BiologicalInformation,causalityandspecificity–anintimate
relationship
KarolaStotz1andPaulGriffiths2
Inthischapterweexaminetherelationshipbetweenbiologicalinformation,thekey
biologicalconceptofspecificity,andrecentphilosophicalworkoncausation.Webegin
byshowinghowtalkofinformationinthemolecularbiosciencesgrewoutofeffortsto
understandthesourcesofbiologicalspecificity.Wethenintroducetheideaof‘causal
specificity’fromrecentworkoncausationinphilosophy,andourown,information
theoreticmeasureofcausalspecificity.Biologicalspecificity,weargue,issimplethe
causalspecificityofcertainbiologicalprocesses.This,wesuggest,meansthatcausal
relationshipsinbiologyare‘informational’relationshipssimplywhentheyarehighly
specificrelationships.Biologicalinformationcanbeidentifiedwiththestorage,
transmissionandexerciseofbiologicalspecificity.Ithasbeenarguedthatcausal
relationshipsshouldnotberegardedasinformationalrelationshipunlesstheyare
‘arbitrary’.Wearguethat,whilstarbitrarinessisanimportantfeatureofmanycausal
relationshipsinlivingsystems,itshouldnotbeusedinthiswaytodelimitbiological
information.Finally,wearguethatbiologicalspecificity,andhencebiological
information,isnotconfinedtonucleicacidsbutdistributedamongawiderangeof
entitiesandprocesses.
1.Introduction
1Correspondingauthor;DepartmentofPhilosophy,MacquarieUniversity,Sydney,NSW2109,Australia.Email:[email protected],UniversityofSydney,NSW2006,Australia.
Thelackofarigorousaccountofbiologicalinformationasaproximalcausalfactor
inbiologicalsystemsisastrikinggapinthescientificworldview.Inthischapterwe
outlineaproposaltofillthatgapbygroundingtheideaofbiologicalinformationina
contemporaryphilosophicalaccountofcausation.Biologicalinformationisacertain
kindofcausalrelationshipbetweencomponentsoflivingsystems.Manyaccountsof
informationinthephilosophyofbiologyhavesetouttovindicatethecommon
assumptionthatnucleicacidsaredistinctivelyinformationalmolecules.Herewe
takeamoreunprejudicedapproach,developinganaccountofbiologicalinformation
andthenseeinghowwidelyitapplies.
InSection2webeginwiththemostprominentinformationalideainmodern
biology–thecodingrelationbetweennucleicacidandprotein.Adeeperlookatthe
backgroundtoFrancisCrick’sCentralDogma,andacomparisonwiththedistinction
indevelopmentalbiologybetweenpermissiveandinstructiveinteractions,reveals
that‘information’isawaytotalkaboutspecificity.Theideaofspecificityhasalong
historyinbiology,andacloselyrelatedideaisakeypartofawidelysupported
contemporaryaccountofcausationinphilosophythatgroundscausalrelationships
inideasaboutmanipulabilityandcontrol.InSection3wedescribetheideaof
‘causalspecificity’andaninformation-theoreticmeasureofthedegreeofspecificity
ofacauseforitseffect.Biologicalspecificity,wesuggest,issimplycausalspecificity
inbiologicalsystems.Sincewehavealreadyarguedthat‘information’isawayto
talkaboutbiologicalspecificity,weconcludethatcausalrelationshipsare
‘informational’simplywhentheyarehighlyspecific.Section4defendsthis
identificationagainsttheclaimthatonlycausalrelationshipsinwhichtherelation
betweencauseandeffectis‘arbitrary’shouldcountasinformational.Arbitrariness
hasanimportantrole,however,inunderstandingtheregulationofgeneexpression
viageneregulatorynetworks.Havingdefendedouridentificationofinformation
withspecificity,wegoininsection5toshowthatinformationismorewidely
distributedinbiologicalsystemsthanisoftensupposed.CodingsequencesofDNA
areonlyonesourceofbiologicalspecificity,andhenceonlyonelocusofbiological
information.
2.Informationinbiology
Oneofthebest-knownusesof‘information’inbiologyoccursinCrick’s1958
statementofthe‘centraldogmaofmolecularbiology’:
TheSequenceHypothesis
…Initssimplestformitassumesthatthespecificityofapieceofnucleicacidis
expressedsolelybythesequenceofitsbases,andthatthissequenceisa
(simple)codefortheaminoacidsequenceofaparticularprotein.…
TheCentralDogma
Thisstatesthatonce‘information’haspassedintoproteinitcannotgetout
again.Inmoredetail,thetransferofinformationfromnucleicacidtoprotein
maybepossible,buttransferfromproteintoprotein,orfromproteinto
nucleicacidisimpossible.Informationmeansheretheprecisedetermination
ofsequence,eitherofbasesinthenucleicacidorofamino-acidresiduesinthe
protein.(Crick,1958,152-153,italicsinoriginal)
HereCricksimplyidentifiesthespecificityofageneforitsproductwiththe
informationcodedinthesequenceofthegene.Bydoingso,helinkedtheideaof
informationverycloselytooneofthefundamentalorganizingconceptsofbiology.
Biologicalspecificityisnothinglessthanthe“orderlypatternsofmetabolicand
developmentalreactionsgivingrisetotheuniquecharacteristicsoftheindividual
andofitsspecies”(Kleinsmith,2014)3.Fromthesecondhalfofthe19thtothefirst
halfofthe20thcenturyspecificitywas“thethematicthreadrunningthroughallthe
lifesciences”(Kay,2000,41),startingwithbotany,bacteriology,immunologyand
serology.Bymid-centuryquantummechanicshadprovidedthenecessaryinsightto
explaintheobservedstructuralcomplementaritybetweenmoleculesintermsofthe3http://www.accessscience.com/content/biological-specificity/082900.Accessed29January2015.
quantum-physicalforcesthatunderlieabilityofenzymeandsubstratetoforma
certainnumberofweakhydrogenbonds.Thisdevelopmentofquantumchemistry,
majorlydrivenbyLinusPaulingandMaxDelbrückinthe1940s,transformedthe
stereochemicalconceptofspecificitybasedontheabstractandintuitiveside-chain
receptortheory(developedbyPaulEhrlich),andtheirlock-and-keyinteractionwith
aligand(animagesuggestedbyEmilFischer,bothattheturnofthecentury),into
stereochemicalspecificitybasedonweakintermolecularforces(Pauling&Delbrück,
1940).
