Paul Nurse - What Is Life

by Understand Biology In Five Steps (pdf)

  Openingthesenewvistasontothecellcreatesnewchallengestoo.AsSydneyBrennerputit:‘Weare drowningindatabutthirstyforknowledge.’Hisconcernwasthattoomanybiologistsspendalotoftime recording and describing the details of living chemistry, without always fully understanding what it all means.Centraltoturningallthisdataintousefulknowledgeisunderstandinghowlivingthings process information.

  Thisisthefifthofbiology’sgreatideas,andtheonewewillconsidernext.

  5.LIFEASINFORMATION

  WorkingasaWhole

  Whatwasitthatmadethatyellowbutterflyventureintomychildhoodgardenallthoseyearsago?Wasit hungry, looking for somewhere to lay its eggs, or perhaps being chased by a bird? Or was it just responding to some inbuilt urge to explore its world? Of course I do not know why that butterfly was behavingasitdid,butwhatIcansayisthatitwasinteractingwithitsworldandthentakingaction.And todothat,ithadtomanageinformation.

  Informationisatthecentreofthebutterfly’sexistenceandindeedatthecentreofalllife.Forliving organisms to work effectively as complex, organized systems they need to constantly collect and use informationaboutboththeouterworldtheyliveinandtheirinternalstateswithin.Whentheseworlds–

  eitherouterorinner–change,organismsneedwaystodetectthosechangesandrespond.Iftheydonot, theirfuturesmightturnouttoberatherbrief.

  Howdoesthisapplytothebutterfly?Whenitwasflyingabout,itssenseswerebuildingupadetailed pictureofmygarden.Itseyesweredetectinglight;itsantennaeweresamplingmoleculesofthedifferent chemicalsubstancesinitsvicinity;anditshairsweremonitoringvibrationsintheair.Altogether,itwas gathering a lot of information about the garden I was sitting in. It then brought all this diverse informationtogether,withtheaimoftransformingitintousefulknowledgethatitcouldthenactupon.

  Thatknowledgemighthavebeendetectingtheshadowofabirdorofaninquisitivechild,orrecognizing the smell of nectar from a flower. This then generated an outcome: an ordered sequence of wing movementsthatledthebutterflytoeitheravoidthebirdortosettleonaflowertofeed.Thebutterflywas combining many different sources of information and using them to make decisions with meaningful consequencesforitsfuture.

  Closelylinkedwiththeirrelianceoninformationisthewaylivingthingsactwithasenseofpurpose.

  Theinformationthebutterflywasgathering meantsomething.Itwasbeingusedbythebutterflytohelp itdecidewhattodonexttoachievesomespecificend.Thatmeantitwasactingwith purpose.

  Biology is a branch of science where it can often make sense to talk about purpose. In the physical sciencesbycontrastwewouldnotaskaboutthepurposeofariver,acometoragravitationalwave.Butit doesmakesensetoaskthatofthe cdc2geneinyeast,oroftheflightofabutterfly.Alllivingorganisms maintainandorganizethemselves,theygrow,andtheyreproduce.Thesearepurposefulbehavioursthat have evolved because they improve the chances of living things achieving their fundamental purpose, whichistoperpetuatethemselvesandtheirprogeny.

  Purposefulbehaviourisoneoflife’sdefiningfeatures,butitisonlypossibleiflivingsystemsoperateas awhole.Oneofthefirstpeopletounderstandthisdistinctivefeatureoflivingthingswasthephilosopher Emmanuel Kant, at the turn of the nineteenth century. In a book called Critique of Judgement, Kant argued that the parts of a living body exist for the sake of the whole being, and that the whole being exists for the sake of its parts. He proposed that living organisms are organized, cohesive and self-regulatingentitiesthatareincontroloftheirowndestiny.

  Considerthisatthelevelofthecell.Eachcellcontainsaprofusionofdifferentchemicalreactionsand physicalactivities.Thingswouldrapidlybreakdownifallthesedifferentprocessesoperatedchaotically, or in direct competition with one another. It is only by managing information that the cell can impose orderontheextremecomplexityofitsoperationsandthereforefulfilitsultimatepurposeofstayingalive andreproducing.

