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CoriBargmann Autobiography MyparentsgrewupinBerlinandmetinNuremburgafterWorldWarII,wheremy fatherwasatranslatorattheNuremburgtrials,andmymother,alsoatranslator, workedfortheAmericans.MyfatherwenttotheUnitedStatesforgraduateschool, andmymotherandoldersisterscameafewyearslater.AfterafewyearsatIBM myfatherbecameaProfessorofStatisticsandComputerScienceattheUniversityof Georgia.Mymother’shumanisticandartisticpassionsmirroredmyfather’sloveof math.Itwasanacademichousehold;weallread,weallplayedthepiano,weall sang.Mymostpleasantmemoriesofmychildhoodareoffallingasleeplisteningto myfatherplayBeethovensonatasfarintothenight. WemovedtoAthens,GeorgiawhenIwasfive.Iwenttopublicschools,whichwere integratedwhenIwasinthesixthgrade.Myfavoriteteachersinhighschoolwere Dr.Hughes,theLatinteacher,andMr.Clark,thechemistryteacher.Ihidinthe chemistrylabwhenIwassupposedtobeatpeprallies.Asanundergraduateatthe UniversityofGeorgiainAthens,IworkedwiththebacterialgeneticistSidney Kushner.Ilovedthelabandtheintensityandtheintellectualcompanionshipofmy fellowresearchers. IwenttograduateschoolatMITin1981,asmoleculargeneticswasexploding. Moleculargeneticsisanincrediblypowerfuldiscipline,inneuroscienceasinother aspectsofbiology.First,geneticsmakesitpossibletoidentifytheessential molecularcomponentsofanybiologicalsystem,includingthebrain.Second,the abilitytomanipulategenefunctioninparticularcellsmakesitpossibletomapthe flowofinformationinmulticellularsystemslikethebrain,andincreasinglyto modifythatflowofinformation.Third,thegenomerepresentsbothacompleteset ofinstructionsandarecordofevolutionaryhistoryforananimal,anddecodingit providesanswerstoquestionsyouhadn’tevenrealizedyouwereasking. AsagraduatestudentIstudiedmutationsthatconvertnormalcellsintocancercells, inBobWeinberg’slabatMIT.TheyearthatIjoined,Weinberg’slabidentifiedthe firstoncogenicmutationsinhumanrasgenes,alandmarkinthefield.Istudiedan oncogenemutatedinanunusualclassofratneuroblastomasandglioblastomas,a receptorcalledneu/Her2,andfoundthemutationsthatactivateditintumors. Later,othergroupsfoundthatneu/Her2wasamplifiedinaggressivehumanbreast cancers.Genentechthendevelopedarationaltherapeuticantibodyagainst neu/Her2calledHerceptin,whichiscurrentlyusedtotreatbreastcancers.It’sbeen arewardingexperiencetoseeadiscoverymovefromthelabtopatients,andto havebeenoneofmanypeoplewhomadethatpossible.Youneverknowinadvance whereprogresswillcomefrom:intheWeinberglab,everyonethoughtthathuman oncogenes,notratoncogenes,wouldleadtothefirsthumantreatments. Weinbergwasaterrificmentor,extremelycreativeandalwaysfocusedonasking themostimportantquestions.Atthesametime,hehadadeepattachmenttohis family,andshowedbyexamplethatyoudon’thavetocompromiseasascientistto beaperson.Inthatrespect,hewasarolemodelforwomeninscience,butreallya rolemodelforeveryoneinscience. Alongstandingcuriosityaboutthebiologyofbehaviorledmetomypostdoctoral field.Theneuroethologistsoftheearly20thcenturyhaddemonstratedtheexistence ofinnate,species‐specificbehaviors,butthebrainandgenesweremysteriesto them.Inthelate1980s,itbegantoseempossibletolinkthebiologyofbehaviorto itsneuronalandmolecularunderpinnings,andfindtherelationshipsbetweengenes andinnatebehaviors.Geneticsandneurosciencewerebarelyconnectedfieldsat thatpoint,sotherewasanopportunity‐‐neuroanatomyandneurophysiologywere