Crickintroducesanew,moreabstractconceptionofhighselectivityorabsolute
specificityintermsofhowonemoleculecanpreciselyspecifythelinearstructureof
another.ForhimitisthecolinearitybetweenDNA,RNAandaminoacidchainsthat
embodiesitsspecificity.Theinformationthatspecifiestheproductisnolonger
carriedbyathree-dimensionalstructurebutinsteadbythelinear,one-dimensional
orderofelementsineachsequence.Amongstotherconsequences,thismeansthat
specificitybecomesindependentofthemediuminwhichthisorderisexpressed(i.e.
DNA,RNAoraminoacidchain)andofthekindofreactionbywhichthespecificityis
transmitted(i.e.transcriptionortranslation).Thesameinformation/specificity
flowscontinuouslythroughthesethreemediaandtwoprocesses.
AccordingtoCricktheprocessofproteinsynthesiscontains“theflowofenergy,the
flowofmatter,andtheflowofinformation.”Whilehenotestheimportanceofthe
“exactchemicalsteps”,heclearlyseparatedthistransferofmaterialsubstances
fromwhatheregardedas“theessenceoftheproblem”,namelytheproblemofhow
tojointheaminoacidsintherightorder.Theflowof“hereditaryinformation”,
definedas“thespecificationoftheaminoacidsequenceoftheprotein”,solvedfor
himthiscriticalproblemof“sequentialization”(Crick1958,143-144).
Inhislaterpaper“CentralDogmaofMolecularBiology”Crickclarifiedtheseearlier
arguments:
Thetwocentralconceptswhichhadbeenproduced…werethoseofsequential
informationandofdefinedalphabets.Neitherofthesestepswastrivial.…This
temporarilyreducedthecentralproblemfromathreedimensionalonetoa
onedimensionalone.…Theprincipalproblemcouldthenbestatedasthe
formulationofthegeneralrulesforinformationtransferfromonepolymer
withadefinedalphabettoanother.(Crick,1970,561)
ThephilosopherGregoryMorgan4correspondedwithCricklateinhiscareerabout
hisoriginalinspirationtousetheterm‘information’.Crick’srepliesofMarch20and
April31998showtheconsistencyofhisviewoverfortyyears.Hestatesthathisuse
of‘information’wasinfluencedbytheideaofMorsecode,ratherthanShannon’s
informationtheory,whichheseesasmoreconcernedwiththereductionofnoise
duringtransmission.LikeShannon,however,hewasnotusingtheideaof
informationtoexpressthe‘meaning’or‘aboutness’ofgenes.Rather,information
was“merelyaconvenientshorthandfortheunderlyingcausaleffect”,namelythe
“precisedeterminationofsequence”.Informationforhimsolelymeant“detailed
residue-by-residuedetermination”.
Theconceptofinformationintermsoftheprecisedeterminationofsequence
primarilyofferedCrickawaytoreducethetransferofspecificityfromathree-
dimensionaltoaone-dimensionalproblembyabstractingawayfromthe
biochemicalandmaterialconnotationsofspecificity.Theconceptionofbiological
informationdefendedinthispapertakesthisabstractionoftheideaofspecificitya
stagefurther,butisverymuchinthespiritofCrick’soriginalproposal.
Anotherbiologicalfieldinwhichtheconceptsofinformationandspecificityhave
beenentwinedisdevelopmentalbiology,althoughheretheideaofinformationis
lesstightlyassociatedwithDNA.Wereferhereparticularlytotheproblemoftissue
differentiation.Interactionbetweenneighboringcellsortissuesindevelopmentcan4Personalcommunication.WeareextremelygratefultoMorganformakingthiscorrespondenceavailabletous.
leadtofurtherdifferentiationinone,theresponder,asaresultofitsinteraction
withtheother,theinducer.Developmentalbiologistscommonlydistinguish
between‘instructive’(oractive,explicit,directive)inductionontheonehandand
‘permissive’(orpassive,implicit)ontheother.
Thenotionofthespecificityofinteractioniscloselyassociatedwiththeterms
‘instructive’and‘permissive’interaction.Whentheactionsystemislargely
responsibleforthespecificityoftheinteractionthroughthetransferofa
specificmessage,towhichthereactionsystemrespondsbyenteringintoa
particularpathwayofdifferentiation,wespeakofaninstructiveaction.When,
ontheotherhand,thespecificityofareactionislargelyduetothestateofthe
competenceofthereactionsystem,sothatevenratherunspecificmessages
canserveassignalstoopenupnewdevelopmentalpathways,wespeakofa
permissiveaction.(Nieuwkoop,Johnen,&Albers,1985,9)
Papersonthissubjectciteasthetwooriginalsourcesofthedistinctionbetween
instructiveandpermissiveinteractionseitherHoltzer(1968)or(Saxen,1977).All
seemtoagreethatinstructiveinteractionsprovideinstructionsormessagessimply
becausetheseinteractionshaveahighdegreeofspecificity.Buttheinformational
languagealsoentersthiscontextregularly:
Embryonicinductionisgenerallydescribedasaninstructiveevent.The
problemitselfisoftenposedintermsimplyingthetransmissionof
informationalmolecules[eitherproteinsornucleicacids]fromonecellto
anothercell….(Holtzer,1968,152,italicsadded)
Gilbert’streatmentofthevitalquestionregardingthesourceofspecificityillustrates
nicelyhowtheinstructive/permissivedistinctionisexplainedbothintermsof
specificityandinformation:“Instructivepartnersprovidespecificitytothereaction,
whereaspermissivepartners…donotprovidespecificity.…[Theyaretherefore
not]onthesameinformationallevel”(Gilbert,2003,349).
