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CRISPR,thedisruptor
ApowerfulgeneeditingtechnologyisthebiggestgamechangertohitbiologysincePCR.But
withitshugepotentialcomepressingconcerns.
HeidiLedford
03June2015 Clarified:08June2015

IllustrationbySbastienThibault

Threeyearsago,BruceConklincameacrossamethodthatmadehimchangethecourseofhislab.
Conklin,ageneticistattheGladstoneInstitutesinSanFrancisco,California,hadbeentryingtoworkout
howvariationsinDNAaffectvarioushumandiseases,buthistoolswerecumbersome.Whenheworked
withcellsfrompatients,itwashardtoknowwhichsequenceswereimportantfordiseaseandwhichwere
justbackgroundnoise.Andengineeringamutationintocellswasexpensiveandlaboriouswork.Itwasa
student'sentirethesistochangeonegene,hesays.

Then,in2012,hereadaboutanewlypublishedtechnique1calledCRISPRthat
wouldallowresearcherstoquicklychangetheDNAofnearlyanyorganism
includinghumans.Soonafter,Conklinabandonedhispreviousapproachto
modellingdiseaseandadoptedthisnewone.Hislabisnowfeverishlyaltering
genesassociatedwithvariousheartconditions.CRISPRisturningeverythingon
itshead,hesays.
Thesentimentiswidelyshared:CRISPRiscausingamajorupheavalin
biomedicalresearch.Unlikeothergeneeditingmethods,itischeap,quickand
easytouse,andithassweptthroughlabsaroundtheworldasaresult.
Researchershopetouseittoadjusthumangenestoeliminatediseases,create

Naturespecial:
CRISPRthegood,
thebadandthe
unknown

hardierplants,wipeoutpathogensandmuchmorebesides.I'veseentwohuge
developmentssinceI'vebeeninscience:CRISPRandPCR,saysJohnSchimenti,ageneticistatCornell
UniversityinIthaca,NewYork.LikePCR,thegeneamplificationmethodthatrevolutionizedgenetic
engineeringafteritsinventionin1985,CRISPRisimpactingthelifesciencesinsomanyways,hesays.
ButalthoughCRISPRhasmuchtooffer,somescientistsare

LISTEN
ReporterKerriSmithinvestigatesthe
meteoricriseofCRISPR
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worriedthatthefield'sbreakneckpaceleaveslittletimefor
addressingtheethicalandsafetyconcernssuchexperiments
canraise.TheproblemwasthrustintothespotlightinApril,
whennewsbrokethatscientistshadusedCRISPRtoengineer
humanembryos(seeNature520,5935952015).Theembryos

theyusedwereunabletoresultinalivebirth,butthereport2hasgeneratedheateddebateoverwhether
andhowCRISPRshouldbeusedtomakeheritablechangestothehumangenome.Andthereareother
concerns.Somescientistswanttoseemorestudiesthatprobewhetherthetechniquegeneratesstrayand
potentiallyriskygenomeeditsothersworrythateditedorganismscoulddisruptentireecosystems.
Thispowerissoeasilyaccessiblebylabsyoudon'tneedaveryexpensivepieceofequipmentand
peopledon'tneedtogetmanyyearsoftrainingtodothis,saysStanleyQi,asystemsbiologistatStanford
UniversityinCalifornia.Weshouldthinkcarefullyabouthowwearegoingtousethatpower.
Researchrevolution
Biologistshavelongbeenabletoeditgenomeswithmoleculartools.Abouttenyearsago,theybecame
excitedbyenzymescalledzincfingernucleasesthatpromisedtodothisaccuratelyandefficiently.Butzinc
fingers,whichcostUS$5,000ormoretoorder,werenotwidelyadoptedbecausetheyaredifficultto
engineerandexpensive,saysJamesHaber,amolecularbiologistatBrandeisUniversityinWaltham,
Massachusetts.CRISPRworksdifferently:itreliesonanenzymecalledCas9thatusesaguideRNA
moleculetohomeinonitstargetDNA,theneditstheDNAtodisruptgenesorinsertdesiredsequences.
ResearchersoftenneedtoorderonlytheRNAfragmenttheothercomponentscanbeboughtofftheshelf.

