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DiscoveryofDNAStructureandFunction:WatsonandCrick
By:LeslieA.Pray,Ph.D.2008NatureEducation
Citation:Pray,L.(2008)DiscoveryofDNAstructureandfunction:Watsonand
Crick.NatureEducation1(1):100

ThelandmarkideasofWatsonandCrickreliedheavilyontheworkofotherscientists.What
didtheduoactuallydiscover?
ManypeoplebelievethatAmericanbiologistJamesWatsonandEnglishphysicistFrancisCrickdiscoveredDNA
inthe1950s.Inreality,thisisnotthecase.Rather,DNAwasfirstidentifiedinthelate1860sbySwisschemist
FriedrichMiescher.Then,inthedecadesfollowingMiescher'sdiscovery,otherscientistsnotably,Phoebus
LeveneandErwinChargaffcarriedoutaseriesofresearcheffortsthatrevealedadditionaldetailsaboutthe
DNAmolecule,includingitsprimarychemicalcomponentsandthewaysinwhichtheyjoinedwithoneanother.
Withoutthescientificfoundationprovidedbythesepioneers,WatsonandCrickmayneverhavereachedtheir
groundbreakingconclusionof1953:thattheDNAmoleculeexistsintheformofathreedimensionaldouble
helix.

TheFirstPieceofthePuzzle:MiescherDiscoversDNA
Althoughfewpeoplerealizeit,1869wasalandmarkyearingeneticresearch,becauseitwastheyearinwhich
SwissphysiologicalchemistFriedrichMiescherfirstidentifiedwhathecalled"nuclein"insidethenucleiofhuman
whitebloodcells.(Theterm"nuclein"waslaterchangedto"nucleicacid"andeventuallyto"deoxyribonucleic
acid,"or"DNA.")Miescher'splanwastoisolateandcharacterizenotthenuclein(whichnobodyatthattime
realizedexisted)butinsteadtheproteincomponentsofleukocytes(whitebloodcells).Miescherthusmade
arrangementsforalocalsurgicalclinictosendhimused,puscoatedpatientbandagesoncehereceivedthe
bandages,heplannedtowashthem,filterouttheleukocytes,andextractandidentifythevariousproteinswithin
thewhitebloodcells.Butwhenhecameacrossasubstancefromthecellnucleithathadchemicalproperties
unlikeanyprotein,includingamuchhigherphosphorouscontentandresistancetoproteolysis(protein
digestion),Miescherrealizedthathehaddiscoveredanewsubstance(Dahm,2008).Sensingtheimportanceof
hisfindings,Miescherwrote,"Itseemsprobabletomethatawholefamilyofsuchslightlyvaryingphosphorous
containingsubstanceswillappear,asagroupofnucleins,equivalenttoproteins"(Wolf,2003).
Morethan50yearspassedbeforethesignificanceofMiescher'sdiscoveryofnucleicacidswaswidely
appreciatedbythescientificcommunity.Forinstance,ina1971essayonthehistoryofnucleicacidresearch,
ErwinChargaffnotedthatina1961historicalaccountofnineteenthcenturyscience,CharlesDarwinwas
mentioned31times,ThomasHuxley14times,butMieschernotevenonce.Thisomissionisallthemore
remarkablegiventhat,asChargaffalsonoted,Miescher'sdiscoveryofnucleicacidswasuniqueamongthe
discoveriesofthefourmajorcellularcomponents(i.e.,proteins,lipids,polysaccharides,andnucleicacids)inthat
itcouldbe"datedprecisely...[to]oneman,oneplace,onedate."

