1987诺贝尔奖.docx
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1987诺贝尔奖.docx
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1987诺贝尔奖
细胞生物学
1987年诺贝尔生理学或医学奖
“抗体多样性的遗传学原理”
获奖者:
利根川进
thegeneticprincipleforgenerationofantibodydiversity
SusumuTonegawa
TheNobelPrizeinPhysiologyorMedicine1987
"forhisdiscoveryofthegeneticprincipleforgenerationofantibodydiversity"
MassachusettsInstituteofTechnology(MIT)
Summary
Manissurroundedbyviruses,bacteriaandothermicroorganismswhichconstituteathreattolifeandhealth.Whenthesecontagiousagentsenterthebodytheyarerecognizedandattackedbytheimmunedefence.Importanttoolsintherecognitionofthislargevarietyofintrudersaretheantibodies.TheyareproducedbywhitebloodcellscalledBlymphocytes.Thepartsofthemicroorganismsagainstwhichantibodiesreactarecalledantigens.Thenumberofdifferentantigensthatthebodymayencounterisenormous.Wearedealingwithhundredsofmillionsofsubstances,allofthemwiththeirspecificstructure.Strangelyenoughourimmunedefensehaveathandantibodieswhichcanidentifyallthesemoleculesandstarttocounterattack-thatis,hundredsofmillionsofdifferentantibodieswhicharereadyinthebodyalreadyinadvancebeforetheyhaveseentheantigenagainstwhichtheycanreact!
Thisfabulouscapacitytovaryofantibodiesisknownsinceacoupleofdecades.Thegeneticbackgroundallowingthisvariationhas,however,beenanunsolvedpuzzle.Thestructureoftheantibodiesisdeterminedbygenesbutasthehumangenomeonlycontainsabout100000genesitseemedunreasonablethattheycouldallowtheproductionofmaybeabilliondifferentantibodies.
ThemanwhoexplainedthismysteryistheJapaneseScientistSusumuTonegawa.Inapioneeringstudypublishedin1976Tonegawacouldthroughaseriesofingeniousexperimentsshowhowpartsofthegenomeofthecell(DNA)isredistributedunderitsdifferentiationfromanembryoniccelltoanantibodyproducingBlymphocyte.DuringthefollowingtwoyearsTonegawacompletelydominatedthisareaofresearch.HecouldinincreasinglygreaterdetailclarifyhowthosepartsofthegenomewhichgivesrisetoantibodyaremovedaroundinordertoalloweachBlymphocytetoproduceitsownuniqueantibody.
Tonegawasdiscoverieshaveincreasedourknowledgeaboutstructureofourimmunedefense.Theyalsoopenuppossibilitiestoincreasetheimmuneresponseagainstpathogenicmicroorganismthroughvaccination-andalsotoimproveinhibitionofunwantedimmunereactions.
Theantibody,amoleculewithmanyfaces
Theantibodyisaproteinwherethebuildingstones-aminoacidsnormallyformfourchains.Twoofthesechains(polypeptides)arelongandidentical.Theothertwoareshortandarelikewiseidentical.TogetherthefourpolypeptidechainsformaY-likesymmetricmolecule(Figure1).
Figure1.Apictureofanantibodymoleculewithtwolong(T)andtwoshort(L)polypeptidechainswhicharekepttogetherbysulphurbridges(-S-S).Thevariablepartsofalongchain(V,D,andJ)andalightchain(YandJ)togetherformtheantigenbindingareaoftheantibody.
InmantherearefivedifferenttypesoflongchainswhichhavebeengivenlettersM,D,G,AandE.Thenamingofthelongchainsformsthebasesforthenamesofthefivesocalledimmunoglobulinclasses:
IgM,IgD,IgGandsoon.Theshortchainsareoftwotypes:
kappaorlambda.Eachantibodymoleculehas-regardlessofclass-eithertwokappaortwolambdachains.
TowardsthebaseoftheYthereisaconstantpartwherethesequenceofaminoacidsisthesameinallantibodiesbelongingtothesameclass.IntheouterendsofthetwoarmsoftheY,however,thereexistasignificantvariationintheaminoacidsequencewhencomparingdifferentantibodies.Inthisvariableparttherearethreeareaswherevariationisverylarge.Theseareasconstitutethewallsina"pocket"wheretheforeignsubstance,theantigen,willfitandcanbind.Youcanmaketheanalogyofanantibodymoleculewithalobsterwheretheclawsofthelobstercorrespondtotheantigenbindingpartsoftheantibody.
ThroughitsY-formtheantibodyaccordinglyisendowtwoidenticalantigenbindingareas.Theseareashaveamoreorlessgoodfittoaparticularantigen.Thebetterthefitthehardertogripoftheantigenandthemoreefficientthedefense.Aswearecontinuouslyconfrontedwithinanenormousvarietyofantigenswealsohavetohavealargenumberofmoleculestherethevariablepartsdofittodifferentantigens.
Theconstantpartoftheantibodydoesalsocontainimportantbiologicalfunctions.Afterthebindingoftheantibodytoanantigenonthesurfaceonforexampleavirus(Figure2)theantibodymoleculeischangedinsuchawaythatitsconstantpartwillactivateimportantpartsoftheimmunedefense.Amongtheseisthecomplementsystemwhichcandirectlymakeholesinbacteriaandothermicroorganismandwhichalsoattractwhitebloodcellssuchasmacrophages("bigeaters")andgranulocytestothebattleground.
