Download Your Inner Fish - 03_Chapter Three

CHAPTERTHREE
HANDYGENES
WhilemycolleaguesandIwerediggingupthefirst
TiktaalikintheArcticinJuly2004,RandyDahn,a
researcherinmylaboratory,wassweatingitoutonthe
SouthSideofChicagodoinggeneticexperimentsonthe
embryosofsharksandskates,cousinsofstingrays.You’ve
probablyseensmallblackeggcases,knownasmermaid’s
purses,onthebeach.Insidethepurseoncelayaneggwith
yolk,whichdevelopedintoanembryonicskateorray.Over
theyears,Randyhasspenthundredsofhours
experimentingwiththeembryosinsidetheseeggcases,
oftenworkingwellpastmidnight.Duringthefateful
summerof2004,Randywastakingthesecasesand
injectingamolecularversionofvitaminAintotheeggs.
Afterthathewouldlettheeggsdevelopforseveralmonths
untiltheyhatched.
Hisexperimentsmayseemtobeabizarrewaytospend
thebetterpartofayear,letaloneforayoungscientistto
launchapromisingscientificcareer.Whysharks?Whya
formofvitaminA?
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Tomakesenseoftheseexperiments,weneedtostep
backandlookatwhatwehopetheymightexplain.Whatwe
arereallygettingatinthischapteristherecipe,writtenin
ourDNA,thatbuildsourbodiesfromasingleegg.When
spermfertilizesanegg,thatfertilizedeggdoesnotcontain
atinyhand,forinstance.Thehandisbuiltfromthe
informationcontainedinthatsinglecell.Thistakesustoa
veryprofoundproblem.Itisonethingtocomparethe
bonesofourhandswiththebonesinfishfins.What
happensifyoucomparethegeneticrecipethatbuildsour
handswiththerecipethatbuildsafish’sfin?Tofind
answerstothisquestion,justlikeRandy,wewillfollowa
trailofdiscoverythattakesusfromourhandstothefinsof
sharksandeventothewingsofflies.
Aswe’veseen,whenwediscovercreaturesthatreveal
differentandoftensimplerversionsofourbodiesinside
theirown,awonderfullydirectwindowopensintothe
distantpast.Butthereisabiglimitationtoworkingwith
fossils.Wecannotdoexperimentsonlong-deadanimals.
Experimentsaregreatbecausewecanactuallymanipulate
somethingtoseetheresults.Forthisreason,mylaboratory
issplitdirectlyintwo:halfisdevotedtofossils,theother
halftoembryosandDNA.Lifeinmylabcanbe
schizophrenic.ThelockedcabinetthatholdsTiktaalik
specimensisadjacenttothefreezercontainingour
preciousDNAsamples.
ExperimentswithDNAhaveenormouspotentialto
revealinnerfish.Whatifyoucoulddoanexperimentin
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whichyoutreatedtheembryoofafishwithvarious
chemicalsandactuallychangeditsbody,makingpartofits
finlooklikeahand?Whatifyoucouldshowthatthegenes
thatbuildafish’sfinarevirtuallythesameasthosethat
buildourhands?
Webeginwithanapparentpuzzle.Ourbodyismadeup
ofhundredsofdifferentkindsofcells.Thiscellulardiversity
givesourtissuesandorganstheirdistinctshapesand
functions.Thecellsthatmakeourbones,nerves,guts,and
soonlookandbehaveentirelydifferently.Despitethese
differences,thereisadeepsimilarityamongeverycell
insideourbodies:allofthemcontainexactlythesameDNA.
IfDNAcontainstheinformationtobuildourbodies,tissues,
andorgans,howisitthatcellsasdifferentasthosefoundin
muscle,nerve,andbonecontainthesameDNA?
TheanswerliesinunderstandingwhatpiecesofDNA
(thegenes)areactuallyturnedonineverycell.Askincellis
differentfromaneuronbecausedifferentgenesareactive
ineachcell.Whenageneisturnedon,itmakesaprotein
thatcanaffectwhatthecelllookslikeandhowitbehaves.
