n COLLEGELECTURES Thegreatideasofbiology SirPaulNurse ABSTRACT–Fourofthegreatideasofbiologyare matter.Biology’satomisthecell,whichisnotonly discussed:thecellasthebasicstructuralandfunc- thebasicstructuralunitofalllivingorganismsbutis tionalunitoflife,thegeneasthemechanismof alsothebasicfunctionalunitoflife.Thecelltheory heredity,evolutionbynaturalselection,andlifeas canbesummarisedasfollows:alllifeiscomposed chemistry.Afifthideaisexploredwherebybio- ofcells,andthecellisthesimplestunitexhibiting logicalorganisationisexplainedintermsoflogical thecharacteristicsoflife.Giventheimportanceof andinformationalprocessesandstructures. thisideaforunderstandingbiology,itisperhapssur- prisingthatithasnotcaughtthepublicimagination TheHarveian KEYWORDS:biochemistry,cell,evolution, morethanithas.Thismightbebecausetheideawas Orationisgiven fermentation,gene,history,hybridisation, annuallyatthe alongtimeindevelopment,takingnearly200years RoyalCollegeof information,organisation tobecomeproperlyformulated,andalsobecause Physiciansof thetheoryultimatelyrequiredtheeffortsofmany Londonunderan WilliamHarveywasnotonlyaneminentphysician, scientistsratherthanafewdominatingpersonalities, indentureof butalsoadistinguishedbiologist.Hewasoneofthe somaylackhumaninterest.Thehistoryofthisidea WilliamHarveyin firstexperimentalscientists,workingsomeyears isexcellentlyreviewedinHarris.1 1656.Thisarticle beforeGalileowhoisthescientistusuallycredited Thestoryofthecellbeginsin1665withRobert isbasedonthe withthisdistinction.SowithHarvey’sexampleas Hooke(1635–1703),experimentalisttothenewly 2003Oration encouragement,IhavedecidedtousethisOrationto formedRoyalSociety.Asisoftenthecaseinscience, givenon16 discussthehistoryandsignificanceoffourofthe itwastechnologythatbegatdiscovery,andforthe October2003by greatideasofbiology,finishingwithdiscussionofa discoveryofcellsitwastheinventionofthemicro- SirPaulNurse fifthideawhichhasyettobeproperlydeveloped. FRSHonFRCP,Nobel scopebasedonimprovementsinlensesduringthe Laureate;Headof Generallybiologyisratherbereftofgreatideasand seventeenthcentury.Hooketurnedhismicroscope theCellCycle grandtheories.Biologistsprefertodealinparticulars onathinsliceofcorkandobservedwalledcavities, Laboratory,Cancer anddetails;theylikecataloguesanddescriptions, illustrationsofwhichcanbefoundinhisbook, ResearchUK suchaslistsofspeciesinparticularhabitats,the Micrographia (Fig 1).Thesehetermedcellsafterthe numberofhairsonabeetleleg,ordeterminingthe Latincella,meaningsmallroomorcubicle.Withina ClinMedJRCPL sequencesofgenes.Buttherearesomegreatideas, fewyears,NehemiahGrew(1641–1711)andMarcello 2003;3:560–8 andthefourIhavechosenarecoretobiologyandare Malpighi(1628–1694)hadcomprehensivelydes- alsoofrelevancetomedicine,soIhopetheywillbe cribedandbeautifullyillustratedplantcells,andtheir ofinteresttomembersoftheCollege. observationshadledtotheviewthatplantsarecom- posedofaggregatesofcells(Fig2).Towardstheend Thecell ofthatcenturyMalpighi,AntonvanLeeuwenhoek andJanSwammerdamhadalsodescribedcellsin Scientistsarealwaysinterestedinidentifyingfunda- animals,observingcorpusclesinblood.Butthediffi- mentalunitsofstructure,thearchetypalexample cultiesinfixingandmicroscopicallyobservingsolid