DeadlyCompanions
HowMicrobesShapedOurHistory
DOROTHYH.CRAWFORD
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DorothyH.Crawford 2007
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5 3 Cholera:thenaturalandepidemiccyclesof Vibriocholera
6 1 Asectionofaleafshowingthepotatoblightfungus growingandproducingspores(Berkley 1846)
8.1 Populationgrowth, 8000bc–ad1974
8.2 MRSAinUKhospitals 2001–2011
8.3 EstimatednewcasesofTBin 2015
8.4 Geographicaldistributionofmalariaworldwide
8.5 Theemergenceofpandemic Xuvirusstrainsafter reassortmentinapig
1.1 R 0 valuesforhumanandanimalmicrobes
3.1 Examplesofspeciesdomesticatedindifferentareas oftheworld
8.1 Asampleofhumanpathogenswhichhave emergedsince 1977
Preface
MicrobesfirstappearedonplanetEartharound 4 billionyears agoandhavecoexistedwithuseversinceweevolvedfromour ape-likeancestors.Bycolonizingourbodiesthesetinycreatures profoundlyinfluencedourevolution,andbycausingepidemics thatkilledsignificantnumbersofourpredecessorstheyhelpedto shapeourhistory.Throughmostofthiscoexistenceourancestors hadnoideawhatcausedthese‘visitations’andwerepowerlessto stopthem.Indeedthefirstmicrobewasonlydiscoveredsome 130 yearsagoandsincethenwehavetriedmanyingeniousways tostopthemfrominvadingourbodiesandcausingdisease.But despitesomeremarkablesuccesses,microbesarestillresponsible for 14 milliondeathsayear.Infactnewmicrobesarenow emergingwithincreasingfrequency,whileoldadversarieslike tuberculosisandmalariahaveresurgedwithrenewedvigour.
Thisbookexploresthelinksbetweentheemergenceof microbesandtheculturalevolutionofthehumanrace.Itcombinesahistoricalaccountofmajorepidemicswithanup-to-date understandingoftheculpritmicrobes.Theirimpactisdiscussedin thecontextofcontemporarysocialandculturaleventsinorderto
showwhytheyemergedatparticularstagesinourhistoryand howtheycausedsuchdevastation.
WebeginwithSARS,thefirstpandemicofthetwenty-first century.Thenwetravelbackintimetotheoriginofmicrobes andseehowtheyevolvedtoinfectandspreadbetweenuswith suchapparentease.Fromtherewefollowtheinterlinkedhistory ofmanandmicrobesfromthe‘plagues’and‘pestilence’ofancient timestothemodernera,identifyingkeyfactorsinhumancultural changesfromhunter-gatherertofarmertocity-dwellerwhich madeusvulnerabletomicrobeattack.
Thefinalchaptersshowhowmoderndiscoveriesandinventionshaveimpactedontoday’sglobalburdenofinfectiousdiseases andaskhow,inanevermorecrowdedworld,wecanovercome thethreatofemergingmicrobes.Willpathogenicmicrobesbe ‘conquered’bya‘fighttothedeath’policy?Orisittimetotake amoremicrobe-centricviewoftheproblem?Ourcontinued disruptionoftheirenvironmentwillinevitablyleadtomore conflictwithmoremicrobes,butnowthatweappreciatethe extentoftheproblemsurelywecanfindawayoflivingin harmonywithourmicroscopiccohabitantsoftheplanet.
Throughoutthisbooktheterm‘microbe’isusedforany organismthatismicroscopic,beitabacterium,virus,orprotozoan(Figure 0.1).Fungiarealsoincludedsincealthoughtheir vegetativegrowthisoftenvisibletothenakedeye,thesporesthat spreadthemfromonehosttoanotheraremicroscopic.Noneof thesetinylifeformshavebrains,sodespitethefactthattheyoften appearingeniousandmanipulative,theyhavenofacilitiestothink orplan.Thehumancharacteristicsoftenattributedtothem actuallycomeaboutbytheirabilitytoadaptrapidlytochanging situations.Thenthenaturalprocessof‘survivalofthefittest’ ensuresthatthebestadaptedprosper,sothatintheendtheyreally
Figure0.1 Relativesizesoforganismsandtheircomponentparts
doseemtolieinwaitforasuitablehostandthen‘jump’,‘attack’, ‘invade’and‘target’.Althoughthesedescriptionsseemaptand arefrequentlyusedinthetextofthisbooktoillustratethelives ofmicrobes,inrealitymicrobesarenotcapableofmaliceaforethought.
