Evolution Beyond Neo-Darwinism: a New Conceptual Framework Denis Noble

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Evolution beyond neo-Darwinism: a new conceptual framework Denis Noble

There was an error published in J. Exp. Biol. 218, 7-13.

The quotation from a Nature 2010 editorial on page 10 of the article does not appear in the final published version of the editorial. The correct quotation is given below.

‘But for all the intellectual ferment of the past decade, has human health truly benefited from the sequencing of the human genome? A startlingly honest response can be found on pages 674 and 676, where the leaders of the public and private efforts, Francis Collins and Craig Venter, both say “not much”.’

We apologise for any inconvenience this may have caused. The Journal of Experimental Biology

1273 comments. been extensivelyhonedinresponsetofurtherquestionsand were writteninpreparationforthepresentarticle.Theideashave in particularthepageentitled © 2015.PublishedbyTheCompanyofBiologistsLtd|JournalExperimentalBiology(2015)218,7-13doi:10.1242/jeb.10631 *Author ([email protected]) for correspondence UK. Physiology, of AnatomyDepartment andGenetics, Parks Road, Oxford OX1 3PT, Synthesis. Infact,severalnew featuresofexperimentalresultson sequences runsstronglycounter tothespiritofModern mechanisms oftrans-generationalinheritanceindependent DNA extension iscalledfor. Thereasonisthattheexistenceofrobust and Müller, 2010).Thispaperexplainswhy replacementratherthan al., 2008;GissisandJablonka,2011; Nobleetal.,2014;Pigliucci extend orreplacetheModern(neo-Darwinist)Synthesis(Beurton et Rechavi etal.,2011; Selaetal.,2014),hascreatedtheneedtoeither Nelson etal.,2012;andNadeau,2010; 2010; Ressler, 2014;Gluckmanetal.,2007;Klironomos etal.,2013; mediated bythosemechanisms(e.g.Danchinetal.,2011; Diasand most particularlyworkfocusedontrans-generationalinheritance described inthisissueandelsewhere(e.g.Nobleetal.,2014), and The recentexplosionofresearchonepigeneticmechanisms menu.html) of to whichthe‘Answers’ pages(http://musicoflife.co.uk/Answers- Those publicationsraisedmanyquestionsfromreadersinresponse (Noble, 2011b; Noble,2012;2013;Nobleetal.,2014). in abook,TheMusicofLife This paperrepresentstheculminationofideaspreviouslydeveloped Lamarck, Systemsbiology KEY WORDS:Epigenetics,Geneticprogram,Modernsynthesis, more favourabletoanintegratedsystemsviewofevolution. framework isproposedthatavoidstheseproblems,andwhich there canbenoprivilegedcause.Analternativeconceptual ‘genes’ incausation,whereasmulti-waynetworksofinteractions causation byDNA sequences).Neo-Darwinismalsoprivileges phenotype itself)toanempiricallytestablehypothesis(intermsof from describinganecessarycause(definedintermsoftheinheritable of thecentralconcept‘gene’,definitionhasmovedallway empirical matters.Theseneedtobeclearlydistinguished.Inthecase extending orreplacingexistingtheoryasitconfusesconceptualand ‘replicator’ and‘vehicle’.Thisformofrepresentationisabarrierto concepts of‘gene’,‘selfish’,‘code’,‘program’,‘blueprint’,‘booklife’, examines theconceptualframeworkofneo-Darwinism,including evolution requireseitherextensionorreplacement.Thisarticle research showthattheModernSynthesis(neo-Darwinist)theoryof Experimental resultsinepigeneticsandrelatedfieldsofbiological Denis Noble* Evolution beyondneo-Darwinism:anewconceptualframework REVIEW Introduction thisarticle Origin of ABSTRACT h MusicofLife The (Noble, 2006),andfourrelatedarticles The languageofNeo-Darwinism, website weredrafted.Thosepages, characteristics. natural selectionandtheseincludedtheinheritanceofacquired a neo-Darwinist.Herecognisedothermechanismsinadditionto to someofDarwin’s ideasthanto neo-Darwinism. Darwinwasnot multi-mechanism theoryofevolution,which,interestingly, iscloser Synthesis (Noble,2013).We aremovingtoamuchmorenuanced rather thanthesinglemechanismpostulatedbyModern variety ofmechanismsevolutionarychangethatmustinteract, Integrative Synthesisasitwouldbebasedontheintegrationofa approach toreplacetheModernSynthesiscouldbecalled called thetheoryofBiologicalRelativity(Noble,2012).The a newtheoryofcausationinbiology(Noble,2008),whichIhave needed, tobecomplementedbyanintegrativeapproach,including evolution) hasbeenveryproductive,butitneeds,andalways inspired theModernSynthesisasagene-centredtheoryof towards systemsapproaches.Thereductionistapproach(which seen tobepartofamoregeneralshiftviewpointwithinbiology the ideaofanextendedModernSynthesis. by PigliucciandMüller(PigliucciMüller, 2010)inexplaining Synthesis. Thediagramisbasedonanextensionoftheused Darwinism, theModernSynthesisandaproposednewIntegrative definitions andrelationshipsbetweenthevariousfeaturesof illustratesthe 1 incompatible withtheModernSynthesis.Fig. inheritance andmechanismsofevolutionaryvariationare many biological scientistsmaynotrecogniseits conceptualnature, literature, includingstandardschool anduniversitytextbooks,that half acentury, itsviewpointisnowsoembeddedinthescientific As theModernSynthesishasdominated biologicalscienceforover impossible tostandoutsideitand toappreciatehowbeguilingitis. and metaphorreinforcesthe overall mind-setuntilitisalmost scheme ofneo-Darwinismthat createsthedifficulty. Eachconcept interpretation. interpretive veneerthatcanhidethosediscoveriesinaweb of 2006; Noble,2011b). Theconceptsthereforeformabiased conceptual interpretationsofthesameexperimentalfindings(Noble, could possiblydistinguishevenbetweencompletelyopposite of ‘selfishgenes’ or‘geneticprogram’,nobiologicalexperiment fact, itcanbeshownthat,inthecaseofsomecentralconcepts which arenotrequiredbythescientificdiscoveriesthemselves. In reductionist philosophicalandscientificviewpoints,theconcepts of language ofneo-Darwinismand20thcenturybiologyreflectshighly which weinterpretandcommunicateexperimentalbiology. The unanticipated experimentalfindings,wehavetoreviewthewayin been interpreted.Inaddition,therefore,totheneedaccommodate express, thewayinwhich20thcenturybiologyhasmostfrequently These formsofrepresentationhavebeenresponsiblefor, and forms ofrepresentationratherthaninexperimentalbiologyitself. the newexperimentalfindingshavetheirorigininneo-Darwinist Many oftheproblemswithModernSynthesisinaccommodating The language of neo-Darwinism of language The The shifttoanewsynthesisinevolutionarybiologycanalsobe I refertoawebofinterpretationasitisthewholeconceptual 0 7

