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CHAPTERSIX THEBEST-LAID(BODY)PLANS Weareapackageofabouttwotrillioncellsassembledina verypreciseway.Ourbodiesexistinthreedimensions, withourcellsandorgansintheirproperplaces.Theheadis ontop.Thespinalcordistowardourback.Ourgutsareon thebellyside.Ourarmsandlegsaretothesides.Thisbasic architecturedistinguishesusfromprimitivecreatures organizedasclumpsordisksofcells. Thesamedesignisalsoanimportantpartofthebodies ofothercreatures.Likeus,fish,lizards,andcowshave bodiesthataresymmetricalwithafront/back,top/bottom, andleft/right.Theirfrontends(correspondingtothetopof anuprighthuman)allhaveheads,withsenseorgansand brainsinside.Theyhaveaspinalcordthatrunsthelength ofthebodyalongtheback.Alsolikeus,theyhaveananus, whichisattheoppositeendoftheirbodiesfromthemouth. Theheadisontheforwardend,inthedirectionthey typicallyswimorwalk.Asyoucanimagine,“anus-forward” wouldn’tworkverywellinmostsettings,particularly aquaticones.Socialsituationswouldbeaproblem,too. 129 Itismoredifficulttofindourbasicdesigninreally primitiveanimals—jellyfish,forexample.Jellyfishhavea differentkindofbodyplan:theircellsareorganizedinto disksthathaveatopandbottom.Lackingafrontandback, aheadandtail,andaleftandright,jellyfishbody organizationappearsverydifferentfromourown.Don’t evenbothertryingtocompareyourbodyplanwitha sponge.Youcouldtry,butthemerefactthatyouwere tryingwouldrevealsomethingmorepsychiatricthan anatomical. Toproperlycompareourselveswiththeseprimitive animals,weneedsometools.Justaswithheadsandlimbs, ourhistoryiswrittenwithinourdevelopmentfromeggto adult.Embryosholdthecluestosomeoftheprofound mysteriesoflife.Theyalsohavetheabilitytoderailmy plans. THECOMMONPLAN:COMPARINGEMBRYOS Ienteredgraduateschooltostudyfossilmammalsand endedupthreeyearslaterstudyingfishandamphibiansfor mydissertation.Myfallfromgrace,ifyouwanttocallit that,happenedwhenIstartedtolookatembryos.Wehada lotofembryosinthelab:salamanderlarvae,fishembryos, evenfertilizedchickeneggs.I’droutinelypopthemunder themicroscopetoseewhatwasgoingon.Theembryosof allthespecieslookedlikelittlewhitishbatchesofcells,no 130 morethananeighthofaninchlong.Itwasexciting watchingdevelopmentprogress;astheembryogotbigger, theyolk,itsfoodsupply,gotsmallerandsmaller.Bythe timetheyolkwasgone,theembryowasusuallybigenough tohatch. Watchingtheprocessofdevelopmentbroughtabouta hugeintellectualtransformationinme.Fromsuchsimple embryonicbeginnings—smallblobsofcells—came wonderfullycomplexbirds,frogs,andtroutcomprising trillionsofcellsarrangedinjusttherightway.Butthere wasmore.Thefish,amphibian,andchickenembryoswere likenothingIhadeverseenbeforeinbiology.Theyall lookedgenerallyalike.Allofthemhadaheadwithgill arches.Allofthemhadalittlebrainthatbeganits developmentwiththreeswellings.Allofthemhadlittle limbbuds.Infact,thelimbsweretobecomemythesis,the focusofmynextthreeyears’work.Here,incomparinghow theskeletondevelopedinbirds,salamanders,frogs,and turtles,Iwasfindingthatlimbsasdifferentasbirdwings andfroglegslookedverysimilarduringtheirdevelopment. Inseeingtheseembryos,Iwasseeingacommon architecture.Thespeciesendeduplookingdifferent,but theystartedfromagenerallysimilarplace.Lookingat embryos,italmostseemsthatthedifferencesamong mammals,birds,amphibians,andfishsimplypalein