Erwin Schroedinger, Francis Crick and epigenetic stability

8/3/2019 Erwin Schroedinger, Francis Crick and epigenetic stability

http://slidepdf.com/reader/full/erwin-schroedinger-francis-crick-and-epigenetic-stability 1/18

ErwinSchroedinger,FrancisCrickandepigeneticstability

VasilyV.Ogryzko

UniversitéParis-Sud11

CNRS,InteractionsmoléculairesetcancerUMR8126

InstitutdeCancérologieGustave-Roussy

Villejuif,France

Emailaddress:[email protected]



Abstract

Schroedinger'sbook'WhatisLife?'iswidelycreditedforhavingplayedacrucialroleindevelopmentof

molecular and cellular biology. My essay revisits the issues raised by this book from the modern

perspective of epigenetics and systems biology. I contrast two classes of potential mechanisms of

epigeneticstability:‘epigenetictemplating’and‘systemsbiology’approaches,andconsiderthemfrom

thepointofviewexpressedbySchroedinger.Ialsodiscusshowquantumentanglement,anonclassical

featureofquantummechanics,canhelptoaddressthe‘problemofsmallnumbers’thatledSchroedinger

topromotetheideaofamolecularcode-scriptforexplainingthestabilityofbiologicalorder.

Reviewers

ThisarticlewasreviewedbyEugeneKoonin,VlatkoVedral(nominatedbySergeiMaslov)andEricKarsenti(nominatedbyArcadyMushegian).Forthefullreviews,pleasegototheReviewers'

Commentssection.

‘Molecularbiologyhasbeensuccessfullargelybecauseithasconcentratedonthetypeofproblem[…]thatcanbeattackedbyisolatinga

ll f bi l i l ’



the role of DNA sequence as the dominant contributor to the persistence of biological order, the

emergingviewoffersaricherspectrumofadditionalfactorsthatcontributetobiologicalorganizationin

amannersomewhatindependentfromDNA.Alargesubsetofthesefactors,summedupunderthename

ofepigeneticinformation,isresponsibleforthemaintenanceofdifferentiatedcelltypesindevelopment,

playsanimportantroleincancerandhasbeenmakingheadlineslatelyastheculpritresponsibleforthe

setbacks in reproductivecloning. Could the insights ofSchroedinger's little book into thephysics of

biologicalorderbeusefulinsortingoutthenatureandpotentialmechanismsofprocessing,storageand

transmissionofepigeneticinformation?

ForSchroedinger,themostobviousmanifestationofbiologicalstabilitywasheredity,hencehisinterest

in thephysicsof inheritance.Likewise, currentepigeneticstudiesalso emphasizeheritableaspectsof

epigeneticphenomena.Thisfocus,however,unnecessarilylimitsthescopeofepigenetics.Terminally

differentiatedcellslivefordecades,maintainingtheirdistinctphenotypictraitsinspiteofenvironmental

stresses,thermalnoiseandDNAdamage/repair.Thesecellsdonotproliferate,thustheterm‘heritable’

does not apply to their traits. The term ‘epigenetic stability’ refers to a broader phenomenon that

encompassesmaintenanceofphenotypictraitsinbothnonreplicatingandreplicatingcellsindependent

f DNA I thi I t t t l f t ti l h i f i ti t bilit



interactions and post-translational modifications) and might propagate independently from theDNA

sequence.

Moreover,itwasCrickwho,laterinhiscareer,becamepreoccupiedwiththemolecularmechanismsof

the essentially ‘epigenetic’ phenomenon of neurobiological memory. Crick did not believe that the

strengthofanindividualsynapse,oftenlocatedfarfromthenucleus,couldbeencodedinanucleicacid,

andinsteadfavoredaproteinmodificationastheeffector.Buthowthencanthesynapticstrength(the

elementalbasisofmemory)persistfordecades,inspiteofthemolecularturnoverthattendstoerase,ina

matterofdaysorweeks,themolecularrecordsstoredinproteinstructures?