Whereverpossiblethescientifictermsusedinthebookare definedinthetext,butthereisalsoaglossaryattheendwhich providesadditionalinformation.
Acknowledgements
Thisbookcouldnothavebeenwrittenwithouthelpandsupport frommanypeopletowhomIamextremelygrateful.Inparticular Ithankmyeditor,LathaMenon,forherhelpandencouragement, andthefollowingcolleaguesforprovidingexpertinformationand advice:ProfessorSebastianAmyes(antibioticresistance),DrTim Brooks(plague),DrHelenBynum(historicalevents),Professor RichardCarter(malaria),DrGarethWGriffith(potatoblight), ProfessorShiroKato(smallpoxinJapaneseculturalhistory),Dr FranciscaMutapi(schistosomiasis),DrGBalakrishNair(cholera), ProfessorTonyNash(flu),DrRichardShattock(potatoblight), ProfessorGeoffSmith(smallpox),DrJohnStewart(bacteria), DrSueWelburn(trypanosomiasis),ProfessorMarkWoolhouse (epidemiology).InadditionIamgratefultothefollowingforreading andcommentingonthemanuscript:DannyAlexander,William Alexander,MartinAllday,RoheenaAnand,JeanneBell,Cathy Boyd,RodDalitz,AnnGuthrie,IngoJohannessen,KarenMcAulay, J.AleroThomas.
IamalsoindebtedtoDrIngoJohannessenforvirologicalresearch, JohnandAnnWardfororganizingavisittoEyam,ElaineEdgar xiii
forliteratureresearch,SirAnthony Epsteinforfacilitatingresearch onthehistoryofsmallpox,andDrTasnimAzimforhostingmy visittotheInternationalCentreforDiarrhoealDiseaseResearch, Bangladesh.
Finally,IthanktheUniversityofEdinburghforgrantingmea sabbaticalyeartoresearchandwritethemanuscript.
Introduction
WhenSARSfirsthitanunsuspectingworldin 2003 thepress hadnoneedtodramatizeorembellish.Thetruestory certainlyrivalledanymodernthrillerwithamysteriouskillervirus onthelooseinSouthernChina,innocentlycarriedinahuman incubatortoitsinternationallaunchpadinHongKong.From therethevirusjettedroundtheworldinfectingover 8,000 people intwenty-sevencountries.Eighthundredpeoplediedbeforethe viruswaseventuallybroughtundercontrolfourmonthslater.
ThewholealarmingepisodebeganinNovember 2002 withanoutbreakofanuntreatable‘atypicalpneumonia’inthe cityofFoshaninGuangdongprovince,China,andbyJanuary 2003 similarcaseswereturningupinGuangdong’scapitalcity,Guangzhou.Theviruswasprobablytransportedtherebyatravelling seafoodmerchantwhowasadmittedtothecity’shospitaland sparkedamajoroutbreakthere.BythetimetheWorldHealth Organisation(WHO)gottohearaboutitjustthreemonthsafter thestartoftheepidemic,therehadbeen 302 casesandatleastfive deaths—toolatetostopitsnowballingoutofcontrol.
AtfirstthemicrobespreadonlylocallywithinChina,butin February 2003,afterasixty-five-year-olddoctorwhoworked
inahospitalinGuangzhouarrivedinHongKongtoattend awedding,itwentglobal.Thedoctorcheckedintoroom 911 on theninthflooroftheMetropoleHotelandbythetimehewas admittedtohospitaltwenty-fourhourslaterhehadinfectedatleast seventeenothersinthehotel.Thesepeoplethendepartedtotheir variousdestinations,carryingtheviruswiththemtofiveseparate countriesandspawningmajorepidemicsinVietnam,Singapore andCanada.Thechainofinfectionwidenedastheypassedthe virusoninhospitals,clinics,hotels,workplaces,homes,trains,taxis andaeroplanes;asinglevirus-carryingpassengerononeflight infectedtwenty-twoofthe 119 othertravellers.
SARS(severeacuterespiratorysyndrome)beginswithaflu-like illness,butinsteadofimprovingafteraweekorsoitprogressesto pneumonia.Sufferersfeelfeverishandincreasinglybreathless,with apersistentcough,astheviruscolonizestheairsacsofthelungs, damagingtheirdelicateliningandfillingthemwithfluid.Bythe timetheyseekmedicalhelpmanyarefightingforbreathandare immediatelyshippedtointensivecareunitsformechanicalventilation.Thecoughgeneratesasprayoftinyvirus-ladenmucus droplets,soanyoneinthevicinityisindangerofpickingupthe infection.Familymembersareathighrisk;andbeforethedanger wasappreciatedmanyhealth-careworkers,wereamongthecasualties,afterstrugglingtosavelivesbyclearingairways,artificially ventilatingandresuscitatingpatients.
