Whenwelookatlifeintermsofinformation,itisimportanttoappreciatethatbiologicalsystemshave evolvedgraduallyovermanymillionsofyears.Aswehaveseen,life’sinnovationsariseasaconsequence of random genetic mutations and variations. These are then sifted by natural selection, with those that work well being assimilated into the surviving, more successful, living organisms. This means that existing systems are changed progressively, by the gradual accretion of ‘add-ons’. This is in some ways analogoustoyourphoneorcomputer,whichfrequentlyrequirethedownloadingandinstallationofnew software updates. The devices gain new functions, but the software that drives them also becomes steadilymorecomplicated.Similarlyforlife,allofthesegenetic‘updates’meanthatthewholesystemof the cell will gradually tend to become more complex with time. This can lead to redundancy: some componentswillhaveoverlappingfunctions;otherswillbetherelicsofsupersededparts;andsomewill bewhollyunnecessaryfornormalfunctioningbutmightbeabletocompensateiftheprimarycomponent breaks.
This all means that living systems are often less efficient and rationally constructed than control circuits designed intelligently by human beings, another reason why analogies between biology and computingcanonlygosofar.AsSydneyBrennerobserved,‘Mathematicsistheartoftheperfect.Physics istheartoftheoptimal.Biology,becauseofevolution,istheartofthesatisfactory.’Thelifeformsthat survivenaturalselectionpersistbecausethey work, not necessarily because they do things in the most efficient or straightforward way possible. All this complexity and redundancy makes the analysis of biological signalling networks and information flow challenging. Very often Occam’s razor – looking for the simplest adequate explanation to explain a phenomenon – simply does not apply. This can disturb some physicists who turn their attentions to biology. Physicists tend to be attracted to elegant, simple solutions,andcanbelesscomfortablewiththemessyandless-than-perfectrealityoflivingsystems.
My lab has frequently wrestled with the redundancies and intricacies brought about by natural selection,becausetheycanobscurethecoreprinciplesofhowbiologicalprocesseswork.Totacklethis wegeneticallyengineeredyeastcellstogenerateamuchsimplifiedcellcyclecontrolcircuit.Itwaslike strippingacarofallthecomponentsthatarenotessentialforitscriticalfunctions,suchasthebodywork, thelightsandtheseats,leavingonlytheessentials–theengine,transmissionandwheels.Thisworked betterthanIhadhoped.Oursimplifiedcellscouldstillcarryoutthemajoraspectsofcellcyclecontrol.
Strippingacomplexmechanismdowntoitsbasicelementsmadeiteasierforustoanalyseinformation flow,andthereforegainnewinsightsintothecellcyclecontrolsystem.
Amongtheselectgroupofindispensablecellcycleregulatorshighlightedbythisexperimentwasthe cdc2gene.Asayeastcellmovesthroughthecellcycle,thecellitselfgrowssteadilyandtheamountof theCdc2-andcyclin-containingCDKproteincomplexincreasestoo.Intermsofinformation,thecelluses theamountofactiveCDKcomplexpresentasbothaninputthatreflectsinformationaboutthesizeofthe cell,andasthecrucialsignalthattriggersthemajoreventsofthecellcycle.Proteinsrequiredearlyin the cell cycle are phosphorylated by the CDK complex early, leading to the copying of DNA during S-phase,andthoserequiredlaterarephosphorylatedlater,leadingtomitosisandcelldivisionattheendof thecellcycle.The‘early’proteinsaremoresensitivetotheCDKenzymeactivitythanthe‘late’ones,so theywillbephosphorylatedwhenthereislessCDKactivityinthecell.
ThissimplemodelofcellcyclecontrolidentifiedCDKactivityasthecrucialco-ordinatinghubatthe centre of cell cycle control. The explanation had just been obscured from our view by the superficial complexities of the network, the redundant functions of different components, the presence of less important control mechanisms, and perhaps also by the tendency of the human mind to embrace complexity,ratherthanseekoutsimplicity.