Crickpostulatedthati)thestrengthofasynapseisdeterminedbyphosphorylationofaproteinmolecule,

ii)thisproteincanformdimers(oroligomers)andiii)thekinaseresponsibleforthemodificationwill

onlymodifymonomer inadimer that alreadyhastheothermonomer phosphorylated.Thismodelofkinaseaction(inspiredby thesemi-conservativemechanismfor themaintenancemethylationofDNA

[2])wouldallow thecell to restore theoverallphosphorylatedstate of thedimer/oligomerwhenever

molecular turnover replaceseithermonomer byanewone.The result isanextended half-life ofthe

structure,i.e.,memory,as‘themoleculesinthesynapse[…]canbereplacedwithnewmaterial,oneat



onmacromolecularcomplexesalreadycontainingthesamemark(Fig.1).

Therecentproposalofasemi-conservativemechanismofnucleosomeduplication[9]mightmeanthat

epigenetic templating alsoworks for chromatinmarks of a different kind, e.g., varianthistones. All

variantsofhistoneH3formsocalledhomotypicnucleosomes,havingbothH3moleculesofthesame

type in the histone octamer.However, newH3histones are deposited onDNA only in the form of

H3/H4dimers[9];thusthedepositionmachinerymustmatchthetypesofnewandoldH3histonesifit

istokeepthenucleosomehomotypic.Suchamechanismcouldcontributetoanunderstandingofthe

role of CenpA, the centromere-specific version of histone H3, in the epigenetic maintenance of

centromerestructureindependentofDNAsequence[10].

Intriguingly,thedesignofsomeproteinkinasesissuggestiveofepigenetictemplatingalsooperatingin

the cytoplasm. Tyrosine kinases often containSH2domains,which recognize phosphotyrosine [11],

whereas some serine/threonine kinases contain FHA domains that recognize

phosphoserine/phosphothreonine[12].Thesestructuralfeaturesareusuallyunderstoodin termsofthe

signaling cascade paradigm, with a phosphoprotein A modulating a protein kinase targeting a

d t t i B H if f th ki t t f di ( li ) th



enforce epigenetic templating, as considered in [8]. Future studies should reveal towhat extent this

model,promisingtocomplementtheCentralDogmaofmolecularbiology,couldexplainthestabilityof

epigeneticphenomena.

‘Systemsbiology’approachestoepigeneticstabilityandtheproblemoffluctuations

ThatFrancisCrick,thefatherofCentralDogma,entertainedideasextendingbeyonditsboundaries, is

notsurprisingandservestoillustratethatthebetteryouknowaconcept,themoreyouseeitslimitations.

Yet,althoughatoddswiththegenocentricviewoflife,theepigenetictemplatingidearemainstruetothe

general spirit of molecular biology, which, following Schroedinger, looks for the keys to life in

molecular structure. The model shares with the Watson-Crick mechanism of DNA replication one

essential feature incommon- thelocalized ‘bit bybit’ characterof informationstorage and transfer.

Informationis stored inaparticularmacromolecularstate (e.g., proteinmodification) andits transfer

reliesoninter-molecularcontactsandphysicallinkagebetweendifferent(modification-depositionand

modification-recognition) activities. Clearly, such a model has the advantage of being testable by

traditionalbiochemicalexperimentsincell-freesystems.However,isittheonlygameintown?



‘systemsbiology’approachestoepigeneticstability?Theharshreality testfacing themisthe intrinsic

noisiness of the intracellular dynamics due to the small numbers of participating molecules. The

fluctuations in thenumbers ofmolecules of transcriptional regulators renderquestionable therole of

genenetworkdynamicsinstabilityofgeneexpressionpatterns[16,17](althoughthestochasticnatureof

geneticcircuitsislikelyinvolvedinmaking choicesbetweenthesepatternsduringdifferentiation).The

‘smallnumbers curse’1 loomsequallywhen theconcepts fromnon-equilibriumstatistical physicsand

classical chemical kinetics, whichwork reasonablywell on amacroscopic scale, are applied to the

organizationofsuchnano-objectsasbacterialcellsoreukaryoticcells’compartments,havingonlyafew

copiesofmanyvitalmolecularcomponents[18].