  Tounderstandhowthisworks,rememberthatthecellisachemicalandphysicalmachinethatbehaves as a whole. You can understand quite a lot about a cell by studying its individual components, but to function properly, the multitude of different chemical reactions operating within the living cell must communicatewitheachotherandworktogethercohesively.Thatway,wheneitheritsenvironmentorits inner state changes – perhaps the cell runs low on sugar, or encounters a poisonous substance – it can sensethatchangeandadjustwhatitdoes,therebykeepingthewholesystemfunctioningasoptimallyas possible. Just as a butterfly gathers information about the world and uses this knowledge to modify its behaviour,cellsareconstantlyassessingthechemicalandphysicalcircumstancesbothwithinandaround them,andusingthatinformationtoregulatetheirownstate.

  Togetabetterhandleonwhatitmeansforcellstouseinformationtoregulatethemselves,itmightbe helpfultofirstconsiderhowitisachievedinmorestraightforwardhuman-designedmachines.Takethe centrifugalgovernor,firstdevelopedforusewithmillstonesbytheDutchpolymathChristiaanHuygens, but adapted with great success by the Scottish engineer and scientist James Watt in 1788. This device couldbefittedtoasteamenginetoensuretheenginerunsataconstantspeed,ratherthanracingaway andperhapsbreakingdown.Itiscomprisedoftwometalballsthatspinaroundacentralaxis,whichis poweredbythesteamengineitself.Astheenginerunsfaster,centrifugalforcespushtheballsoutwards and upwards. This has the effect of opening a valve, which releases steam from the engine’s piston, slowing the steam engine down. As the engine slows, gravity pulls the steel balls of the governor back down,closingthevalveandallowingthesteamenginetospeedupagain,towardsthedesiredspeed.

  WecanunderstandWatt’sgovernorbestintermsofinformation.Thepositionoftheballsactasaread-

  outforinformationaboutthespeedoftheengine.Ifthatspeedexceedsthedesiredlevel,thenaswitchis activated – the steam valve – which reduces the speed. This creates an information-processing device whichthemachinecanusetoregulateitself,withoutneedinganyinputfromahumanoperator.Watthad built a simple mechanical device that behaves in a purposeful way. Its purpose was to keep the steam engineoperatingatconstantspeed,anditachievedthatpurposebrilliantly.

  Systemsthatworkinaconceptuallysimilarway,althoughoftenthroughverymuchmorecomplexand adjustable mechanisms, are used widely in living cells. Such mechanisms provide an efficient way of achieving homeostasis, which is the active process of maintaining conditions that are conducive to survival. It’s through homeostasis that your body works to maintain a consistent temperature, fluid volumeandbloodsugar,forexample.

  Information processing permeates all aspects of life. To illustrate this, let’s look at two examples of complexcellularcomponentsandprocessesthatarebestunderstoodthroughthelensofinformation.

  ThefirstisDNAandthewayitsmolecularstructureexplainsheredity.ThecriticalfactaboutDNAis that each gene is a linear sequence of information written in the four-letter language of DNA. Linear sequencesareafamiliarandhighlyeffectivestrategyforstoringandconveyinginformation;it’stheone usedbythewordsandsentencesthatyouarereadinghere,andalsotheoneusedbytheprogrammers whowrotethecodeforthecomputeronyourdeskandthephoneinyourpocket.

  These different codes all store information digitally. Digital here means that information is stored in differentcombinatio
nsofasmallnumberofdigits.TheEnglishlanguageuses26basicdigits,theletters ofthealphabet;computersandsmartphonesusepatternsof‘1’sand‘0’s;andDNA’sdigitsarethefour nucleotidebases.Onegreatadvantageofdigitalcodesisthattheyarereadilytranslatedfromonecoding system into another. This is what cells do when they translate the DNA code into RNA and then into protein. In doing so, they transform genetic information into physical action, in a seamless and flexible way that no human-engineered system can yet match. And whilst computer systems must ‘write’

  informationontoadifferentphysicalmediuminordertostoreit,theDNAmolecule‘is’theinformation, whichmakesitacompactwaytostoredata.Technologistshaverecognizedthisandaredevelopingways toencodeinformationinDNAmoleculestoarchiveitinthemoststableandspace-efficientwaypossible.