Therefore,tounderstandwhatmakesacellintheeye
differentfromacellinthebonesofthehand,weneedto
knowaboutthegeneticswitchesthatcontroltheactivityof
genesineachcellandtissue.
Here’stheimportantfact:thesegeneticswitcheshelpto
assembleus.Atconception,westartasasinglecellthat
containsalltheDNAneededtobuildourbody.Theplanfor
thatentirebodyunfoldsviatheinstructionscontainedin
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thissinglemicroscopiccell.Togofromthisgeneralizedegg
celltoacompletehuman,withtrillionsofspecializedcells
organizedinjusttherightway,wholebatteriesofgenes
needtobeturnedonandoffatjusttherightstagesof
development.Likeaconcertocomposedofindividualnotes
playedbymanyinstruments,ourbodiesareacomposition
ofindividualgenesturningonandoffinsideeachcell
duringourdevelopment.
GenesarestretchesofDNAcontainedineverycellof
ourbodies.
Thisinformationisaboontothosewhoworkto
understandbodies,becausewecannowcomparethe
activityofdifferentgenestoassesswhatkindsofchanges
areinvolvedintheoriginofneworgans.Takelimbs,for
example.Whenwecomparetheensembleofgenesactivein
thedevelopmentofafishfintothoseactiveinthe
developmentofahumanhand,wecancataloguethegenetic
differencesbetweenfinsandlimbs.Thiskindof
comparisongivesussomelikelyculprits—thegenetic
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switchesthatmayhavechangedduringtheoriginoflimbs.
Wecanthenstudywhatthesegenesaredoinginthe
embryoandhowtheymighthavechanged.Wecanevendo
experimentsinwhichwemanipulatethegenestoseehow
bodiesactuallychangeinresponsetodifferentconditions
orstimuli.
Toseethegenesthatbuildourhandsandfeet,weneed
totakeapagefromascriptfortheTVshowCSI:CrimeScene
Investigation—startatthebodyandworkourwayin.We
willbeginbylookingatthestructureofourlimbs,andzoom
allthewaydowntothetissues,cells,andgenesthatmake
it.
MAKINGHANDS
Ourlimbsexistinthreedimensions:theyhaveatopanda
bottom,apinkysideandathumbside,abaseandatip.The
bonesatthetips,inourfingers,aredifferentfromthe
bonesattheshoulder.Likewise,ourhandsaredifferent
fromonesidetotheother.Ourpinkiesareshaped
differentlyfromourthumbs.TheHolyGrailofour
developmentalresearchistounderstandwhatgenes
differentiatethevariousbonesofourlimb,andwhat
controlsdevelopmentinthesethreedimensions.WhatDNA
actuallymakesapinkydifferentfromathumb?Whatmakes
ourfingersdistinctfromourarmbones?Ifwecan
understandthegenesthatcontrolsuchpatterns,wewillbe
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privytotherecipethatbuildsus.
Allthegeneticswitchesthatmakefingers,armbones,
andtoesdotheirthingduringthethirdtoeighthweekafter
conception.Limbsbegintheirdevelopmentastinybuds
thatextendfromourembryonicbodies.Thebudsgrow
overtwoweeks,untilthetipformsalittlepaddle.Inside
thispaddlearemillionsofcellswhichwillultimatelygive
risetotheskeleton,nerves,andmusclesthatwe’llhavefor
therestofourlives.
Thedevelopmentofalimb,inthiscaseachickenwing.
Allofthekeystagesinthedevelopmentofawing
skeletonhappeninsidetheegg.
Tostudyhowthispatternemerges,weneedtolookat
embryosandsometimesinterferewiththeirdevelopment
toassesswhathappenswhenthingsgowrong.Moreover,
weneedtolookatmutantsandattheirinternalstructures
andgenes,oftenbymakingwholemutantpopulations
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throughcarefulbreeding.Obviously,wecannotstudy
humansintheseways.Thechallengeforthepioneersin
thisfieldwastofindtheanimalsthatcouldbeuseful
windowsintoourowndevelopment.Thefirstexperimental
embryologistsinterestedinlimbsinthe1930sand1940s
facedseveralproblems.Theyneededanorganisminwhich
thelimbswereaccessibleforobservationandexperiment.