Exacerbating the ‘small numbers’ problem are two factors: the great variety of different molecular

speciespresentineventhesimplestlivingcellandtheneedtotakeintoaccountthelocalcontextofeach

molecule.Bothleadtoaverylargenumberofvariablesnecessarytodescribethestateofacell.Tosee

howtheproblemsoffluctuationsandhighdimensionalityofintracellulardynamicscombine,consider

thefollowingtoyexample.Asingle E.colicellcontains2000moleculesofRNA-polymeraseenzyme

[19].Asameasureofthestabilityofaparticularvariabler ,letustakethecostofitsmaintenance( Mr ),

i d d t b di i t d i d t k th l f i t bl f th



insteadofasingleone)becomesproportionalto Nrinsteadof√ Nr(sinceifthenumberoflabels i=N ,

theΣ√ Nr i=Nr dueto√1=1).

If molecular biology tellsusanything, it is that themorewe learn of the intricacies of intracellular

regulation,themorefunctionaldifferencesbetweendifferentmoleculesofthesamespecieswefind,due

totheirmanymodificationsandtheirplacementinparticularintracellularcontexts.If,inthespiritofthe

‘omics’ approach, we consider all this information to be essential for the complete description of

intracellular dynamics, the number of variables will expand dramatically, together with the cost of

keepingfluctuationsundercontrol.Thisreflectsthefactthatincreasingtheresolutioninourdescription

ofthecellstateisthereverseof‘coarsegraining’,aprocedureusedinstatisticalmechanicstotransit

from a detailed ‘microscopic’ description of a physical system to its description in terms of

‘macroscopic’ degrees of freedom by averaging out all nonessential variables. Thus, the more

informationaboutthecellweconsiderasessential,thelesswecanrelyonthelawoflargenumbersto

accountforthestabilityofintracellulardynamics.

CouldthelessonsofSchroedinger’sbookhelptogetusoutoftrouble?Infact,theverysame‘small



contributetothe‘systemsbiology’approachestoepigeneticstability,similarlyhelpingthemtodealwith

the‘smallnumbersproblem’?

Schroedingerandquantumentanglement

At first glance, appealing to quantum mechanics to solve the fluctuation problem only seems to

complicatethesituation. Inquantum theory,the dimensionalityof acomposite systemdoesnotgrow

linearlywiththenumberofitsparts(asitdoesintheclassicalcase),butexponentially[21].Thus,asthe

numberof variablesused todescribeintracellulardynamicsmultiplies,the Mr neededtokeepallthe

fluctuationsundercontrolhastogrowexponentially.Wouldnot,then,appealingtoquantummechanical

principlesinexplainingintracellulardynamicsamounttoshootingourselvesinthefoot?Woulditbe

wiser of us to restrict the biological applications of quantum theory to the time-honed studies of

molecular structure and intermolecularinteractions only?This does notseem tobe thebest strategy.

Quantum theory is a general theory of the stability of matter, indispensable for understanding the

behaviorofobjectsbothsmallandlarge.Beingaparticularcaseofcondensedmatterphysics,itisvery

unlikelythatthephysicsoflifecanbeproperlyunderstoodwithoutquantumtheory.Asweperfectour

t h l t th hi h t l ti th d i ti f i t ll l d i t ti f fi t (i



materialsystems[27,28].Myexpectationisthatthephysicaldescriptionofintracellularprocessesfrom

firstprincipleswillrequiretakingentanglementintoaccount.Thesystemsbiologyapproachesbasedon

approximations that get ridofentanglement at theoutsetwillhave seriousdifficulties explaining the

stabilityofintracellulardynamics.

