- the instruction bookfor building a human being. That meansworking out the exact order of the roughly 3 billion chemical "letters"that make up the entire complementof DNA, or genome,including the 100,000 i or so genes. Understanding this human instruction manual promises to transform biology and , medicine in the 21st century. GENETICS101 '~, ' ~1"i!iA"'.-

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. : TodeC'tpher the human genetic code, researchers have to determine the exact order of the 3 billion chemica/letters that make up ~: i our DNA. Here is how they are doing it: '";;;; i I~:' : m The book of life ~;'.~;,; The genome, the complete set of genetic instructions, . '" . - is often called the .-' "book of life." This .: book is arranged .: into 23 distinct ;:.1, volumes, or ~1I - chromosomes.

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J ~ ~ . ~, ~ ..WI-'",,-," f."y:"' ,,'~ , .. - c~,~ -,'.~ c~ - ,. , , USING THE GENE SEQUENCE Even before the is complete, the information buried in the genes is being used to trace human origins and to uncover clues to human diseases.Many more applications are in the wings.

Human origi[~; .;- Preventive medicine Rational drug design By examiningtiny changesin the DNA of Understandingour Most pharmaceutical modern-day populations,moiecular genes and the role drugs are blunt anthropologistsare tracking where humans they play in common weapons,Many were came from, the routes they traveled, and diseases should identified by trial and how they are related,Clues hidden in DNA makepossible a new error, and scientists reveal a family tree in which all 6 billion type of preventive often know little people now livingtrace their ancestryback medicine, Most about how they work, to a group of 50,000humans who lived in diseases,from Cancer therapy, for Africa 150,000years ago, DNA evidence cancer and heart disease to Alzheimer's, instance, involves is also illuminatingmore-recent history, have a genetic component, with several bombarding the body with toxic such as thE:'peopling of Europe, genes interacting to increase a person's chemicals that damage normal cells risk, As these genes are identified,it should along with the cancer cells, and be possible to design tests to determine a cause dangerous side effects. : person's chance of developing, say, Increased understanding of the ~ diabetes or colon cancer.Knowing that risk genetic changes at work in cancer could be a powerful impetus for taking steps cells may make it possible to design to avoid the disease, perhaps by changing "smart bomb" drugs that attack only diet or getting regular screening tests, cancerous cells,

DNA fingerprinting A genomecomparison Wings or arms? ~ On Aug, 8, 1986, in Leicestershire, The a!!)ountofgenetic material in (iving Biologists are excited about England, Richard Bucklandwas creat4resvarieswjdely.l~this chart, each their ability to compare the arrested for t~e rape and murder of a human DNA seque:ncewith 15-year-oldgirl, About three months '~i.,~;'c'" cc,- ,c ;" . ;..";;;'CCC" that of other organisms, later he was released-the first accused ~i:; ;"\:;'~ III - I . I -" from lowly fruit flies to murdererto be freed on the basis of a f~;{li;[~, iI1\i)~:;j;~. -~ worms or to mice, Key

~~~ t~:~ds:~~e9t~e;i~gN~u~~~rho~ve~:~I;"';' ~e~nu~~teS~~I~~~~i;~~~~~~~ar criminal investigationsworldwide. By 1~i';ii;~' '. 'c,:c'";'.c ;"' I ~"!2",,'c""""': """:':!~f; remarkably similar from I :£;j compari,ng the DNA left at ~ crime >;~ \; ,', I 811 . spe~ies t~ species, By, , scene-ln blood, semen, hair, or flecks ;" ¥'c ':q":..""'-(f~,","'!':"'" "r""'i'~'.1:.('j mampulatlng the genes In simpler of skin-wit,, . h t h,at 0f a ; ",z;;' ~".,:'"' 811111 ,-",:~* ?rea tures, sclen' t IS' t ~ gal~'.. Inslght s suspect, SCientists ~i: ' .i,1~- ,,' ~:"..,"', , '.".r"..!~ Ii:; Into fun~amental biological P ~ - ':j; mechamsms, And by comparing can determine ~jJ"i ,jkic." II 81' 11 , , ,i' , ,:~;,,'" ,I withamazing i;~c.c",". t;",, " , , i~ gene sequences ~'i: ~"' 2" ~" C' " """ :jJ amongspecies, precision . ;J;c14::~ !i;c", "I I 11I I whether the : ij,,~,:; hi.","': , ~!;i they c~n probe the two match, ih ~~;j~~~~r;f:~i;"'I"""""" I""'I"'-"!i" I" ""'"1-""' 1"'"""" ~i#, mysterl~s of "."..".'\""",,'O""""",,c ,"C embryo IC , !~i{¥'JfJ;~- '~'1,f":\ ,'iii!} -

"';c"'"""""'J""~ c C "cC"V""""""'C"""""",c,",."" "&.i %"" development. ' I j"co II" ,cl c...~~" c "" ~~ ;:~! ~c,! d h "'J ","" I I !~i('"" Fitting the rug to t e patient :i';;:: """"ifJ(~ I" $~II""";"';"'f'I~""!';j1ii",j/!~!,""[1!i(fti!i;:~Beyon dh t e genes i,~h1:::i;;i';JJf,'~'f¥:\ii" ,,8'ibillie_"~~!i Howa person responds to drugs is 1~;!!~c"'"'O~~"'~t'~:t:§ b~s~~~IR~~~;~r The HumanGenome " "" :1"";""!,":;ji",'J",\;'jC"',;,,,,... .""c c t¥...tc ,:;\ ,,' , determined, In part, by tIny varIations In Project IS deciphering a the DNA, By anaIYZi~!o=~:~~~~~!:~f;: fl~1~~~~~:~i~~~~~~;

in advance whether a " . 11 ~ 1 160"'T1.'J);!.e",c,; there is no generic human ::: d ' II k ". Frultfly .' base pairs c rug WI wor ,or ; c ';"" c"','!, ,:' "'",'" genome. Eac h person ':JIS ;1 ~~; whether it will cause unique, with millions of d ' C angerou~side ',,"'/'~ ".cc,:'c" "',"cc";:',,':,c: dIstlnguls" ' h In~' genetic, ~ffects,This a,pproach :" 11'100~illibri;:,:::~:!: changesthat Infl.uencehow IS already being Nematode b air ,"'\ we look, what diseases we applied to breast casep S ::" get, and how we behave. cancer.These techniques could usher in . c...cc, '/""c,, As scientists delve into an eraof "personalized"medicine, with ~ c c.. :::;:":~:::\"; thesevariations, they will drugs tailor-madefor an individual's ,"~ I :" 15 ml!llon :!,:~:;,;;:::::: gain insights into what genetic profile. Yeast , base pairs ::", ":;: makes each person unique c , GRAPHK:BYRODu,,~-USN&"",~. ~ at the genetic level. But the ~ mass of genetic' data AESE.ARCHBY LESUE ROBERTS AND , FIODUTTlE-USN&W1I I 5 million cannot,explaln ea~h SourC8S;Nationallnst/tutesofH8aJ1h,National Humon E r basePairs person s personality or , Genome ResoarchIns"'ule c.Jero GOnomlCS . co I potential-those are factors, m:~~!~ml far bigger than the genes, ,~

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