Theembryohadtoberelativelylarge,sothattheycould
performsurgicalproceduresonit.Importantly,theembryo
hadtogrowinaprotectedplace,inacontainerthat
sheltereditfromjostlingandotherenvironmental
disturbances.Also,andcritically,theembryoshadtobe
abundantandavailableyear-round.Theobvioussolutionto
thisscientificneedisatyourlocalgrocerystore:chicken
eggs.
Inthe1950sand1960sanumberofbiologists,including
EdgarZwillingandJohnSaunders,didextraordinarily
creativeexperimentsonchickeneggstounderstandhow
thepatternoftheskeletonforms.Thiswasaneraofslice
anddice.Embryoswerecutupandvarioustissuesmoved
abouttoseewhateffectthishadondevelopment.The
approachinvolvedverycarefulmicrosurgery,manipulating
patchesoftissuenomorethanamillimeterthick.Inthat
way,bymovingtissuesaboutinthedevelopinglimb,
SaundersandZwillinguncoveredsomeofthekey
mechanismsthatbuildlimbsasdifferentasbirdwings,
whaleflippers,andhumanhands.
Theydiscoveredthattwolittlepatchesoftissue
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essentiallycontrolthedevelopmentofthepatternofbones
insidelimbs.Astripoftissueattheextremeendofthelimb
budisessentialforalllimbdevelopment.Removeit,and
developmentstops.Removeitearly,andweareleftwith
onlyanupperarm,orapieceofanarm.Removeitslightly
later,andweendupwithanupperarmandaforearm.
Removeitevenlater,andthearmisalmostcomplete,
exceptthatthedigitsareshortanddeformed.
Anotherexperiment,initiallydonebyMaryGasselingin
JohnSaunders’slaboratory,ledtoapowerfulnewlineof
research.Takealittlepatchoftissuefromwhatwillbecome
thepinkysideofalimbbud,earlyindevelopment,and
transplantitontheoppositeside,justunderwherethefirst
fingerwillform.Letthechickdevelopandformawing.The
resultsurprisednearlyeverybody.Thewingdeveloped
normallyexceptthatitalsohadafullduplicatesetofdigits.
Evenmoreremarkablewasthepatternofthedigits:the
newfingersweremirrorimagesofthenormalset.
Obviously,somethinginsidethatpatchoftissue,some
moleculeorgene,wasabletodirectthedevelopmentofthe
patternofthefingers.Thisresultspawnedablizzardofnew
experiments,andwelearnedthatthiseffectcanbe
mimickedbyavarietyofothermeans.Forexample,takea
chickenembryoanddabalittlevitaminAonitslimbbud,
orsimplyinjectvitaminAintotheegg,andlettheembryo
develop.IfyousupplythevitaminAattheright
concentrationandattherightstage,you’llgetthesame
mirror-imageduplicationthatGasseling,Saunders,and
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Zwillinggotfromthegraftingexperiments.Thispatchof
tissuewasnamedthezoneofpolarizingactivity(ZPA).
Essentially,theZPAisapatchoftissuethatcausesthe
pinkysidetobedifferentfromthethumbside.Obviously
chicksdonothaveapinkyandathumb.Theterminology
weuseistonumberthedigits,withourpinky
correspondingtodigitfiveofotheranimalsandourthumb
correspondingtodigitone.
MovingalittlepatchoftissuecalledtheZPAcausesthe
fingerstobeduplicated.
TheZPAdrewinterestbecauseitappeared,insomeway,
tocontroltheformationoffingersandtoes.Buthow?Some
peoplebelievedthatthecellsintheZPAmadeamolecule
thatthenspreadacrossthelimbtoinstructcellstomake
differentfingers.Thekeyproposalwasthatitwasthe
concentrationofthisunnamedmoleculethatwasthe
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importantfactor.InareasclosetotheZPA,wherethereisa
highconcentrationofthismolecule,cellswouldrespondby
makingapinky.Intheoppositesideofthedevelopinghand,
fartherfromtheZPAsothatthemoleculewasmore
diffused,thecellswouldrespondbymakingathumb.Cells
inthemiddlewouldeachrespondaccordingtothe
concentrationofthismoleculetomakethesecond,third,
andfourthfingers.
