Paul Nurse - What Is Life

by Understand Biology In Five Steps (pdf)

  Cell division also explains the apparently miraculous ways the body heals itself. If you were to cut yourselfwiththeedgeofthispage,itwouldbelocalizedcelldivisionaroundthecutthatwouldrepairthe wound, helping to maintain a healthy body. Cancers, however, are the unfortunate counterpoint to the body’sabilitytoinstigatenewroundsofcelldivision.Canceriscausedbytheuncontrolledgrowthand divisionofcellsthatcanspreadtheirmalignancy,damagingorevenkillingthebody.

  Growth,repair,degenerationandmalignancyarealllinkedtochangesinthepropertiesofourcells,in sickness and in health, in youth and in old age. In fact, most diseases can be traced back to the malfunctionofcells,andunderstandingwhatgoeswrongincellsunderpinshowwedevelopnewwaysto treatdisease.

  Celltheorycontinuestoinfluencethetrajectoryofresearchinthelifesciencesandinmedicalpractice.

  It drastically shaped the course of my life too. Ever since my thirteen-year-old self squinted down a microscopeandsawthecellsofthatonionroottip,Ihavebeencuriousaboutcellsandhowtheywork.

  When I started as a biology researcher, I decided to study cells, in particular how cells reproduce themselvesandcontroltheirdivision.

  ThecellsIstartedtoworkwithinthe1970swereyeastcells,whichmostpeoplethinkareonlygood formakingwine,beerorbread,notfortacklingfundamentalbiologicalproblems.Buttheyare,infact,a greatmodelforunderstandinghowcellsofmorecomplexorganismswork.Yeastisafungus,butitscells aresurprisinglysimilartoplantandanimalcells.Theyarealsosmall,relativelysimple,andgrowquickly andinexpensivelywhenfedonsimplenutrients.Inthelabwegrowthemeitherfloatingfreelyinaliquid brothorontopofalayerofjellyinaplasticPetridish,wheretheyformcream-colouredcoloniesafew millimetresacross,eachcontainingmanymillionsofcells.Despite,ormoreaccurately,becauseoftheir simplicity,yeastcellshavehelpedustounderstandhowcellsdivideinmostlivingorganisms,including humancells.Quitealotofwhatweknowabouttheuncontrolledcelldivisionsofcancercellscamefirst fromstudyingthehumbleyeasts.

  Cellsarethebasicunitoflife.Theyareindividuallivingentities,surroundedbymembranesmadefrom fat-like lipids. But, just as atoms contain electrons and protons, cells contain smaller components too.

  Microscopes today are very powerful and biologists use them to reveal the intricate and often very beautiful structures within cells. The largest of these structures are called organelles, which are each wrappedintheirownlayerofmembrane.Ofthese,the nucleusisacommandcentreofthecell,sinceit contains the genetic instructions written into the chromosomes, while mitochondria – and there can be hundreds of these in some cells – act as miniature power plants, supplying the cell with the energy it needs to grow and survive. A variety of other containers and compartments within cells perform sophisticatedlogisticsfunctions,building,breakingdownorrecyclingcellularparts,aswellasshuttling materialsinandoutofthecellandtransportingthemaroundthecell’sinterior.

  Not all living organisms are based on cells that contain these membrane-bounded organelles and complex internal structures, however. The presence or absence of a nucleus divides life into two major branches.Thoseorganismswhosecellscontainanucleus–suchasanimals,plantsandfungi–arecalled

  eukaryotes. Those without a nucleus are called prokaryotes, which are either bacteria or archaea.

  Archaeaappeartobesimilartobacteriaintermsoftheirsizeandstructurebutareactuallytheirdistant relatives.Insomerespectstheirmolecularworkingsaremoresimilartoeukaryoteslikeus,thantheyare tobacteria.

  Acriticallyimportantpartofacell,beitaprokaryoteoraeukaryote,isitsoutermembrane.Although justtwomoleculesthick,thisoutermembraneformsaflexible‘wall’orbarrierthatseparateseachcell from its environment, defining what is ‘in’ and what is ‘out’. Both philosophically and practically, this barrier is crucial. Ultimately, it explains why life forms can successfully resist the overall drive of the universetowardsdisorderandchaos.Withintheirinsulatingmembranes,cellscanestablishandcultivate the order they need to operate, whilst at the same time creating disorder in their local surroundings outsidethecell.ThatwaylifedoesnotcontravenetheSecondLawofThermodynamics.

