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HowGeneticsGotaChemicalEducationERWINCHARGAFF350CentralParkWest,NewYork,NewYork10025
AnnalsoftheNewYorkAcademyofSciences(1979)325,345360.[WiththepermissionofErwinChargaff]
[CommentsbyDRFinsquarebrackets.]
NOWADAYSWEARE,ofcourse,familiarwithsuchtermsas"molecularbiology,""moleculargenetics"or"molecularpharmacology."Thecuriousumbrellaofmolecularityunderwhichthevariousbiologicaldisciplinespracticeapreviouslyunimaginableformoftogethernesstestifiestotheextenttowhichchemistrytheveryscienceofmoleculesand,therefore,oneofthefewnottoleratingtheallembracingadjectivehasactedasacementholdingtogethertheseveralbranchesofbiology.Inthisrespectbiochemistrynaturallysharestheroleofchemistry,andnobodyhasyetcomeforwardwithsuchathingasmolecularbiochemistry.Ifwehadtogiveupmolecules,whatwouldbeleftofus?Well,perhapsmolecularbiologywouldbeleft.
Therewere,however,
timeswhenthebiologicalscienceswerenotyetdomesticatedanddidnotmarchnicely
inpairson the leashofchemistry.Theywere robust
fellows,eachwithhisowncodeofhonorandjealousofhisindependenceandtheylefteachothermoreorlessalone.Irememberthesedaysquitevividly,andhowastonishedwestudentswerewhenat
the chemistry colloquiumat theUniversity ofVienna a straybotanist
orpathologistputinanappearance.InanevenearliergenerationthegreatKarlLandsteinerwasoneof
theexceptions.WhenImethim in1935 inSiasconsetonNantucket
Islandandhetoldme,walkingonthebeachorsittinginhissomberhouse,ofhisearlydaysinEmilFischer'slaboratoryinBerlin,Iwassurprisedaboutthewiderangeofhisscientificinterests.Now,whenIammucholderthanhewasatthattime,Irealizethatthisformofopennessisnolongerpossible,andthesciences,astheyhavegrowntogether,havebecomemorehermetic
than they everwere.There existed, of course, and there
stillexist,afewpeopleabletobreakthroughtheboundaries.
Oftheexactsciences,physicsandsomewhatlaterchemistrywerethefirsttodevelopgreatly.Beforetheyreachedthestageatwhichtheycouldsupportthebiologicalsciences,itisnotsurprisingthatbiologistshadlittleuseforchemistryandphysics.Forthisreason,biochemistry,nottospeakofbiophysics,representsarelativelylatedevelopment.Aswasto
be expected, among the biological disciplines, physiology was
perhaps the first toexperience a need for chemical assistance and
here lies, in fact, the origin ofbiochemistry. Itbegan as abranch
of physiology andwas, for a long time, designated
-
physiologicalchemistry.
The"molecularrevolution"10%advanceand90%verbiagecameabout,however,in
a surprisingly different fashion. Not so much physiology as two
other branches
ofbiology,microbiologytoagreatextentandimmunologytoalesser,wereinvolvedandtherealbeneficiarywasafourthbranch,namely,genetics.OfimmunologyIdonotwantto
speak here. I already havementioned one of the greatmenwho brought
about theassociation of immunology and chemistry, Karl Landsteiner
and it is moving
andsurprisingtomethatmanyofusknowtheappealingfigureofMichaelHeidelberger,thetruefounderofwhatisessentiallyascienceinitself,immunochemistry.
Ishould,however,liketosayafewwordsaboutgenetics,doingjusticetothetitleofmytalk.IfwearetobelievetheOxfordEnglishDictionary,thewordgeneticswasfirstusedin1905or1906[Huxleyuseditatleastasearlyas1862].Themanusuallycreditedwiththe
introduction of this term is theEnglish biologistWilliamBateson. It
is one of
theyoungestsciences,beingdatedfromtheyear1900,whenGregorMendel'sobservationswere
rediscovered. To the extent that its first tools consisted in
breeding experiments,geneticsalso isaveryoldscience
indeed:animalandplantbreederspracticedanearlyformofappliedgenetics.Forsomereasonpopularideasofheredityhavealwaysinvolvedsomekindof"bloodandsoil"mythology.Therefore,Icouldreadonlyrecentlyinabookon
theBach family that some of Johann SebastianBach's blood still
rolls through
thevesselsofaMr.Colson[ThiswasnearthetimeoftheWatergateinvestigationintheUSA.].Theauthorwouldclearlyhavebeenunabletotellme,morescientifically,whatpercentageofJS.Bach'sDNAstillwasaround.Evenifhecouldhavedoneso,Idaresayitwouldhavebeen
of no interest whatever. DNA does not compose heavenly cantatas,
nor evenmusical trash, although a lot of other trash has been
produced through its help. If
theballyhoohadtakenplaceahundredyearsearlier,JohannStrausswouldundoubtedlyhavecomposeda"DoubleHelixPolka."Our
timeswould at best be capable of producing
adancethatmightperhapsbecalledthe"dobblewobble."