comparisonwiththeirfundamentalsimilarities.ThenI learnedoftheworkofKarlErnstvonBaer. Inthe1800s,somenaturalphilosopherslookedto 131 embryostotrytofindthecommonplanforlifeonearth. ParamountamongtheseobserverswasKarlErnstvon Baer.Borntoanoblefamily,heinitiallytrainedtobea physician.Hisacademicmentorsuggestedthathestudy chickendevelopmentandtrytounderstandhowchicken organsdeveloped. Unfortunately,vonBaercouldnotaffordincubatorsto workonchickens,norcouldheaffordmanyeggs.Thiswas notverypromising.Luckyforhim,hehadanaffluentfriend, ChristianPander,whocouldaffordtodotheexperiments. Astheylookedatembryos,theyfoundsomething fundamental:allorgansinthechickencanbetracedtooneof threelayersoftissueinthedevelopingembryo.Thesethree layersbecameknownasthegermlayers.Theyachieved almostlegendarystatus,whichtheyretaineventothisday. Pander’sthreelayersgavevonBaerthemeanstoask importantquestions.Doallanimalssharethispattern?Are thehearts,lungs,andmusclesofallanimalsderivedfrom theselayers?And,importantly,dothesamelayersdevelop intothesameorgansindifferentspecies? VonBaercomparedthethreelayersofPander’schicken embryoswitheverythingelsehecouldgethishandson: fish,reptiles,andmammals.Yes,everyanimalorgan originatedinoneofthesethreelayers.Significantly,the threelayersformedthesamestructuresineveryspecies. Everyheartofeveryspeciesformedfromthesamelayer. Anotherlayergaverisetoeverybrainofeveryanimal.And soon.Nomatterhowdifferentthespecieslookasadults,as 132 tinyembryostheyallgothroughthesamestagesof development. Tofullyappreciatetheimportanceofthis,weneedto lookagainatourfirstthreeweeksafterconception.Atthe momentoffertilization,majorchangeshappeninsidethe egg—thegeneticmaterialofthespermandeggfusesand theeggbeginstodivide.Ultimately,thecellsformaball.In humans,overaboutfivedays,thesingle-cellbodydivides fourtimes,toproduceaballofsixteencells.Thisballof cells,knownasablastocyst,resemblesafluid-filledballoon. Athinsphericalwallofcellssurroundssomefluidinthe center.Atthis“blastocyststage”therestilldoesnotappear tobeanybodyplan—thereisnofrontandback,and certainlytherearenotyetanydifferentorgansortissues. Onaboutthesixthdayafterconception,theballofcells attachestoitsmother’suterusandbeginstheprocessof connectingtoitsothatmotherandembryocanjoin bloodstreams.Thereisstillnoevidenceofthebodyplan.It isafarcryfromthisballofcellstoanythingthatyou’d recognizeasanymammal,reptile,orfish,muchlessa human. Ifwearelucky,ourballofcellshasimplantedinour mother’suterus.Whenablastocystimplantsinthewrong place—whenthereisan“ectopicimplantation”—the resultscanbedangerous.About96percentofectopic implantationshappenintheuterine(orfallopian)tubes, nearwhereconceptionhappens.Sometimesmucusblocks theeasypassageoftheblastocysttotheuterus,causingit 133 toimplantimproperlyinthetubes.Ectopicpregnancycan causevarioustissuerupturesifnotcaughtintime.Inreally rarecases,theblastocystisexpelledintothemother’sbody cavity,thespacebetweenhergutsandbodywall.Ineven rarercases,theseblastocystswillimplantontheoutside liningofthemother’srectumoruterusandthefetus developstofullterm!Althoughthesefetusescan sometimesbedeliveredbyanabdominalincision,such implantationisgenerallyverydangerousbecauseit increasestheriskofmaternaldeathbybleedingbyafactor of90,ascomparedwithanormalimplantationinsidethe