AyoungHongKongresidentwhovisitedafriendattheMetropoleHotelonthedaytheSARS-infecteddoctorwasinresidence waslateradmittedtoHongKong’sPrinceofWalesHospital,where hestartedanoutbreakamongdoctors,nurses,students,patients, visitorsandrelativesthateventuallyresultedin 100 cases.Oneof thesecarriedthevirustoAmoyGardens,aprivatehousingestatein HongKong,whereitspreadlikewildfire.Over 300 peopleonthe
estatecaughttheinfectionandforty-twodied.AlthoughSARS ismainlyspreadbycoughing,thevirusisexcretedinfaecesandsince mostSARSvictimsdevelopwaterydiarrhoeathisisanother possiblerouteofinfection.Infact diarrhoeawasaprominentfeature amongtheAmoyGardensSARSvictims,andsomeexpertsthink theunprecedentedattackratetherewascausedbyapartiallyblocked sewagesystemwhich,combinedwithstrongexhaustfansin thetoilets,createdarisingplumeofcontaminatedwarmairinthe airshaftthatspreadtolivingquartersthroughoutthebuilding.1 Thus theepidemicinHongKongtookoff,infectingsome 1,755 people beforeitwasbroughtundercontrol(Figure 0.2).
MeanwhilethevirusarrivedintheUSandCanada,seededdirectly fromtheMetropoleHotelinHongKong.Andalthoughitdidnot spreadintheUS,thevirustookholdinTorontobeforedoctors realizedwhatwashappening.Sixofthefirsttencaseswerefromthe familyofanelderlycouplewhostayedattheMetropoleHotel(ninth floor)whilevisitingtheirson inHongKong.Theirfamilydoctor becametheseventhvictimandalthoughsherecovered,anelderly manwhohappenedtobeinthehospitalemergencydepartmentat thesametimeasoneofthefamilycaughtthevirusanddied.2 The microbethenmovedoutintotheGreaterTorontoarea,infecting 438 andkillingforty-threebeforeitsspreadwasfinallyhalted.
DrCarloUrbani,aWHOinfectiousdiseaseexpertworking withateamfromMedecinssansFrontie ` resattheFrenchHospital inHanoi,Vietnam,wasamongthefirsttorecognizeSARSasa newanddangerousinfectionandtonoteitshighrateamong health-careworkers,whoaccountedforthirtyofthefirstsixty casesinHanoi.Bywarningtheworldofitsdangerstheyensured instigationofthenecessaryprecautionsworldwide,butsadlyitwas toolateforDrUrbani.Hefelttheominoussymptomsdeveloping duringaflightfromHanoitoBangkokandalertedtheauthorities
Number of cases
Date of onset (2003)
Source: I.T.S.YuandJ.J.Y.Sung,‘TheEpidemiologyoftheOutbreakofSevereAcute RespiratorySyndrome(SARS)inHongKong–WhatWeKnowandWhatWeDon’t’, EpidemiologyandInfection, vol. 132 (2005)(CambridgeUniversityPress, 2005),pp 781–6
onhisarrival.Hebattledwiththevirusforeighteendaysina makeshiftisolationroominBangkokhospitalbutdiedattheendof March.3 Fiveofhiscolleaguesalsofellvictimtothedisease.
WHO’sglobalhealthalertissuedon 12 Marchcausedlongunusedtraditionalpublichealthmeasurestoswingintoaction. TheseincludedroutineisolationofSARScasesandquarantinefor anyonewhohadcontactedacasetopreventspreadinhospitals, whiletravelrestrictionswithcountryentryandexitscreening wereimposedtointerruptthemicrobe’sspreadinthecommunity.Theseprecautions,alongwithahigh-profilemediaawarenesscampaign,broughtthepandemicundercontrolbyJuly 2003. Butbeforethewholeepisodewasovertherewasafinalstingin thetail.Inlate 2003 thevirusjumpedtotwolaboratoryworkers,
Figure 0.2 SARSinHongKong
oneinSingapore,theotherinTaiwan,whiletheywerehandlingit. Fortunatelytheseinfectionswerenotfatalandtherewasno furtherspread,buttheninspring 2004 twomorelaboratory workers,thistimeinBeijing,developedSARS,precipitatingan outbreakofsixfurthercasesandonedeath.