Even the earlyworkerswho experimentedwith living cells or
tissues orwith
bloodmusthavehadaperceptionoftheghostlikepresenceofchemistryinalltheyweredoing.Theyknew,ofcourse,somechemistryandtheyknewthatchemistrywasthescienceofsubstances,
of compounds. Theymust have realized that protoplasmwas composed
ofcompounds that, at leastonone levelof their existence,obeyed the
lawsof
chemistry.ButdespitetheearlyappearanceofsuchmenasFriedrichMiescherorHoppeSeylerIdonotthinkthatmanybridgesexistedbetweenbiologyandchemistry.Thereasonswhytheearlybiologistskept
theirdistance from theexact sciencesdonot all speak against
theprofundity of their perceptions.Reductionism had not yet
entirely taken over theirwaysof thinking, as it hasdonenow,
andwhatone could call the
technicalizationofbiologythewheelsandthegearsandthepulleys,thefuel,thelubricants,thetemplates,andsoonhadnotyetwonitsshallowvictory.Therewasstillsomereverenceleft,anawebefore
theeverlastingmysteryof life.Those thatweregoodamong
theseoldmensteppedsoftly.
WhenIturntotheearlystageofgeneticsIgettheimpression,perhapsmistakenly,thattheinitialexponentsofthissciencewereparticularlyunableorunwillingtothinkintermsofchemistry.Oncethegene,as
theunitofheredity,wasdefinedand its localization
inthechromosomesmadeprobable,therewas,ofcourse,enoughreasontoassumethatthisunitwasasubstanceoraconglomerateofsubstancesand,thereby,subjecttothescrutinyofthechemist.Iamnotabletodeterminehowmuchspeculationonthechemicalnature
-
ofthegenedidtakeplaceintheearlydaysofgenetics[seeBatesononthesewebpagesClickHere]butIamsurethatageneticist,hadhebeenpressedtorevealhis
thoughts,wouldhaveguessedthatthegenemaybeaprotein,forproteinswereatthattimethereceptaclesof
all thatwasmysterious and refractory.Of course, the term
"biological
information"couldnotyetexistthosewerethetimesofthelogtable,ifnottheabacus,andnotofthecomputer.
Iamnotsure if Iamright insaying that
ifonewantstodecipheranasyetunreadlanguage,simple,primitivetextsmaybemoreusefulthancomplex,poeticdocuments.Inthecaseofthechemicalbasisofhereditythisis,however,unquestionablytrue.Withoutthe
use of phages and of microorganisms little could have been achieved
in
thisregard.Thisstagewasreachedintheearlyforties,i.e.,atthetimewhenOswaldT.Averyandhiscollaboratorsbegantoworkonthetransformationofpneumococci,andDelbruckandLuriaonthephagesofE.coli,althoughAvery'slaboratorywasmuchmorereceptivetotheapplicationofchemistrythanwastheothergroup.ItisreallywithAverythattherebeganwhatIhavecalled,inmytitle,thechemicaleducationofgenetics.Itis,perhaps,characteristicofthewayinwhichscienceoperatesthattheeducatorwasneitherageneticist
nor a chemist. The learning process was slow and weary: the
cardcarrying members of the guild and their assorted acolytes
refused as long
aspossible,andevenbeyondthatpoint,totakecognizance.
The path of careful, conscientious, and responsible research
that led Avery
andcollaborators(1)totherecognitionthatthehereditaryunits,thegenes,werecomposedofDNAhas
been described excellently in theDubos book (2).The amazing
difficultiesthat this truly epochal observation experienced before
being accepted have
beennarratedcomprehensivelyinOlby'sbook(3).IshouldalsoliketorefertomyreviewsofthebooksofDubos(4)andOlby(5).