  DNA’sothercriticalfunction,itsabilitytocopyitselfveryprecisely,isalsoadirectconsequenceofits molecularstructure.Consideredintermsofinformation,themolecularattractionsbetweenthepairsof bases(AtoT,andGtoC)provideawaytomakeverypreciseandreliablecopiesoftheinformationheld by the DNA molecule. This intrinsic replicability ultimately explains why information held in DNA is so stable. Some gene sequences have persisted through unbroken series of cell divisions over immense durationsoftime.Largepartsofthegeneticcodeneededtobuildthevariouscellularcomponents,such as the ribosomes, for example, are recognizably the same in all organisms, be they bacteria, archaea, fungi,plantsoranimals.Thatmeansthecoreinformationinthosegeneshasbeenpreservedforprobably threebillionyears.

  Thisexplainswhythedoublehelixstructureissoimportant.Byrevealingit,CrickandWatsoncreated a bridge linking together the geneticists’ ‘top down’ conceptual understanding of how the information neededforlifeispasseddownthroughthegenerations,withthe‘bottomup’mechanisticunderstanding ofhowthecellisbuiltandoperatedatthemolecularscale.Itemphasizeswhythechemistryoflifeonly makessensewhenitisconsideredintermsofinformation.

  The second example where information is key to understanding life is gene regulation, the set of chemicalreactionscellsusetoturngenes‘on’and‘off’.Whatthisprovidesisawayforcellstouseonly thespecificportionsofthetotalsetofgeneticinformationthattheyactuallyneedatanygivenmomentin time. The critical importance of being able to do this is illustrated by the development of a formless embryo into a fully formed human being. The cells in your kidney, skin and brain all contain the same totalsetof22,000genes,butgeneregulationmeansthegenesneededtomakeakidneywereturned‘on’

  in embryonic kidney cells, and those that function specifically to create skin or brain were turned ‘off’, and viceversa.Ultimately,thecellsineachofyourorgansaredifferentbecausetheyuseverydifferent combinationsofgenes.Infact,onlyabout4,000,orafifth,ofyourtotalsetofgenesarethoughttobe turnedonandusedbyallthedifferenttypesofcellsinyourbodytosupportthebasicoperationsneeded fortheirsurvival.Therestareonlyusedsporadically,eitherbecausetheyperformspecificfunctionsonly requiredbysometypesofcell,orbecausetheyareonlyneededatspecifictimes.

  Gene regulation also means that exactly the same set of genes can be used to create dramatically different creatures at different stages of their lives. Every elaborate and complex brimstone butterfly startsoutasaratherlessimpressivegreencaterpillar;thedramaticmetamorphosisfromoneformtothe otherisachievedbydrawingondifferentportionsofthesametotalsetofinformationstoredinthesame genome and using it in different ways. But gene regulation is not only important when organisms are growinganddeveloping,itisalsooneofthemainwaysallcellsadjusttheirworkingsandstructuresto surviveandadaptwhentheirenvironmentschange.Forexample,ifabacteriumencountersanewsource of sugar, it will quickly turn on the genes it needs to digest that sugar. In other words, the bacterium contains a self-regulating system that automatically selects the precise genetic information it needs to improveitschancesofsurvivingandreproducing.

  Biochemistshaveidentifiedmanyofthebasicmechanismsusedtoachievethesevariousfeatsofgene regulation. There are proteins that function as so-called ‘repressors’ that turn genes off, or ‘activators’

  thatturngeneson.TheydothisbyseekingoutandbindingtospecificDNAsequencesinthevicinityof the gene being regulated, which then makes it either more or less likely that a messenger RNA is producedandsenttoaribosometomakeaprotein.

  Itisimportanttoknowhowallthisworksatthechemicallevel,butaswellasasking howgenesare regulated,wewillalsowanttounderstand whichgenesareregulated,whetherthey’rebeingturnedonor off,and why.Answeringthesequestionscanleadtonewlevelsofunderstanding.Theycanstarttotellus abouthowtheinformationheldinthegenomeofaratheruniformhumaneggcellisusedtoinstructthe formationofallthehundredsofdifferenttypesofcellpresentinanentirebaby;howanewheartdrug canturngenesonandofftocorrectthebehaviourofcardiacmusclecells;howwemightre-engineerthe genes of bacteria to make a new antibiotic; and much more besides. When we start to look at gene regulation in this way it is clear that concepts based on information processing are essential to understandinghowlifeworks.

  This powerful way of thinking emerged from studies made by Jacques Monod and his colleague FrançoisJacob;workthatearnedthemaNobelPrizein1965.Theyknewthatthe E. coli bacteria they studiedcouldliveononeortheotheroftwosugars.Eachsugarneededenzymesmadebydifferentgenes tobreakitdown.Thequestionwas,howdidthebacteriadecidehowtoswitchbetweenthetwosugars?