Weconcludefromtheseexamplesthatthereareatleastsomecontextsinwhichthe
languageofinformationisawaytotalkabouttherelativelyhighdegreeof
specificityseeninsomecausalprocessesinbiology.Thismatterstous,sinceinthe
nextsectionwewillpresentaninformation-theoreticanalysisofspecificity.Ifthe
argumentofthislastsectioniscorrect,thenwhatfollowsisalsoaninformation-
theoreticanalysisofbiologicalinformation.
3.CausalSpecificity:aninformation-theoreticapproach
JamesWoodward(2010),andourselves(Griffiths&Stotz,2013;Stotz,2006)have
arguedthattheideaofcausalspecificityiscloselyrelatedtotheideaofbiological
specificity.Causalspecificityisanideafromthecontemporaryphilosophyof
causation.Thephilosophyofcausationhasmanyconcerns,someofthementirelyin
thedomainofmetaphysics.Theinterventionist(orsometimes‘manipulatibility’)
accountofcausation,however,isprimarilyaimedatexplainingwhysciencecares
aboutcausation,andusingthatexplanationtothinkmoreclearlyaboutcausationin
scientificpractice.Becauseofitsapplicabilitytoactualcasesofscientificreasoning
ithasbeenwidelyappliedtoproblemsinthecontemporaryphilosophyofthelife
andsocialsciences.Thisaccountofcausationfocusesontheideathat“causal
relationshipsarerelationshipsthatarepotentiallyexploitableforpurposesof
manipulationandcontrol”(Woodward2010,314).Causationisconceivedasa
relationbetweenvariablesinanorganizedsystemthatcanbyrepresentedbya
directedgraph.AvariableXisacauseofvariableYwhenasuitablyisolated
manipulationofXwouldchangeY.Thistheoryofcausation,initsimplestform,can
beusedtopickoutwhichvariablesarecausesratherthanmerelycorrelates.
However,agreatmanythingsgetidentifiedascauses.So,forexample,agenemight
beacauseforaphenotype,becauseamutation(a‘manipulation’)wouldchangethe
phenotype.Butequally,achangeintheenvironment(another‘manipulation’)will
bepickedoutasacauseifitchangesthatphenotype.
Acomprehensivetheoryofcausationdoesn’tjustdistinguishcausefromnon-cause,
butcanalsodifferentiatebetweencausesinvariousways—toidentifyonesthat
“arelikelytobemoreusefulformanypurposesassociatedwithmanipulationand
controlthanlessstablerelationships”(Woodward2010,315).Anumberof
differentwaystodistinguishtypesofcauseshavebeensuggested,andtwoof
these—StabilityandSpecificity—areparticularlyrelevanttounderstanding
biologicalinformation.Stabilityreferstowhetheraninterventioncontinuestohold
acrossarangeofbackgroundconditions,andwewillnotpursueithere.Specificity
referstothefine-grainedcontrolthataninterventionmighthave,controllinga
gradientofchange,ratherthanasimpleon-offswitch,forexample(Griffiths&Stotz,
2013;Stotz,2006;Waters,2007;Woodward,2010).
Theintuitiveideaisthatinterventionsonahighlyspecificcausalvariable𝐶canbe
usedtoproduceanyoneofalargenumberofvaluesofaneffectvariable𝐸,
providingwhatWoodwardterms‘fine-grainedinfluence’overtheeffectvariable
(Woodward2010,302).Theideallimitoffine-grainedinfluence,Woodward
explains,wouldbeabijectivemappingbetweenthevaluesofthecauseandeffect
variables:everyvalueofEisproducedbyoneandonlyonevalueofCandviceversa.
Theideaofabijectivemappingdoesnotadmitofdegrees,butinearlierworkwith
collaboratorswehavedevelopedaninformation-theoreticframeworkwithwhichto
measurethespecificityofcausalrelationshipswithintheinterventionistaccount
(Griffithsetal.,Inpress;Pocheville,Underreview).Ourworkformalizesthesimple
ideathatthemorespecifictherelationshipbetweenacausevariableandaneffect
variable,themoreinformationwewillhaveabouttheeffectafterweperforman
interventiononthecause.Thisledustoproposeasimplemeasureofspecificity:
𝑆𝑝𝑒𝑐:thespecificityofacausalvariableisobtainedbymeasuringhowmuchmutual
informationinterventionsonthatvariablecarryabouttheeffectvariable
Themutualinformationoftwovariablesissimplytheredundantinformation
presentinbothvariables.Where𝐻(𝑋)istheShannonentropyof𝑋,andH(𝑋 ∣ 𝑌)the
conditionalentropyofXonY,themutualinformationof𝑋withanothervariable𝑌,
or𝐼 (𝑋;𝑌),isgivenby:
𝐼(𝑋;𝑌) = 𝐻(𝑋)− 𝐻(𝑋 ∣ 𝑌)
Mutualinformationissymmetrical:𝐼(𝑋;𝑌) = 𝐼(𝑌;𝑋).Sovariablescanhavemutual
informationwithoutbeingrelatedinthemannerrequiredby the interventionist
criterionofcausation.However,ourmeasureofspecificitymeasuresthemutual
informationbetweeninterventionson𝐶andthevariable𝐸.Thisisnotasymmetrical
measurebecausethefactthatinterventionson𝐶change𝐸doesnotimplythat
interventionson𝐸willchange𝐶:𝐼(𝐶;𝐸) ≠ 𝐼(𝐸;𝐶),where𝐶isread‘doC’and
meansthatthevalueof𝐶resultsfromaninterventionon𝐶(Pearl,2009).
Thismeasureaddsprecisiontoseveralaspectsoftheinterventionistaccountof
causation.Anytwovariablesthatsatisfytheinterventionistcriterionofcausation
willshowsomedegreeofmutualinformationbetweeninterventionsandeffects.
Thiscriterionissometimescalled‘minimalinvariance’–thereareatleasttwo
valuesofCsuchthatamanipulationofCfromonevaluetotheotherchangesthe
valueofE.Iftherelationship𝐶 → 𝐸isminimallyinvariant,thatis,invariantunderat
leastoneinterventionon𝐶,thenChassomespecificityforE,thatis,𝐼(𝐶;𝐸) > 0.