For much of this chapter I have focused on cells because they are the basic units of life, but the implicationsofthinkingaboutlifeasinformationextendbeyondthecell.Thereisrealpotentialtogain powerful new insights into all parts of biology by looking for ways to understand how molecular interactions, enzyme activities and physical mechanisms produce, transmit, receive, store and process information.Asthisbecomesamoreprevalentapproach,itispossiblethatbiologywillshiftawayfrom therathercommon-senseandfamiliarworldthatithasgenerallyoccupiedinthepast,toonethatismore abstract. In this, it might parallel the great shifts that took place in physics, from Isaac Newton’s essentially common-sense world to Albert Einstein’s universe, ruled by relativity, and on further to the quantum‘weirdness’revealedbyWernerHeisenberg,aswellasErwinSchrödinger,inthefirsthalfofthe twentieth century. It might be that the complexity of biology will lead to strange and non-intuitive explanations, and to work these out biologists will need ever more assistance from scientists in other disciplines, such as mathematicians, computer scientists and physicists – even philosophers, who are moreusedtothinkingabstractlyandarelessfocusedonoureverydayexperiencesoftheworld.
A view of life that is centred on information will also help us understand higher levels of biological organization.Itcanshedlightonhowcellsinteractwitheachothertogeneratetissues,howtissuesmake organs,andhoworgansworktogethertoproduceafullyoperationallivingorganism,suchasahuman being.Thesameistrueatevenbiggerscales,whenwelookathowlivingorganismsinteractwitheach other,bothwithinspeciesandbetweenspecies,andhowecosystemsandthebiosphereoperate.Thefact that information management occurs at all scales, from the molecular to the planetary biosphere, has important implications for how biologists try to make sense of life’s processes. Often, it is best to seek explanationsclosetothelevelofthephenomenonbeingstudied.Tobesatisfactory,thoseexplanationsdo notalwaysneedtobereduceddowntothemolecular-scalerealmofgenesandproteins.
However,itmaywellbethattherearecommonalitiesbetweenthewayinformationismanagedatone scalethatcanilluminatehowthingsworkinasystemthatiseitherlargerorsmaller.Forexample,the logicunderpinningfeedbackmodulesthatcontrolmetabolicenzymes,regulategenesormaintainbodily homeostasis, will have similarities with the feedback modules that allow ecologists to make better predictions about how natural environments are likely to change when specific species go extinct or migrateoutoftheirtraditionalrangesasaresultofclimatechangeorhabitatdestruction.
Givenmyinterestinbeetlesandbutterfliesandinsectsingeneral,Iamincreasinglyworriedaboutthe falling numbers and diversity of insects that are being observed in many parts of the world. What is particularly disturbing is that we do not know why this is happening. Is it habitat destruction, climate change,agriculturalmonocultures,lightpollution,overuseofinsecticides,orsomethingelse?Thereare manyexplanationsproposedandsomepeoplefeelverycertainoftheirparticulartheories,butthetruth iswedonotreallyknow.Ifwearetodosomethingtohelpreversedeclininginsectpopulations,weneed tounderstandtheinteractionsbetweenthemandtherestoftheirworlds.Thiswillbegreatlyinformedby scientists who work in different ways, collaborating and thinking about these issues in terms of information.
Whicheverlevelofbiologicalorganizationwelookat,attemptstodeepenourcomprehensionwillhinge onourabilitytounderstandhowinformationismanagedwithinthem.Itisawaytomovefrom describing complexityto understandingcom
plexity.Oncewecandothis,wecanstarttoseehowflittingbutterflies, sugar-consuming bacteria, developing embryos and all other life forms make the crucial leap of transforminginformationintomeaningfulknowledgethattheycanusetofulfiltheirpurposeofsurviving, growing,reproducingandevolving.
From our advancing understanding of the chemical and informational foundations of life springs the growing ability not only to comprehend life, but also to intervene in the workings of living things. So before I use the insights we have gained from climbing our five steps to define what life is, I want to considerhowwecanuseknowledgeofbiologytochangetheworld.
CHANGINGTHEWORLD
In2012,IwasduetotraveltotheAntarcticresearchstationatScottBase.Ihadalwayswantedtovisit the vast frozen desert of the South Polar regions – literally the end of the Earth – and finally I had my chance.BeforethetripIhadtohavearoutinemedicalcheck-up,buttheresultsturnedouttobefarfrom routine.ForthefirsttimeinmylifeIhadtodirectlyconfrontmyownmortality.