Howmayentanglementsubstitute‘largenumbers’instabilizingbiologicalorder?Similartothecoarse

graining procedure, it can reduce the number of degrees of freedom that have tobeprotected from

fluctuations,butinamoresubtlewaythanbysimpleaveraging.Considerthesimplestexampleofan

entangledsystem–socalledBellpairofelementaryparticles[26]:

Ψ⟩ = (↑⟩1↓⟩2 + ↓⟩1↑⟩2)/√2, (1)

wherethearrowsdesignatethespinorientationofparticles1and2,

andcompareitwithanon-entangledpair(productstate):

Ψ⟩ = →⟩1→⟩2=((↑⟩1+ ↓⟩1)/√2)((↑⟩2+ ↓⟩2)/√2) =

= (↑⟩1↓⟩2+ ↑⟩1↑⟩2 + ↓⟩1↑⟩2 + ↓⟩1↓⟩2)/2 (2)

Whereas, in the ‘spin up’/’spin down’ representation, all combinations of the states of the two

particles areallowedfor theproductstate(2),in the caseof theBellpair(1)onlytwoare.It is



concomitant growth in the cost of maintenance4. These arguments suggest that the proper

descriptionofthecell’sfunctioningwillrequiretakingsomeofthisentanglementintoaccount,in

ordertokeeptheexpectedtotalcostofmaintenanceundercontrol.Theresultantacknowledgment

ofcorrelations betweenmolecularevents inside thecell can help tounderstand howintracellular

dynamics remains robust in spite of the fluctuations in the numbers of its many participating

components.

Findingsupport for theproposed role of entanglementmeetswithboth experimental and theoretical

challenges.First,wewillneedtolearnhowtodetectcorrelationsinthefluctuationsofmanyobservable

characteristicsoflivingcells,andtobeabletodoitona singlecelllevel.Thistaskisstilldifficultwith

currenttechnologyandwillrequirethemarriageof‘nano-’and‘-omic’approaches,stillintheirinfancy.

Second,entanglementiscommonlyperceivedtobeveryfragileandtobequicklydestroyedduetothe

interaction of the physical system with its environment. This phenomenon, called environmentally

induceddecoherence(EID),hashindered theotherwiseremarkabledevelopmentofprotocolsthatuse

entanglement for more efficient computation and secure cryptography [24]. There are grounds for

optimism,however.Theperceivedfragilityof anyentanglementisamisconceptionresultingfromthe

k h ll i t lli ti l l f t l d t t f th f t



‘decoherence free subspaces’ are related to the concept of ‘preferred states’ proposed to explain

transition from the quantumworld to the classical [36]. In this approach, EID does not destroy all

entangled states - some are stabilized via a process called environmentally-induced superselection.

Accordingly, theentangled states inbiologicalsystems couldbeprotected fromEIDexactlybecause

theyarethe‘preferredstates’ survivinginteractionwiththeenvironment.Theimplicationsofthisidea

could be interesting for both information technology and the understanding of life. It suggests a

perspectiveontheadaptationoflifetoitsenvironmentthatdiffersfromthecanonicalDarwinianviewin

thatadaptationvia‘survivalofthefittest’canhappenonthelevelofanindividualobject,i.e.,doesnot

involvereplication[22,23].Ontheotherhand,itindicatesanewpotentialsourceofentangledstates

preparedforusbybiologicalevolution,whichcouldbeusedinquantuminformationprotocols.

Tosummarize,entanglementcanprovidebiologywithaconceptualingredientthathadbeenmissing

fromthemolecularexplanationsoflifedominatingthefieldforthelast50years.Aphilosophercould

seeinitthephysicalcounterpartofanolddictum–‘thewholeismorethanasumofitsparts’,reflecting

theaspectoflifethatcannotbereducedtomolecularstructureandinteractions.Amoderninformation

theoristwouldseeentanglementasanindependentresourceforinformationprocessingin livingcells,

dditi l t th l l ‘ t d b lt ’ h i (i l di i ti t l ti ) hi h ld



shedmorelightontheimportanceofepigenetictemplatingbyagenome-widecomputationalanalysisof

proteindomainarchitectures.