Moreover,ourmeasureofspecificityisameasureofwhatWoodwardcallsthe
‘rangeofinvariance’ofacausalrelationship–therangeofvaluesofCandEacross
whichtheonecanbeusedtointerveneontheother.Relationshipswithalarge
rangeofinvariancehavehighspecificityaccordingtoourmeasure(Griffithset.al.,
Inpress;Pocheville,Underreview).5
5 Here we give a simple, absolute measure of specificity. Normalised relatives of our measure are available, as we discuss in these papers.
InlightoftheexamplesinSections2,weproposethatcausalrelationshipsin
biologicalsystemscanberegardedasinformationalwhentheyarehighlycausally
specific.Biologicalspecificity,whetherstereochemicalorinformational,seemstous
tobesimplytheapplicationoftheideaofcausalspecificitytobiologicalsystems.
Theremarkablespecificityofreactionsinlivingsystemsthatbiologyhassoughtto
explainsincethelateC19thcanequallybedescribedasthefactthatlivingsystems
exercise‘finegrainedcontrol’overmanyvariableswithinthosesystems.Organisms
exercisefine-grainedcontroloverwhichsubstancesprovokeanimmuneresponse
throughvaryingthestereochemistryofrecognitionsitesonantibodiesforantigens.
Theycatalyzeveryspecificreactionsthroughvaryingthestereochemistryof
enzymesfortheirsubstrates,orofreceptorsandtheirligands.Organismsreproduce
withahighdegreeoffidelitythroughtheinformationalspecificityofnucleicacids
forproteinsandfunctionalRNAs.Genesareregulatedinahighlyspecificmanner
acrosstimeandtissuethroughtheregulatedrecruitmentoftrans-actingfactorsand
thecombinatorialcontrolofgeneexpressionandpost-transcriptionalprocessingby
thesefactorsandthecis-actingsitestowhichtheybind.Theseareallimportant
aspectsofwhylivingsystemsappeartobe‘informed’systems,andwhatis
distinctiveaboutalltheseprocessesisthattheyarehighlycausallyspecific.
4.Arbitrariness,informationandregulation
Inthissectionweconsideranotherpropertythathasbeensaidtoessentially
characterizeinformationalrelationshipsinbiology.Thisis‘arbitrariness’,theidea
thattherelationshipbetweensymbolsandthethingstheysymbolizerepresentonly
onepermutationsofmanypossiblerelationshipsbetweenthem.Thisisafamiliar
propertyofhumanlanguages–‘cat’couldequallywellbeusedtomean‘cow’and
vice-versa.LikeCrick,wehavesofareschewedideasofmeaningandrepresentation,
sowithrespecttoourproposalarbitrarinesswouldmeanthatthesystematic
mappingbetweenvaluesofCandEisonlyoneofmaypossiblesystematicmappings.
SahotraSarkarimposesjustsuchaconditionontheinformationalrelationshipsin
biology.Sarkar,knownforhiscriticalstancetowardstheuseofinformational
languageinbiology,arguedthat“[e]itherinformationaltalkshouldbeabandoned
altogetheroranattemptmustbemadetoprovideaformalexplicationof
‘information’thatshowsthatitcanbeusedconsistentlyinthiscontextand,
moreover,isuseful”(Sarkar,2004,261).Hemakesaseriousattempttoprovidethe
requiredformalexplication,adefinitionofinformationthatbothperformsa
significantexplanatoryorpredictiveroleandappliestoinformationasitis
customarilyused.Heproposestwoadequacyconditionsforabiologicalorgenetic
accountofinformation:
Whatevertheappropriateexplicationofinformationforgeneticsis,ithasto
cometotermswithspecificityandtheexistenceofthiscodingrelationship.…
Alongwithspecificity,thisarbitrarinessiswhatmakesaninformational
accountofgeneticsuseful.(Sarkar2004,261and266)
Sarkar’sanalysisofspecificityissimilartoWoodward’sandwewouldurgethathe
adoptourinformation-theoreticextensionofthatanalysis.Hissecondcondition,
arbitrariness,reliesonhisinterpretationoftheCentralDogma,accordingtowhich
itintroducestwodifferenttypesofspecificity,namely“thatofeachDNAsequence
foritscomplementarystrand,asmodulatedthroughbasepairing;andthatofthe
relationshipbetweenDNAandprotein.Thelatterwasmodulatedbygenetic
information”(Sarkar,1996b,858).Sarkarneedstodistinguishthesetwobecause
therelationshipbetweenDNAandRNAisnotarbitrary–itisdictatedbythelawsof
chemistry.OnlytherelationshipbetweenRNAandproteinisarbitrary,becauseit
dependsontheavailablet-RNAs.Manydifferentt-RNAsareavailable,and
substitutingthesewouldleadtodifferentgeneticcodes.
Inourview,however,Crickclearlystatesthat‘geneticinformation’appliestothe
specification“eitherofbasesinthenucleicacidorinaminoacidresiduesinthe
protein”(Crick1958,153).DNAprovidesinformationalspecificityforRNAasmuch
asRNAprovidesspecificityforaminoacidchains.UlrichStegmannagreesthatthe
differencebetweenthetwois“irrelevanttothequestionofwhethertheycarry
information:theyalldo”(Stegmann,2014,460).Thereisjustonetypeof
informationalspecificity,andwhatdistinguishesitfromconformationalspecificity
isitsindependencefromthemediuminwhichitisexpressedorthemechanismby
whichitistransferred.Henceifarbitrarinessshouldberegardedasanimportant
conditionforinformationallanguageinbiology,itshouldbeforthereasonofthis
medium-independenceingeneral,ratherthanthecodingrelationshipbetweenRNA
andaminoacidsinparticular.ThecodingrelationshipbetweenRNAandaminoacid
isnotthereasonthatledtoCrick’suseoftheideaofinformationinformulatingthe
centraldogma.
Likeourselves,Sarkaraimstoexplicatethenotionofinformationinsuchawayasto
makeitausefultoolforbiology.Butaddingthesecondconditionofarbitrariness,at
leastwhenappliedjusttothecodingrelationship,tohisdefinitionofinformation
seemstoustocomewithsomesubstantialcosts.Itmayexcludetheconceptof
informationfromwhatseemstousoneofitsmostusefulroles,namelyasawayto
comparedifferentsourcesofbiologicalspecificity,aswedoinSection5.Thisis
becausemanyofthesealternativesourcesofspecificity,liketheDNA-RNA
relationship,arenotarbitrary.