HowprofoundtheimpressionwasthatAvery'sdiscoverymadeonmeIhaveattemptedtorelatemorethanonce(6,7).Ishallreturntoitpresently.Oneshouldhavethoughtthatif
I, a simple chemist only distantly interested in themechanisms of
heredity, was sodeeplymovedby the sudden appearance of a giant
bridge between chemistry andgenetics, the practitioners of the
latter science would have been alerted even moreforcefully.
Ihad,however, at that time the impression that thiswas far
frombeing
thecase.InpreparingthepresentessayIwantedtoconfirmtheaccuracyofmyrecollection.Iwent,
therefore, back to the library and looked through a few genetics
texts that
werecurrentintheperiodfollowingthe1944paperbytheAverygroup.
TheoldestbookIconsultedwasthefourthedition,publishedin1950,ofawidelyreadintroductionbySinnot,Dunn,andDobzhansky(8).Thelasttwoofthethreeauthors,bothColumbiaprofessors,
I hadknownverywellduring their
lifetimes.ThenamesBeadle,Delbruck,Lederberg,Luria,andTatumappearintheindex,andsodoes,moremodestly,DNAasacomponentofchromosomesandsomeviruses.ThenameofAvery,however,doesnotappearandsofarasIcanseeIdidnotagainreadtheentire500pageshisdiscoveryisnotmentioned.
Ina textbookpublished threeyears later (9)Avery is listed in the
index.My
joyfulexclamationwas,however,stifledwhenIdiscoveredthatitwas,alas,thewrongAvery.The"tetranucleotidetheoryofLevene"isdiscussedatlengthinancienttermsbut,again,norippleofthewaveofthefuture.
-
Thenextcandidateisasmallmonographonthebiochemistryofgenetics,publishedin1954(10).AswastobeexpectedofsointelligentanauthorasJ.B.S.Haldanewas,thediscovery
of pneumococcal transformation byDNA ismentioned (p. 49) but there
islittleevidenceofanawarenessofwhatAvery'sdiscoverymeantintermsofthechemicalstructureofDNAanditsroleinthechromosomes.Thenucleoproteinsofthenucleusareregardedascatalysts(p.117),perhapsinfixingATP(p.126).IfthefirsttwobooksrateanF,thisonewouldrateC+.
Mylastwitnessisabookpublishedin1958(11).Mostofthestandardnamescanbefound
in the index,butneitherAverynorCrickandWatson.One shouldhave
thoughtthatenoughtimehadthenelapsedtodigestthedigestible,nottospeakoftheprecooked,suchasthedoublehelix.Mentionismadeoftransformationbeinginducedbya"nucleicacid,ofaspecifictype"butthatisaboutall.Fourteenyearsafterhisdiscovery,andthreeyearsafterhisdeath,Averydidnotevenratehonorablemention.Onegetstheimpressionthatthetenaciouslyengrainedconceptionof
theclassicalgeneactedasavanishingcapforitsrealunraveler.
ThetitleIhavechosenis,therefore,possiblywrong,anditshouldread:"HowGeneticsRefusedtoGetaChemicalEducation."But"genetics"is,ofcourse,asvagueanentityas"thepeople"andthecollectiveismadeupofallsortsofindividuals,eachonedoinghisown
thing. Besides, it is a fortunate fact that amateurs often are
better in advancingscience than are the professionals.Nothingmore
deadening than being a specialist, anexpert.You lecture before a
perpetually somnolent audience the people change,
buttheyareequallyboredorobtuse or, if you are lucky,you teach in
aworkshopon
abeautifulisland,andyouteachthemtobecomeasyouarewhereaswhatascientistoughtto
do is to teach others to become as different from himself as
possible. Vive ladifference! should be the battle cry. Instead, it
is "like begets alike," until at the
enddismalsociobiologytakesovertotellusthatyoumustbeprogrammedinyourgenestoattendAsilomar[aplaceofscientificmeetings].Scientificlifenowadayswouldbefunnyifitwerenotsad.
So letmethinkofbetter times. Ihavebeen trying to recollectwhenI
firstheardofnucleicacids:probablyduringmyUniversitytime,butIcannothavelearnedmorethanwhat
I learned about insect pigments or anthocyanins. As a postdoc at
Yale I saw,however, T. B. Johnson every day, and there the purines
and pyrimidines madethemselves knownplentifully.As a
youngAssistentat theBacteriologyDepartment ofthe University of
Berlin I earned a little extra money, writing abstracts for
theCentralblatt, and one day I got the newly published book by P.
