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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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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