powerfulexistingtools,butitseemedthattakingadifferentapproachcouldleadto differentinsights. Mydecisionofwhichsystemtostudywasinspiredbythepublication,in1986,of thecompletewiringdiagramoftheC.elegansnervoussystembyJohnWhiteand SydneyBrenner.Toexploreanynewcountry,youneedamap,andnobrainhad everbeenmappedwiththeextraordinarylevelofdetailthatWhitebroughttoC. elegans.IjoinedBobHorvitz’sC.eleganslabatMIT.BobHorvitzhasanincisive mindandtheviewthatanybiologicalproblemofanysortcanbestudiedwithC. elegansgenetics.Thebreadthofhisownworkcertainlysupportsthatview:he’s madekeyinsightsintomanyareas,includingcellsignaling,apoptosis,and developmentaltiming.Armedwiththenewwiringdiagram,Horvitz’s encouragement,andreportsfromthe1970sthatwormscouldchemotaxto attractivechemicals,Istartedtomapsensoryneuronsandbehavior,andtolearn moreabouthowthewormrespondedtoitsenvironment. In1991ImovedtotheUniversityofCalifornia,SanFrancisco,tostartalabinthe DepartmentofAnatomy.Thefactthatamedicalschoolanatomydepartmentwould recruitmewasasignoftheunifiedvisionofUCSF,whichsawallofbasicand translationalscienceasanorganicwhole.TheNeuroscienceprograminparticular sawitselfasasinglediscipline,spanningtherangefromBiophysicstoNeurology andPsychiatry.UCSFiswhereIlearnedneuroscience(especiallyfrommynewlab neighbor,MarcTessier‐Lavigne). ItwasatUCSFthatmylabbegantoworkseriouslyonthemoleculargeneticsof olfactorybehaviorinC.elegans.Wedidgeneticscreensforolfactorymutants, clonedthegenes,andporedoverthefirstbitsoftheC.elegansgenome.These approachesledustothemolecularbasisofodorantsensation.Ashadbeenshown byBuckandAxelinmice,theC.elegansolfactorysystemwascomposedofan enormousarrayofGprotein‐coupledreceptorsthatwerespecificallyexpressedin subsetsofolfactoryneurons.About2000C.elegansgenesencodereceptorsinthese genefamilies(about10%ofitsgenes);tomyknowledge,C.elegansstillholdsthe recordforthelargestnumberofchemoreceptorgenesinanyanimal.Happily,the factthatonegeneemergedfromaclassicalgeneticscreenmeantthatweknewwhat itdetected:odr‐10,anolfactorymutantidentifiedbyPialiSengupta,wasrequired forthebehavioralresponsetotheodordiacetyl. Thegeneticscreensyieldedmorethanonegene,ofcourse:theseinitialscreensand laterscreensprovidedabroadviewofthedevelopmentandfunctionoftheC. elegansnervoussystem.Particularlyinterestingweresensorytransduction pathwaysregulatedbycGMPandTRPVchannels;agapjunction/calciumchannel pathwaythatlinkedneuronaldevelopmentwithearlyneuronalactivity;and receptorsthatdirectedaxonguidanceandsynapseformation. Thediacetylreceptorodr‐10helpedustounderstandthemolecularbasisofodor sensation,andwasalsoawedgetodriveintothebehaviorasawhole.Havingthe one‐and‐only‐onediacetylreceptorinthewormgenomegaveustheabilityto decidewhetherandhowthewormwasgoingtosensediacetyl.EmilyTroemel geneticallymodifiedanimalstomoveodr‐10fromitsnormalhomeinaneuronthat sensesattractantsintoanadjacentneuronthatsensesrepellents.Wormswiththis molecularconfusioncouldsensediacetyl,buttheyavoidedit,thebehavior appropriateforthehostneuron,insteadofapproachingitastheynormallywould. Thisexperimentsuggeststhatthewormhasdedicatedsensoryneuronsfor attractionorrepulsion,formingaprepatternedtemplateforitsbehavioral preferences. Theideaofageneticallyhard‐wiredprepatternfortasteandsmellbehaviormaybe ageneralprinciple.Forexample,CharlesZukerandNickRybasubsequently