The Journal of Experimental Biology 8 for thetheory. seriously, thedifferent definitionshaveincompatibleconsequences may seem,thereisnosingleagreeddefinitionof‘gene’.Evenmore central notion,the‘gene’,isanunstableconcept.Surprisingasit Neo-Darwinism isagene-centredtheoryofevolution.Yet, its ‘vehicle’. We alsoneedtoexaminesecondaryconceptslike‘replicator’ and are ‘gene’,‘selfish’,‘code’,‘program’,‘blueprint’ and‘bookoflife’. a newmoreintegratedsystemsview. Thetermsthatrequireanalysis approach betterfittedtowhatwenowknowexperimentallyand complete narrative.We canthenaskwhatwouldbeanalternative individually, andthenshowhowtheylinktogethertoformthe for, theexperimentalscienceitself. conceptual schemeisneitherrequiredby, noranylongerproductive I thinkiswrongormisleadingand,aboveall,itshowsthatthe future offspring. Whatiswrongwiththat?Thisarticleanalyseswhat generations andwhichdefinesdeterminestheorganism andits organisms viaageneticprograminheritedfrompreceding the ideainanutshellisthatgenescodeforproteinsform see itasmerelyadescriptionofwhatexperimentalworkhasshown: let alonequestionincoherencesoridentifyflaws.Manyscientists REVIEW ‘Gene’ I willanalysethemainconceptsandassociatedmetaphors seFg 2). (see Fig. concept ofagenehaschangedfundamentally. Gene Johannsen’s (butessentiallyalsoMendel’s) meaning.Sincethen,the produce thephenotype.Iwillcallthisdefinitionofa‘gene’ gene made, whichinturninteractswiththerestoforganism to sequence asthatformsthetemplatetodeterminewhichproteinis cause ofphenotypecharacteristicswasstillthoughttobetheDNA discovery ofregulatoryelements(essentiallyswitches),butthebasic beginnings andendings.Complexitywasaddedthroughthe definition shiftedtolocatableDNA sequenceswithidentifiable Following thediscoverythatDNA formstemplatesforproteins,the traits suchasintelligence,personalityandsexuality. legs/arms/wings, towhichwecouldperhapsaddmorecomplex as eye/hair/skincolour, bodyshapeandmass,numberof cause ofaspecificinheritablephenotypecharacteristic(trait),such retained. Iwillcallthisdefinitionofa‘gene’ gene is asimple1:1relation,butthelanguageofdirectcausationhasbeen and character’ (Mayr, 1982).Ofcourse,no-onenow thinksthatthere universally thatthereisa1:1relationbetweengeneticfactor(gene) and wasbasedon‘thesilentassumption[that]madealmost plant hybrids,publishedin1866(seeDrueryandBateson,1901), But theconcepthadalreadyexistedsinceMendel’s experimentson The molecularbiologicaldefinitionofageneisverydifferent. The word‘gene’ wasintroducedbyJohannsen(Johannsen,1909). The JournalofExperimentalBiology(2015)doi:10.1242/jeb.106310 extension. which thereforebecomesareplacementratherthanan extending outsidetherangeofextendedsynthesis, consequence, theModernSynthesisisshownasanoval to extendorreplacetheModernSynthesis;(3)in the ModernSynthesisliebeyondrangeofwhatneeds coloured elementsontheleft.Thesethreeassumptionsof incompatibility areshowninthethreecorresponding coloured ontheright;(2)reasonsfor are incompatiblewiththeModernSynthesisshown their diagram.Thedifferences are:(1)theelementsthat Extended Synthesis.Alltheelementsarealsopresentin (PigliucciandMüller,Müller’s 2010)presentationofan Synthesis. Modern Synthesis(neo-Darwinism)andIntegrated Fig.

