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Chapter 4 The life of cells（第2页）

11。RNApolymeraseisalargeplexofproteins，whidstospecificsitesatthestartofgeunwindstheDNAhelixarandtogiveaentaryRNAstrand。ThesugarmoleRNAaredifferenttothosefoundinDhefourbases（A，C，G）arethesamebutTissubstitutedforU。AstheRNApolymerasemovesalosstraoformahelix

Althoughthemeisareuood，howgeedfortransislessclear。Thephenomenonof‘geneexpression’hasoccupiedthousandsofmistsformanydecades。Basiesrequiredtomaintainthegorder（housekeepinggenes）arealressedbutmanyeneswillospecifictimesduringthelifeanism。Somegenes，suchasthetwoglobimakeuphaemoglobin，arerequiredinsutsthatredcellsswitchtlobinprodu。Thealsoswitesonandoffinaveryplexpatterionornon-produofproteinsahecell’smainondingtoanystance。Wehavearound200differeypesinourbodies，allwithspecializedroles。Thesedifferentiatedcellsresultfreoroffiissues。Cellsalsohavetobeabletorespondrapidlytesbyswitesonandoff。Theseswitchesaretrolledbyagroupofaround3000differentproteiransfaegenesrequiremanyfactors，othersoransfactorsresideioplasmaheoaccesstheirgeransfactorsrequiredforrapidrespoleinandoutofthenuaintainingatstateofreadiness。

Howcellsmove

Muchofofthemeismsofhowaesfromwatgfibroblasttissueculture。Thecellmovesbyextendingabroadleadingedge，alamellipodium（seeFigure3c）whichmovesbyaeoftheundersidemembrasurface，ratherliketheiningtidemoviheuppersurfaellipodiumhasruffles，activewavesoffoldedmembrane，ardstherearofthecell。Allthisactivityisgehecellmembraionofsubunitstothefrontendsworkofafilaments。Attherearofthecell，theafilamentsbreakdowoberecycledtothefrontofthelamellipodium。Fiionstermedfilopodia（similartomicrovilli）‘feelout’gapsbetweencells，allowingfibroblaststhsolidtissue。Thismigratihtissuesisentirelynormalforbothfibroblastsandwhitebloodcellsastheygoabouttheirnormaldutiesoftenandimmuthesametimerepresentsthemajorproblemiumoursareinitiatedbyalocallossoftrolofcelldivision。Ifthemassofnewlydividedcellsstaysput，theumnandusuallybesuccessfullyremovedbysurgeryorkilledbyradiatiohebiggestproblemwithcerismetastasis，wherecellsdissotheprimarytumour，pehesurroundiimatelyaccessthebloodstream，fromwhittheyerateseoursvirtuallyahebody。Aalyhowalandtumour）mhtissuebarriersisthefirststeptofiswhichhibitmetastasis，andnewdrugswhichcouldstopthespreadofcercellawayfrinal（primary）site。Ifewyears，sresshasbeeifyiareametastasis（unsurprisiarealsoinvolvediion）andinhibitorsoftheirmeisms。suchdiversesourcesascitruspeel（modifiedcitruspedoliveoil（oleamides）haveshowicproperties。

&，aproperty?

&roeofthepioneersofarkedin1824that‘life，asfarasphysicalorderised，isnothiha;ahissimplytheofthismovement’。Nearly200yearslater，justhowbihevariouspohecytoskeletontofunasasinglemoviyisstillabitofamystery。entrequiresbiochemicalals），anenergysupply，aionofstructuralelements。Cytoskeletalelemeogrowandshrinkandtethemselvesfora，butmuchfordwhentostue-BuehlerfromeryinChicago，acellbiologiststudyingthebehaviourofculture，‘thefunsanismiroltheiiosmolecules’—whichisawayofsayingthewholeisgreaterthaheparts。Somethingthathappeheiionofmaemsisemergey。Iheclassicexamplessosects，suchasthemassivecathedral-likestructuresproducedbytermiteies，oreveionofahohemovementofacellcouldbesideredapropertyofthemoleculesofthecytoskeleton，supportedbyenergyproduitodria，andinformationstoredinDNA。Thusitseemsfeasiblethatthemilliohinatissuepreofulfllthepurposeofthetissue，andthenaddaissuesfaherlevelsasaireanism。Thisviewmaygosomewaytoagfor（iflyexplaining）theplexitiesofourowence。

Iseelyrandom?

After30yearsexaminingthebehaviourofindividualculture，andreenormousamountoftimelapsefootage，thestudiesofAlbrecht-Buehlerhaveproduefasgobservationswhichmaysuggestthatcellsbothrequireandindeedpossess‘iheirsurroundingstoactastheydo。Theideathataoingisreiheirbehaviourwheherdthe，moveoffiions。Thisshowsa‘choithereatoaedeveio-Buehler’spublishedobservationsofthebehaviourofaculturedishappeartoiedmovemeappreofothercellsatadistanceofseveralcelldiameters。Albrecht-Buehlertermsthis‘telligendpointsoutthatthisbehaviourrequiresininginformation，whichhesuggestsmayinvht。Hesuggeststhatsigheroveradistanceofseveralcelldiametersbytheemissioiht。Intheabsenygreatbodyofworkinthisareaofresearch，itishardtoassessthetruesighesestudies，buttheyareextremelyintriguing。Inhisownwords，Albrecht-Buehlersuggeststhat‘cellbehaviouristrolledbyveryplexdataiioare，sofar，unknowntobiology’。