uterus. Inanyevent,atthisstageofdevelopmentweare extremelyhumble-lookingcreatures.Aroundthebeginning ofoursecondweekafterconception,theblastocysthas implanted,withonepartoftheballembeddedinthewallof theuterus,andtheotherfree.Thinkofaballoonpushed intoawall:thisflatteneddiskbecomesthehumanembryo. Ourentirebodyformsfromonlythetoppartofthisball,the partthatismushedintothewall.Thepartoftheblastocyst belowthediskcoverstheyolk.Atthisstageof development,welooklikeaFrisbee,asimpletwo-layered disk. HowdoesthisovalFrisbeeendupwithvonBaer’sthree germlayersandgoontolookanythinglikeahuman?First, cellsdivideandmove,causingtissuestofoldinon themselves.Eventually,astissuesmoveandfold,we becomeatubewithafoldedswellingattheheadendand 134 anotheratthetail.Ifweweretocutourselvesinhalfright aboutnow,wewouldfindatubewithinatube.Theouter tubewouldbeourbodywall,theinnertubeoureventual digestivetract.Aspace,thefuturebodycavity,separates thetwotubes.Thistube-within-a-tubestructurestayswith usourentirelives.Theguttubegetsmorecomplicated, withabigsacforastomachandlongintestinaltwistsand turns.Theoutertubeiscomplicatedbyhair,skin,ribs,and limbsthatpushout.Butthebasicplanpersists.Wemaybe morecomplicatedthanwewereattwenty-onedaysafter conception,butwearestillatubewithinatube,andallof ourorgansderivefromoneofthethreelayersoftissuethat appearedinoursecondweekafterconception. Thenamesofthesethreeall-importantlayersare derivedfromtheirposition:theouterlayeriscalled ectoderm,theinnerlayerendoderm,andthemiddlelayer mesoderm.Ectodermformsmuchoftheouterpartofthe body(theskin)andthenervoussystem.Endoderm,the insidelayer,formsmanyoftheinnerstructuresofthebody, includingourdigestivetractandnumerousglands associatedwithit.Themiddlelayer,themesoderm,forms tissueinbetweenthegutsandskin,includingmuchofour skeletonandourmuscles.Whetherthebodybelongstoa salmon,achicken,afrog,oramouse,allofitsorgansare formedbyendoderm,ectoderm,andmesoderm. 135 Ourearlydays,thefirstthreeweeksafterconception. Wegofrombeingasinglecelltoaballofcellsandend upasatube. VonBaersawhowembryosrevealfundamentalpatterns oflife.Hecontrastedtwokindsoffeaturesindevelopment: featuressharedbyeveryspecies,andfeaturesthatvary fromspeciestospecies.Featuressuchasthetube-withina-tubearrangementaresharedbyallanimalswitha backbone:fish,amphibians,reptiles,birds,andmammals. Thesecommonfeaturesappearrelativelyearlyin development.Thefeaturesthatdistinguishus—bigger brainsinhumans,shellsonturtles,feathersonbirds—arise 136 relativelylater. VonBaer’sapproachisverydifferentfromthe“ontogeny recapitulatesphylogeny”ideayoumighthavelearnedin school.VonBaersimplycomparedembryosandnotedthat theembryosofdifferentspecieslookedmoresimilarto eachotherthandotheadultsofthosespecies.The “ontogenyrecapitulatesphylogeny”approachchampioned decadeslaterbyErnstHaeckelmadetheclaimthateach speciestrackeditsevolutionaryhistoryasitproceeded throughdevelopment.Accordingly,theembryoofahuman wentthroughafish,areptile,andamammalstage.Haeckel wouldcompareahumanembryotoanadultfishoralizard. ThedifferencesbetweentheideasofvonBaerandHaeckel mightseemsubtle,buttheyarenot.Inthepastone hundredyears,timeandnewevidencehavetreatedvon Baermuchmorekindly.Incomparingembryosofone speciestoadultsofanother,Haeckelwascomparingapples tooranges.Amoremeaningfulcomparisonisonewherewe canultimatelyuncoverthemechanismsthatdrive evolution.Forthat,wecompareembryosofonespeciesto embryosofanother.Theembryosofdifferentspeciesare notcompletelyidentical,buttheirsimilaritiesare profound.Allhavegillarches,notochords,andlooklikea tubewithinatubeatsomestageoftheirdevelopment.And, importantly,embryosasdistinctasfishandpeoplehave PanderandvonBaer’sthreegermlayers. 