.DiagramillustratingdefinitionsofDarwinism, 1. definition asaDNA sequence(gene a particularphenotype(gene the originalconceptofageneascause also helpstoexplainthedifference between the phenotype(right-handarrow).Thisdiagram very different fromtheidea thatgenes‘cause’ three influencesonthenetworks.Thisviewis causation occursinbothdirectionsbetweenall occurring throughbiologicalnetworks.The sequences, environmentandphenotypeas represents theinteractionbetweenDNA biochemical understanding.Thisdiagram according tocurrentphysiologicaland environment andphenotypecharacters Fig. (Kohl etal.,2010). further descriptionandanalysissee Kohletal. The diagramisderivedfromPigliucciand

.Relationshipsbetweengenes, 2. J ) andthemodern J referred tothe J to signify M ). For M

The Journal of Experimental Biology entities thatarenecessarilythecause)andgene a gene anything newdiscoveredtobeincludedwouldalsowelcomedas factors. Noexperimentcoulddisprovea‘catch-all’ conceptas whether thatwasDNA orsomethingelseanycombinationof this ‘catch-all’ definitionas‘aninheritableunit’.Itwouldnotmatter chromosomes’ (Wanscher, 1975).Dawkins(Dawkins,1982)alsouses very uncertain,“einEtwas”[‘anything’],withnoconnectiontothe answer onwhatagenemightbevague:‘Thewassomething organism isthecauseofthatphenotype.Johanssenevenleft phenotypes becausethatishowtheyweredefined:aswhateverinthe that onlythemolecular biologicaldefinition, gene definitions haveincompatible consequences forneo-Darwinismis chromatin [e.g.figure organism’s functionalnetworks and thestructurefunctionof opens thewaytoanextensive two-wayinteractionbetweenthe gene expressionisstochastic(Chang etal.,2008)andthatthisitself content ofDNA.’ Thisviewisgreatlyreinforcedbythefactthat even movedaroundinthegenomethusmodifyinginformation largely ofsemistablegenetic elementsthatmayberearrangedor actively manipulatingDNA todothisorthat.A genomeconsists 2008) comment:‘Itseemsthatacell’s enzymesarecapableof ‘gene’, exceptininvertedcommas.AsBeurtonetal.(Beurton et al., understood. Fig. level biologyareprofoundandtheymuchlesswidely But themorephilosophicalconsequencesofthischangeforhigher triumphs of20thcenturybiology, andwidelyacknowledgedassuch. clarification ofmolecularmechanisms,surelyonethegreatest then significantlychangedbymolecularbiology. Thisledtoagreat through extensiveback-upmechanisms. (Foster andKreitzman,2004)arebuffered againstgenomicchange like thecardiacpacemaker(Noble,2011a) orcircadianrhythm silent (Hillenmeyeretal.,2008),whilecriticalbiologicaloscillators Eighty percentofknockoutsinyeast,forexample,arenormally are verygoodatbuffering themselvesagainstgenomicchange. DNA donotnecessarilycauseachange inphenotype.Organisms in thisarticle.Thedifference isinfactlarge asmostchanges in is opentoexperimentation)centralandIwilluseitseveraltimes Gene phenotype. Thatquestionisopentoexperimentalinvestigation. whether gene the peastobesmoothorwrinkled.Itwouldnotmakesenseask specific DNA sequence,gene some don’t.) Bycontrast,itmakesperfectsensetoaskwhethera REVIEW the originalview, genes about genes (Of course,different questionsofanempiricalnaturecouldbeasked is everythingthatdeterminestheinheritedphenotype,i.e.trait. precisely becausethemoderndefinition,genes of acompletecell),gene DNA sequences(whichisfalse:DNA doesnotactoutsidethecontext the phenotype. wrinkled surfacesofpeas.Gene experiments showingspecificphenotypes,suchassmoothor other factors.To appreciatethedifference, considerMendel’s instead withDNA sequencesalone,whichomitsreferencetoall The reasonthattheoriginal andthemolecularbiological Some biologicalscientistshaveevengivenupusingtheword The originalconceptofagenehasthereforebeenadopted,but The questionofcausationisnowanempiricalinvestigation But unlessallphenotypecharacteristicsareattributableentirelyto This difference betweengene J J could onlybethesameasgene . Theideabecomesunfalsifiable. J , suchaswhethertheyfollowMendel’s laws.Somedo; J was thecause.Thatishowitdefined.Itsimply 2 summarizesthedifference.