Totalcost:aslittleas$30.Thateffectivelydemocratizedthetechnologysothateveryoneisusingit,says
Haber.It'sahugerevolution.
CRISPRmethodologyisquicklyeclipsingzincfingernucleasesandothereditingtools(see'Theriseof
CRISPR').Forsome,thatmeansabandoningtechniquestheyhadtakenyearstoperfect.I'mdepressed,
saysBillSkarnes,ageneticistattheWellcomeTrustSangerInstituteinHinxton,UK,butI'malsoexcited.
Skarneshadspentmuchofhiscareerusingatechnologyintroducedinthemid1980s:insertingDNAinto
embryonicstemcellsandthenusingthosecellstogenerategeneticallymodifiedmice.Thetechnique
becamealaboratoryworkhorse,butitwasalsotimeconsumingandcostly.CRISPRtakesafractionofthe
time,andSkarnesadoptedthetechniquetwoyearsago.

Publications:ScopusPatents:TheLensFunding:NIHRePORTER.

Researchershavetraditionallyreliedheavilyonmodelorganismssuchasmiceandfruitflies,partly
becausetheyweretheonlyspeciesthatcamewithagoodtoolkitforgeneticmanipulation.NowCRISPRis
makingitpossibletoeditgenesinmanymoreorganisms.InApril,forexample,researchersatthe
WhiteheadInstituteforBiomedicalResearchinCambridge,Massachusetts,reportedusingCRISPRto
studyCandidaalbicans,afungusthatisparticularlydeadlyinpeoplewithweakenedimmunesystems,but
hadbeendifficulttogeneticallymanipulateinthelab 3.JenniferDoudna,aCRISPRpioneeratthe
UniversityofCalifornia,Berkeley,iskeepingalistofCRISPRalteredcreatures.Sofar,shehasthree
dozenentries,includingdiseasecausingparasitescalledtrypanosomesandyeastsusedtomakebiofuels.
Yettherapidprogresshasitsdrawbacks.Peoplejustdon'thavethetime
tocharacterizesomeoftheverybasicparametersofthesystem,says
BoHuang,abiophysicistattheUniversityofCalifornia,SanFrancisco.
Thereisamentalitythataslongasitworks,wedon'thavetounderstand

Relatedstories
USscienceacademies
takeonhumangenome

howorwhyitworks.Thatmeansthatresearchersoccasionallyrunup

editing

againstglitches.Huangandhislabstruggledfortwomonthstoadapt

Regulategeneeditingin

CRISPRforuseinimagingstudies.Hesuspectsthatthedelaywould

wildanimals

havebeenshorterhadmorebeenknownabouthowtooptimizethe
designofguideRNAs,abasicbutimportantnuance.