137 Atfourweeksafterconception,weareatubewithina tubeandhavethethreegermlayersthatgiverisetoall ourorgans. Allofthesecomparisonsleadustotherealissueatstake. Howdoestheembryo“know”todevelopaheadatthefront endandananusattheback?Whatmechanismsdrive developmentandmakecellsandtissuesabletoform bodies? Toanswerthesequestionsrequiredawholenew approach.Ratherthansimplycomparingembryosasinvon Baer’sday,wehadtofindanewwayofanalyzingthem.The latterpartofthenineteenthcenturyusheredintheera, 138 whichwefirstdiscussedinChapter3,whenembryoswere chopped,grafted,split,andtreatedwithvirtuallyeverykind ofchemicalimaginable.Allinthenameofscience. EXPERIMENTINGWITHEMBRYOS Biologistsattheturnofthetwentiethcenturywere grapplingwithfundamentalquestionsaboutbodies.Where intheembryodoestheinformationtobuildthemlie?Is thisinformationcontainedineverycellorinpatchesof cells?Andwhatformdoesthisinformationtake—isita specialkindofchemical? Beginningin1903,theGermanembryologistHans Spemannbegantoinvestigatehowcellslearnedtobuild bodiesduringdevelopment.Hisgoalwastofindwherethe body-buildinginformationresides.Thebigquestionfor Spemannwaswhetherallthecellsintheembryohave enoughinformationtobuildwholebodies,orwhetherthat informationisconfinedtocertainpartsofthedeveloping embryo. Workingwithnewteggs,whichwereeasytoobtainand relativelyeasytofiddlewithinthelab,Spemanndeviseda cleverexperiment.Hecutoffastrandofhisinfant daughter’shairandmadeaminiaturelassooutofit.Baby hairisremarkablestuff;soft,thin,andpliant,itmadethe idealmaterialfortyingupatinyspheresuchasanewtegg. Spemanndidexactlythattoadevelopingnewtegg, 139 pinchingonesideofffromtheother.Manipulatingthe nucleiofthecellsabit,helettheresultingcontraption developandwatchedwhathappened.Theembryoformed twins:twocompletesalamandersemerged,eachwitha normalbodyplanandeachentirelyviable.Theconclusion wasobvious:fromoneeggcancomemorethanone individual.Thisiswhatidenticaltwinsare.Biologically, Spemannhaddemonstratedthatintheearlyembryosome cellshavethecapacitytoformawholenewindividualon theirown. Thisexperimentwasonlythebeginningofawholenew phaseofdiscovery. Inthe1920sHildeMangold,agraduatestudentin Spemann’slaboratory,startedtoworkwithsmallembryos. Thefinecontrolshehadofherfingersmadeherabletodo someincrediblydemandingexperiments.Atthestageof developmentwithwhichMangoldworked,thesalamander embryoisasphereaboutasixteenthofaninchindiameter. Sheloppedoffatinypieceoftissue,smallerthanapinhead, fromonepartoftheembryoandgrafteditontotheembryo ofanotherspecies.WhatMangoldtransplantedwasn’tjust anypatch,butanareawherecellsthatweretoformmuch ofthethreegermlayersweremovingandfolding.Mangold wassoskilledthatthegraftedembryosactuallycontinued todevelop,givingherapleasantsurprise.Thegraftedpatch ledtotheformationofawholenewbody,includingaspinal cord,back,belly,evenahead. 