Thisconcentration-dependentideacouldbetested.In
1979,DenisSummerbellplacedanextremelysmallpieceof
foilbetweentheZPApatchandtherestofthelimb.Theidea
wastousethisbarriertopreventanykindofmoleculefrom
diffusingfromtheZPAtotheotherside.Summerbell
studiedwhathappenedtothecellsoneachsideofthe
barrier.CellsontheZPAsideformeddigits.Cellsonthe
oppositesideoftendidnotformdigits;iftheydid,the
digitswerebadlymalformed.Theconclusionwasobvious.
SomethingwasemanatingfromtheZPAthatcontrolled
howthedigitsformedandwhattheylookedlike.To
identifythatsomething,researchersneededtolookatDNA.
THEDNARECIPE
Thatprojectwaslefttoanewgenerationofscientists.Not
untilthe1990s,whennewmoleculartechniquesbecame
available,wasthegeneticcontrolfortheZPA’soperation
unraveled.
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Amajorbreakthroughhappenedin1993,whenCliff
Tabin’slaboratoryatHarvardstartedhuntingforthegenes
thatcontroltheZPA.Theirpreywasthemolecular
mechanismsthatgavetheZPAitsabilitytomakeourpinky
differentfromourthumb.Bythetimehisgroupstartedto
workintheearly1990s,anumberofexperimentslikethe
onesI’vedescribedhadledustobelievethatsomesortof
moleculecausedthewholething.Thiswasagrandtheory,
butnobodyknewwhatthismoleculewas.Peoplewould
proposeonemoleculeafteranother,onlytofindthatnone
wasuptothejob.Finally,theTabinlabcameupwitha
novelnotion,andoneveryrelevanttothethemeofthis
book.Looktofliesfortheanswer.
Geneticexperimentsinthe1980shadrevealedthe
wonderfulpatternofgeneactivitythatsculptsthebodyofa
flyfromasingle-celledegg.Thebodyofafruitflyis
organizedfromfronttoback,withtheheadatthefrontand
thewingsattheback.Wholebatteriesofgenesareturned
onandoffduringflydevelopment,andthispatternofgene
activityservestodemarcatethedifferentregionsofthefly.
Tabindidn’tknowitatthetime,buttwoother
laboratories—thoseofAndyMacMahonandPhilIngham—
hadalreadycomeupwiththesamegeneralidea
independently.Whatemergedwasaremarkablysuccessful
collaborationamongthreedifferentlabgroups.Oneofthe
flygenescaughttheattentionofTabin,McMahon,and
Ingham.Theynotedthatthisgenemadeoneendofabody
segmentlookdifferentfromtheother.Flygeneticists
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namedithedgehog.Doesn’tthefunctionofhedgehoginthe
flybody—tomakeoneregiondifferentfromanother—
soundlikewhattheZPAdoesinmakingthepinkydifferent
fromthethumb?Thatparallelwasnotlostonthethree
labs.Soofftheywent,lookingforahedgehoggenein
creatureslikechickens,mice,andfish.
Becausethelabgroupsknewthestructureofthefly’s
hedgehoggene,theyhadasearchimagetohelpthemsingle
outthegeneinchickens.Eachgenehasadistinctive
sequence;usinganumberofmoleculartools,the
researcherscouldscanthechicken’sDNAforthehedgehog
sequence.Afteralotoftrialanderror,theyfoundachicken
hedgehoggene.
Justaspaleontologistsgettonamenewspecies,
geneticistsgettonamenewgenes.Theflygeneticistswho
discoveredhedgehoghadnameditthatbecausetheflies
withamutationinthegenehadbristlesthatreminded
themofalittlehedgehog.Tabin,McMahon,andIngham
namedthechickenversionofthegeneSonichedgehog,after
theSegaGenesisvideogame.