Embryoeditingsparks
epicdebate

Byandlarge,researchersseethesegapsasaminorpricetopayfora

Morerelatedstories

powerfultechnique.ButDoudnahasbeguntohavemoreserious
concernsaboutsafety.Herworriesbeganatameetingin2014,whenshesawapostdocpresentworkin
whichaviruswasengineeredtocarrytheCRISPRcomponentsintomice.Themicebreathedinthevirus,
allowingtheCRISPRsystemtoengineermutationsandcreateamodelforhumanlungcancer4.Doudna
gotachillaminormistakeinthedesignoftheguideRNAcouldresultinaCRISPRthatworkedinhuman
lungsaswell.Itseemedincrediblyscarythatyoumighthavestudentswhowereworkingwithsucha
thing,shesays.It'simportantforpeopletoappreciatewhatthistechnologycando.
AndreaVentura,acancerresearcheratMemorialSloanKetteringCancerCenterinNewYorkandalead
authorofthework,saysthathislabcarefullyconsideredthesafetyimplications:theguidesequenceswere
designedtotargetgenomeregionsthatwereuniquetomice,andtheviruswasdisabledsuchthatitcould
notreplicate.Heagreesthatitisimportanttoanticipateevenremoterisks.Theguidesarenotdesignedto
cutthehumangenome,butyouneverknow,hesays.It'snotverylikely,butitstillneedstobe
considered.
Editingoutdisease
Lastyear,bioengineerDanielAndersonoftheMassachusettsInstituteofTechnologyinCambridgeandhis
colleaguesusedCRISPRinmicetocorrectamutationassociatedwithahumanmetabolicdiseasecalled
tyrosinaemia5.ItwasthefirstuseofCRISPRtofixadiseasecausingmutationinanadultanimalandan
importantsteptowardsusingthetechnologyforgenetherapyinhumans(seeAbriefhistoryofCRISPR).
TheideathatCRISPRcouldacceleratethegenetherapyfieldisamajorsourceofexcitementinscientific
andbiotechnologycircles.Butaswellashighlightingthepotential,Anderson'sstudyshowedhowfarthere
istogo.TodelivertheCas9enzymeanditsguideRNAintothetargetorgan,theliver,theteamhadto
pumplargevolumesofliquidintobloodvesselssomethingthatisnotgenerallyconsideredfeasiblein
people.Andtheexperimentscorrectedthediseasecausingmutationinjust0.4%ofthecells,whichisnot
enoughtohaveanimpactonmanydiseases.
Overthepasttwoyears,ahandfulofcompanieshavesprunguptodevelopCRISPRbasedgenetherapy,
andAndersonandotherssaythatthefirstclinicaltrialsofsuchatreatmentcouldhappeninthenextoneor
twoyears.ThosefirsttrialswillprobablybescenariosinwhichtheCRISPRcomponentscanbeinjected
directlyintotissues,suchasthoseintheeye,orinwhichcellscanberemovedfromthebody,engineered

inthelabandthenputback.Forexample,bloodformingstemcellsmightbecorrectedtotreatconditions
suchassicklecelldiseaseorthalassaemia.Itwillbeabiggerchallengetodelivertheenzymeandguide
RNAintomanyothertissues,butresearchershopethatthetechniquecouldonedaybeusedtotacklea
widerrangeofgeneticdiseases.

YetmanyscientistscautionthatthereismuchtodobeforeCRISPRcanbedeployedsafelyandefficiently.

Scientistsneedtoincreasetheefficiencyofediting,butatthesametimemakesurethattheydonot
introducechangeselsewhereinthegenomethathaveconsequencesforhealth.Theseenzymeswillcutin
placesotherthantheplacesyouhavedesignedthemtocut,andthathaslotsofimplications,saysHaber.
Ifyou'regoingtoreplacesomebody'ssicklecellgeneinastemcell,you'regoingtobeasked,'Well,what
otherdamagemightyouhavedoneatothersitesinthegenome?'
KeithJoung,whostudiesgeneeditingatMassachusettsGeneralHospitalinBoston,hasbeendeveloping
methodstohuntdownCas9'sofftargetcuts.Hesaysthatthefrequencyofsuchcutsvarieswidelyfromcell
tocellandfromonesequencetoanother:hislabandothershaveseenofftargetsiteswithmutation
frequenciesrangingfrom0.1%tomorethan60%.Evenlowfrequencyeventscouldpotentiallybe
dangerousiftheyaccelerateacell'sgrowthandleadtocancer,hesays.
Withsomanyunansweredquestions,itisimportanttokeepexpectationsofCRISPRundercontrol,says
KatrineBosley,chiefexecutiveofEditas,acompanyinCambridge,Massachusetts,thatispursuing
CRISPRmediatedgenetherapy.Bosleyisaveteranofcommercializingnewtechnologies,andsaysthat
usuallythehardpartisconvincingothersthatanapproachwillwork.WithCRISPRit'salmostthe
opposite,shesays.There'ssomuchexcitementandsupport,butwehavetoberealisticaboutwhatit
takestogetthere.
CRISPRonthefarm
WhileAndersonandothersareaimingtomodifyDNAinhumancells,othersaretargetingcropsand
livestock.Beforethearrivalofgeneeditingtechniques,thiswasgenerallydonebyinsertingageneintothe
genomeatrandompositions,alongwithsequencesfrombacteria,virusesorotherspeciesthatdrive
expressionofthegene.Buttheprocessisinefficient,andithasalwaysbeenfodderforcriticswhodislike
themixingofDNAfromdifferentspeciesorworrythattheinsertioncouldinterruptothergenes.Whatis
more,gettinggeneticallymodifiedcropsapprovedforuseissocomplexandexpensivethatmostofthose
thathavebeenmodifiedarelargecommoditycropssuchasmaize(corn)andsoyabeans.