Ihadseriousheartdisease.WithinacoupleofweeksofthisunwelcomerevelationIwasanaesthetized and laid out in an operating theatre. The surgeon opened my chest and identified the defective blood vessels that were failing to supply the muscles of my heart with enough blood. He then harvested four shortlengthsofanarteryfrommychestandaveinfrommyleg,andplumbedthemintomyheartinsuch awaythatbloodcouldbypasstheproblemareas.Afewhourslater,Iwokeup,batteredandbruised,but witharepairedheart.
Thatoperationsavedmylife.Aswellasthegreatskillandcompassionofthemedicalstaffwhotreated me, the success of the operation rested entirely on our understanding of what life is. Every step was guidedbyknowledgeofthehumanbodyandthetissues,cellsandchemistrywithin.Theanaesthetistwas confident that the drugs they delivered would make my brain lose consciousness in a reversible way. A solution was infused into my heart, which completely stopped it beating for some hours. It contained potassiumataconcentrationthedoctorsknewwasjusthighenoughtoalterthechemistryofmyheart muscle cells to make them relax. A machine stood in for my heart and lungs, oxygenating my blood properlyanddeliveringitatthecorrectrate.Duringandaftertheoperation,Iwasgivenantibioticsto keep infectious bacteria at bay. Without all that accumulated knowledge about life, the chances are I wouldnotbewritingthesewordstoday.
Asourunderstandingoflifehasgrownwehaveacquiredgreatnewpowerstomanipulateandchange livingthings.Butwemustwieldthesepowersproperly.Livingsystemsarecomplicated,soifweinterfere withthembeforeweunderstandthemwellenough,wewillgetitwrongandcouldcausemoreproblems thanwesolve.
Throughouthistory,mosthumanliveshavebeenendednotbyoldage,butbyinfectiousdiseases.The attacks made by bacteria, viruses, fungi, worms and a host of other parasites and pestilences have claimed countless millions of lives, many of them before they leave infancy. The bubonic plague that sweptaroundtheworldinthefourteenthcenturykillednearlyhalfofallpeopleinEurope.Formuchof history,deathwasaconstantpresenceindailylife.
That is not quite so true today. Where vaccines, sanitation and antimicrobial drugs are available, we havethetoolsweneedtoprevent,treatorcontainawiderangeofonce-deadlyinfectiousdiseases.Even HIV, once billed by some as the next great plague, can now, with the right care, be treated as a stable chroniccondition.Aftermillenniainwhichhealthcarereliedchieflyuponsuperstition,vagueexplanations andahostofunprovenandsometimesriskyremedies,thistransitionisatrulymiraculouschange.Itall restsuponourknowledgeoflife,generatedbyscience,andthenappliedtotheworld.
However,thereisstillalongwaytogoinfightingtheancientscourgeofinfectiousdisease.AsIwrite these words in spring 2020, the coronavirus pandemic is spreading turmoil across the world. Like the diseasecausedbythiscoronavirus,COVID-19,manyviralinfectionscanbeimmobilizing,orevenlethal.
AndalthoughtheoutbreakofEbolathatrippedthroughWestAfricain2014–15inspiredtheimpressively rapid development of effective vaccines, such interventions are only helpful when they can get to the peoplewhoneedthemattherighttime.Inrichandpoorcountriesalike,toomanypopulationsstilllack goodaccesstoproventreatments.Itisalsoastonishingthatpoliticiansinsomedevelopednationsshould haveignoredadvicefromscientistsandexpertsandhaveweakenedmeasurestodealwithepidemicsand pandemicssuchasthese.Thisneglecthasalreadyledtograveconsequences.Puttingallthisrightshould beanurgentpriorityforhumanity.
Those of us lucky enough to live in societies that provide good medical care should cherish the protectionitaffordsus.ItisamarkofacivilizedsocietythatmedicalcaresuchastheheartsurgeryI receivedfromtheUK’sNationalHealthServiceisfreeatthepointofdelivery,regardlessofthepatient’s ability to pay. ‘Pay as you go’ healthcare systems punish the poorest, and risk-based insurance systems punish the most needy. And then there are those who wilfully criticize the safety and effectiveness of vaccines without adequate evidence. They should remember that rejecting proven, clinically approved vaccinesisaquestionofmorality.Bydoingsotheyarenotjustimperillingthesafetyofthemselvesand their families, but also that of many others around them by disrupting herd immunity and allowing infectiousdiseasestospreadmoreeasily.