140 Justbymovingasmallpatchoftissueintheembryo, Mangoldproducedtwins. Whyisallthisimportant?Mangoldhaddiscovereda smallpatchoftissuethatwasabletodirectothercellsto formanentirebodyplan.Thetiny,incrediblyimportant patchoftissuecontainingallthisinformationwastobe knownastheOrganizer. Mangold’sdissertationworkwasultimatelytowinthe NobelPrize,butnotforher.HildeMangolddiedtragically (thegasolinestoveinherkitchencaughtfire)beforeher thesiscouldevenbepublished.SpemannwontheNobel PrizeinMedicinein1935,andtheawardcites“his discoveryoftheOrganizeranditseffectinembryonic development.” Today,manyscientistsconsiderMangold’sworktobe thesinglemostimportantexperimentinthehistoryof embryology. AtroughlythesametimethatMangoldwasdoing experimentsinSpemann’slab,W.Vogt(alsoinGermany) wasdesigningclevertechniquestolabelcells,orbatchesof them,andthusallowtheexperimentertowatchwhat happensastheeggdevelops.Vogtwasabletoproducea 141 mapoftheembryothatshowswhereeveryorgan originatesintheegg.Weseetheantecedentsofthebody planinthecellfatesoftheearlyembryo. Fromtheearlyembryologists,peoplelikevonBaer, Pander,Mangold,andSpemann,wehavelearnedthatallthe partsofouradultbodiescanbemappedtoindividual batchesofcellsinthesimplethree-layeredFrisbee,andthe generalstructureofthebodyisinitiatedbytheOrganizer regiondiscoveredbyMangoldandSpemann. Cut,slice,anddice,andyou’llfindthatallmammals, birds,amphibians,andfishhaveOrganizers.Youcaneven sometimesswaponespecies’Organizerforanother.Take theOrganizerregionfromachickenandgraftittoa salamanderembryo:yougetatwinnedsalamander. ButjustwhatisanOrganizer?Whatinsideittellscells howtobuildbodies?DNA,ofcourse.AnditisinthisDNA thatwewillfindtheinnerrecipethatwesharewiththerest ofanimallife. OFFLIESANDMEN VonBaerwatchedembryosdevelop,comparedonespecies toanother,andsawfundamentalpatternsinbodies. MangoldandSpemannphysicallydistortedembryosto learnhowtheirtissuesbuildbodies.IntheDNAage,wecan askquestionsaboutourowngeneticmakeup.Howdoour genescontrolthedevelopmentofourtissuesandour 142 bodies?Ifyoueverthoughtthatfliesareunimportant, considerthis:mutationsinfliesgaveusimportantcluesto themajorbodyplangenesactiveinhumanembryos.We putthiskindofthinkingtouseinthediscoveryofgenes thatbuildfingersandtoes.Nowwe’llseehowittellsus aboutthewaysentirebodiesarebuilt. Flieshaveabodyplan.Theyhaveafrontandaback,atop andabottom,andsoon.Theirantennae,wings,andother appendagespopoutofthebodyintherightplace.Except whentheydon’t.Somemutantflieshavelimbsgrowingout oftheirheads.Othershaveduplicatewingsandextrabody segments.Theseareamongtheflymutantsthattelluswhy ourvertebraechangeshapefromtheheadendtotheanal endofthebody. Peoplehavebeenstudyingabnormalfliesforovera hundredyears.Mutantswithoneparticularkindof abnormalitygotspecialattention.Theseflieshadorgansin thewrongplaces—alegwhereanantennashouldhave been;anextrasetofwings—orweremissingbody segments.Somethingwasmessingwiththeirfundamental bodyplan.Ultimately,thesemutantsarisefromsomesort oferrorintheDNA.Rememberthatgenesarestretchesof DNAthatlieonthechromosome.Usingavarietyof techniquesthatallowustovisualizethechromosome,we canidentifythepatchofthechromosomeresponsiblefor themutanteffect.Essentially,webreedmutantstomakea wholepopulationwhereeveryindividualhasthegenetic error.Then,usingavarietyofmolecularmarkers,we 143 