Nowcamethefunquestion:WhatdoesSonichedgehog
actuallydointhelimb?TheTabingroupattachedadyetoa
moleculethatwouldsticktothegene,enablingthemto
visualizewherethegeneisactiveinthelimb.Totheirgreat
surprise,theyfoundthatonlycellsinatinypatchofthe
limbhadgeneactivity:theZPA.
Sothenextstepsbecameobvious.Thepatternsof
activityintheSonichedgehoggeneshouldmimicthoseof
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theZPAtissueitself.Recallthatwhenyoutreatthelimb
withretinoicacid,aformofvitaminA,yougetaZPAactive
ontheoppositeside.Guesswhathappenswhenyoutreata
limbwithretinoicacid,thenmapwhereSonichedgehogis
active?Sonichedgehogbecomesactiveonbothsides—
pinkyandthumb—justastheZPAdoeswhenitistreated
withretinoicacid.
KnowingthestructureofthechickenSonichedgehog
gaveotherresearchersthetoolstolookforitineverything
elsethathasfingers,fromfrogstohumans.Everylimbed
animalhastheSonichedgehoggene.Andineverysingle
animalthatwehavestudied,Sonichedgehogisactiveinthe
ZPAtissue.IfSonichedgehoghadn’tturnedonproperly
duringtheeighthweekofyourowndevelopment,thenyou
eitherwouldhaveextrafingersoryourpinkyandthumb
wouldlookalike.Occasionally,whenthingsgowrongwith
Sonichedgehog,thehandendsuplookinglikeabroad
paddlewithasmanyastwelvefingersthatalllookalike.
WenowknowthatSonichedgehogisoneofdozensof
genesthatacttosculptourlimbsfromshouldertofingertip
byturningonandoffattherighttime.Remarkably,workin
chickens,frogs,andmicewastellingusthesamething.The
DNArecipetobuildupperarms,forearms,wrists,anddigits
isvirtuallyidenticalineverycreaturethathaslimbs.
HowfarbackcanwetraceSonichedgehogandtheother
bitsofDNAthatbuildlimbs?Isthisstuffactiveinbuilding
theskeletonoffishfins?Orarehandsgenetically
completelydifferentfromfishfins?Wesawaninnerfishin
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theanatomyofourarmsandhands.WhatabouttheDNA
thatbuildsit?
EnterRandyDahnwithhismermaid’spurses.
GIVINGSHARKSAHAND
RandyDahnenteredmylaboratorywithasimplebutvery
elegantidea:treatskateembryosjustthewayCliffTabin
treatedchickeneggs.Randy’sgoalwastoperformallthe
experimentsonskatesthatchickenbiologistshad
performedonchickeneggs,fromSaundersandZwilling’s
tissuesurgeriesallthewaytoCliffTabin’sgene
experiments.Skatesdevelopinaneggwithakindofshell
andayolk.Skatesevenhavebigembryos,justaschickens
do.Becauseoftheseconvenientfacts,wecouldapplyto
skatesmanyofthegeneticandexperimentaltoolspeople
haddevelopedtounderstandchickens.
Whatcouldwelearnbycomparingthedevelopmentofa
sharkfintothatofachickenleg?Evenmorerelevant,what
couldwelearnaboutourselvesfromallthis?
Chickens,asSaunders,Zwilling,andTabinshowed,area
surprisinglygoodproxyforourownlimbs.Everythingthat
wasdiscoveredbySaundersandZwilling’scuttingand
graftingexperimentsandbyTabin’sDNAworkappliesto
ourownlimbsaswell:wehaveaZPA,wehaveSonic
hedgehog,andbothhaveagreatbearingonourwell-being.
Aswesaw,amalfunctioningZPAoramutationinSonic
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hedgehogcancausemajormalformationsinhumanhands.
Randywantedtodeterminehowdifferenttheapparatus
isthatbuildsourhands.Howdeepisourconnectiontothe
restoflife?Istherecipethatbuildsourhandsnew,ordoes
it,too,havedeeprootsinothercreatures?Ifso,howdeep?