Thesecondfacetofepigeneticstabilitydiscussedhereiscompletelydifferentincharacteranddecidedlynon-orthodox.Inessence,Ogryzkoproposesthatthe“smallnumberscurse”,whichisatthe

centerofSchroedinger’treatise,i.e.,thewayacellcopeswithdisruptiveeffectsofmolecular

fluctuations,couldinvolvequantumentanglement,thefamednon-localaspectofquantumphysics.The

fluctuationsproblemisrealandtroubling,andtheproposedsolutionseemstobeingeniousand,potentially,powerful(caveatemptor:myownunderstandingofentanglementisatthelevelofNews&

Viewsarticles).Theideaofstabilizationofparticularentangledstatesviaenvironmentallyinduced

superselectionisparticularlyattractive.Inprinciple,thiscouldbe“it”,theHolyGrailofBiological

Physics,anon-trivial(notlimitedtopropertiesofmolecules)roleofquantumeffectsinbiologicalsystems.Ofcourse,itmustbeclearlyrealizedthattheproposaloutlinedinthispaperisnotatheoryand

notevenafull-fledgedhypothesis:itis“just”anideabut,Ithink,onethatbiologistscannotaffordto

dismiss.

Thehistoricalcontextofthepaper,withallthemultifacetedramificationsofCrick’sandSchroedinger’s

classics,mightnotbeexactlyessentialforthepresentationsofOgryzko’sideas,butthissurelymakes

forenticingreading.TheonlyaspectofthepaperthatIdonotlikeistheuseofthe“systemsbiology”

jargoninthesecondpart.Itrequiresthinkingbuttheresurelymustbeabetterwaytodescribetheeffectsoffluctuationsoncellfunctioning.

Author'sresponse–IthankDr.Kooninforhiscomments.Iappreciatetheideaofusinggenome-wide

computationalanalysisofproteindomainstotestthecontributionoftemplatingmechanismsto

epigeneticstability;somethingdefinitelycouldbedonewiththis.

I l th t th id b t th t ti l l f t l t i i th ‘ ll b ’



toharnessitforthepurposesofquantuminformationprocessing,butagain,itcouldbedoneonlywith

thehelpofbiologists.

EricKarsenti,CellBiologyandBiophysicsunit,EMBLHeidelberg,Heidelberg,Germany.

Idon'tfindanythingdramaticallywronginwhatOgryzkowritesaboutbiology,andIthinkthat

theideaisveryinteresting.Istillthinkthatineukaryoticcells,statisticalmechanicsandreactiondiffusionmechanismsarethemostrelevantscaletoanalyzetheself-organizationofhighlydynamic

steadystateofrelativelylargestructureslikethespindle,organellesandoverallcellorganization.

However,itisquitepossiblethatcoherencederivedfromentanglementisalsoatworkunderneaththe

averagingoflargenumbersofmolecules.Obviously,somekindofexperimentalapproacheswouldbewelcometoaddressthisquestionofentanglementatthecelllevel.

Author'sresponse–IthankDr.Karsentiforhiscommentsandagreethatexperimenterswillhavethe

lastwordinthismatter.

Endnotes1.AcaseinpointisthecalculationofthenumberoffreeprotonsinasinglecellofE.coli[38].Giventhe

intracellularpH7.5andcellvolumeπ /6x10-15liters,thereare,ontheaverage,only10protonsincell[39].

2.Aresource,whichhelpstoovercomelimitationsonwhatcanbeachievedbythesocalledLOCC(Local

OperationsandClassicalCommunications)classofprocessesinquantuminformationtheory[26].



References

1. CrickF:Centraldogmaofmolecularbiology. Nature1970,227:561-563.

2. RazinA,Friedman J:DNAmethylationanditspossiblebiologicalroles. ProgNucleicAcidResMolBiol1981,

25:33-52.

3. CrickF:Memoryandmolecularturnover. Nature1984,312:101.

4. SiK,LindquistS,KandelER:AneuronalisoformoftheaplysiaCPEBhasprion-likeproperties.Cell2003,

115:879-891.