10.5 inKupiec(Kupiec,2014)]. M J were necessarilythecauseofinheritable cannot bethesameasgene M , isresponsiblefordeterminingthe J J was whateverintheplantcaused (which referstoindeterminate M if DNA alonedetermined M M (whose causation , identifiesthem J . Accordingto M , couldbe phenotypic characteristics(i.e.gene to, bycontrast,isaconceptualone.Thedifference betweengene include theseadditionalfunctionalsequences.Thedifference Irefer extension ofthedefinitiongene between necessaryandempiricallytestablecausality, notjustan Dawkins inhisbook operative genes’.ThispointwasconcededlongagobyRichard selfish genetheoryanditsopposites,suchas‘imprisoned’ or‘co- There isnobiologicalexperimentthatcoulddistinguishbetweenthe and gene ‘vehicle’. AsillustratedinFig. compatible withastrictseparationbetweenthe‘replicator’ andthe is activated. functional networksofinteractions thatdeterminehowthegenome acting asotherwiseinerttemplates, andactivecausalitybythe is circular, acting bothways:passivecausalitybyDNA sequences round isconfusingandhasfar-reaching consequences.Thecausality (McClintock, 1984). genome isan‘organ ofthe cell’,nottheotherwayround genome. AstheNobel-prizewinnerBarbaraMcClintocksaid, the ‘instruction’ isusefulatall,itratherthatthecellinstructs speed oftranscriptiondifferent partsofthegenome.Ifword binding tothetailsofhistones,allwhichinfluencepattern and the DNA bytranscriptionfactors,methylationpatternsand different celltypesandstates. Thesepatternsarecommunicatedto themselves becausetheydeterminetheexpressionpatternsfor the themselves activecauses.Thecausesliewithinthe cells Templates areusedonly when required(activated);theyarenot program. Themoreneutralword‘template’ wouldbebetter. computer iscausedtofollowtheinstructionsofa active andevencompletecauses,inmuchthesamewayasa The word‘code’ hasunfortunatelyreinforcedtheideathatgenesare to communicate.Thegenetic‘code’ isnotintentionalinthatsense. that weavoidthoseovertones. the word‘code’ shouldnotbeused.Itspurposeisrathertoensure confusing. Thissectionofthearticleisnotintendedtoproposethat this usageoftheword‘code’ carriesovertonesthatcanbe described asthegenetic‘code’,butitisimportanttounderstandthat U, C,A andGinRNA andT, C,A andGinDNA.Theyareoften triplet patternsareformedfromanycombinationofthefourbases corresponds toasingleaminoacidinproteinsequence.These found thateachsequenceofthreebasesinDNA orRNA After thediscoveryofdoublehelicalstructureDNA,itwas transcriptions asRNAsfunctional?Thatwouldextendgene definition. Thosefindingsraiseanempiricalquestion:arethose 2012) andwhichalsomightbeincludedinthemolecularbiological now knowntobetranscribed(The_Encode_Project_Consortium, findings ingenomics,suchasthe80%of‘non-coding’ DNA thatis fundamental thansomeotherchangesthatarerequiredbyrecent in definitionofagenethatIamreferringtohereismore vehicle isnolongervalid(Noble,2011b). Notealsothatthechange more thantheDNA,sothatdistinctionbetweenreplicatorand 2011b). interpretations ofselfishgenetheorycanbefoundinNoble(Noble, more completedissectionofthelanguageandpossibleempirical any experimentthatcouldprovemyclaim’ (Dawkins,1982).A ‘Selfish’ ‘Code’ Representing thedirectionofcausality inbiologythewrongway A codewasoriginallyanintentional encryptionusedbyhumans M would stillbefundamentalbecauseitisthedifference The JournalofExperimentalBiology(2015)doi:10.1242/jeb.106310 The ExtendedPhenotype

2, adefinitionintermsofinheritable M . J ) necessarilyincludesmuch : ‘Idoubtthatthereis M to 9 J

The Journal of Experimental Biology 10 et al.,2006). information wasdeveloped(Müller andNewman,2003;Newman been determinedbyphysicalconstraints beforetherelevantgenomic organisation bothofcellsandmulticellularorganisms musthave connection itisworthnoting that thebasicfeaturesofstructural and expressionpatternsaswell as theDNA (Sunetal.,2005).Inthis do work,theoutcomeisdetermined bythecytoplasmicstructures generally work.Moreover, when,veryrarely, cross-speciesclones structure isspecifictodifferent species.Cross-speciesclonesdonot inheritance ofcellstructureisequallyimportant.Moreover, this organism isfullydefined by itsgenome,whereasinfactthe dynamic structuresofthecells,tissuesandorgans. sequences. Itdoesn’t. Italso liesinthethree-dimensionalstaticand the activecausaldeterminationliesinone-dimensional DNA programs’ or‘genenetworks’ istofuelthemisconceptionthatall essential toinheritanceacrosscellandorganism generations. which replicatethemselvesviaself-templating,andare also tissue andorgan structuresthatarenotspecifiedbyDNA sequences, much morethanthegenome.Itdependsalsoonintricatecellular, of thisisnecessarytoproduceafeedbackcircuitthatdependson interaction withthegenetranscriptioncontrolsite(theswitch).All cytoplasm, therateoftransportacrossnuclearmembrane,and ribosomes, therateofchangeconcentrationswithin to producea24 But itisimportanttonotethattheimplementationofthis‘program’ LEVEL XISSMALLERTHANY CONTINUEPRODUCINGX. IF LEVEL XEXCEEDSY STOP PRODUCINGX,BUT IF the kindthatcanberepresentedasimplementinga‘program’ like (Foster andKreitzman,2004).Thisisanegativefeedbackloopof the nuclearlevelincreases,itinhibitstranscriptionof in thecytoplasm.Itdiffuses throughthenuclearmembraneand,as the productionofaproteinPERwhoseconcentrationthenbuildsup process dependsonaDNA sequence Period not justinthegenome. type instructions?Theanswerisinthecellororganism asawhole, Where, forexample,dowefindtheequivalentof‘IF-THEN-ELSE’ a program,thisisincomplete. methylation andothercontrollingprocessestriggertheireffects. As locations ontheDNA orhistoneswheretranscriptionfactors, amino acidsequencesortheRNA sequences.The‘switches’ arethe switches. The‘templates’ arethetripletsequencesthatspecify we findisbettercharacterisedasamixtureoftemplatesand no completealgorithmscanbefoundintheDNA sequences.What performed intheformofcompletealgorithms.Theproblemisthat example, itwouldcontainaspecificationofthecomputationtobe satisfied. Iftheprogramspecifiesamathematicalcomputation,for sufficient tospecifywhatwillhappenwhentheinstructionsare machine thatimplementsit,inthesensecodeitselfis what thecomputerdoes.Inprinciple,codeisindependentof body justasthecodeinacomputerprogramcausallydetermines analogy wasthatDNA ‘programs’ thecell,tissuesandorgans ofthe material withthemagnetictapeofacomputer’ (Jacob,1982).The model borrowedfromelectroniccomputers.Itequatesthegenetic programmed bypaperormagnetictapes:‘Theprogrammeisa specifically tothewayinwhichearlyelectroniccomputerswere laureates JacquesMonodandFrancoisJacob.Theyreferred The ideaofa‘geneticprogram’ wasintroducedbytheFrenchNobel REVIEW ‘Program’ The postulateofa‘geneticprogram’ ledtotheideathatan This istrueofallsuch‘programs’.To callthem‘genetic Take asanexamplecircadianrhythm.Thesimplestversionofthis Where thendoesthefullalgorithmiclogicofaprogramlie?