LayingtheGroundwork:LeveneInvestigatestheStructureofDNA
Meanwhile,evenasMiescher'snamefellintoobscuritybythetwentiethcentury,otherscientistscontinuedto
investigatethechemicalnatureofthemoleculeformerlyknownasnuclein.Oneoftheseotherscientistswas
RussianbiochemistPhoebusLevene.Aphysicianturnedchemist,Levenewasaprolificresearcher,publishing
morethan700papersonthechemistryofbiologicalmoleculesoverthecourseofhiscareer.Leveneiscredited
withmanyfirsts.Forinstance,hewasthefirsttodiscovertheorderofthethreemajorcomponentsofasingle
nucleotide(phosphatesugarbase)thefirsttodiscoverthecarbohydratecomponentofRNA(ribose)thefirstto
discoverthecarbohydratecomponentofDNA(deoxyribose)andthefirsttocorrectlyidentifythewayRNAand
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DNAmoleculesareputtogether.
DuringtheearlyyearsofLevene'scareer,neitherLevenenoranyotherscientistofthetimeknewhowthe
individualnucleotidecomponentsofDNAwerearrangedinspacediscoveryofthesugarphosphatebackbone
oftheDNAmoleculewasstillyearsaway.Thelargenumberofmoleculargroupsmadeavailableforbindingby
eachnucleotidecomponentmeantthattherewerenumerousalternatewaysthatthecomponentscould
combine.Severalscientistsputforthsuggestionsforhowthismightoccur,butitwasLevene's"polynucleotide"
modelthatprovedtobethecorrectone.Baseduponyearsofworkusinghydrolysistobreakdownandanalyze
yeastnucleicacids,Leveneproposedthatnucleicacidswerecomposedofaseriesofnucleotides,andthateach
nucleotidewasinturncomposedofjustoneoffournitrogencontainingbases,asugarmolecule,anda
phosphategroup.Levenemadehisinitialproposalin1919,discreditingothersuggestionsthathadbeenput
forthaboutthestructureofnucleicacids.InLevene'sownwords,"Newfactsandnewevidencemaycauseits
alteration,butthereisnodoubtastothepolynucleotidestructureoftheyeastnucleicacid"(1919).
Indeed,manynewfactsandmuchnewevidencesoonemergedandcausedalterationstoLevene'sproposal.
Onekeydiscoveryduringthisperiodinvolvedthewayinwhichnucleotidesareordered.Leveneproposedwhat
hecalledatetranucleotidestructure,inwhichthenucleotideswerealwayslinkedinthesameorder(i.e.,GCT
AGCTAandsoon).However,scientistseventuallyrealizedthatLevene'sproposedtetranucleotidestructure
wasoverlysimplisticandthattheorderofnucleotidesalongastretchofDNA(orRNA)is,infact,highlyvariable.
Despitethisrealization,Levene'sproposedpolynucleotidestructurewasaccurateinmanyregards.For
example,wenowknowthatDNAisinfactcomposedofaseriesofnucleotidesandthateachnucleotidehas
threecomponents:aphosphategroupeitheraribose(inthecaseofRNA)oradeoxyribose(inthecaseof
DNA)sugarandasinglenitrogencontainingbase.Wealsoknowthattherearetwobasiccategoriesof
nitrogenousbases:thepurines(adenine[A]andguanine[G]),eachwithtwofusedrings,andthepyrimidines
(cytosine[C],thymine[T],anduracil[U]),eachwithasinglering.Furthermore,itisnowwidelyacceptedthat
RNAcontainsonlyA,G,C,andU(noT),whereasDNAcontainsonlyA,G,C,andT(noU)(Figure1).

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Figure1:Thechemicalstructureofanucleotide.
Asinglenucleotideismadeupofthreecomponents:anitrogencontainingbase,afivecarbonsugar,andaphosphategroup.
Thenitrogenousbaseiseitherapurineorapyrimidine.Thefivecarbonsugariseitheraribose(inRNA)oradeoxyribose(in
DNA)molecule.
2013NatureEducationAllrightsreserved.

FigureDetail

StrengtheningtheFoundation:ChargaffFormulatesHis"Rules"
ErwinChargaffwasoneofahandfulofscientistswhoexpandedonLevene'sworkbyuncoveringadditional
detailsofthestructureofDNA,thusfurtherpavingthewayforWatsonandCrick.Chargaff,anAustrian
biochemist,hadreadthefamous1944paperbyOswaldAveryandhiscolleaguesatRockefellerUniversity,
whichdemonstratedthathereditaryunits,orgenes,arecomposedofDNA.Thispaperhadaprofoundimpact
onChargaff,inspiringhimtolauncharesearchprogramthatrevolvedaroundthechemistryofnucleicacids.Of
Avery'swork,Chargaff(1971)wrotethefollowing:
"Thisdiscovery,almostabruptly,appearedtoforeshadowachemistryofheredityand,moreover,madeprobablethenucleicacidcharacterofthe