  All cells can detect and respond to changes in their inner state and in the state of the world around them. So although separated from the environment they live in, they are in close communication with theirsurroundings.Theyarealsoconstantlyactiveandworkingtomaintaintheinternalconditionsthat allow them to survive and to flourish. They share this with more visible living organisms, such as the butterflyIwatchedasachild,orforthatmatterwithourselves.

  In fact, cells share many characteristics with all kinds of animals, plants and fungi. They grow, they reproduce, they maintain themselves, and in doing all of this they display a sense of purpose: an imperative to persist, to stay alive and to reproduce, come what may. All cells, from the bacteria Leeuwenhoek found between his teeth to the neurons that allow you to read these words, share these propertieswithalllivingbeings.Understandinghowcellsworkbringsusclosertounderstandinghowlife works.

  Coretotheexistenceofthecellarethegenes,whichwewillturntonext.Theseencodeinstructions thateachcellusestobuildandorganizeitself,andtheymustbepassedtoeverynewgenerationwhen cellsandorganismsreproduce.

  2.THEGENE

  TheTestofTime

  Ihavetwodaughtersandfourgrandchildren.Allofthemarewonderfullyunique.Forexample,oneofmy daughters, Sarah, is a TV producer and the other, Emily, a professor of physics. But there are also characteristics that they share between themselves, their children, with me, and my wife Anne. Family resemblancescanbestrongorsubtle–height,eyecolour,thecurveofthemouthornose,evenparticular mannerismsorfacialexpressions.Therearemanyvariationstoo,butthecontinuitybetweengenerations isundeniablythere.

  The existence of similarities between parents and offspring is a defining characteristic of all living organisms.ItwassomethingthatAristotleandotherclassicalthinkersrecognizedlongago,butthebasis of biological inheritance remained a stubborn mystery. Various explanations were given over the years, someofwhichsoundabitpeculiartoday.Aristotle,forexample,suspectedthatmothersonlyinfluenced thedevelopmentoftheirunbornchildreninthesamewaythatthequalitiesofaparticularsoilinfluenced thegrowthofaplantfromaseed.Othersthoughtthattheexplanationwas‘blendingoftheblood’;thatis theideathatchildreninheritanaveragemixtureoftheirtwoparents’characteristics.

  Ittookthediscoveryofthegenetopavethewaytoamorerealisticunderstandingofhowinheritance works. As well as providing a way to help make sense of the complicated mixture of resemblances and unique characteristics that run through families, genes are the key source of information life uses to build,maintainandreproducecellsand,byextension,organismsmadefromcells.

  Gregor Mendel, Abbot of Brno Monastery, now in the Czech Republic, was the first person to make somesenseofthemysteriesofinheritance.Buthedidn’tdothisbystudyingtheoftenbafflingpatternsof inheritanceinhumanfamilies.Instead,hecarriedoutcarefulexperimentswithpeaplants,hatchingthe ideasthatledeventuallytothediscoveryofthethingswenowcallgenes.

  Mendel wasn’t the first person to use scientific experiments to ask questions about inheritance, nor even the first to use plants
to look for answers. These earlier plant breeders had described how some characteristicsofplantswerepassedthroughthegenerationsincounterintuitiveways.Theoffspringofa crossbetweentwodifferentparentalplantswouldsometimeslooklikeablendbetweenthetwoofthem.

  For example, crossing a purple-flowered plant and a white-flowered plant might give rise to a pink-floweredplant.Butothercharacteristicsalwaysseemedtodominateinaparticulargeneration.Inthese situations, the offspring of a purple-flowered plant and a white-flowered plant would all have purple flowers, for example. The early pioneers had gathered lots of intriguing clues, but none of them had managed to reach a satisfying understanding of how genetic inheritance operates in plants, let alone explainhowitworksinessentiallyalllivingthings,includingushumans.That,however,isexactlywhat Mendelstartedtorevealwithhisworkonpeas.