comparethegenesofindividualswiththemutationto thosewithout.Thisallowsustopinpointtheregionandthe likelystretchofchromosomeresponsibleforthemutant effect.Itturnsoutthataflyhaseightgenesthatmakesuch mutants.Thesegeneslienexttooneanotherononeofthe longDNAstrandsofthefly.Thegenesthataffectthehead segmentslienexttothosethataffectthesegmentsinthe middleofthefly,thepartofthebodythatcontainsthe wings.ThesebitsofDNA,inturn,lieadjacenttotheones thatcontrolthedevelopmentoftherearpartofthefly. Thereisawonderfulordertothewaythegenesare organized:theirpositionalongtheDNAstrandparallelsthe structureofthebodyfromfronttoback. Nowthechallengewastoidentifythestructureofthe DNAactuallyresponsibleforthemutation.MikeLevineand BillMcGinnis,inWalterGehring’slabinSwitzerland,and MattScott,inTomKauffman’slabinIndiana,noticedthatin themiddleofeachgenewasashortDNAsequencethatwas virtuallyidenticalineachspeciestheylookedat.Thislittle sequenceiscalledahomeobox.Theeightgenesthat containthehomeoboxarecalledHoxgenes.Whenthe scientistsfishedaroundforthisgenesequenceinother species,theyfoundsomethingsouniformthatitcameasa truesurprise:versionsoftheHoxgenesappearinevery animalwithabody. 144 Hoxgenesinfliesandpeople.Thehead-to-tail organizationofthebodyisunderthecontrolof differentHoxgenes.Flieshaveonesetofeighthox genes,eachrepresentedasalittleboxinthediagram. Humanshavefoursetsofthesegenes.Infliesand 145 people,theactivityofagenematchesitspositionon theDNA:genesactiveintheheadlieatoneend,those inthetailatanother,withgenesaffectingthemiddleof thebodylyinginbetween. Versionsofthesamegenessculptthefront-to-back organizationofthebodiesofcreaturesasdifferentasflies andmice.MesswiththeHoxgenesandyoumesswiththe bodyplaninpredictableways.Ifyoumakeaflythatlacksa geneactiveinamiddlesegment,themidsectionoftheflyis missingoraltered.Makeamousethatlacksoneofthe genesthatspecifiesthoracicsegments,andyoutransform partsoftheback. Hoxgenesalsoestablishtheproportionsofourbodies— thesizesofthedifferentregionsofourhead,chest,and lowerback.Theyareinvolvedinthedevelopmentof individualorgans,limbs,genitalia,andguts.Changesin thembringaboutchangesinthewaysourbodiesareput together. Differentkindsofcreatureshavedifferentnumbersof Hoxgenes.Fliesandotherinsectshaveeight,miceand othermammalsthirty-nine.Thethirty-nineHoxgenesin miceareallversionsoftheonesthatarefoundinflies.This similarityhasledtotheideathatthelargenumberof mammalianHoxgenesarosefromaduplicationofthe smallercomplementofgenesinthefly.Despitethese differencesinnumber,themousegenesareactivefrom fronttobackinaverypreciseorderjustastheflygenesare. Canwegoevendeeperinourfamilytree,findingsimilar 146 stretchesofDNAinvolvedinmakingevenmore fundamentalpartsofourbodies?Theanswer,surprisingly, isyes.Anditlinksustoanimalsevensimplerthanflies. DNAANDTHEORGANIZER AtthetimewhenSpemannwontheNobelPrize,the Organizerwasalltherage.Scientistssoughtthemysterious chemicalthatcouldinducetheentirebodyplan.Butjustas popularculturehasyo-yosandTickleMeElmodolls,so sciencehasfadsthatwaxandwane.Bythe1970s,the Organizerwasviewedaslittlemorethanacuriosity,a cleveranecdoteinthehistoryofembryology.Thereason forthisfallfromgracewasthatnoonecoulddecipherthe mechanismsthatmadeitwork. ThediscoveryofHoxgenesinthe1980schanged