h rhythmdependsonratesofproteinproductionby used asatemplatefor Period process ofcarryingthemout,todistinguishplanfromexecution.’ instructions. Thereisnoeasywaytoseparateinstructionsfromthe ‘Organisms arenotsimplymanufacturedaccordingtoasetof Enrico Coen(Coen,1999)putthepointbeautifullywhenhewrote: between replicatorandvehicleinselfishgenetheory. full specification.Italsoblursandlargely nullifiesthedistinction a whole.Butthatdestroysthewholeideaofgenomebeing inherited byself-templating.The‘blueprint’,therefore,isthecellas The completecellisalsorequired,anditscomplexstructuresare construction ofanorganism liesintheDNA.Thisisclearlynottrue. it canbemistakentoimplythatalltheinformationnecessaryfor from asimilarproblemtotheconceptof‘program’,whichisthat ‘Blueprint’ isavariationontheideaofprogram.Thewordsuffers editorial in pharmaceutical targets. Asweallknow, itdidn’t happen.An cancer, heartdisease,nervousdiseases,diabetes,withaneweraof that, withinaboutadecade,thatbookwouldrevealhowtotreat life’ andunravelling itssecrets?Andwhocouldresistthepromise relations move.Whocouldnotbeintriguedbyreadingthe‘bookof sequencing thecompletehumangenome.Itwasabrilliantpublic of thecolourfulmetaphorsusedwhenprojectingidea The genomeisoftendescribedasthe‘bookoflife’.Thiswasone concept thenbecomesredundant[p. is thesameasfunctionitsupposedtobeprogramming.The when alltherelevantcomponentshavebeenaddedin,‘program’ way ofdeterminingwhethera‘geneticprogram’ exists.Atthelimit, testable. Bynecessarilyincludingnon-DNA elements,thereisno That isalsothereasonwhyconceptofa‘geneticprogram’ isnot The pointisthatsucha‘program’ doesnotlieintheDNA alone. program isnormal,‘program’ canbeusedinmanydifferent ways. in moderncomputingsciencewheretheconceptofadistributed In theextendedusestowhichwordhasbeenputinbiology, and simplistic interpretationsoftheimplicationsword‘program’. ‘Blueprint’ ‘Book of life’ ‘Book of sequencing of genomes willeventuallycontribute tohealthcare comparative biologyinparticular havebeenimmense,andthe for sequencingwholegenomes. Thebenefitstoevolutionaryand speaks volumes.Ofcourse,there wereverygoodscientificreasons developed. Itsfailuretodeliver thepromisedadvancesinhealthcare enthusiasm withwhichthe language ofneo-Darwinismwas genome mightbelesslikealistofpartsandmore liketheweather small proportion oftheinheritance…thefailure toanticipatesuch encoded inthegenome,suchashowchromosomal materialis component, theknowngenesinvolvedseemtoaccountforonly a Watson crackedtheriddleofDNA’s molecularstructure in1953, packaged upandhowitislabelledwithchemicalmarkers.Even could beread likeaninstructionmanual.Itnowseemsthatthe As with‘code’,thepurposeofthissectionistowarnagainst The ‘bookoflife’ representsthehigh watermark ofthe shouting. TheybegantoseeDNA asthe“bookoflife,”which system, fullofcomplicatedfeedbacksandinterdependencies. ‘ complexity inthegenomemustbeblamedpartlyoncosy fallacies ofgeneticresearch. AfterFrancisCrickandJames The activityofgenesisaffectedbymanythingsnotexplicitly geneticists couldnotresist assumingitwasalloverbarthe for diseaseslikediabetes,whichhaveaclearinherited Nature The JournalofExperimentalBiology(2015)doi:10.1242/jeb.106310 spelt thisout:

53 ofNoble(Noble,2006)]. (Editorial, 2010) ’

The Journal of Experimental Biology networks theyform ininteractionwiththeenvironment (Noble,2008). membranes, metabolites,organelles, etc.,andthedynamicfunctional do nothinguntilactivated.Active causationlieswithproteins, REVIEW do soinphysiologicalexperiments. 1976; Goldmanetal.,1973)or anyotherenucleatedcelltype,can DNA. Others,suchasisolated nerve axons,fibroblasts(Coxetal., naturally, e.g.redbloodcells,whichliveforabout100 continue tofunctionforsometimewithoutDNA.Somecellsdo that experiments. DNA alonedoesnothing.Bycontrast,cellscan inert, dead’ (Noble,2011b). Butatleastthathasapointinactual to singletheDNA outasuniquelyimmortal. not workwithoutacell.Itissimplyanincorrectplayingwithwords help toformthenextgeneration,donotsoseparately. DNA does me. Thosethatdosurvive,whicharethegermcellsandDNA that as theirDNA.Moreover, nearlyallofmy cellsandDNA diewith Newman etal.,2006). the developmentofrelevantDNA (MüllerandNewman,2003; replication tobecorrected.Self-templatingmusthavebeenprior necessary structuresandprocessestoenableerrorsinDNA of thecelltoreplicateitselfbecauseitisthatcontains 2011a). Faithfulgenomereplicationalsodependsonthepriorability a cellascontainingmuchinformationthegenome’ (Noble, therefore easytorepresentthethree-dimensionalimagestructureof complexity ofthestructureineachcaseiscomparable:‘It of inheritanceoccursonlywhenthecellisdividing.Moreover, the machinery anditsorganelles, whereascopyingDNA forthepurpose each daughtercellhasafullcomplementofthecomplex which isanexampleofself-templating)andthendividingsothat itself bygrowing(copyingitsowndetailedstructuregradually, between copyingacellandDNA isthatthecellcopies the DNA andthecellhavetobe copied.Theonlydifference always perfect).Inorderforacelltogiverisedaughtercells,both perfect). ThecellthatcarriestheDNA isalsoacopy(alsonot one generationtothenextisbasedoncopies(thoughnotalways incorrect experimentally(Noble,2011b). TheDNA passedonfrom genome needstoreplicate,leavinganyoldvehiclecarryit. of theorganism doesseemtobeadisposablevehicle.Onlythe algorithms fortheprocessesoflifelieingenomethenrest as theculminationofneo-Darwinistwaythinking.Ifall a completeprogram. lies inacceptingthefirststep,ideathatthereisa‘code’ forming lead tothedistinctionbetweenreplicatorsandvehicles.Theproblem causality, inwhichcausation runsinbothdirections.Thosemistakes the manyfeedbacksontogenomethatcontributecircular active causes,whereastheyarepassivetemplates.Second,itignores which getscausalitywrongintwoways.First,itrepresentsgenesas [genes] createdusbodyandmind’ (Dawkins,1976;Dawkins,2006), program’ followsnaturally. Thatleadsontostatementslike‘they the DNA andRNA templatesforma‘code’,theideaof‘genetic use andacceptanceoftheotherparts.Onceoneacceptsideathat All partsoftheneo-Darwinistformsrepresentationencourage mistake. peep intothe‘bookoflife’ leadingtoacureforalldiseaseswas essential aspectsofphysiologicalfunction.Butthepromisea when thesequencescanbebetterunderstoodincontextofother The language of neo-Darwinism asawhole of language The Genes I wasalsoplayingwithwordswhenwrotethat‘DNA aloneis My germlinecellsarethereforejustasmuch‘immortal’ (ornot) The distinction,however, isalinguisticconfusionandit The distinctionbetweenthereplicatorandvehiclecanbeseen M are bestviewedthereforeascauses inapassivesense.They