A. Levene (12)
forreview.Thiswaslatein1931oratthebeginningof1932.Ireaditdutifully,butIdonotrememberanymorewhatIsaidaboutit.Thebookcertainlywasnotparticularlypleasanttoread,althoughIhavekeptmyreviewcopytothisday.
InmyownworkIencounteredDNAwhenSeymourCohenstudiedthecompositionofrickettsiae
(13)and
togetherwithhimandAaronBendichwecameacrossRNAinourworkonthethromboplasticprotein(14).WhatajobitwastodoaspectrumontheHilgerspectrograph!Besides,thewetblanketofthetetranucleotidehypothesisextinguishedallenthusiasmfortheseunpleasantlaboratorycuriosities.ButataboutthetimewhenIwrotethose
two papers, deoxyribonucleic acid captivated my attention in a much
morecompellingmanner.
Was it in theatthattime still pleasant dining room?Was it in one
of the cheerless
-
corridorsoftheCollegeofPhysiciansandSurgeons?Anyway,somebodycameandtoldme
to readapaperbyAveryin theJournalofExperimentalMedicine.Thiswas
thearticleImentionedbefore(1).Associationsofthoughtnormallycannotbereconstructedafter
theevent, for theyhave the logicofdreamsbut itwasobvious
tomethatImustwork on the chemistry of the nucleic acids. The road
to take was, in fact,
clearlydelineatedbeforemyeyeswhatIdidnotknowwashowtogettothebeginningoftheroad.Iknewthatwehadtofindmethodsfor
thecompleteandaccurateanalysisof
thenitrogenouscomponentsandthesugarsofseveralDNAspecimenswidelyseparatedastotheir
origins. Since most specimens would be difficult to come by, the
methods,moreover,hadtobeapplicabletominuteamounts.
The immediate problems, then,were (1) to develop procedures for
the quantitativeanalysis of eachof thepurines and thepyrimidines
present in aDNA (2) to establishsatisfactorybalances in termsof
totalNandP (3) to identify the sugar,or the
sugars,presentinagivennucleicacid(4)tosecureavarietyofintactDNAspecimens.
Memory,unlessitiscommittedtowriting(andeventhen),isthemostevanescentofgifts.
How many are there still left who remember what it meant to
determine
thecomposition,letalonetheexactcomposition,ofanucleicacidin,say,theyear1945?Ifyou
consider that at that time the quantitative analysis even of a
protein could not beachieved and proteins had been studiedmuch
longer andmore intensively than thenucleic acids you will conclude,
and rightly so, that nothing could be done for
thenucleicacids.Levene'sbookepitomizedthesituation.Forinstance,onpage113ofthistreatise
the following statement will be found: "No methods exist for the
quantitativedetermination of the individual purines when present in
mixtures." For the qualitativeisolation of the constituent purines,
procedures requiring 50 g of nucleic acid
aredescribed,andthesameistrueofthepyrimidines.
Itis,therefore,perhapsnotsurprisingthatintheabsenceofanymeansofascertainingthe
truth about the composition of the nucleic acids, a form ofmock
democracy wasobserved by the investigatorwho proclaimed: "All
nucleic acid bases are
equal."Thatsomecouldbemoreequalthanothersdidnotevendawnonthearchreductionist.Thisledtothebaselesstetranucleotidetheory{*Footnote:Muchlatersomepeoplecameandtoldmethattheyneverhadbelievedinthetetranucleotidestructure.Thismaybesobutbysittingsolidlyonone'shaunches,whilehavinghunches,onedoesnotadvancescience.}IonlyregretthatP.A.Levenedidnotcallitthe"CentralTetranucleotideDogma,"assilliertimeswouldundoubtedlyhavedone.Totoppleadogmaismorefunthantodisproveatheory,fortoppleordisprovewecertainlydid.
Whenin1946,togetherwithErnstVischerandCharlotteGreen,IsetouttodevelopaquantitativemicromethodforthecompleteanalysisfirstofDNA,andalittlelateralsoofRNA,wewerefavoredbyanunusualconjunctionofluckycircumstances.
Firstofall, the introductionofpaperchromatography
twoyearsearlier, for
thequalitativeseparationofaminoacids(15)hadshownthepossibilityofseparating,and
in most cases identifying unambiguously, minute quantities of
organicsubstances.