everything.Intheearly1990s,whentheOrganizerconcept wasstilldecidedlyunfashionable,EddieDeRobertis’s laboratoryatUCLAwaslookingforHoxgenesinfrogs,using techniqueslikeLevineandMcGinnis’s.Thesearchwas broadanditnettedmanydifferentkindsofgenes.Oneof thesehadaveryspecialpatternofactivity.Itwasactiveat theexactsiteintheembryothatcontainstheOrganizer, anditwasactiveatexactlytherighttimeofdevelopment.I canonlyimaginewhatDeRobertisfeltwhenhefoundthat gene.HewaslookingattheOrganizer,andthereinthe Organizerwasagenethatseemedspecificallytocontrolit 147 orbelinkedtoitsactivityintheembryo.TheOrganizerwas back. Organizergenesstartedpoppingupinlaboratories everywhere.Whiledoingadifferentkindofexperiment, RichardHarlandatBerkeleyfoundanothergene,whichhe calledNoggin.NoggindoesexactlywhatanOrganizergene should.WhenHarlandtooksomeNogginandinjecteditinto therightplaceinanembryo,itfunctionedexactlylikethe Organizer.Theembryodevelopedtwobodyaxes,including twoheads. AreDeRobertis’sgeneandNoggintheactualbitsofDNA thatmakeuptheOrganizer?Theanswerisyesandno. Manygenes,includingthesetwo,interacttoorganizethe bodyplan.Suchsystemsarecomplex,becausegenescan playmanydifferentrolesduringdevelopment.Noggin,for example,playsaroleinthedevelopmentofthebodyaxis butisalsoinvolvedwithahostofotherorgans. Furthermore,genesdonotactalonetospecifycomplicated cellbehaviorslikethoseweseeinheaddevelopment.Genes interactwithothergenesatallstagesofdevelopment.One genemayinhibittheactivityofanotherorpromoteit. Sometimesmanygenesinteracttoturnanothergeneonor off.Fortunately,newtoolsallowustostudytheactivityof thousandsofgenesinacellatonce.Couplethistechnology withnewcomputer-basedwaysofinterpretinggene functionandwehaveenormouspotentialtounderstand howgenesbuildcells,tissues,andbodies. Understandingthesecomplexinteractionsbetween 148 batteriesofgenesshedslightontheactualmechanisms thatbuildbodies.Nogginservesasagreatexample.Noggin alonedoesnotinstructanycellintheembryoaboutits positiononthetop–bottomaxis;rather,itactsinconcert withseveralothergenestodothis.Anothergene,BMP-4,is abottomgene;itisturnedonincellsthatwillmakethe bottom,orbellyside,ofanembryo.Thereisanimportant interactionbetweenBMP-4andNoggin.WhereverNogginis active,BMP-4cannotdoitsjob.TheupshotisthatNoggin doesnottellcellstodevelopas“cellsonthetopofthe body”instead,itturnsoffthesignalthatwouldmakethem bottomcells.Theseoff-oninteractionsunderlievirtuallyall developmentalprocesses. ANINNERSEAANEMONE Itisonethingtocompareourbodieswiththoseoffrogs andfish.Inarealsenseweandtheyaremuchalike:weall haveabackbone,twolegs,twoarms,ahead,andsoon. Whatifwecompareourselveswithsomethingutterly different,forexamplejellyfishandtheirrelatives? Mostanimalshavebodyaxesdefinedbytheirdirection ofmovementorbywheretheirmouthandanuslierelative toeachother.Thinkaboutit:ourmouthisontheopposite endofthebodyfromouranusand,asinfishandinsects,it isusuallyinthedirection“forward.” Howcanwetrytoseeourselvesinanimalsthathaveno 149 nervecordatall?Howaboutnoanusandnomouth? Creatureslikejellyfish,corals,andseaanemoneshavea mouth,butnoanus.Theopeningthatservesasamouth alsoservestoexpelwaste.Whilethatoddarrangement maybeconvenientforjellyfishandtheirrelatives,itgives biologistsvertigowhentheytrytocomparethesecreatures toanythingelse. Anumberofcolleagues,MarkMartindaleandJohn