IllustrationbySbastienThibault

WithCRISPR,thesituationcouldchange:theeaseandlowcostmaymakegenomeeditingaviableoption
forsmaller,specialitycrops,aswellasanimals.Inthepastfewyears,researchershaveusedthemethodto
engineerpetitepigsandtomakediseaseresistantwheatandrice.Theyhavealsomadeprogresstowards
engineeringdehornedcattle,diseaseresistantgoatsandvitaminenrichedsweetoranges.Doudna
anticipatesthatherlistofCRISPRmodifiedorganismswillgrow.There'saninterestingopportunityto
considerdoingexperimentsorengineeringpathwaysinplantsthatarenotasimportantcommerciallybut
areveryinterestingfromaresearchperspectiveorforhomevegetablegardens,shesays.
CRISPR'sabilitytopreciselyeditexistingDNAsequencesmakesformoreaccuratemodifications,butit
alsomakesitmoredifficultforregulatorsandfarmerstoidentifyamodifiedorganismonceithasbeen
released.Withgeneediting,there'snolongertheabilitytoreallytrackengineeredproducts,saysJennifer
Kuzma,whostudiessciencepolicyatNorthCarolinaStateUniversityinRaleigh.Itwillbehardtodetect
whethersomethinghasbeenmutatedconventionallyorgeneticallyengineered.

Thatringsalarmbellsforopponentsofgeneticallymodifiedcrops,anditposesdifficultquestionsfor
countriestryingtoworkouthowtoregulategeneeditedplantsandanimals.IntheUnitedStates,theFood
andDrugAdministrationhasyettoapproveanygeneticallymodifiedanimalforhumanconsumption,andit
hasnotyetannouncedhowitwillhandlegeneeditedanimals.
Underexistingrules,notallcropsmadebygenomeeditingwouldrequireregulationbytheUSDepartment
ofAgriculture(seeNature500,3893902013).ButinMay,theagriculturedepartmentbegantoseek
inputonhowitcanimproveregulationofgeneticallymodifiedcropsamovethatmanyhavetakenasa
signthattheagencyisreevaluatingitsrulesinlightoftechnologiessuchasCRISPR.Thewindowhas
beencracked,saysKuzma.Whatgoesthroughthewindowremainstobeseen.Butthefactthatit'seven
beencrackedisprettyexciting.
Engineeredecosystems
Beyondthefarm,researchersareconsideringhowCRISPRcouldorshouldbedeployedonorganismsin
thewild.Muchoftheattentionhasfocusedonamethodcalledgenedrive,whichcanquicklysweepan
editedgenethroughapopulation.Theworkisatanearlystage,butsuchatechniquecouldbeusedto
wipeoutdiseasecarryingmosquitoesorticks,eliminateinvasiveplantsoreradicateherbicideresistancein
pigweed,whichplaguessomeUSfarmers.
Usually,ageneticchangeinoneorganismtakesalongtimetospreadthroughapopulation.Thatis
becauseamutationcarriedononeofapairofchromosomesisinheritedbyonlyhalftheoffspring.Buta
genedriveallowsamutationmadebyCRISPRononechromosometocopyitselftoitspartnerinevery
generation,sothatnearlyalloffspringwillinheritthechange.Thismeansthatitwillspeedthrougha
populationexponentiallyfasterthannormal(see'Genedrive')amutationengineeredintoamosquito
couldspreadthroughalargepopulationwithinaseason.Ifthatmutationreducedthenumberofoffspringa
mosquitoproduced,thenthepopulationcouldbewipedout,alongwithanymalariaparasitesitiscarrying.