Thisisnottosaythatarbitraryrelationshipsplaynovitalroleinbiology.Itis
interestingthatthenotionofarbitrarinesshasbeenintroducedinanotherareaof
biologythatregularlydeploysinformationallanguage,namelytheregulationof
geneexpressionthroughgeneregulatorynetworks.
Thepioneersofresearchintogeneregulation,FrancoisJacobandJacquesMonod,
derivedanotionofarbitrarinessfromtheiroperonmodel(Jacob&Monod,1961).
Thebiosynthesisoftheenzymeß-galactosidaseisindirectlycontrolledbyits
substrate,ß-galactosides.Thisindirectcontrolismadepossiblebytheintervening
repressorofthegene,anallostericprotein,whichisrenderedinactivebyitseffector,
thesubstrateoftheenzymeexpressedbythegene.Therepressortherebyindirectly
transducesthecontrollingsignal.
Thereisnochemicallynecessaryrelationshipbetweenthefactthat
ß-galactosidasehydrolysesß-galactosides,andthefactthatitsbiosynthesisis
inducedbythesamecompounds.Physiologicallyusefulor“rational”,this
relationshipischemicallyarbitrary–“gratuitous”,onemaysay.This
fundamentalconceptofgratuity–i.e.,theindependence,chemicallyspeaking,
betweenthefunctionitselfandthenatureofthechemicalsignalcontrollingit
–appliestoallostericproteins.(Monod,1971,78)
Mostcontrollingenvironmentalstimulihaveonlyanindirectcontrollingeffecton
geneexpression,whichismediatedortransducedbytheprocessesoftranscription,
splicingoreditingfactors.Thelatterrelaytheenvironmentalinformationtothe
genome.Sotheroleofallostericproteinsinsignaltransductionduetotheir
chemicalarbitrarinessthatMonodhasidentified,couldbeassignedtomany
signalingmoleculesinbiologicalsignaltransductionsystems,justasisthecasefor
manyhuman-designedsignalingsystems.Itisthisarbitrarinessthatrendersthe
systemflexibleandevolutionarilyevolvable.
“Theresult–andthisistheessentialpoint–isthat…everythingispossible.
Anallostericproteinshouldbeseenasaspecializedproductofmolecular
“engineering”enablinganinteraction,positiveornegative,totakeplace
betweencompoundswithoutchemicalaffinity,andtherebyeventually
subordinatinganyreactiontotheinterventionofcompoundsthatare
chemicallyforeignandindifferenttothisreaction.Thewayhenceinwhich
allostericinteractionsworkpermitsacompletefreedominthechoiceof
control.Andthesecontrols,subjecttonochemicalrequirements,willbethe
moreresponsivetophysiologicalrequirements,byvirtueofwhichtheywillbe
selectedaccordingtotheincreasedcoherenceandefficiencytheyconferon
thecellororganism.Inshort,theverygratuitousnessofthesystems,giving
molecularevolutionapracticallylimitlessfieldforexplorationandexperiment,
enabledItoelaboratethehugenetworkofcyberneticinterconnectionswhich
makeseachorganismanautonomousfunctionalunit,whoseperformances
appeartotranscend,ifnottoescape,thelawsofchemistry.”(Monod1971,78-
9)
Themutualinformationbetweenthespecificityoftheenvironmentalsignalforthe
regulatoryfactorontheonehand,andthespecificityoftheregulatoryfactorsfora
certaingeneviaitsregulatorysequence,arechemicallyarbitraryandsubjecttothe
conventionofaninterveningallostericbiomolecule.
Thecentralfeatureofsucharelationshipbetweenanytwopathwaysisthatitis
subjecttoheritablevariation.Thismeansthatanenvironmentalstimulusmaylead
infuturetoaquitedifferent,adaptiveresponsebythesystem,ifmediatedbya
novelsignalingproteinthathasevolvedindependentspecificitiestoboththe
environmentalstimulus(itseffector)andtheappropriateregulatorysequence(its
substrate).Wecanunderstandtheregulationofgeneexpressionasaninternal
signalinggamewheresenderandreceiverarenottwoorganismsbutpartswithin
oneplasticorganism(Calcott,2014).Theorganismencounterstwoenvironments,
andadifferentbehaviourisoptimalineachenvironment.Thesenderisasense
organ,ortransducer,reactingtotheenvironmentbysendingasignalinsidethe
organism.Thereceiverisaneffectorconvertingthesignalintosomebehaviourthat
changeshowtheorganismasawholeinteractswiththatenvironment.Signaling
occursinsidetheorganism,andtheevolutionofasignalingsystemallowsitto
optimallymapthedifferentenvironmentstotheappropriatebehaviour.Signaling
arosebecausethemodularstructure–theseparationoftransducerandeffector–
createdacoordinationproblem.Fortheorganismtorespondadaptively,itneeded
tocoordinatetheseparts,andasignalingsystemprovidedthesolution.Signaling,
fromthisinternalperspective,isawayofbuildingadaptive,plasticorganisms.
Whatsuchasignalingsystemallowsisthedecouplingofinformationaldynamics
fromthedictatesoflocalchemistry.AccordingtoWalkerandDaviesoneofthe
hallmarkofbiologicalversusnon-biologicalsystemsistheseparationbetweentheir
informationalandmechanicalaspects(WalkerandDavies2012,4).Thisremindsus
ofCrick’sinsistenceontheimportanceofthemediumindependenceof
informationalspecificity.Butmoreimportantly,itstressestherelationshipbetween
arbitrarinessandinformationalcontrol.
Soarbitrarinessis,indeed,animportantfeatureofinformationprocessinginliving
systems.Itisatlastoneofthefundamentalkeystoevolvability.Butthis,wewould
argue,isnotagoodreasontoaddarbitrarinesstothedefinitionofbiological
information.Arbitraryrelationshipsareprevalentinbiologicalsignalingnetworks
becauseoftheirbiologicalutility,notbecauseofthedefinitionofinformation!
