Download Cornelia Bargmann

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.