The battle with infectious disease is one that we will never wholly win, however. That’s because of evolution by natural selection. Since most bacteria and viruses can reproduce very quickly, their genes can also adapt rapidly. This means new strains of disease can emerge at any moment, and they are constantlyevolvingingeniouswaystoeludeortrickourimmunesystemsandmedicines.That’swhythe rise of antimicrobial resistance is such a threat. It is natural selection in action and it is taking place before our eyes, with alarming consequences. Exposing bacteria to antibiotics without actually killing them off entirely, makes it more likely that they will evolve resistance to the drugs. That’s why it is
importanttotaketherightdoseofantibiotics–andonlywhentrulyneeded–andtofinishthecourseof treatment you are prescribed. Not doing so may not only put your health at risk, but also that of other people. Just as dangerous, or even more so, are the farming systems that drip-feed low doses of these drugstoanimalstomakethemgrowfaster.
We are now seeing the emergence of strains of bacteria that can resist every intervention we can make;thediseasestheycausearebecominguntreatable.Resistantbacterialikethiscouldcastmedicine backintime,puttingmillionsoflivesatrisk.Imagineaworldwhereyouoryourfamilycouldbestruck downbyanincurableinfectionbecauseofascratchfromarosethorn,anipfromadogorevenavisitto ahospital.Butwemustnotbefatalisticaboutthisthreat.Identifyingaproblemisthecrucialfirststep towardssolvingit.Wecanandmustusetheantimicrobialdrugswedohavemorecarefully;wecanalso design better ways to detect and track drug-resistant infections; and we need to develop potent new antimicrobialdrugsandmakesuretheresearcherswhodothisarewellsupported.Wemustuseallour knowledgeaboutlifetosolvethisproblem–ourfuturemaydependonit.
As healthcare has improved and the threat posed by infectious diseases has been gradually pushed back, average life expectancy has crept steadily upwards. But as people live longer, they have had to confrontahostofunpleasantnon-infectiousconditionsofillhealth,includingheartdisease,diabetes,a
range of mental health conditions and cancer. Their fundamental causes are old age and unhealthy lifestyles. Globally, they are all on the rise, and they create big challenges for both sufferers and the scientistswhowanttounderstandandtreatthem.
Considercancer–itisactuallynotonedisease,butmany.Everycancerisdifferent,andeachincidence changeswithtime,sothatanadvancedcancerisoftenabitlikeanecosysteminitsownright,containing manydifferenttypesofcancercell,eachcontainingdifferentgeneticmutations.Onceagain,thisisthe work of evolution by natural selection. Cancers begin when cells acquire new genetic changes and mutationsthatcausethemtostartdividingandgrowinginuncontrolledways.Theyflourishbecausethey haveaselectiveadvantage:theycanmonopolizethebody’sresources,growmorethanthenon-mutated cellsaroundthem,andignorethebody’s‘stop’signals.
Someofthemostpromisingnewapproachestocancertherapyhavebeeninformedbyourimproved understandingoflife.Cancerimmunotherapies,forexample,seektoeducatethebody’simmunesystem to recognize and attack cancer cells. This is a smart approach because the immune system can launch extremelypreciseassaultsoncancercells,whileignoringhealthycellsnearby.Newtreatmentsarealso emergingfromworkthatmycolleaguesandIstartedonthecellcycleofthelowlyyeasts.Drugsthatbind to and inactivate human versions of the CDK cell cycle control proteins are now used to treat many women with breast cancer. Four decades ago, I had no idea that work on the cells of yeast would eventuallyleadsodirectlytonewcancertreatments.Becausecancerisaninevitableresultofthecell’s capacity to adapt and evolve, we will never entirely eliminate it. But as our understanding of life gets betterwewillincreasinglybeabletospotcancerearlyandtreatitmoreeffectively.Iamconfidentthere willcomeatimewhencancernolongerarousesfear,asitstilldoestoday.
Paul Nurse - What Is Life Page 10