Publications:ScopusPatents:TheLensFunding:NIHRePORTER.

Butmanyresearchersaredeeplyworriedthatalteringanentirepopulation,oreliminatingitaltogether,
couldhavedrasticandunknownconsequencesforanecosystem:itmightmeanthatotherpestsemerge,
forexample,oritcouldaffectpredatorshigherupthefoodchain.Andresearchersarealsomindfulthata
guideRNAcouldmutateovertimesuchthatittargetsadifferentpartofthegenome.Thismutationcould
thenracethroughthepopulation,withunpredictableeffects.
Ithastohaveafairlyhighpayoff,becauseithasariskofirreversibilityandunintendedorhardto
calculateconsequencesforotherspecies,saysGeorgeChurch,abioengineeratHarvardMedicalSchool
inBoston.InApril2014,Churchandateamofscientistsandpolicyexpertswroteacommentaryin
Science 6warningresearchersabouttherisksandproposingwaystoguardagainstaccidentalreleaseof
experimentalgenedrives.

Atthetime,genedrivesseemedadistantprospect.Butlessthanayearlater,developmentalbiologist
EthanBieroftheUniversityofCalifornia,SanDiego,andhisstudentValentinoGantzreportedthatthey
haddesignedjustsuchasysteminfruitflies7.BierandGantzhadusedthreelayersofboxestocontain
theirfliesandadoptedlabsafetymeasuresusuallyusedformalariacarryingmosquitoes.Buttheydidnot
followalltheguidelinesurgedbytheauthorsofthecommentary,suchasdevisingamethodtoreversethe
engineeredchange.Biersaysthattheywereconductingtheirfirstproofofprincipleexperiments,and
wantedtoknowwhetherthesystemworkedatallbeforetheymadeitmorecomplex.
ForChurchandothers,thiswasaclearwarningthatthedemocratizationofgenomeeditingthrough
CRISPRcouldhaveunexpectedandundesirableoutcomes.Itisessentialthatnationalregulatory
authoritiesandinternationalorganizationsgetontopofthisreallygetontopofit,saysKennethOye,a
politicalscientistattheMassachusettsInstituteofTechnologyandleadauthoroftheSciencecommentary.
Weneedmoreaction.TheUSNationalResearchCouncilhasformedapaneltodiscussgenedrives,and
otherhighleveldiscussionsarestartingtotakeplace.ButOyeisconcernedthatthescienceismovingat
lightningspeed,andthatregulatorychangesmayhappenonlyafterahighprofilegenedriverelease.
Theissueisnotblackandwhite.MickyEubanks,aninsectecologistatTexasA&MUniversityinCollege
Station,saysthattheideaofgenedrivesshockedhimatfirst.Myinitialgutreactionwas'Ohmygod,this
isterrible.It'ssoscary',hesays.Butwhenyougiveitmorethoughtandweighitagainstthe
environmentalchangesthatwehavealreadymadeandcontinuetomake,itwouldbeadropintheocean.
SomeresearchersseelessonsforCRISPRinthearcofothernewtechnologiesthatpromptedgreat
excitement,concernandthendisappointmentwhenteethingtroubleshit.MedicalgeneticistJamesWilson
oftheUniversityofPennsylvaniainPhiladelphiawasatthecentreofboomingenthusiasmovergene
therapyinthe1990sonlytowitnessitsdownfallwhenaclinicaltrialwentwrongandkilledayoungman.
Thefieldwentintoatailspinandhasonlyrecentlybeguntorecover.TheCRISPRfieldisstillyoung,Wilson
says,anditcouldbeyearsbeforeitspotentialisrealized.It'sintheexplorationstage.Theseideasneedto
ferment.
Thenagain,WilsonhasbeenbittenbytheCRISPRbug.Hesaysthathewasscepticalofallthepromises
beingmadeaboutituntilhisownlabbegantoplaywiththetechnique.It'sultimatelygoingtohavearolein
humantherapeutics,hesays.It'sjustreallyspectacular.
Nature 522, 2024 (04June2015) doi:10.1038/522020a
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Clarifications