Secondly,at theendof thewar, in
thebeginningof1946,excellentphotoelectricquartzspectrophotometers
became available commercially, andwewere
amongtheearlyacquirersofaBeckmaninstrument.And
-
thirdly, andmost importantly, the possession by the purines and
pyrimidines
ofspecificandcharacteristicabsorptionspectraintheultraviolet,
togetherwiththearrangementsmentionedjustnow,renderedfeasibleforthefirsttimethedevelopmentofanexactprocedureforquantitativemicroestimationbypaperchromatography.OurfirstpreliminarynotewassubmittedinApril1947(16)andadetailedpaperinJune1948(17).
Onemonthlater,wesentintwopapersonthecompletequantitativeanalysisofseveralDNApreparations:onedealtwiththepurinesandpyrimidinesoftheDNAofcalfthymusand
beef spleen (18), the otherwith those of theDNAof tubercle bacilli
and of yeast(19).
Onecuriouscircumstanceattendingthepublicationof
thesepapersdeservesmentionbecause it illustrates the ignorance
about nucleic acids that then prevailed among thescientific elite.
I had, at that time, already published something like 75 articles
in theJournal of BiologicalChemistrywithout ever having one sent
back by the editor
forclarificationorrevision.ThepapersaboutDNAcomposition,however,werereturnedtome
with a particularly silly objection. How could I, the editor asked,
express thecompositionofaDNAasmolesofadenineorguanine,cytosineor
thymine,pergramatomofphosphorus,sincethepurinesandpyrimidinesdidnotcontainanyphosphorus?After
Ihadrepeated, inmyanswer to theeditor,partof the introductory
lectureon
thenucleicacids,whichatthattimeIwasalreadygivingtothefirstyearmedicalstudentsatColumbia,weachievedgrudgingreconciliation.
TheemphasisthatIplacedonmolarrelationshipsunderlinesthefactthatIapproachedthe
problem as a chemist. The phosphorus and nitrogen contents of a
nucleic
acidpreparationcanbeascertainedbyelementaryanalysis,andwedidnotrestsatisfieduntilouranalyticalmethodspermittedrecoveriesofthetotalbasesintherangeof96%to98%.ThisisnolongerdoneinexperimentalstudiesonDNA.Sometimescompletenucleotidesequencesarenowpublishedwithoutanyproof
that thesecorrespond to the
totalP,N,andpurineandpyrimidinecontentsofthespecimen.Inthisway,halftruthsarepiledonquartertruthsuntilonedaytheentirestructureswillcollapse.Inmyopinion,molecularbiologyisdisregardingchemistryatitsownperil.
AnotherutopianattemptofourswastheinvestigationofthenatureofthedeoxysugarineveryDNAspecimenpreparedbyus.
It is true,nothingbutdeoxyribosewas foundbut there was no reason to
assume beforehand this to be the case. In other
words,someonehadtodowhatmodernscientistswouldconsideras"dirtywork,"andwewerenotloathtodoit.
I have recently described the path that led us to our present
viewof the
chemicalnatureofDNA(7),andIshouldnotwishtorepeatmyselfhere.Whenthetimehadcomeformetoattemptafirstsummary(20[1950]),thisiswhatIwrote:
"Westartedinourworkfromtheassumptionthatthenucleicacidswerecomplicatedandintricatehighpolymers,comparableinthisrespecttotheproteins,andthatthedeterminationoftheirstructuresandtheir
-
structuraldifferenceswouldrequirethedevelopmentofmethodssuitableforthepreciseanalysisofallconstituentsofnucleicacidspreparedfromalargenumberofdifferentcelltypes.Thesemethodshadtopermitthestudyofminuteamounts,sinceitwasclearthatmuchofthematerialwouldnotbereadilyavailable....Thedesoxypentosenucleicacidsfromanimalandmicrobialcellscontainvaryingproportionsofthesamefournitrogenousconstituents,namelyadenine,guanine,cytosine,thymine.Theircompositionappearstobecharacteristicofthespecies,butnotofthetissue,fromwhichtheyarederived.Thepresumption,therefore,isthatthereexistsanenormousnumberofstructuraldifferentnucleicacidsanumbercertainlymuchlargerthantheanalyticalmethodsavailabletousatpresentcanreveal....Desoxypentosenucleicacidsfromdifferentspeciesdifferintheirchemicalcomposition,asIhaveshownbeforeandIthinktherewillbenoobjectiontothestatementthat,asfaraschemicalpossibilitiesgo,theycouldverywellserveasoneoftheagents,orpossiblyastheagent,concernedwiththetransmissionofinheritedproperties."