Bytheendofthepandemictherehadbeenover 8,000 SARScasesand 800 deathsinvolvingthirty-twocountries.Worst affectedwasChinawithtwothirdsofcasesandonethirdofdeaths. Despitethedeathtollthewholeepisodemustberegardedasa victoryforthosewhoworkedsohardtocontainthemicrobe; itcouldhavebeenalotworse.Asitwas,itcostanestimated 140 billionUSdollars,mostlyfromreducedtravelto,andinvestmentin,Asia.
Incontrasttotherathermedieval-soundingquarantinemeasuresthatwereneededtocurtailthespreadoftheSARSvirus,the searchfortheculpritusedtwenty-first-centurymoleculartechnologyandwasaccomplishedwithamazingspeed.Acoronavirus (so-calledbecauseofitscrown-likestructure)wasidentifiedin SARSvictimsbytheendofMarch 2003 andconfirmedtobethe causebythemiddleofApril,justtwomonthsafterthedoctorin HongKonginitiateditsglobalspread.
ThesedaysacompletelynewhumanmicrobeliketheSARS coronavirusismostlikelytobea zoonosis—ananimalmicrobe thathasjumpedfromitsnaturalhosttohumans.Andsincemore thanathirdoftheearlySARSsufferersinGuangdongwerefoodor animalhandlers,scientistshuntingforitsoriginheadedforthe wetmarketsofGuangdong,wherewildanimalsaresoldlivefor thetable.ArmedwithmolecularprobestheyfoundaSARS-like coronaviruswhichwasvirtuallyidenticaltothepandemicvirus straininseveralspecies,butmostoftenintheHimalayanmasked palmcivetcat,amemberofthemongoosefamily,whichisfarmed
inthearea.4 Fortunatelytheseanimalsarenotverywidespread inthewild,butmanyexpertssuspectedthattheywerenotthe virus’snaturalhost.Indeed,itlaterturnedoutthatChinese horseshoebatsaretheprimaryhostforSARScoronavirus andthecivetcatactsasago-between,passingthevirusonto humans.
BloodtestsshowevidenceofpastSARSinfectionin 13 per centofGuangdongwet-markettradersandanimalhandlers,5 indicatingthatthecoronavirushasjumpedtohumanslivingin thisareabefore,andsuggestingthatitislikelytodosoagain. IndeedfournewcasesappearedinChinainJanuary 2004,and althoughtheywererelativelymildanddidnotspreadfurther, theyareareminderthatthevirusisstillouttherewaitingfor anotheropportunitytopounce.
SARSwasthefirstpandemicmicrobeofthetwenty-first century,butitwillcertainlynotbethelast.EversinceHIV emergedoverthirtyyearsagowehavewitnessedincreasingnumbersofnewmicrobes,whicharenowhittingusatanaverageof oneayear.WhiletheSARSpandemicmaybeapreviewofwhatis tocome,italsogivesusaglimpseofwhatourancestorssuffered overthousandsofyears:unpredictableepidemicscausedbylethal microbesappearingoutoftheblue,killingindiscriminatelyand spreadingfearandpanic.Wewerefortunateinknowinghow tostopSARS,but,asthisbookillustrates,ourpredecessorswere notsoluckyandtheconsequencesweresometimesdevastating. Inlaterchapterswewilllookatwell-knownepidemicmicrobes suchasbubonicplagueandsmallpox,aswellaslesser-known killerssuchasthetrypanosomeandschistosomeparasites.We willseehowandwhytheseandothermicrobesrosetoprominenceatdifferentstagesinourculturalhistoryandtheprofound effecttheyhadonthelivesofourancestors.Butfirst,backtothe
dawnoftimetotracktheoriginandevolutionofkillermicrobes, toseehowtheyspreadandinvadeourbodies,andhowour immunesystemrespondstothechallenge.
Whenoursolarsystem Wrstformedsome 4.6 billionyears agoplanetEarthwasaveryunfriendlyplace.Ratherlike
theplanetVenustoday,Earthwassohotthatcarbondioxidegas bubbledfrommoltenrockand Wlledtheatmosphere,causingsuch amassivegreenhouseeVectthattheplanetliterallyboileddry.No livingorganismcouldsurviveunderthoseconditions.Butwhen EarthhadcooledsuYcientlyforwatervapourtoliquefyjust under 4 billionyearsago,lifeappearedontheplanet.Thiswas notlifeasweknowittoday,butmoleculesthatcouldreplicateto producedaughtermoleculeswithinheritedcharacteristics.Darwinianevolutionwassetinmotionandeventuallymicroscopic single-celledorganismsevolved.