Sharksandtheirrelativesaretheearliestcreaturesthat
havefinswithaskeletoninside.Ideally,toanswerRandy’s
question,youwouldwanttobringa400-million-year-old
sharkfossilintothelaboratory,grinditup,andlookatits
geneticstructure.Thenyou’dtrytomanipulateitsfossil
embryostolearnwhetherSonichedgehogisactiveinthe
samegeneralplaceasinourlimbstoday.Thiswouldbea
wonderfulexperiment,butitisimpossible.Wecannot
extractDNAfromfossilssoold,and,evenifwecould,we
couldneverfindembryosofthosefossilanimalsonwhich
todoexperiments.
Livingsharksandtheirrelativesarethenextbestthing.
Nobodywouldeverconfuseasharkfinwithahumanhand:
youcouldn’taskfortwomoredifferentkindsof
appendages.Notonlyaresharksandhumansverydistantly
related,butalsotheskeletalstructuresoftheirappendages
looknothingalike.NothingevenremotelysimilartoOwen’s
onebone–twobones–lotsablobs–digitspatternisinsidea
shark’sfin.Instead,thebonesinsideareshapedlikerods,
longandshort,thinandwide.Wecallthemboneseven
thoughtheyaremadeofcartilage(sharksandskatesare
knownascartilaginousfish,becausetheirskeletonsnever
turnintohardbone).IfyouwanttoassesswhetherSonic
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hedgehog’sroleinlimbsisuniquetolimbedanimals,why
notchooseaspeciesutterlydifferentinalmosteveryway?
Inaddition,whynotchoosethespeciesthatisthemost
primitivelivingfishwithanykindofpairedappendage,
whetherfinorlimb?Sharksfitbothbillsperfectly.
Ourfirstproblemwasasimpleone.Weneededareliable
sourcefortheembryosofsharksandskates.Sharksproved
difficulttoobtainwithanydegreeofregularity,butskates,
theircloserelatives,wereanothermatter.Sowestarted
withsharksandusedskatesasoursupplyofsharks
dwindled.Wefoundasupplierwhowouldshipusevery
monthortwoabatchoftwentyorthirtyeggcaseswith
embryosinside.Webecameavirtualcargocultaswe
waitedeachmonthforourshipmentofpreciouseggcases.
WorkbyTabin’sgroupandothersgaveRandyimportant
cluestobeginhissearch.SinceTabin’sworkin1993,
peoplehadfoundSonichedgehoginanumberofdifferent
species,everythingfromfishtohumans.Withthe
knowledgeofthestructureofthegene,Randywasableto
searchalltheDNAoftheskateandsharkforSonic
hedgehog.Inaveryshorttimehefoundit:asharkSonic
hedgehoggene.
ThekeyquestionstoanswerwereWhereisSonic
hedgehogactive?,and,evenmoreimportant,Whatisit
doing?
TheeggcaseswereputtouseasRandyvisualizedwhere
andwhenSonichedgehogisactiveinthedevelopmentof
skates.HefirststudiedwhetherSonichedgehogturnsonat
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thesametimeinskatefindevelopmentasitdoesin
chickenlimbs.Yes,itdoes.Thenhestudiedwhetheritis
turnedoninthepatchoftissueatthebackendofthefin,
theequivalentofourpinky.Yesagain.Nowhedidhis
vitaminAexperiment.Thiswasthemillion-dollarmoment.
Ifyoutreatthelimbofachickenormammalwiththis
compound,yougetapatchoftissuethathasSonichedgehog
activityontheoppositeside,andthisresultiscoupledwith
aduplicationofthebones.Randyinjectedtheegg,waiteda
dayorso,andthencheckedwhether,asinchickens,the
vitaminAcausedSonichedgehogtoturnonintheopposite
sideofthelimb.Itdid.Nowcamethelongwait.Weknew
thatSonichedgehogwasbehavingthesamewayinour
handsandinskates’andsharks’fins.Butwhatwouldthe
effectofallthisbeontheskeleton?Wewouldhavetowait
twomonthsfortheanswer.