Figure2.ApoliovirusparticleisattackedbyfourIgGantibodies.Throughthisattacktheinfectiouscapacityofthevirusisdestroyed.Itismainlythroughthismechanismthatpoliovaccineisfunctioning.
Therichnessofvariety,anequationwhichdidn'taddup
AntibodiesareproducedbyaspecialkindofwhitebloodcellswhicharecalledBlymphocytesandwhichinanadulthumanbeingamountstoonemillionmillioncells(1012).AsasingleBlymphocyteonlycanproduceitsownuniqueantibodythenumberofdifferentantibodiesinanindividualcantheoreticallynotexceedthatofthenumberofBlymphocytes.
TheinformationhowantibodiesshouldbeconstructedliesinthegenomeoftheBlymphocytes.Onehypothesissuggested,thatinthisgenomethereexistonegeneresponsibleforeachtypeofpolypeptidechainintheantibody.ButheretheproblemwasthattheimmunedefensecontainshundredsofthousandstimesmoredifferentantibodytypesthantherearetotalnumberofgenesintheBcells.Theequationsimplydidn'taddupandthehypothesishadtobeabandoned.ItwasreplacedbyasecondonewhichexplainedthealmostlimitlesscapacityofvariationinantibodiesasaresultofsomechangesintheDNAoftheBcellduringthedevelopmentoftheindividual.
SusumuTonegawawastheonewhofinallyansweredthequestionhowthegenematerialinBcellscouldsufficetocreatethestructuresofaseeminglyendlessnumberofdifferentantibodies.In1976hecouldinaconvincingandelegantmannershowhowdifferentimmunoglobulingeneswhichwerefarapartintheembryoniccellintheBlymphocytehadbeenmovedinclosercontact.Underdevelopmentfromthegermcells(thespermandeggcell)toanantibodyproducingBlymphocytethegenesformingtheimmunoglobulinshadaccordinglybeenredistributed.InsubsequentexperimentTonegawacouldclarifyhowdifferentpiecesofthegenomeweremovedaround,recombinedandevencouldbe"lost"tofinallygiverisetotheDNAwhichisfoundinthematureBlymphocyte.
Inthehumanthegenesforthelongchainsarepresentonchromosome14,forthekappachainsonchromosome2andforthelambdachainsonchromosome22.ThankstoTonegawa'spioneeringworkwenowknowhowmanyimmunoglobulingenesthereareinman,howtheyareputtogetherandhowtheycangiverisetothishighnumberofdifferentantibodies.
Figure3.Redistributionofimmunoglobulingenesforthelongchainduringthedevelopmentfromanembryoniccell(top)toanantibodyproducingBlymphocyte(bottom).GenesfromeachgroupV,DandJarebroughttogetherinthefinalformforfunctioninggeneforthevariablepartofthelongchainofanantibodymolecule.
Economythroughwaste
Todayweknowthatthreegroupsofgenesparticipateinthecreationofthevariablepartofthelongchain,thatisthepartwhichtogetherwiththevariablepartoftheshortchainisspecificforeachantibody.ThesegeneshavethenamesV,DandJ(Figure3).TheshortchainhasVandJgenes.InmanthenumberofdifferentYgenesforthelongchainsarearound200towhichshouldbeaddedabout20Dgenesand4Jgenes.WhenthefunctioninggeneofanantibodyistobecreatedasingleV,DandJgenearedrawnatrandomfromthethreegroupsofgenes.Theprocesscanbecomparedtoanumberslottery(Figure4).200x20x4willgiveriseto16000differentvariableparts.
Figure4.Aregistrationsignforacarwithitsuniqueregistrationnumberproducedthroughlotterycanillustratetheprocesswhichleadstothecreationofauniqueantibodymolecule.ThisregistrationnumberstandsforSusumuTonegawa,the144thNobelLaureateinPhysiologyorMedicine.
V,DandJareputtogetherinanirregularmannerwhichwillfurtherenhancetherichnessofvariation.AndastheVandDgenesoftenaredifferentwheninheritedfromourfatherandmotherthiswillmeanthatalreadyherepossibilityhasbeencreatedforsomethinglikefivemilliondifferentformsofthevariablepartofthelongchain.Ontopofthisthelightchaincontributeswithmorethan10000variants.Thefinalsumwillbemanybillionspossibilitiesofvariation.
Weareaccordinglywellpreparedforanencounterwithanypossibleantigen.Itislikelythatnormallyonlyaminorpartoftheantibodyvariancewilleverbeputintousage.TheimmunesystemisextremelyeconomicwhenusingtheDNAoftheindividual.Atthesametimealargenumberoflymphocytesareproducedandonlyafewofthesewilleverhavetoparticipateintheimmunedefenseofthebody.TheeconomyintheusageofDNAisthuscombinedwithaseemingwasteofcells.Thisis,however,necessarytomaintainthehighstateofalertnesswhichisrequiredagainstpossiblenewinfections.
ThediscoveriesofTonegawaexplainthegeneticbackgroundallowingtheenormousrichne
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