IamnotahistorianofscienceifthereissuchathingandIam,therefore,notsurethatIamcorrectinsayingthatthisisamongtheearlystatementsconcerningchemicallyencoded
biological information.My claim is perhaps strengthened by another
passagefromthesamereview,affirmingthebiologicalimportanceofnucleotidesequence:
"Wemustrealizethatminutechangesinthenucleicacid,e.g.,thedisappearanceofoneguaninemoleculeoutofahundred,couldproducefarreachingchanges...anditisnotimpossiblethatrearrangementsofthistypeareamongthecausesoftheoccurrenceofmutations."
Oneothershortparagraphofthesamearticle(20)carriedtheseedsofthefuture.Itreads:
"Theresultsservetodisprovethetetranucleotidehypothesis.Itis,however,noteworthywhetherthisismorethanaccidentalcannotyetbesaidthatinalldesoxypentosenucleicacidsexaminedthusfarthemolarratiosoftotalpurinestototalpyrimidines,andalsoofadeninetothymineandofguaninetocytosine,were
-
notfarfrom1."
Howthisstatementcametobeinsertedintothegalley,proofsofthereviewarticle(20),Ihave
recounted in my forthcoming book (7). Our first results, marred by
the initialnecessity of determining the purines and pyrimidines
separately and by an
indirectprocedureofdemonstratingtheseparatedspotsonthefilterpaper,didnotleadobviouslytosuchaconclusion.Withoutthecompletebalanceofrecoveriesintermsofnucleotidephosphorus,whichweestablishedinallouranalyses,weshouldneverhavecometotherecognitionof
the remarkablepairing rules.The first twoobservationswemadeon
thebasisof thesebalanceswere (1) therecoveriesofpurineswere
invariablymuchhigherthanthoseofpyrimidines:adifferenceattributabletothedifferenthydrolysisproceduresthenemployedfortheliberationofthesetwoclassesofcornpounds(2)eveninthefirststudiesonDNAofbeef
tissue (18),anddespite thehigheryieldofpurities that
Ihavementioned,themolarratiosofadeninetoguaninewereverysimilartothoseofthyminetocytosine:theaverageforA/Gwas1.3andthatforT/C1.4.
WhenIgaveaseriesoflecturesin1949,Imentionedtheseandrelatedobservations,butwhenitcametorewritingthemintheformoftheExperientiareview(20),Ihesitatedfirst
to emphasize any compositional regularities, owing perhaps to my
skeptical
andantidogmaticcharacter.Butinthemeantimewehadbeguntoimproveourinitialmethodsconsiderablybyintroducingformicacidhydrolysisforthesimultaneousliberationofallnitrogenousconstituents
andbyusinga suitableUV lamp for thedemonstrationof theseparated
adsorption zones on the filter strip. The rapidly accumulating new
resultsencouragedmetoinsertthewellknownparagraph.
The relationships inDNAwhich probably contributed a
greatdealtothechemicaleducationofbiologists,areasfollows.
(1)A+G=T+C
(2)A=T
(3) G = C and as a logical consequence of these
threeequations:
(4)A+C=G+T,i.e.,thesumofthe6aminocompoundsequalsthatofthe6oxoderivatives.
Thelastmentionedregularity,theequalityof6amino[AandC]and6oxocompounds[GandT],alsoapplies,intheabsenceoftheotherregularities,tothetotalRNAofacell(21).Notunrelatedtothisasyetunexplainedfindingmaybelaterobservationsfrommylaboratory,namely,thatinmicrobialDNAtheseparatedheavyandlightstrands[singleDNAstrands],althoughcomplementarytoeachotherwithrespecttobasecomposition,bothexhibitthesameequivalenceof6aminoand6oxobases(2224).
-
Tomyknowledge,therehavebeennofollowupstudiesofthelastmentionedobservationsinotherlaboratories.Thisis,perhaps,not
surprising, since in the present turmoil prevailing inmolecular
biology all chemical concepts appear to have
beendisplaced.Ouroriginalfindingsled,ofcourse,tothedoublehelixproposalofCrickandWatson.
IsthetitlethatIhavechosenforthisbriefaccountjustified?Didgenetics,didbiologyingeneral,receiveachemicaleducationduringtheperiodthroughwhichIhavelived?Towhat
extent did my own laboratory participate in this effort? The answer
to the lastquestion I shall have to leave to others. But as
concerns chemistry supplying
thefoundationofthelifesciencesinourdays,notjustanunderpinning,theanswerisYes.Eventhemostrecalcitrantgeneticist,eventhemostnebulousofimmunologists,canno
longer disregard the very science of substances that is chemistry.