  In1981,inthemiddleoftheColdWar,IwentonmyownpilgrimagetotheAugustinianmonasteryin Brno to see where Mendel worked. This was long before it had become the tourist attraction that it is today. The garden, then rather overgrown, was surprisingly big. I could easily imagine the rows upon rowsofpeasthatMendeloncegrewthere.HehadstudiedphysicalsciencesattheUniversityofVienna but failed to qualify as a teacher. However, something from his training in physics stuck with him. He clearly understood that he would need a lot of data: big samples are more likely to uncover important patterns.Someofhisexperimentsinvolved10,000differentpeaplants.Noneoftheplantbreedersbefore himhadtakensucharigorous,extensivequantitativeapproach.

  To reduce the complexity of his experiments, Mendel focused only on characteristics that displayed clear-cutdifferences.Overseveralyears,hecarefullyrecordedtheoutcomesofthecrosseshesetup,and detectedpatternsthatothershadmissed.Mostimportantly,heobserveddistinctivearithmeticratiosof pea plants that either exhibited or lacked specific characteristics, such as particular flower colours or seedshapes.OneofthecrucialthingsMendeldidwastodescribetheseratiosintermsofamathematical series. This led him to propose that the male pollen and female ovules within the pea flowers, contain things he called ‘elements’ that are associated with the different characteristics of the parental plants.

  When these elements come together through fertilization they influence the characteristics of the next generationofplants.However,Mendeldidnotknowwhattheelementswereorhowtheymightwork.

  Byintriguingcoincidence,anotherfamousbiologist,CharlesDarwin,wasstudyingplantcrosseswith flowerscalledsnapdragonsataroundthesametimeasMendel.Heobservedsimilarratios,butdidnot tryandinterpretwhattheymightmean.Inanycase,Mendel’sworkwasalmostentirelyignoredbyhis contemporariesanditwasanotherwholegenerationbeforeanyonetookhimseriously.

  Then,around1900,otherbiologistsworkingindependentlyrepeatedMendel’sresults,developedthem further,andstartedmakingmoreexplicitpredictionsabout howinheritancemightwork.Thisworkledto the theory of Mendelism, named in the pioneering monk’s honour, and the birth of genetics. Now the worldbegantotakenotice.

  Mendelism proposes that inherited characteristics are determined by the presence of physical particles, which exist as a pair. These ‘particles’ are what Mendel called ‘elements’ and we now call genes.Mendelismdidnothavemuchtosayaboutwhattheseparticleswere,butitdescribedinavery

  precisewayhowtheyareinherited.Andmostcrucially,itgraduallybecameclearthattheseconclusions not only applied to peas, but to all sexually reproducing species, from a yeast to humans and all organisms in between. Every one of your genes exists as a pair; you inherited one from each of your biologicalparents.Theyweretransmittedthroughthespermandeggthatfusedtogetheratthemoment ofyourconception.

  SciencehadnotstoodstillduringthefinalthirdofthenineteenthcenturywhenMendel’sdiscoveries hadlainfallow.Inparticular,researchershadfinallymanagedtogetaclearerviewofcellsengagedinthe process of cell division. When these observations were eventually linked to the inherited particles proposedbyMendelism,thegene’scentralroleinlifecameintoasharperfocus.

  An early clue was the discovery of microscopic structures within cells that looked like tiny threads.

  Thesewerefirstspottedinthe1870sbyaGermanmilitaryphysicianturnedcellbiologistcalledWalther Flemming.Usingthebestmicroscopesofhisday,hedescribedhowthesemicroscopicthreadsbehavedin anintriguingway.Asacellgotreadytodivide,Flemmingsawthesethreadssplittinginhalflengthwise, beforebecomingshorterandthicker.Then,whenthecelldividedintotwo,thethreadswere separated, withonehalfendingupineachofthenewlyformeddaughtercells.

  WhatFlemmingwaslookingat,butdidnotfullyunderstandatthetime,wasthephysicalmanifestation ofthegenes,theinheritableparticlesproposedbyMendelism.WhatFlemmingcalled‘threads’,wenow call chromosomes.Chromosomesarethephysicalstructurespresentinallcellsthatcontainthegenes.

  Aroundthesametime,anothercrucialclueaboutgenesandchromosomesemergedfromanunlikely source: the fertilized eggs of parasitic roundworms. When the Belgian biologist Edouard van Beneden examined carefully the very earliest stages of roundworm development, he saw through his microscope thatthefirstcellofeachnewlyfertilizedembryocontainedfourchromosomes.Itreceivedpreciselytwo fromtheeggandtwofromthesperm.