days without causes. Genes concepts. Thefirstoneisthedistinctionbetweenactiveandpassive The alternativeformofrepresentationdependsontwofundamental Conrad Waddington –theterm‘canalised’ isonethat heoftenused. responses arecanalized.’ Theirideasalso owemuchtothoseof stimuli aswellthemechanisms wherebynoveldevelopmental dynamics oftheepigeneticsystem anditsresponsetoenvironmental a properstudyofevolutionconsists intheworkingoutof of non-randomvariationswhich directevolutionarychange,andthat system itself,initsinteraction with theenvironment,issource who wrote:‘Theintrinsicdynamicalstructureoftheepigenetic over 30 networks thatdeterminewhathappens. DNA templates.Itisthephysicsandchemistryofthosedynamic networks, whichincludemanycomponentsforthereare no passive causes,usedwhenneeded.Activecausationresidesin the is thatgenes which Fig. be foundinthearticleonBiologicalRelativity(Noble,2012), from causality. A morecompleteanalysisofthisalternativeapproachcan the caseinorganisms, which workthroughmanyformsofcircular causality, beyondtherepresentationofscales,perhaps.Thismustbe point isthemoreneutralstatement:therenoprivilegedscaleof here arealsometaphorsandshouldbetreatedcarefully. Theessential causation asupward(Ellisetal.,2012).‘Down’ and‘up’ causation, todistinguishitfromthereductionistinterpretationof and proteins,atthelowerscales.Thisissometimescalleddownward cells, tissuesandorgans influenceactivitiesofelements,suchasgenes multi-scale natureofbiologicalnetworks.Propertiesatthescale networks asthethirddimensioncanbeviewedrepresenting landscape network( is noprivilegedlocationwithinthenetwork. bottom, thetoporsides.Allcanberegardedasequivalent.There to move(cf.Ingber, 1998).Itdoesn’t matterwhetheryoupullonthe any partofthethree-dimensionalstructurewillcauseallotherparts probably don’t actuallyknowhowtoknitsuchathing.Pullingon dynamically functional. idea ofanyspecificelementasprimemover. Itisnetworksthatare adjusting tothetension.Actually, itwouldbebetterstilltodropthe prime mover, andbethecauseofrestnetworkmoving connects toeverythingelse.Anypartofthenetworkcanbe different way. Thisisapropertyofnetworks.Everythingultimately on theothercorner. Again,thewholenetworkmoves,thoughina network ofknittedknotsmoves.Nowreversethecornersandpull keeping theoppositecornerfixed.Whathappens?Thewhole old knittedscarf.Nowpullononecorneroftherectanglewhile a rectangle.Ifyoudon’t knit,justimaginetherectangle.Orusean mathematical way. Take someknittingneedlesandwool.Knit context (Noble,2012). theory ofbiologicalrelativity, whichisformulatedinamathematical necessarily true,anditisthecentralfeatureofwhatIhavecalled there isnoprivilegedlevelofcausation.Innetworks,that dynamic cellnetworksactivatethem.Thesecondconceptisthat would surelywishtoavoidanthropomorphisingscientificdiscovery. anthropomorphic. Thisisstrange,giventhatmostneo-Darwinists An alternative form of representation of form An alternative In certainrespects,myarticlereflectssomeofthepointsmade The three-dimensionalnetworkrecallsWaddington’s epigenetic Now knitathree-dimensionalnetwork.Again,imagineit.You I willillustratethesecondpointinamorefamiliarnon- Notice alsothatthelanguageasawholeisstrongly years agobyHoandSaunders(HoSaunders,1979), 4 istaken.Oneoftheconsequencesrelativisticview The JournalofExperimentalBiology(2015)doi:10.1242/jeb.106310 M M cease toberepresentedasactivecauses.Templates are are passivecauses;theytemplatesusedwhenthe i.3)andisquiteagoodanalogytobiological Fig. 11

The Journal of Experimental Biology 12 wide public.Theintegrationoftheearlydiscoveriesmolecular and itssubsequentformulationastheModernSynthesistoavery many biologistsandtotheirabilitycommunicatetheoriginalidea remarkable. Itisatributetotheinventivenessandpersuasivenessof invented theterminaletterto biological thoughtforoveracenturysinceGeorge Romanes The extenttowhichthelanguageofneo-Darwinismhasdominated REVIEW has beenpresentedasliteraltruth. has broughttobiology, mademoreproblematicbythefactthatit ourselves fromthebiasedconceptualschemethatneo-Darwinism doesn’t reallymatterwhichyouuse.Theaimissimplytodistance other formsofrepresentationthatcanachievethesameresult.It contravening asinglebiologicalexperimentalfact.Theremaybe features oftheneo-Darwinistlanguagecanbeeliminated,without concepts proposedhereisthatmostoralltheanthropomorphic Conclusions An importantlinguisticfeatureofthealternative,relativistic, Nature (Romanes, 1883)is It damagedthereputationofLamarck,possiblyirretrievably. research inrecentyears. might be.We cannowdosothankstosomeingeniousexperimental statement in1998wasthathecouldn’t seewhatthemechanism(s) within theModernSynthesisframework.Hisqualificationonthis more significantfrombeingmadebysomeoneworkingentirely obviously falseasissometimesmadeout’,astatementthatallthe (Maynard Smith,1998)admitted:‘It[Lamarckism]isnotso assumed whatcouldn’t beproved.AsJohnMaynardSmith excluding anythingthatmightbeinterpretedasLamarckism,it biology andover-reached itselfinitsrhetoric.Bysoconclusively lifestyle oftheorganism anditsenvironment. assumption, whichwasthatthegenomeisolatedfrom (incorrectly asitsubsequentlyturnedout)toconfirmacentral Central DogmaofMolecularBiology(Crick,1970)wasperceived biology alsocontributedgreatmomentum,particularlyasthe Nevertheless, thedogmatismwasunnecessaryanduncalledfor. In retrospect,neo-Darwinismcanbeseentohaveoversimplified The JournalofExperimentalBiology(2015)doi:10.1242/jeb.106310 (2014) byRoutledgeLibraryEditions. Strategy oftheGenes Imagetakenfrom biology couldhavebeenavoided. 20th centurypopularisationsofgeneticsandevolutionary word. Ifwehadfollowedhisleadmanyofthemorenaive Waddington wasasystemsbiologistinthefullsenseof these couldthenbeassimilatedintothegenome. landscapes inresponsetoenvironmentalpressure,andthat forms couldarisethroughnewcombinationstoproduce development occurs.Waddington’s insightwasthatnew produce thephenotypiclandscape(top)throughwhich interact betweenthemselvesandwiththephenotypeto parts ofcomplexnetworkssothatmanygeneproducts landscape. Fig.