Theembryosweredevelopinginsideanopaqueeggcase.
Allwecouldtellwaswhetherthecreaturewasalive;the
insideofthefinwasinvisibletous.
Theendresultwasastunningexampleofsimilarity
amongus,sharks,andskates:amirror-imagefin.The
dorsalfinsduplicatedtheirstructuresinawonderfulfrontto-backpattern,thesamekindwesawwithexperimentsin
limbs.Limbsduplicatealimbstructure.Sharkfinsduplicate
asharkfinstructureasdoskates.Sonichedgehoghasa
similareffectineventhemostdifferentkindsofappendage
skeletonsfoundonearthtoday.
OneeffectofSonichedgehog,youmayrecall,istomake
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thefingersdistinctfromoneanother.Aswesawwith
respecttotheZPA,whatkindofdigitdevelopsdependson
howclosethedigitistothesourceofSonichedgehog.A
normaladultskatefincontainsmanyskeletalrods,which
alllookalike.Couldwemaketheserodsdifferentfromone
another,likeourdigits?Randytookasmallbead
impregnatedwiththeproteinmadebySonichedgehogand
putitinbetweentheseidenticalskeletalrods.Thekeyto
hisexperimentisthatheusedmouseSonichedgehog.So
nowwehavearealcontraption:askateembryowithabead
insidethatisgraduallyleakingmouseSonichedgehog
protein.Wouldthatmouseproteinhaveanyeffectona
sharkoraskate?
Therearetwoextremeoutcomestoanexperimentlike
this.Oneisthatnothinghappens.Thiswouldmeanthat
skatesaresodifferentfrommicethatSonichedgehog
proteinhasnoeffect.Theotherextremeoutcomewould
presentastunningexampleofourinnerfish.Thisoutcome
wouldbethattherodsdevelopdifferentlyfromone
another,demonstratingthatSonichedgehogdoes
somethingsimilarinskatesandinus.Andlet’snotforget
thatsinceRandyisusingtheproteinfromamammal,it
meansthatthegeneticrecipewouldbereally,reallysimilar.
Notonlydidtherodsenduplookingdifferentfromone
another,theyrespondedtoSonichedgehog,muchasfingers
do,onthebasisofhowclosetheyweretotheSonic
hedgehogbead:thecloserrodsdevelopedadifferentshape
fromtheonesfartheraway.Totopmattersoff,itwasthe
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mouseproteinthatdidthejobsoeffectivelyintheskates.
Normalfins(left)andRandy’streatedfins.Thetreated
finsshowedamirror-imageduplicationjustaschicken
wingsdid.PhotographscourtesyofRandallDahn,
UniversityofChicago.
The“innerfish”thatRandyfoundwasnotasinglebone,
orevenasectionoftheskeleton.Randy’sinnerfishlayin
thebiologicaltoolsthatactuallybuildfins.Experimentafter
experimentoncreaturesasdifferentasmice,sharks,and
fliesshowsusthatthelessonsofSonichedgehogarevery
general.Allappendages,whethertheyarefinsorlimbs,are
builtbysimilarkindsofgenes.Whatdoesthismeanforthe
problemwelookedatinthefirsttwochapters—the
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transitionoffishfinsintolimbs?Itmeansthatthisgreat
evolutionarytransformationdidnotinvolvetheoriginof
newDNA:muchoftheshiftlikelyinvolvedusingancient
genes,suchasthoseinvolvedinsharkfindevelopment,in
newwaystomakelimbswithfingersandtoes.
Butthereisadeeperbeautytotheseexperimentson
limbsandfins.Tabin’slabusedworkinfliestofindagenein
chickensthattellsusabouthumanbirthdefects.Randy
usedtheTabinlabdiscoverytotellussomethingaboutour
connectionstoskates.An“innerfly”helpedfindan“inner
chicken,”whichultimatelyhelpedRandyfindan“inner
skate.”Theconnectionsamonglivingcreaturesrundeep.
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