beingthediscoveryoftheatomasthebasicunitof animaltissuesmeantthatitwasoveracenturybefore itwasfullyrecognisedthatanimalswerealsoaggre- gatesofcells.Animalcellsalsopresentedamore KeyPoints fibrousappearanceandlackedthewell-defined geometryofplantcellswhichmeantthatinterpreta- Thecellisthebasicstructuralandfunctionalunitoflife tionofthemicroscopicimageswasmoredifficult. Leeuwenhoek(1632–1723)wasalsothefirsttodes- Thegeneisthebasisofheredity cribesingle-celledorganismsor‘animalcules’which Evolutionbynaturalselectionisacharacteristicoflife hefoundgrowingintheextractsofplants.Leeuwen- hoekisanappealingcharacter,notagentleman Lifeisbasedonchemistry scientistlikemostFellowsoftheRoyalSocietyatthat time,butaDelftspectacle-makerwithinsatiable Biologicalorganisationisbasedonlogicalandinformationalprocesses andstructures curiosity.Ashewasthefriendandtrusteeofthe painterJohannesVermeer,Iliketoimaginethatthe 560 ClinicalMedicine Vol3 No6November/December2003 Thegreatideasofbiology VermeerportraitsofapparentlythesamemaninThe geographer pioneerpathologist,RudolfVirchow(1821–1902),wroteinhis andThe astronomer,bothtobefoundintheLouvre,mightbe 1858book,Cellularpathologie,‘thateveryanimalappearsasa baseduponthespectacle-makerscientist. sumofvitalunits,eachofwhichbearsinitselfthecomplete Duringtheeighteenthcenturyandintothebeginningofthe characteristicsoflife’.Thisdiscoverywasamajorlandmarkin nineteenthcentury,fixationandmicroscopictechniques thehistoryofbiology. improved,allowingtheidentificationofmorecellsinanimaltis- SchleidenandSchwanndidnotunderstandhowcellswere sues.Therewasalsoanincreasinginterestinfundamentalunits formed.Theythoughtcellsarosebyaprocessrelatedtoprecip- ofstructure,particularlyofmatter.Theideathatmattercon- itationofcrystallisationwhichoccurredinpartofapre-existing sistedofindivisibleunitsoratomshaditsoriginsinAncient cell.Infact,alreadyinthepreviouscenturyAbrahamTrembley Greece,butexperimentalsupportfortheideaemergedfrom haddescribedtheprotozoanSynhedrareproducing,andhis researchworkersinchemistryonlytowardstheendoftheeigh- illustrationsclearlydemonstratethebinaryfissionofcells. teenthcentury.Giventhisincreasinginterestinfundamental Others,likeBarthelemyDumortierworkingwithplantscells unitsofmatter,itwasnaturalforbiologiststobeginthinking andRobertRemakwithanimalcells,clearlyrecognisedthatcells aboutthefundamentalunitsoflife.Animportantspeculation arosebybinaryfissionofpre-existingcells.Thisviewwas wasmadebyLorenzOkenin1805whoarguedthatplantsand furtherchampionedbyVirchowwhopopularisedthephrase animalsareassemblagesoftheanimalculesor‘infusoria’suchas ‘Omniscellulaecellula’,thatis,allcellscomefromcells. protozoathatgrewinanimalandplantextracts,2 andthisspec- Oncecelldivisionwasunderstood,itcouldbeseentobethe ulationsetthestageforthecelltheorytobeformulated. basisofthegrowthanddevelopmentofalllivingorganisms. Afterthislonggestationthecelltheorywasbornduringthe RudolfKollikerinthe1860sobservedthatcleavageofearly firsthalfofthenineteenthcentury.Itwaspopularisedbytwo embryoswastheconsequenceofcelldivision.4 Itbecameclear Germans,thebotanistMatthiasSchleidenandthezoologist thatembryogenesiswasbasedonrepeatedroundsofcelldivision