  ThisfittedexactlywiththepredictionsofMendelism–twosetsofpairedgenes,broughttogetherat themomentoffertilization.VanBeneden’sresultshavesincebeenconfirmedmanytimesover.Thereare halfthechromosomesineggsandsperm,andthefullnumberofchromosomesareformedwhenthetwo fusetomakeafertilizedegg.Wenowknowthatwhatistrueforsexualreproductioninroundwormsis trueforalleukaryoticlife,includingushumans.

  Thenumberofchromosomesvarieswidely:peaplantshave14ineachcell,wehave46,andthecellsof theAtlasbluebutterflyhavemorethan400.FortunatelyforvanBeneden,theroundwormhasjustfour.If therehadbeenmorechromosomes,hecouldnothaveeasilycountedthem.Bypayingcloseattentionto the relatively simple case of the roundworm, van Beneden glimpsed a universal truth about genetic inheritance.Startingwithaclearlyinterpretableexperimentwithasimplebiologicalsystemcanleadtoa widerinsightrelevantmoregenerallytohowlifeworks.ForpreciselythisreasonIhavespentmostofmy careerinvestigatingthesimpleandeasilystudiedyeastcells,ratherthanmorecomplexhumancells.

  Putting the discoveries made by Flemming and van Beneden together, it became clear that chromosomes convey genes both between the generations of dividing cells, and also between the generationsofwholeorganisms.Apartfromafewspecializedexceptions–likeredbloodcellswhich,as theymature,losetheirentirenucleusandthereforealltheirgenes–everycellinyourbodycontainsa copy of your entire complement of genes. Together, those genes play a big role in directing the developmentofafullyformedbodyfromalonefertilizedeggcell.Andacrosstheentirelifespanofeach living organism, the genes provide each cell with essential information it needs to build and maintain itself. It follows, therefore, that every time a cell divides, the entire set of genes must be copied and shared equally between the two newly formed cells. This means that cell division is the fundamental exampleofreproductioninbiology.

  Thenextgreatchallengeforbiologistswastounderstandwhatgenesactuallyareandhowtheywork.

  Thefirstbiginsightcamein1944,whenasmallgroupofscientistsinNewYork,ledbythemicrobiologist Oswald
Avery,carriedoutanexperimentthatidentifiedthesubstancethatgenesaremadefrom.Avery and his colleagues were studying bacteria that cause pneumonia. They knew that harmless strains of thesebacteriacouldbetransformedintodangerous,virulentformswhentheyweremixedwithremnants ofdeadcellsfromavirulentstrain.Critically,thischangewasinheritable;oncetheybecamevirulent,the bacteria passed that characteristic on to all their descendants. This led Avery to reason that a gene or geneshadbeenpassed,asachemicalentity,fromtheremainsofthedead,harmfulbacteriatothelive, harmlessbacteria,changingtheirnatureforever.Herealizedthatifhecouldfindthepartofthedead bacteriaresponsibleforthis genetictransformation,hecouldfinallyshowtheworldwhatgenesaremade of.

  It turned out that it was, in fact, a substance called deoxyribonucleic acid – which you will probably recognizefromitsmorefamousacronymDNA–thathadthekeytransformativeproperty.Bythen,itwas widely known that the gene-carrying chromosomes within cells contained DNA, but most biologists thought that DNA was too simple and boring a molecule to be responsible for such a complex phenomenonasheredity.Theywerewrong.

  Eachofyourchromosomeshasatitscoreasingle,unbrokenmoleculeofDNA.Thesecanbeextremely longandeachcancontainhundredsoreventhousandsofgenesarrangedinachain,oneafteranother.

  Human chromosome number 2, for example, contains a string of over 1,300 different genes, and if you stretched that piece of DNA out, it would measure more than 8 cm in length. This leads to the extraordinarystatisticthat,together,the46chromosomesineachofyourtinycellswouldadduptomore thantwometresofDNA.Throughsomemiracleofpacking,itallfitsintoacellthatmeasuresnomore thanafewthousandthsofamillimetreacross.Whatismore,ifyoucouldsomehowjointogetherandthen