The
victorymayhavebeen,however,aPyrrhicone.Inteachingthemthenomenclature,wemaynothavetaughtthemtheskill.Compoundsthathadtobepreparedinthelaboratory,inapainfulstruggleforpurity,nowaresuppliedatgreatcostbysloppymerchants,painlessly,dirtily.For
this reason, large areas of molecular biology appear to operate in
a cloud ofambiguitythatmayturnouttobelethal.
Inanyevent,itlooksasifthesmatteringofchemistryacquiredbybiologyhaskilledbiochemistry.Doesanyonecare?Hasthehistoryofthedeclineandfallofascienceeverbeenwritten?Canitbe,exceptatadistanceofmanycenturies?
Dailyweare toldabout thegreat successofone scienceor
theadvancesmadebyanother.Whatissuccessinscience,whatisadvance?Isthereafinalgoal,istheresuchathingasabettertruth?Likeeverythingelse,thesciencesaregovernedbytheprincipleofchangebutIshouldhesitatetoreplacetheletterGinthatwordbytheletterC,aswasdonebythelateJacquesMonod.Infact,ChangeandInertiawouldbeabettertitlethanChanceandNecessity[thetitleofabookbyMonod].Thewavesrollonandbreak,andthentherecomeotherwaves.Eachisdifferent,althoughtheyallarewaves.Wetry
toadaptourselvestowhateverforcecarriesusatanygiventime.Confidentofleavingourimprintonthem,weareactuallyshapedbythewaveofthemoment.
Whengeneticswasripeforachemicaleducation,theeducatorsaroseinunexpectedquarters.Theforemostwasabiologistwithadeepregardforchemistry,amongtheotherswasachemistwithagreatreverenceforlife.Asistrueofallteachersinourtime,theyreapedlittlehonor.Therewillbeotherteachersandotheringratitudes.Whattheywillteach,Icannotpredict,forIamconvincedthatthewaveofextremereductionismthathasbeencarryingusisabouttospenditself.
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17.VISCHER,E.&E.CHARGAFF.1948.The separation andquantitative
estimation of purines
andpyrimidinesinminuteamounts.J.Biol.Chem.176:703714.
18.CHARGAFF,E.,E.VISCHER,R.DONIGER,C.GREEN&F.MISANI.1949.Thecompositionofthedesoxypentoscnucleicacidsofthymusandspleen.J.Biol.Chem.177:405416.
19.VISCHER,E.,S.ZAMENHOF&E.CHARGAFF.1949.Microbialnucleicacids:Thedesoxypentosenucleicacidsofaviantuberclebacilliandyeast.J.Biol.Chem.177:429438.
20. CHARGAFF, E. 1950. Chemical specificity of nucleic acids and
mechanism of their enzymaticdegradation.Experientia6:201209.
21.ELSON,D.&E.CHARGAFF.1955.Evidenceofcommonregularitiesinthecompositionofpentosenucleicacids.Biochim.Biophys.Acta17:367376.
22. KARKAS, J. D., R. RUDNER & E. CHARGAFF. 1968. Separation
of B. subtilis DNA
intocomplementarystrands,II.TemplatefunctionsandcompositionasdeterminedbytranscriptionwithRNA
-
polymcrase.Proc.Nat.Acad.Sci.U.S.A.60:915920.
23.RUDNER,R.,J.D.KARKAS&E.CHARGAFF.1968.SeparationofB.subtilisDNAintocomplementarystrands,111.Directanalysis.Proc.Nat.Acad.Sci.U.S.A.60:921922.
24. KARKAS, J. D., R. RUDNER & E. CHARGAFF. 1970. Template
properties of
complementaryfractionsofdenaturedmicrobialdeoxyribonucleicacids.Proc.Nat.Acad.Sci.U.S.A.65:10491056.
DISCUSSIONOFTHEPAPER[afterChargaff'saddress].
EDSALL:IwouldsupplementDr.Chargaff'sremarksaboutAverybymentioninganotheritem.IhappenedtonoteinlookingatthelistofrecipientsofthePassanoAwardformedicalresearchthatAveryreceivedthatawardin1949.Thecitationdescribedhisearlierworkonthevariousspecificcarbohydratesofvarioustypesofpneumococci,whichwascertainlyworkthatwelldeservedsuchanaward.However,thecitationmadenomentionofhisworkonDNAyetthiswasin1949,aboutsixyearsaftertheDNApaperwaspublished.