TheodoreSchwann,whoin1839wrote‘wehaveseenthatall followedbythedifferentiationofcellsintomorespecialised organismsarecomposedofessentiallylikeparts,namelyofcells’. tissuesandorgans(Fig3).Bythe1880sitwasacceptedthatall Overthenexttwodecadesthisideawasfurtherdeveloped,with livingorganisms,regardlessoftheircomplexity,emergedfroma cellsbeingrecognisednotonlyasthebasicstructuralunit singlecell(Fig4).Weshouldallrespectcellsalittlemorewhen butalsoasthebasicfunctionalunitofalllivingorganisms.3 The werecognisethateveryoneofuswasonceasinglecell! Figl. RobertHooke’smicroscopeandanillustrationofcork Fig2.NehemiahGrew’ssectionofavinestemillustrating cellsfromhisbook,Micrographia.ReproducedfromRef 1. plantcells. ReproducedfromRef1. ClinicalMedicine Vol3 No6November/December2003 561 SirPaulNurse Thegene otheroftheoriginatingparents.Anotherimportantprecursor ofMendelwasCarlFriedrichvonGaertner(1786–1833)who Auniversalcharacteristicofalllivingorganismsistheirability workedwithbothpeasandmaizeduringthefirstpartofthe toreproduce,generatingoffspringwhichresembletheirparents. nineteenthcentury.Hereportedthedominanceofcertainchar- Thesimilaritiesbetweenparentsandoffspringwererecognised actersintheF1hybridsandtheirsubsequentreappearanceor inclassicaltimesandthisledtospeculationsfromthetimeof segregationintheF2hybrids.Bothoftheseobservationswere theGreeksonwardsaboutissueslikehowmuchwascontributed importantforMendel’ssubsequentwork. fromeachsexualpartnerduringreproduction,didthedifferent TheseobservationssetthestageforMendel’sfamouspea sexualpartnersdeterminedifferentpartsoftheoffspring,and hybridisationexperimentswhichhestartedinBrnoin1856. howmuchdidcharacteristicsliketheheatofthewomborthe Probablybecauseofhistrainingasaphysicalscientistandhis qualityofthetestesinfluencetheoutcome.Ittookthediscovery meteorologicalstudies,heemployedaquantitativeapproach, andcharacterisationofgenestoprovidethefoundationfor countingthedifferentphenotypesproducedintheF1andF2 understandingheredity,andthisisthesecondgreatideaof hybrids.Thisrevealedthefamoussimpleratioswhichled biologythatIwanttodiscuss. Mendeltoproposeanelegantparticulatetheoryforheredity, Asiswellknown,itwasGregorMendel(1822–1884),Abbot withphenotypicattributesdeterminedbytheactionofpairsof ofBrnoMonasterynowintheCzechRepublic,whofirstpostu- factorspassedonasunchangingdiscreteentitiesorparticles, latedtheexistenceofgenes.Itwashiscarefulcrosseswithplants onefromeachparenttothehybridoffspring.Hisexperiments andincisiveanalysisoftheoutcomescarriedoutinthe wereverycarefulandtheresultsimpressive;infact,toomuchso Monasterygardenduringthe1860sthatledhimtobecomethe forthestatisticalgeneticistRonaldFisherwhothoughtthey fatherofgenetics.Itisperhapslesswellknownthatother weretoogoodtobetrue.OfcourseMendel’sgardenerwas researchershadalsoexperimentedwithplanthybridisation blamed,toleavethegreatman’sreputationintact!Mendel’s beforehim,andhadmadeimportantdiscoveriesrelevantto analysisandsubsequentabstractreasoningwerebrilliantand 5 Mendel’ssubsequenttheories. Inparticular,theGermanJoseph awesome.However,hisworkremainedunrecognisedforover30 Kolreuter(1733–1806),workinginthemid-eighteenthcentury, years,untilthebeginningofthetwentiethcenturywhenitwas