5.Distributedspecificity
GriffithsandStotz(Griffiths&Stotz,2013)havetermedtheencodingofspecificity
‘Crickinformation’.Ifacausemakesaspecificdifferencetothelinearsequenceofa
biomolecule,itcontainsCrickinformationforthatmolecule.Thisdefinition
embodiestheessentialideaofCrick’ssequencehypothesis,withoutinprinciple
limitingthelocationofinformationtonucleicacidsequencesasCrickdoes.Our
definitionofCrickinformationcanclearlybeappliedtoothercausalfactorsthat
affectgeneexpression.However,itisaspecificallybiologicalconceptionof
information,ratherthanageneralonesuchasShannon’smutualinformation,orour
measureofcausalspecificity,becausebydefinitionitonlyappliestocausesthat
specifytheorderofelementsinabiomolecule.
Crick’sCentralDogmawasbasedonaverysimplepictureofhowthespecificityof
biomoleculesisencodedinlivingcells.Wenowknowthatineukaryotescoding
regionsaresurroundedbyalargenumberofnon-codingsequencesthatregulate
geneexpression.Thediscrepancybetweenthenumberofcodingsequencesandthe
numberofgeneproductsleadtotheinsightthattheinformationalspecificityin
codingregionsofDNAmustbeamplifiedbyotherbiomoleculesinordertospecify
thewholerangeofproducts.‘Precisedetermination’impliesaone-to-one
relationship,andifwefocusoncodingsequencesalone,wefindaone-to-many
relationshipbetweensequenceandproduct.Differentmechanismsofgene
regulationco-specifythefinallinearproductofthegeneinquestion,firstby
activatingthegenesoitcangettranscribed,secondbyselectingachosensubsetof
theentirecodingsequence(e.g.alternativesplicing),andthirdlybycreatingnew
sequenceinformationthroughtheinsertion,deletionorexchangeofsingle
nucleotidelettersoftheRNA(e.g.RNAediting).Thusspecificity,andhenceCrick
information,isdistributedbetweenarangeoffactorsotherthantheoriginalcoding
sequence:DNAsequenceswithregulatoryfunctions,diversegeneproductssuchas
transcription,splicingandeditingfactors(usuallyproteins),andnon-codingRNAs
(Stotz,2006).
Absolutespecificityturnsouttobenotinherentinanysinglebiomoleculeinthese
molecularnetworksbutinducedbyregulatedrecruitmentandcombinatorial
control.AnditisherethatwewillfindthatthenetworkscannotbereducedtoDNA
sequencesplusgeneproducts,becausemanyofthelatterneedtoberecruited,
activatedortransportedtorenderthemfunctional.Therecruitment,activationor
transportationoftranscription,splicingandeditingfactorsallowtheenvironment
tohavespecificeffectsongeneexpression(being‘instructive’ratherthanmerely
‘permissive’inthetermsintroducedinsection2).Somegeneproductsserveto
relayenvironmental(Crick)informationtothegenome.Whileinembryologyand
morphogenesisitisoftenacknowledgedthatenvironmentalsignalsplayarolein
theorganisationofglobalactivities,theyarerarelyseentocarryinformationforthe
precisedeterminationofthenucleicacidoraminoacidchainsingeneproducts.But
thisispreciselywhatoccurs.Notjustmorphogenesisathigherlevelsoforganisation,
buteventhedeterminationoftheprimarysequenceofgeneproductsisacreative
processof(molecular)epigenesisthatcannotbereducedtotheinformation
encodedinthegenomealone(Stotz2006;GriffithsandStotz2013).
Interestingly,concurrentwithCrick’sCentralDogma,theciliatebiologistDavidL.
Nanneyacknowledgedthatthe‘libraryofspecificities’foundincodingsequences
neededtobeunderthecontrolofanepigeneticcontrolsystem.Inotherwords,in
additiontorequiringbothananalogueandadigitalconceptionofspecificity,the
studyofbiologicaldevelopmentrequirestwosourcesofinformation.Inan
immediateresponsetoCrick’snewpictureofsequentialinformationcodedinDNA,
Nanneypointedout:
Thisviewofthenatureofthegeneticmaterial…permits,moreover,aclearer
conceptualdistinctionthanhaspreviouslybeenpossiblebetweentwotypesof
cellularcontrolsystems.Ontheonehand,themaintenanceofa"libraryof
specificities,"bothexpressedandunexpressed,isaccomplishedbyatemplate
replicatingmechanism.Ontheotherhand,auxiliarymechanismswith
differentprinciplesofoperationareinvolvedindeterminingwhich
specificitiesaretobeexpressedinanyparticularcell.…Tosimplifythe
discussionofthesetwotypesofsystems,theywillbereferredtoas"genetic
systems"and"epigeneticsystems".(Nanney1958,712)
Inasimilarvein,Crick’sbiographerRobertOlbyremarksoftheCentralDogmathat
Clearly,inconcentratingonthisaspectofinformationaltransferhewassetting
asidetwoquestionsaboutthecontrolofgeneexpression–wheninthelifeofa
cellthegeneisexpressedandwhereintheorganism.Butthesearealso
questionsofaninformationalnature,althoughnotfallingwithinCrick’s
definition.(Olby,2009,251,italicsadded)
Asithasturnedout,manyepigeneticmechanismsarestronglyassociatedwithDNA.
DevelopmentalbiologistScottGilbertarguesthatthespecificityofareaction“hasto
comefromsomewhere,andthatisoftenapropertyofthegenome”(2003,349).But
sinceallcellsstartwithexactlythesamegenetic“libraryofspecificities”thatcan’t
bethewholestoryofdifferentiation.Nanneydescribesthisasadevelopmental
paradox:“Howdocellswithidenticalgeneticcompositionacquireadaptive
differencescapableofbeingmaintainedinclonalheredity”(Nanney,1989)?Gilbert
indeedacknowledgesthattheactionofageneitself“dependsuponitscontext.