  Thesetwoscientistsdevisedabrilliantseriesofgeneticexperimentsthatrevealedthelogicunderlying thisparticularexampleofgeneregulation.Theyshowedthatwhenbacteriaarefeedingononesugar,a generepressorproteinswitchesoffthekeygeneneededforfeedingonthealternativesugar.Butwhen the alternative sugar is available, the bacteria rapidly switch back on the repressed gene for digesting thatsugar.Thekeytothatswitchisthealternativesugaritself:itbindstotherepressorprotein,stopping it from working properly, and thereby allowing the repressed gene to be turned back on. This is an economical and precise way of achieving purposeful behaviour. Evolution has devised a way for the bacteriumtosensethepresenceofanalternativeenergysource,andtousethatinformationtoadjustits internalchemistryappropriately.

  Most impressively, Jacob and Monod managed to work all of this out at a time when nobody could directly purify the specific genes and proteins involved in this process. They solved the problem by lookingattheirbacteriathroughtheprismofinformation,whichmeanttheydidnotneedtoknowabout allthespecific‘nutsandbolts’ofthechemicalsandcomponentsunderpinningthecellularprocessthey werestudying.Instead,theyusedanapproachbasedongenetics,mutatinggenesinvolvedintheprocess andtreatinggenesasabstractinformationalcomponentsthatcontrolledgeneexpression.

  Jacobwroteabookcalled TheLogicofLifeandMonodwroteonecalled ChanceandNecessity.Both coveredsimilarissuestothoseIamdiscussinginthisbookandbothgreatlyinfluencedme.Ineverknew Monod, but met Jacob a number of times. The last time I saw him, he invited me to lunch in Paris. He wanted to talk about his life and discuss ideas: how to define life, the philosophical implications of evolutionandthecontrastingcontributionsmadebyFrenchandAnglo-Saxonscientiststothehistoryof biology.Constantlyfidgetingduetooldwarwounds,hewasthearchetypalFrenchintel
lectual,incredibly well-read,philosophical,literaryandpolitical–agreatandmemorablemeetingforme.

  JacobandMonodwereworkingatatimewhenunderstandingwasemergingofhowinformationflowed from gene sequence to protein to cellular function, and how that flow was managed. This information-centredapproachalsoguidedmythinking.WhenIstartedmyresearchcareerIwantedtoknowhowthe cellinterpreteditsownstateandorganizeditsinternalchemistrytocontrolthecellcycle.Ididnotwant justtodescribewhathappensduringthecellcycle,Iwantedtounderstandwhat controlledthecellcycle.

  ThatmeantIoftencamebacktothinkingaboutthecellcycleintermsofinformationandconsideringthe cellnotonlyasachemicalmachinebutalsoasalogicalandcomputationalmachine,asJacobandMonod consideredit–onethatowesitsexistenceandfuturetoitsabilitytoprocessandmanageinformation.

  In recent decades biologists have developed powerful tools and invested a lot of effort in identifying and counting the diverse components of living cells. For example, my lab put a lot of work into sequencing the whole genome of the fission yeast. We did this with Bart Barrell, who had worked with FredSanger,thepersonwhoinventedthefirstpracticalandreliablewaytosequenceDNAbackinthe 1970s.ImetFredseveraltimesduringthisproject,althoughhehadofficiallyretiredbythen.Hewasa ratherquiet,gentleman,wholikedgrowingroses,and,similartomanyofthemostsuccessfulscientistsI havemetovertheyears,alwaysgenerouswithhistime,talkingtoandencouragingyoungerscientists.

  When he came to Bart’s lab, he looked like a gardener who had lost his way, a gardener who had, of course,wontwoNobelPrizes!

  Together,BartandIorganizedacollaborativeeffortofaboutadozenlabsfromaroundEuropetoread alloftheapproximately14millionDNAlettersinthefissionyeastgenome.Ittookabout100peopleand aroundthreeyearstocomplete,andwas,ifIremembercorrectly,thethirdeukaryotetobecompletely andaccuratelysequenced.Thatwasaround2000.Nowthesamegenomecouldbesequencedbyacouple ofpeopleinaboutaday!SuchhavebeentheadvancesinDNAsequencingoverthelasttwodecades.