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:karola.stotz@mq.edu.au2DepartmentofPhilosophy,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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