Therearetimeswheretheenvironmentgetstoprovidethespecificityof
developmentalinteraction”(2003,350).Soweconcludethatwhilegenesareseen
asakeysourceofspecificity,inbiologycausesarenotregardedasinformative
merelybecausetheyaregenetic,butwhenevertheyarehighlyspecific.
ManyyearslaterNanneylookedbackonthisperiodinthelate1950sasonein
whichthepowerfulimageofthedoublehelixcauseda“neardisruptionofan
incipientmergingofcyberneticswithregulatorybiology”.It“mayhavehinderedthe
explorationofthesystemiccomponentsoflivingsystems,whicharenotjust
creaturesreifiedfromthe‘blueprints’,butessentialcomplementarycomponentsof
lifethatreciprocallyregulatethenucleicsystem”(Nanney1989).Inrecentyears,
however,ourimageofhowbiologicalsystemsexercisefine-grainedcontrolover
theirinternalprocesseshasdevelopedtothepointwherehisdescriptionofthetwo
complementarycontrolsystemsseemquiteconservative.
Itisnowclearthattheepigeneticcontrolsystem,ifwestillwanttocallitthat,not
onlyregulateswhenandwherethespecificitiesencodedintheDNAlibraryaretobe
expressed6.Italsosubstantiallyaugmentstheinformationoftheliteralcoding
sequence.Astrangeaspectofthemanagementofgeneticinformationisthatthe
epigeneticcontrolsystem–whichPaulDavieslikensto“anemergentself-
organizingphenomenon”(Davies,2012,42)–doesnotjustprovideasupervising
6Woodwardsuggeststhatspecificityincludesboththe“systematicdependenciesbetweenarangeofdifferentpossiblestatesofthecauseanddifferentpossiblestatesoftheeffect,aswellasdependenciesofthetimeandplaceofoccurrenceofEonthetimeandplaceofC”(Woodward2010,304-305,italicsadded).SoeveninNanney’soriginalvision,theepigeneticsystemsisanadditionalsourceofspecificity.
functionontheexpressionofthespecificitiesencodedintheDNA,inthesenseof
when,where,andhowmuchwillbeexpressed.Sincetheinformationencodedinthe
DNAdoesnotentailacompletesetofinstructionforwhichbiomoleculesshallbe
synthesized,theepigeneticcontrolsystemamplifiestheinformationoftheliteral
code(Davidson,2002).Genesarenotonlyswitchedonandoff,eventhoughthis
already“leadstoexponentiallymoreinformationbeingstoredinthesystem(sincea
setofNgenescanhave2Ndistinctstates)”(Davies,2012,43).Eukaryoteshave
epigeneticmechanismsthatallowthemtoproducemanyproductsfromasingle
codingregion,rangingfromjusttwouptothousandsofisoformsoftheresulting
protein.
Mostepigeneticmechanismsarenowfairlywellunderstoodatthemolecularlevel,
mostofthemincludechemicalmodificationsoftheDNAorthetailsofthehistone
proteinaroundwhichtheDNAiswrapped.Theposttranscriptionalprocessing
mechanisms,mainlyalternativeslicingandRNAeditingthatcreatethislargerange
ofgeneproduct,arealsofairlywellunderstood.Butifepigeneticmechanismsare
simplyasetofphysicalmodificationsofDNA,isn’ttheorganismstillanexpression
ofitsgenome,evenifthegenomeisalittlemorecomplexthaninitiallysupposed?
Thiswillnotdobecausethemolecularmechanismsandepigeneticmarksarejust
thefinalstagesofregulatoryprocessesthatstartfarfromthegenome.Forinstance
theup-ordown-regulationoftheglucocorticoidreceptorgeneinthehypothalamus
ofaratpupisproximallycausedbytheincreasedordecreasedmethylationstateof
thereceptor’spromoterregion.Thisinturnisinfluencedbytheincreasedor
decreasedexpressionandactivationofthetranscriptionfactorNGF1-A.Increased
expressionofNGF1-Aisduetoanincreasedserotonintoneinthehippocampus.But
thisinturnisbeingcausedbythemotherrat’slickingandgroomingofherpup,
whichinturnreflectsthemoreorlessstressedstateofthemotherduetothe
environmentinwhichshefindsherself.Themother’smaternalcarebehavior
comprisedpartoftheenvironmentalcontextoftheratpup.Theincreasedserotonin
tonerepresentsachangeoftheoverallstateofthewholesystem,witharangeof
downstreameffects,oneofwhichisachangeintheexpressionoftheglucocorticoid
receptor.Thisinturnproducesarangeofbottom-upeffectsonthesysteminterms
ofachangedbehavioralrepertoire.Thisisjustoneexampleofhowtheenvironment
orthesystemasthewholeisultimatelyaffectingtheexpressionofgenes(Meaney,
2001;Weaveretal.,2007).Thereforewecansaythatasubstantialamountof
informationneededtoconstructanorganismisderivedfromelsewhere,suchasthe
organism’senvironment.Thisinformationaugmentsoramplifiestheinformation
inheritedviathegenome.
6.Informationand‘downwardscausation’
Wehavearguedthatadditionalspecificity,orinformation,isderivedfromthe
environmentalcontext,butitmayalsobegenerateddenovobyphysicalprocesses
ofself-organisation.Self-organisationisthespontaneousformationofwell-
organizedstructures,patterns,orbehaviors.Inbiologyitmeanstheself-
maintainingorganisationofconstraintsthatharnessflowsofmatteranenergyand
allowthe“constrainedreleaseofenergyintorelativelyfewdegreesoffreedom”
(Kauffman,2003,1094).Biologicalsystems,inKauffman’sterm,‘actingontheirown
behalf’whentheyconstrainexergonicprocessesinaspecificwaytoproducework,
whichcanbeusedtogenerateendergonicprocesses,whichinturngeneratethose
constraintscanalizingexergonicprocesses.7Ithasoftenbeensuggestedthatsuch
processesareanadditionalsourceoforderinbiologicalsystems.
WalkerandDavieshaverecentlycharacterizedlifeby“context-dependentcausal
influences,andinparticular,thattop-down(ordownward)causation–where
higher-levelsinfluenceandconstrainthedynamicsoflower-levelsinorganizational
hierarchies–maybeamajorcontributortothehierarchalstructureofliving
systems”(Walker&Davies,2013,1).