5. JenuweinT,AllisCD:Translatingthehistonecode.Science2001,293:1074-1080.

6. OgryzkoVV:Mammalianhistoneacetyltransferasesandtheircomplexes.CellMolLifeSci2001,58:683-692.

7. TurnerBM:Histoneacetylationandanepigeneticcode. Bioessays2000,22:836-845.

8. ViensA,MecholdU,BrouillardF,GilbertC,LeclercP,OgryzkoV:AnalysisofhumanhistoneH2AZdeposition

invivoarguesagainstitsdirectroleinepigenetictemplatingmechanisms. MolCellBiol2006,26:5325-5335.9. Tagami H,Ray-Gallet D,Almouzni G,Nakatani Y:HistoneH3.1 and H3.3 complexes mediate nucleosome

assemblypathwaysdependentorindependentofDNAsynthesis.Cell2004,116:51-61.

10. ChooKH:Centromerization.TrendsCellBiol2000,10:182-188.

11. YaffeMB:Phosphotyrosine-bindingdomainsinsignaltransduction. NatRevMolCellBiol2002,3:177-186.

12. YaffeMB,EliaAE:Phosphoserine/threonine-bindingdomains.CurrOpinCellBiol2001,13:131-138.

13. KauffmanS:Homeostasisanddifferentiationinrandomgeneticcontrolnetworks. Nature1969,224:177-178.

14. KarsentiE:Self-OrganizationInCellBiology:ABriefHistory. Naturereviewsinmolecularcellbiology2008.

15. NicolisG,PrigogineI:Self-OrganizationinNonequilibriumSystems:FromDissipativeStructurestoOrderthrough

Fluctuations.NewYork:Wiley;1977.16. Elowitz MB, Levine AJ, Siggia ED, Swain PS: Stochastic gene expression in a single cell. Science 2002,

297:1183-1186.

17. KaernM,ElstonTC,BlakeWJ,CollinsJJ:Stochasticityingeneexpression:fromtheories tophenotypes. Nat

RevGenet2005,6:451-464.

18. HessB,MikhailovA:Self-organizationinlivingcells.Science1994,264:223-224.

19. IshihamaA:FunctionalmodulationofEscherichiacoliRNApolymerase. AnnuRevMicrobiol2000,54:499-518.

20. SchroedingerE:WhatisLifeCambridge:CambridgeUniversityPress;1944.



37. SchroedingerE:Discussionofprobabilityrelationsbetweenseparatedsystems. ProceedingsoftheCambridge

PhilosophicalSociety1935,31:555-563.

38. Maloney PC:Coupling to anEnergizedMembrane: Role of Ion-MotiveGradients in the Transduction of

MethabolicEnergy.In Escherihia coliand Salmonella TyphimuriumCellularandmolecularbiologyVolume1.EditedbyNeidhardtFC.Washington,D.C.:AmericanSocietyforMicrobiology;1987:222-243

39. PadanE,SchuldinerS:IntracellularpHregulationinbacterialcells. MethodsEnzymol1986,125:337-352.

40. VonNeumannJ:MathematicalFoundationsofQuantumMechanics.Princeton:Princeton.UniversityPress,;1955.

Figurelegends

Figure1.Generalschemeofepigenetictemplating.

Thismechanism impliestwoessential features: a.Physical linkagebetween theenzymatic activitydepositingaparticular

epigeneticmark(covalentmodification,alternativehistone,etc.)andtherecognitionmoduleforthismark;b.Formationof

dimers(oroligomers)bythetargetofenzymaticactivity(protein,nucleicacid,etc.).Shownarethreescenarios:I–presence

ofthemarkononemonomerwilldirectitsdepositiononthesecondmonomerviarecruitmentofthedepositingactivity(can

alsoinvolveallostericeffectsofR-modulebindingonD-moduleactivity),II–unmarkeddimerwillnotrecruitmodifier,III–

ifbothmonomersaremarked,theywillnotbeaffected.R–recognitionmodule,D–depositionmodule,T–target.

Figure2.Quantumentanglement.

2.A.Oneexampleofsystemsetuptoobservequantumentanglement



Figure 2

Erwin Schroedinger, Francis Crick and epigenetic stability

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