gene...Averygaveusthefirsttextofanewlanguage,orratherheshoweduswheretolookforit.Iresolvedtosearchforthistext."
Ashisfirststepinthissearch,ChargaffsetouttoseewhethertherewereanydifferencesinDNAamong
differentspecies.Afterdevelopinganewpaperchromatographymethodforseparatingandidentifyingsmall
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amountsoforganicmaterial,Chargaffreachedtwomajorconclusions(Chargaff,1950).First,henotedthatthe
nucleotidecompositionofDNAvariesamongspecies.Inotherwords,thesamenucleotidesdonotrepeatinthe
sameorder,asproposedbyLevene.Second,ChargaffconcludedthatalmostallDNAnomatterwhat
organismortissuetypeitcomesfrommaintainscertainproperties,evenasitscompositionvaries.Inparticular,
theamountofadenine(A)isusuallysimilartotheamountofthymine(T),andtheamountofguanine(G)usually
approximatestheamountofcytosine(C).Inotherwords,thetotalamountofpurines(A+G)andthetotal
amountofpyrimidines(C+T)areusuallynearlyequal.(Thissecondmajorconclusionisnowknownas
"Chargaff'srule.")Chargaff'sresearchwasvitaltothelaterworkofWatsonandCrick,butChargaffhimself
couldnotimaginetheexplanationoftheserelationshipsspecifically,thatAboundtoTandCboundtoGwithin
themolecularstructureofDNA(Figure2).

Figure2:WhatisChargaff'srule?
AllDNAfollowsChargaff'sRule,whichstatesthatthetotalnumberofpurinesinaDNAmoleculeisequaltothetotalnumberof
pyrimidines.
2013NatureEducationAllrightsreserved.

PuttingtheEvidenceTogether:WatsonandCrickProposetheDoubleHelix
Chargaff'srealizationthatA=TandC=G,combinedwithsomecruciallyimportantXraycrystallographywork
byEnglishresearchersRosalindFranklinandMauriceWilkins,contributedtoWatsonandCrick'sderivationof
thethreedimensional,doublehelicalmodelforthestructureofDNA.WatsonandCrick'sdiscoverywasalso
madepossiblebyrecentadvancesinmodelbuilding,ortheassemblyofpossiblethreedimensionalstructures
baseduponknownmoleculardistancesandbondangles,atechniqueadvancedbyAmericanbiochemistLinus
Pauling.Infact,WatsonandCrickwereworriedthattheywouldbe"scooped"byPauling,whoproposeda
differentmodelforthethreedimensionalstructureofDNAjustmonthsbeforetheydid.Intheend,however,
Pauling'spredictionwasincorrect.
Usingcardboardcutoutsrepresentingtheindividualchemicalcomponentsofthefourbasesandothernucleotide
subunits,WatsonandCrickshiftedmoleculesaroundontheirdesktops,asthoughputtingtogetherapuzzle.
Theyweremisledforawhilebyanerroneousunderstandingofhowthedifferentelementsinthymineand
guanine(specifically,thecarbon,nitrogen,hydrogen,andoxygenrings)wereconfigured.Onlyuponthe
suggestionofAmericanscientistJerryDonohuedidWatsondecidetomakenewcardboardcutoutsofthetwo
bases,toseeifperhapsadifferentatomicconfigurationwouldmakeadifference.Itdid.Notonlydidthe
complementarybasesnowfittogetherperfectly(i.e.,AwithTandCwithG),witheachpairheldtogetherby
hydrogenbonds,butthestructurealsoreflectedChargaff'srule(Figure3).

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Figure3:ThedoublehelicalstructureofDNA.
The3dimensionaldoublehelixstructureofDNA,correctlyelucidatedbyJamesWatsonandFrancisCrick.Complementary
basesareheldtogetherasapairbyhydrogenbonds.
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FigureDetail