Clarified: AnearlierversionofthegraphicentitledAbriefhistoryofCRISPR'hadanambiguousentryfor
June2012.Thetexthasnowbeenmadeclearer.

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Relatedstoriesandlinks
Fromnature.com
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18May2015
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12May2015
Embryoeditingsparksepicdebate
29April2015
Chinesescientistsgeneticallymodifyhumanembryos
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Minienzymemovesgeneeditingclosertotheclinic
01April2015
Naturespecial:CRISPR
Fromelsewhere
Video:GenomeEditingwithCRISPRCas9

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Subscribetocomments

LucaPinello 2015060711:13PM

Greatarticle.CRISPRhasanhugepotential,butthereisstillaneedtounderstandbetterthedata
comingoutoftheseexperiments.Ihavebeenputsomeefforttohelpthecommunitytoanalyze
genomeeditingdatafromtargetdeepsequencingexperiment.Inparticular,Ihavedevelopafree
onlinetoolcalledCRISPRessothatallowsthequantificationofbothnonhomologousendjoining
(NHEJ)andhomologousdirectedrepair(HDR)occurrences.Iwouldlovetohearsomefeedback
fromthecommunity:http://crispresso.rc.fas.harvard.edu/oryoucanusetheshortcut:

http://crispresso.rocks
Reportthiscomment

GerryAtrickseeeker 2015060509:08PM

TheCRISPRCastechnologyclearlyhasenormouspotential.However,itneedstobeviewedinthe
sameperspectiveasallnewbiomedicaltechnologies.Monoclonalantibodies,siRNA,
nanomedicineeachofthesepotentiallytransformativetechnologieshasfollowedthesamepath,
withaninitialperiodofalmostirrationalexuberance,followedbydisillusionmentasproblems
inevitablyemerged,followedbyamoreconsideredassessmentofultimatetherapeuticpotential.So
willitbewithCRISPR.http://scienceforthefuture.blogspot.com/
Reportthiscomment

GenePartlow 2015060411:08PM

CRISPRandsimilaremergingtoolsarewonderfulandshowpromise,andIamactuallyoneof
thosecheeringonthebroadthemeofcarefulandthoughtfulgeneticengineering.Normally.Butthe
merethoughtofprivatecompanies,hotforsuccessandhugeshorttermprofit,thunderingaheadin
anescalatingcompetition,usinglifespreciousgeneticmaterialasinvestmentcapitalis,frankly,
horrifying.Suchdelicateandyetastronomicallypowerfulinformation,theveryfuseoflife,must
neverbeleftaloneinthehandsofcorporateentitiesnotonlyblindtotheconcatenationsof
complexities,butwhohaveshowncontemptforthosewhocanseefarahead.Nottomentionthey
arehistoricallyuntrammeledanduntaintedbyanythingresemblingresponsibilityandselfregulation
regardingthewelfareofthelargerworldcommunity.Careful,sanestudyandregulationmust
prevailacrosstheboardhere.Thisisthefutureoflifeitself.
Reportthiscomment

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