OLBY:Icannotreallystaysittingdowninthefaceoftheveryprovocative
remarks Prof. Chargaff has made about recenthistory. Perhaps I
should not try to say that one attempts towritelivinghistory,but
Iwould like to take issuewithyouover the question of recent history
on the followinggrounds.
First, I thinkwehavebehindusnowa largenumberofexamples of
historical interpretations of older sciencewhich, in the light of
what is now revealed, display adeplorable misinterpretation of the
way in which majordiscoveriesweremade, for instance,notonly in
thecaseofLavoisier,butcertainlyinthecaseofDarwin,whereweareonly
just beginning to come to grips with the sort
ofintellectualchallengeandthestateofinformationinwhichhemadehisdevelopmentsweareonlybeginning
tocometo grips with what it was like in the 1830s because of
theavailabilitynowofsomanyof thenotebookswhichhithertohad not been
brought together in Cambridge.What I wouldlike to suggest therefore
is that confiningourselves tomuchearlier periods does not only
guarantee that we will writebetterhistoryofscience.
ThesecondpointIwouldisthat,ifyouareonlypresentedwiththedocumentsfromaperiodsomewayback,theremaybe
certainly in some cases a greater tendency to adopt apresentists
standpoint, that is to say, to interpret thediscoveries of
earlierperiods in the light of the successes
-
that have subsequently been recognized and have led toimportant
developments. [This is the socalled "judgement
ofhistory".Ifwearenottoallowjudgementthroughhistory,howarewetojudge,Dr.Olby?]Andthiswhiginterpretationofhistory,asitisreferredto,
is somethingwhichoneought tobeable toguardagainstifone
speakswithpeoplewhoactuallymadethose discoveries. I do agree that
this is by no means aguarantee, but I do think one has a better
chance if
oneactuallycanspeakwiththepeople.[Thereisgoodhistoryandbadhistory.Why"presentist"historyisnecessarilybadhistoryisnotcleartothe
author of these webpages. "Whig historians" were those
whoevaluatedearlierworkintermsoftheextenttowhichitaccordedwiththesubsequentlyelaboratedWhigpoliticaldoctrine.Suchadoctrineneitherwas,norperhapsevercouldbe,conclusivelyproven.Popperaside,mostofthefactsChargafftalksaboutareprovenandincontrovertible.Thus,itis
likely to serve current science to point to those
pastmethodologieswhichledexpeditiouslytothetruth,andthosewhichdivertedfromthetruth.Ashasbeenoftensaid,
thosewhodonotstudyhistory, repeat it.The idea thatWhig history is
bad history is very convenient for thosebiohistorians whose
training is predominantly historical. It means
thattheywillnotbepenalizedforfailingtokeepupwithlatestdevelopmentsinthescienceforwhichtheyhaveoptedtowriteahistory.]
The lastpoint is thatProf.Chargaffhassufferedfromanumber of
interviewers, including myself no doubt, and
Imustputtheselfishpointofviewonthis,namely,thattogetintothepublicationsoffieldthatyouhavenotbeentrainedin,it
is a tremendous advantage to have discussion with
thepersonthatdidthework.ImustsaywhatatremendoushelpthishasbeentomeandtomanyothersIknowwhowouldbetemptedtodothesametypeofthing.AndagainIfeelthatthisisanadvantageforwritingrecenthistory.
Iwouldhave thought thatProf.Chargaffwouldagreeonthis point. I
would like to know that facts in science ofcourse are very
dependent upon the circumstances
inwhichtheyareviewedandinterpreted,andthatalthoughthescientistisseekingthetruthofcourse,thetruthisnotnecessarily
as easily attained. The hard socalled facts ofscience are not so
easily to be assured of as perhaps
manyempiricistscientistshaveinthepastassumed.Oneonlyhastotakeexamplesfromthefactsaboutthegeneticdeterminationresulting
from individual nucleotides changes. How
werethosefactsseeninthe1950sandhowaretheyseennow?What seem to have
been hard, good solid facts are notconsidered so at the present
time.[Here Dr. Olby seems to
becontradictinghimself,nowimplyingthatthe"judgementofhistory"isagood
thing in that factsacceptedatone timepointare
reevaluatedatalatertimepoint]
Inawaywearebothinglasshousesonthis.YourpositionIamsureisastrongeronethanthehistorian's,butwearenotthe
only people who suffer from the relativism of the
-
approachtotruth.
FRUTON:Tosumupwhathasjustbeensaid,thereisnothingmore permanent
than a theory, and there is nothing
moretemporarythanafact.[FurtherDiscussionomitted.]
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