showedthatsweetandbittertastesinmicearedetectedbydifferenttastecellsthat directeitheracceptanceorrejectionbehavior. Havingsaidthat,theexistenceofaninnatemapdoesnotprecludelatermodification basedonexperience.Allanimalslearn,andC.eleganscanlearnaboutodors,touch, temperature,andtaste.Inaddition,C.elegansbehaviorsarerapidlyandreversibly remodeleddependingoncontextandtheanimal’sinternalstate.Variabilityand flexibilityareattheheartofbehavior. AnexampleofbehavioralflexibilityisC.elegans’sresponsetoothermembersofits species.Thedecisiontojoinoravoidotheranimalsismadebyaswitchdrivenby neuromodulatorysignalingthatchangesinformationflowthroughneuralcircuits. Bothcontextcuesandindividualgeneticdifferencescontributetothedecision, convergingonaneuralcircuitthatintegratesgenesandtheenvironment.Asinour studiesofolfaction,agene(theneuropeptidereceptornpr‐1)providedawedgeto driveintothissocialdecision.Tounderstandit,weneededallofthetoolsatour disposal:theC.eleganswiringdiagram,thenpr‐1gene,anunderstandingofcontext cues(environmentaloxygen),anunderstandingoftheanimal’spheromones (happily,workedoutbyseveralexcellentchemistrylabsoverthepastfewyears), andevenanunderstandingofhowthelabisdifferentfromtheworm’snatural environment.Amajorstepforwardforunderstandingthiscircuitandotherscame fromthedevelopmentofgenetically‐encodedcalciumindicators,beginningwith RogerTsien,JunichiNakai,and(inC.elegans)BillSchafer.NikosChronisinmylab combinedthisgenetictechnologywithmicrofluidicstovisualizetheeffectsof definedsensorystimuliandcontextonneuralactivity,providinganewmechanistic viewofgeneandcircuitfunction. Itmayseemaquirkychoicetostudythebrainsofworms.Butfromagenetic perspective,itwasasmarterchoicethananyonewouldhaveguessedatthetime. Humanbiology,especiallyhumanneurobiology,isverycomplex,andourviewofthe humanbrainisfragmentary.However,thegenomesofhumansandwormsshare moregenesthananyofusexpected,includingmostclassesofgenesthatare importantinthenervoussystem.(Thecomplexityofthehumannervoussystem comesfromregulatingthegenesindifferentways,andfromdeployingthemin vastlylargernumbersofneurons.)Thebasicfunctionsofthosegenesaresimilarin allanimals,soifweviewonegoalofbiologyasbuildinga“dictionary”containing themeaningofeachgene,wecanassembledefinitionsinthatdictionaryfromany animal,withagoodchancethatthedefinitionsandgrammarwillapplyacrossall animalsandhumans.Thoseofuswhostudywormshopetomeetthosewhostudy humanbrainsinthemiddle,usingtheuniversalityofbiologytotranslate understandingacrossorganisms. Weareprivilegedtobescientists.Thelabisanendlesslyrewardingenvironment, fullofsmart,lively,andcuriousstudentsandpostdocs.Collaborationswithother scientistsletusbranchoutandexplorenewintellectualareaswithoutsacrificing highstandards.Oneofthegreatestprivilegesofscienceisthecompanyofother scientists,andtheexcitementthatcomesfromotherpeoples’discoveriesaswellas yourown.IamnowatTheRockefellerUniversityinNewYork,surroundedby colleaguesofdazzlingaccomplishment.Thelabisveryfortunatetoenjoythe intellectualfreedomprovidedbythesupportoftheHowardHughesMedical Institute. MysistersMonika,Eve,andDoriearebrilliant,witty,loving,andthoughtful.They gracethefieldsofEnglishliterature,medicine,andlaw,andIthinktheyarethe highestformoflifeontheplanet.Myhusband,RichardAxel,isaneuroscientistat ColumbiaUniversitywithapassionforopera,artandliterature.Hemakesme happyinwaysthatIhadnotthoughtpossible.