Finnertyamongthem,havedivedintothisproblemby studyingthedevelopmentofthisgroupofanimals.Sea anemoneshavebeenremarkablyinformative,becausethey arecloserelativesofjellyfishandtheyhaveaveryprimitive bodypattern.Also,seaanemoneshaveaveryunusual shape,onethatatfirstglancewouldseemtomakethem worthlessasaformtocomparetous.Aseaanemoneis shapedlikeatreetrunkwithalongcentralstumpanda bunchoftentaclesattheend.Thisoddshapemakesit particularlyappealing,sinceitmighthaveafrontanda back,atopandabottom.Drawalinefromthemouthtothe baseoftheanimal.Biologistshavegiventhatlineaname: theoral–aboralaxis.Butnamingitdoesn’tmakeitmore thananarbitraryline.Ifitisreal,thenitsdevelopment shouldresemblethedevelopmentofoneofourownbody dimensions. Martindaleandhiscolleaguesdiscoveredthatprimitive versionsofsomeofourmajorbodyplangenes—thosethat determineourhead-to-anusaxis—areindeedpresentin theseaanemone.And,moreimportant,thesegenesare 150 activealongtheoral–aboralaxis.Thisinturnmeansthat theoral–aboralaxisoftheseprimitivecreaturesis geneticallyequivalenttoourhead-to-anusaxis. Oneaxisdown,anothertogo.Doseaanemoneshave anythinganalogoustoourbelly-to-backaxis?Sea anemonesdon’tseemtohaveanythingcomparable. Despitethis,Martindaleandhiscolleaguestookthebold stepofsearchingintheseaanemoneforthegenesthat specifyourbelly-to-backaxis.Theyknewwhatourgenes lookedlike,andthisgavethemasearchimage.They uncoverednotone,butmanydifferentbelly-to-backgenes intheseaanemone.Butalthoughthesegeneswereactive alonganaxisintheseaanemone,thataxisdidn’tseemto correlatewithanypatterninhowtheadultanimal’sorgans areputtogether. 151 Jellyfishrelatives,suchasseaanemones,haveafront andabackaswedo,abodyplansetupbyversionsof thesamegenes. Justwhatthishiddenaxiscouldbeisnotapparentfrom theoutsideoftheanimal.Ifwecutoneinhalf,however,we findanimportantclue,anotheraxisofsymmetry.Calledthe directiveaxis,itseemstodefinetwodistinctsidesofthe creature,almostaleftandaright.Thisobscureaxiswas knowntoanatomistsbackinthe1920sbutremaineda curiosityinthescientificliterature.Martindale,Finnerty, andtheirteamchangedthat. Allanimalsarethesamebutdifferent.Likeacakerecipe passeddownfromgenerationtogeneration—with enhancementstothecakeineach—therecipethatbuilds ourbodieshasbeenpasseddown,andmodified,foreons. Wemaynotlookmuchlikeseaanemonesandjellyfish,but therecipethatbuildsusisamoreintricateversionofthe onethatbuildsthem. Powerfulevidenceforacommongeneticrecipefor animalbodiesisfoundwhenweswapgenesbetween species.Whathappenswhenyouswapabody-building genefromananimalthathasacomplexbodyplanlikeours withonefromaseaanemone?RecallthegeneNoggin, whichinfrogs,mice,andhumansisturnedoninplacesthat willdevelopintobackstructures.Injectextraamountsof frogNogginintoafrogegg,andthefrogwillgrowextra backstructures,sometimesevenasecondhead.Insea anemoneembryos,aversionofNogginisalsoturnedonat 152 oneendofthedirectiveaxis.Now,themillion-dollar experiment:taketheproductofNogginfromasea anemoneandinjectitintoafrogembryo.Theresult:afrog withextrabackstructures,almostthesameresultasifthe frogwereinjectedwithitsownNoggin. Now,though,aswegobackintime,weareleftwithwhat lookslikeahugegap.Everythinginthischapterhadabody. Howdowecompareourselveswiththingsthathaveno bodiesatall—withsingle-celledmicrobes? 153