.ConradWaddington’s diagramoftheepigenetic 3. diagram arereproducedfromNoble (Noble,2012). conditions forthenextintegrationstep. Legendand (although notuniquely),anddetermines theinitial the outputcontributestoboundary conditions The dottedarrowscompletethediagram toshowthat equations. Thearrowsarenotreallyunidirectional. conditions forafurtherperiodofintegrationthe conditions, whiletheyinturnarealsotheinitial output parameterscanalsoinfluencetheboundary also involvedindetermininginitialconditionsandthe mathematically. Inreality, boundaryconditionsare simplified torepresentwhatweactuallysolve causation fromahigherscale.Thisdiagramishighly therefore beconsideredasaformofcontextual imposed onthesystembyitsenvironmentandcan boundary conditionsdefinewhatconstraintsare simulation begins)andtheboundaryconditions.The state ofthecomponentsattimewhich (the output)withoutsettingtheinitialconditions component. Theseequationscannotgiveasolution of differentialequationsforthekineticseach Fig.

4. Manymodelsofbiologicalsystemsconsist Genes (solidpegsatthebottom)areviewedas (Waddington, 1957).Reprinted The

The Journal of Experimental Biology holes. holes theyfallinto.Biologyhasitsownversionofthoseconceptual because theydon’t evenrecognisetheexistenceofconceptual are notphilosophers(Poincaré,1902;Poincaré,1968).Theydoso that theworstphilosophicalerrorsaremadebythosewhoclaimthey pointed out,inconnectionwiththerelativityprinciplephysics, would havebeenawiserstrategy. ThegreatphysicistPoincaré they thinkcanignoresomebasicphilosophicalprinciples more humilityinrecognisingthepitfallsthatbesetunwarywhen REVIEW http://jeb.biologists.org/lookup/suppl/doi:10.1242/jeb.106310/-/DC1 Supplementary materialavailableonlineat commercial, ornot-for-profitsectors. This researchreceivednospecificgrantfromanyfundingagencyinthepublic, The authordeclaresnocompetingfinancialinterests. Designer, MayoClinicCreativeMedia,forthedesignofFig. (http://musicoflife.co.uk/Answers-menu.html). IthankBryceBergene,Senior further questionsonthe on thepaperitself,andmanycorrespondentswhocommentedorasked Müller, RaymondNobleandAmitSaadforvaluablediscussionscomments I thankPeterHacker, MichaelJoyner, PeterKohl,Jean-Jacques Kupiec,Gerd edition of including man,aredescendedfromotherspecies’ (prefacetothe4th celebrated naturalist…whoupholdsthedoctrinethatallspecies, Darwin praisedLamarckforthisachievement:‘Thisjustly the transformationofspeciesagainstsomeverypowerfulcritics. science, andbyevolutionarybiologistsinparticularforchampioning very firsttocoinandusetheterm‘biology’ todistinguishour Lamarck shouldberecognisedbybiologistsgenerallyasoneofthe aci,É,Camnir . hman,F . eod,A,Pjl .and B. Pujol, A., Mesoudi, F. A., Champagne, A., Charmantier, J. É., Dancis, Danchin, and M.E. F. Crick, Balis, M.R., Krauss, R.P., S. Cox, Huang, E. and Coen, D.E. Ingber, M., Barahona, M., Hemberg, H.H., Chang, H.-J. Rheinberger, and R. Falk, P. J., Beurton, (supplementary materialMovie1). this figureinrelationtotheoriginalextendedsynthesiscanbeviewedonline References Supplementary material Funding Competing interests Acknowledgements akn,R. Dawkins, akn,R. Dawkins, is .G n ese,K.J. Ressler, and B.G. Dias, rey .T n aeo,W. Bateson, and C.T. Druery, Editorial li,G .R,Nbe .adOCno,T. O’Connor, and D. Noble, G.F. R., Ellis, theory ofevolution. S. Blanchet, communication withenucleatedhumanfibroblasts. Nature Transcriptome-wide noisecontrolslineagechoiceinmammalianprogenitorcells. Cambridge: CambridgeUniversityPress. Development andEvolution:HistoricalEpistemologicalPerspectives behavior andneuralstructureinsubsequentgenerations. the RoyalHorticulturalSociety theme withinandacrossthesciences. Many othersweredamagedtoo,Waddington included.A little (1970). Centraldogmaofmolecularbiology. (2010). Thehumangenomeatten. (1999). 453 (1976, 2006). (1982). The OriginofSpecies , 544-547. (2011). BeyondDNA:integratinginclusiveinheritanceintoanextended The ArtofGenes.Oxford:OxfordUniversityPress. The ExtendedPhenotype Nat. Rev. Genet. Answers The SelfishGene (1901). Experimentsinplanthybridization. 26, 1-32. pages ontheMusicofLifewebsite (2014). Parentalolfactoryexperienceinfluences 12, 475-486. Interface Focus , 1866). (2012). Top-down causation:anintegrating . Oxford:OxfordUniversityPress. Nature . London:Freeman. (2008). 464 J. CellBiol. Nature , 649-650. 2 The ConceptoftheGenein , 1-3. Nat. Neurosci. 227

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