TheseearlylifeformshadtowithstandEarth’shighlyvolatile atmospherewithtoxicgasesspewingfromeruptingvolcanoes, dramaticelectricalstormsandthesun’sunscreenedultravioletrays allpromotinguncontrolledelectrochemicalandphotochemical reactions.Themicrobesaroundatthistimeprobablyresembled today’s‘extremophiles’,so-calledbecausetheythriveinallthe particularlyhostilecornersoftheglobe.Extremophilesinhabit acidlakes,hyper-salinesaltmarshesandthesuperheatedwater
issuingfromhotventsatthebottomofthedeepestoceantrenches wheretheysurvivetemperaturesupto 115 8Cand 250 atmospheresofpressure.Theylieburied 4 kilometresdeepinthe polaricecaps,andlurkinrocksupto 10 kilometresbelow ground.Indeeditispossiblethatlifebeganwithmicrobesin rocksdeepunderground,wheretheheatisintenseandthereis anamplesupplyofwaterandchemicalstogetthewholeprocess started.
Extremophilesoftencongregateincoral-likestructurescalled stromatolites,alsoknownasmicrobial‘mats’becausefromthe outsidetheylooklikedoormats; Xat,brownandhairy.Theseare hometothrivingcommunitiesofinterdependentmicrobes,each utilizinganother’swastetoproduceenergyinaself-sustaining foodchainormicro-ecosystem.Today,microbialmatscanstillbe seenincornersoftheworldsuchasYellowstonePark,Wyoming, USA,lakesfedbyancientaquifersinNorthMexico,andalong theshoresofWesternAustralia,wherethewaterisrichinchemicalsandundisturbedbyotherformsoflife.Ancientlayeredrock structuresfoundintheseplacesarethoughttorepresentthe fossilizedremainsofstromatolitesthatdominatedaquaticecosystemsintheArcheaneon(2.5 billionto 4 billionyearsago).
Foraround 3 billionyearsbacteriahadEarthalltothemselvesandtheydiversiWedtooccupyeverypossibleniche.At thisstagetherewasnooxygenintheatmospheresotheyevolved manydiVerentwaysofunlockingtheenergyboundupinrocks, utilizingchemicalcompoundsofsulphur,nitrogenandiron.
Thenaround 2.7 billionyearsagoagroupofinnovativemicrobes calledthecyanobacteria(previouslycalledblue-greenalgae)learnt thetrickofphotosynthesis,usingsunlighttoconvertcarbon dioxideandwaterintoenergy-richcarbohydrates.Asaresult, oxygen,awasteproductofthisreaction,slowlyaccumulatedin
Earth’satmosphere.At Wrstoxygenwaspoisonoustoearlylife forms,butthenotheringeniousbacteriadiscoveredthatitcould alsobeusedtogenerateenergy.Thesenewenergysourceswere richenoughtosupportmorecomplexlifeforms,buttheemergenceofmulticellularorganismshadtoawaittheevolutionof eukaryoticcells.
Bacteriaareprokaryotes,meaningthattheircellsaresmaller thanthoseofallhigherorganisms(eukaryotes)andhaveasimpler structure,lackingawell-deWnednucleus.Butaround 2 billion yearsagoagroupoffree-livingphotosyntheticcyanobacteria tookupresidenceinsideotherprimitivesingle-celledorganisms toformtheenergy-generatingchloroplastofthe Wrstplantcells. Andinasimilarlyextraordinarymanoeuvreoxygen-utilizingmicrobescalledalpha-proteobacteriabecameincorporatedinto othermicrobesasmitochondria,thepowerhouseofanimalcells.
So Wnally,amere 600 millionyearsago,thestagewassetforthe evolutionofmulticellularorganismsmadeupofeukaryoticcells, andeventuallytheemergenceoftheplantsandanimalsweknow today.Butcomparedtothediversityofbacteria,allotherlife forms,howeverdiVerenttheymayseem,arehomogeneous, lockedintothesamebiochemicalcycleforenergyproduction, andrequiringsunlightforplantphotosynthesistogeneratethe oxygenusedbyanimalsforrespiration.Westillrelyonbacteria (intheformofchloroplastsandmitochondria)forthesereactions, andonfree-livingbacteriaforallotherchemicalprocessesneeded tomaintainthestabilityoftheplanet.Thesebacteriarecyclethe elementswhichareessentialforlifeonEarthandareattheheart ofourbalancedecosystems,thosecomplexinterdependentrelationshipsthatexistbetweenplants,animalsandtheenvironment.
Althoughbacteriawerethe WrsttoinhabitEarththeyare nottheonlymicrobes.Single-celledprotozoa,includingthe