7Anendergenicreactionabsorbsandstoresenergyfromthesurrounding.Duringexergenicreactionsstoredenergyisreleasedtodrivevariousfunctions.
Downwardcausationshouldn’tbeunderstoodasthedirectdynamicinteractionof
thewholewithsomeoftheirparts.Ithaslongbeenacknowledgedinthephysical
sciencethatindynamic-efficient-causation,onlytheinteractionbetweenpartsat
thesameontologicallevelhascausaleffectiveness.Thewaythattheoverall
biologicalsystemisstillabletoexertrealcausaleffectsisbywayofinformational
controlviafeedbackmechanismsthatinfluencesthedynamicinteractionbetween
theparts(Auletta,Ellis,&Jaeger,2008).PhilosophersCarlCraverandWilliam
Bechtelhaveadvocatedthisviewmoregenerally,inanattempttoridtheideaof
downwardscausationofanymysteriousovertones(2006).Theysuggestthat
interlevelrelationships,suchastheinteractionsbetweenpartsandwhole,should
notbeunderstoodascausalrelationshipsatall,eventhoughtheserelationships
exertrealinfluencesonthesystematdifferentlevels.Bothtop-downandbottom-up
causation,
…describemechanisticallymediatedeffects.Mechanisticallymediatedeffects
arehybridsofconstitutiveandcausalrelationsinamechanism,wherethe
constitutiverelationsareinterlevel,andthecausalrelationsareexclusively
intralevel.(Craver&Bechtel,2006,547)
Asystemasawhole–ahigherlevelentity–isengagedinaprocessthatwould
nothappenwithoutsomeaspectsoftheorganizationofthatsystem,andwhich
thereforeneedstobeunderstoodatthehigherlevel.Butthissystemiscomposed
ofparts,andasthesystemasawholechanges,sodotheparts,obviously.The
relationbetweentheprocessgoingonatthesystemslevelandachangeinone
partisnotbecauseofanadditionalcausalrelationbetweensystemasawhole
andthatpart(overandabovetheinteractionofthepartwithotherparts)butthe
relationofconstitutionbetweenthesystemanditsparts.
ItisinthissensethatweunderstandandendorseWalkerandDavies’claimthat,
“algorithmicinformationgainsdirect,context-dependent,causalefficacyover
matter”(2013,2).Thatdoesnotjustmeanthatthedigitalinformationwithinthe
geneticcodejustbyitselfgainssuchcontrolovermatter.Afterall,asNanneyhas
alreadyrealizedsome65yearsago,theexpressionoftherepositoryofinformation
withinDNAisinneedofepigeneticcontrol.“Thealgorithmitselfisthereforehighly
delocalized,distributedinextricablythroughouttheveryphysicalsystemwhose
dynamicsitencodes”(Walker&Davies2013,5).Thecausalefficacyisachieved
throughsome“uniqueinformationalmanagementproperties.…Focusingstrictly
ondigitalstoragethereforeneglectsthiscriticalaspectofhowbiological
informationisprocessed”(Walker&Davies2012,2-3).
7.Conclusion
Sarkarhasarguedthattheconventionalaccountofbiologicalinformationascoded
instructionsinthesequenceofDNAnucleotideslacksexplanatorypower.Hecalls
for,first,thedevelopmentofa“systematicaccountofspecificity”,andsecond,an
“elaborationofanewinformationalaccount”withwiderapplicabilitythannucleic
acidalone(Sarkar,1996a,222).Ifthelattercoursewastobeadopted,hesuggested,
itwouldbe“highlyunintuitivenottoregard[epigeneticspecifications]as‘transfers
ofinformation’if‘information’istohaveanyplausiblebiologicalsignificance”
(Sarkar1996a,220).Ourproposalinthispaperrepresentsasynthesisbetween
Sarkar’stwowaysforward,namelyasystematicaccountofspecificityandanew
approachtobiologicalinformation(seeGriffithsetal.,Forthcoming;Pocheville,
Underreview).
Biologicalspecificityissimplycausalspecificityinbiologicalsystems.Causal
specificityisadegreepropertyofcausalrelationships–themorespecifica
relationshipthemoreaptitisfortheexerciseoffine-grainedcontrolovertheeffect.
Insection3wegaveabriefsummaryofhowthispropertycanbemeasuredusing
toolsfrominformationtheory.Informationallanguageinbiologyrepresentsaway
totalkaboutspecificity.Nodoubtinformationallanguageisusedformanyother
purposesinbiologyaswell,butthecaseswehavepresentedinwhichitrelatesto
specificityarecentraltomolecularanddevelopmentalbiology.Asaresultwefeel
justifiedincallingourinformation-theoreticanalysisofspecificityananalysisof
biologicalinformation.
Whatisdistinctiveaboutlivingsystems,wewouldargue,isthattheyarestructured
sothatmanyoftheirinternalprocesseshaveanoutstandingdegreeofcausal
specificitywhencomparedtomostnon-livingsystems.Thisunderliesthe
phenomenonthatfirstattractedthelabelof‘specificity’inbiology–theabilityof
organismstodevelopinaverypreciseway,andtorespondinaveryselectiveand
precisewaytotheircircumstances.Theideathatlivingsystemsdifferfromnon-
livingsystemsbybeing‘informed’–underthecontrolofinformation–makesa
greatdealofsenseintermsofouranalysisofbiologicalinformationascausal
specificity.However,thereisagreatdistancebetweenabroad,philosophical
interpretationlikethisandanactualscientifictheoryoftheinformationalnatureof
livingsystems.Inthefinaltwosectionswehavereviewedsomeoftheideasthatwe
thinkmayformpartofsuchatheory.
Acknowledgments
Thispublicationwasmadepossiblethroughthesupportofagrantfromthe
TempletonWorldCharityFoundation,“CausalFoundationsofBiological
Information”,TWCF0063/AB37.Theopinionsexpressedinthispublicationare
thoseoftheauthorsanddonotnecessarilyreflecttheviewsoftheTempletonWorld
CharityFoundation.
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