AlthoughscientistshavemadesomeminorchangestotheWatsonandCrickmodel,orhaveelaborateduponit,
sinceitsinceptionin1953,themodel'sfourmajorfeaturesremainthesameyettoday.Thesefeaturesareas
follows:
DNAisadoublestrandedhelix,withthetwostrandsconnectedbyhydrogenbonds.Abasesare
alwayspairedwithTs,andCsarealwayspairedwithGs,whichisconsistentwithandaccountsfor
Chargaff'srule.
MostDNAdoublehelicesarerighthandedthatis,ifyouweretoholdyourrighthandout,withyour
thumbpointedupandyourfingerscurledaroundyourthumb,yourthumbwouldrepresenttheaxisof
thehelixandyourfingerswouldrepresentthesugarphosphatebackbone.OnlyonetypeofDNA,
calledZDNA,islefthanded.
TheDNAdoublehelixisantiparallel,whichmeansthatthe5'endofonestrandispairedwiththe3'
endofitscomplementarystrand(andviceversa).AsshowninFigure4,nucleotidesarelinkedtoeach
otherbytheirphosphategroups,whichbindthe3'endofonesugartothe5'endofthenextsugar.
NotonlyaretheDNAbasepairsconnectedviahydrogenbonding,buttheouteredgesofthe
nitrogencontainingbasesareexposedandavailableforpotentialhydrogenbondingaswell.These
hydrogenbondsprovideeasyaccesstotheDNAforothermolecules,includingtheproteinsthatplay
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vitalrolesinthereplicationandexpressionofDNA(Figure4).

Figure4:BasepairinginDNA.
TwohydrogenbondsconnectTtoAthreehydrogenbondsconnectGtoC.Thesugarphosphatebackbones(grey)runanti
paralleltoeachother,sothatthe3and5endsofthetwostrandsarealigned.
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FigureDetail

OneofthewaysthatscientistshaveelaboratedonWatsonandCrick'smodelisthroughtheidentificationof
threedifferentconformationsoftheDNAdoublehelix.Inotherwords,theprecisegeometriesanddimensionsof
thedoublehelixcanvary.Themostcommonconformationinmostlivingcells(whichistheonedepictedinmost
diagramsofthedoublehelix,andtheoneproposedbyWatsonandCrick)isknownasBDNA.Therearealso
twootherconformations:ADNA,ashorterandwiderformthathasbeenfoundindehydratedsamplesofDNA
andrarelyundernormalphysiologicalcircumstancesandZDNA,alefthandedconformation.ZDNAisa
transientformofDNA,onlyoccasionallyexistinginresponsetocertaintypesofbiologicalactivity(Figure5).Z
DNAwasfirstdiscoveredin1979,butitsexistencewaslargelyignoreduntilrecently.Scientistshavesince
discoveredthatcertainproteinsbindverystronglytoZDNA,suggestingthatZDNAplaysanimportant
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biologicalroleinprotectionagainstviraldisease(Rich&Zhang,2003).

Figure5:ThreedifferentconformationsoftheDNAdoublehelix.
(A)ADNAisashort,wide,righthandedhelix.(B)BDNA,thestructureproposedbyWatsonandCrick,isthemostcommon
conformationinmostlivingcells.(C)ZDNA,unlikeAandBDNA,isalefthandedhelix.
2014NatureEducationAdaptedfromPierce,Benjamin.Genetics:AConceptualApproach,2nded.All
rightsreserved.

Summary
WatsonandCrickwerenotthediscoverersofDNA,butratherthefirstscientiststoformulateanaccurate
descriptionofthismolecule'scomplex,doublehelicalstructure.Moreover,WatsonandCrick'sworkwasdirectly
dependentontheresearchofnumerousscientistsbeforethem,includingFriedrichMiescher,PhoebusLevene,
andErwinChargaff.Thankstoresearcherssuchasthese,wenowknowagreatdealaboutgeneticstructure,
andwecontinuetomakegreatstridesinunderstandingthehumangenomeandtheimportanceofDNAtolife
andhealth.

ReferencesandRecommendedReading

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Chargaff,E.Chemicalspecificityofnucleicacidsandmechanismoftheirenzymaticdegradation.Experientia6,201209(1950)
.Prefacetoagrammarofbiology.Science171,637642(1971)
Dahm,R.DiscoveringDNA:FriedrichMiescherandtheearlyyearsofnucleicacidresearch.HumanGenetics122,565581(2008)
Levene,P.A.Thestructureofyeastnucleicacid.IV.Ammoniahydrolysis.JournalofBiologicalChemistry40,415424(1919)
Rich,A.,&.Zhang,S.ZDNA:Thelongroadtobiologicalfunction.NatureReviewsGenetics4,566572(2003)( linktoarticle)
Watson,J.D.,&Crick,F.H.C.Astructurefordeoxyribosenucleicacid.Nature171,737738(1953)( linktoarticle)
Wolf,G.FriedrichMiescher:ThemanwhodiscoveredDNA.ChemicalHeritage21,1011,3741(2003)

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