Ifwhatovemeivesimplicityofaplasticdishisplex，thensoisentwithinthehumanbody。Bloodcellsarepumpedarouiontoprovideoxygenationoftissuesbyreddtomaintainimmunesurveillahavarietyofwhitebloodcellscalledleucocytes。Toreachsitesofinjuryoriioesmustleavethecirculatoryflow。Thisisachievedbyattagthemselvestothewallofsmallbloodvessels，firstrollingtoastopusingadhesivemoleculescalledles，abitlikegrapplingiroabiliziatusingstroeiegrins。Atthispoiesmigratebetweehelialcellsthatlihebloodvessels（ratherlikeelbowingawaythroughacrowd），readytotinvadingbadmaybeitsuicidebyburstiheiraents（thiswillbedesmoredetailinChapter6）。Oeriahavesuccumbed，theirculfedbymacrophagesthathavealsomigratedtothesite。Thespeedayofthisresponseisimpressive，albeitthatthereare‘patrolliantlygthroughthewholebloodsystem。Thereisalsulardirectedmigratioionofanotherclassofwhitebloodcells（Tcells），whichleavethebonemarrorecursordpletetheirdevelopmehymususingsimilarhomingandadhesiohethemeigrationsinthebody，wearefarfrthewholepicture。

Howoldareourcells?

BenjaminFranklihattheoiesihandtaxesonlypartiallyappliestocells。Theoptionsfor‘theeermsaretodivideordie。Acell‘avoids’deathbydividihelesssacrificesitsowewodaughtercells。Mostdaughtercellsareidentidwillhaveidenticalfates，whichistodiffereoperformaparti，eventuallydie，ahismayinvolvealifespanofhanafewhours，asistheewhitebloodeutrophils），orupto120daysforredbloodcells。Mostcellsthroughoutourbodieswillbereplacedoverthecourseofourlifetime，withanaverageofseventotenyearsagtoJoheKarolinskaIo。Thereare，however，threetypesofcellthatwethecottothegrave:theneuronsofthecerebralcortexofthebraiheioftheeyelens;and，perhapssurprisimusclecells，whichmusthavetradbogglingthreebilliontimesinanyonewhoreaches1e。Thetheioftheleurallyverysimilartokeratinizedskihattheyarelargelyfilledwithkeratilaiddowninahighlyaalliallowingthemaximumamountoflighttotravelthroughthem。Ihiseanizationmaybreakdownaheeyelensbeeincataracts。

&h

Aswehaveseen，thelifespahinthehumanbodymayvarybetweenhoursaheactualproayeaboutiyofwaysfromavarietyofcauses。Directtraumasuchasmeicaldamage，orextremeheatorcold，produtassuchasruptureofthecellmembraaiohisproducesabalanceofdisorderoverorderthatotbereversed，sothecelldies，ratherlikethesuddenandusuallyviolehofanindividual，maybeinaroadatorwarsituatiohistypeofdeathistermednecrosis。

Adifferentariguihisonewhichisaverynecessaryproallmultis，iifiedinstudiesofdevelopmentbutsubsequentlyasa‘suicidepathway’forallcellsthathavefailedtoreproducethemselvesinasatisfaanner，endingaposedbytheuedrepliue’cells。Thisisknrammedcelldeath，or‘apoptreek，‘thefallingoftheleaves’），firstreizedinthe1970sbyAlastairCurrie，JohnKerr，andAndreathologistsinAberdeey，whoobserved（maironmicroscopy）acharacteristicseriesofgesleadih。Ittookoveradecadebeforethisprocesswasfullyacceptedasamajiismformaintaiusquooftissues。Apoptosisderanimmuneresponse（asocecrosis），astheteively‘recycled’，withthefragmesofthedeadup（phagocytosed）bytheirhealthyneighbours。Apoptosisisroutialprocessessuchastheremovalofwebbiweenfingersinhumans，thelossoftadpoletailsinamphibians，aamorphosis。Cellsthatarenolongerrequiredduribegintoshrink，andtheirsurfaeratesphericalprotuberancescalledblebs（Figure12a），averyactiveproobservedbytime-lapsemicroscopy，withthesurfaceofthecellresemblingboilingmudpoolsinvolicsites。Iheutentsbreakdowiocharacteristisemassesthatbecamethebenchmarkappearaoticcells（Figure　12c），astheDNAischoppedupintosmallpieces。

12。Apoptrammedcelldeath）。（a）Initially，thesurfaceofaesblebbed，（b）mitodrialosetheiriructure，（tentsofthenucleusaggregate，and（d）poresdevelopinthesurfaitodria

&wasrealizedthatapoptosiswasauniversalprothedemiseofcells，theseariofindhowthis‘cellsuicide’wasiwopathwaysemerged，depeoosiswastriggeredexterrinsiternally（intririnsicapoptosisresultsfromsighecellmembrane，whidto‘deathreceptors’onthecellsurfacethattheheprocessofcellsuicide。Thistypeofapoptosisusuallyoccursasamethodofcellkillinginimmunologicalreatrinsicapoptembryowhereitisprogrammedforaparticularstageor，alterriggeredasaresultofexteoDNA，suchasthatcausedbyionizingradiation。Apoptosisisalseredlipromisedahepresenceofrepairmeisms，theprqualitysstillfindiroduutatedproteins。

Themeicsofcellsuicide

Sohowdoesacellgoaboutendingitsowheactualmeismof‘cellsuicide’dependsuponmitodria，termedthe‘angelsofdeath’byNihisbook，Power，SexaodriaandtheMeanihefirstgeothemitodrialinnermembrane，whiagedbyaberraivity，leadiiohemitoembrane（Figure　12b，d）。Atthispoioesittedterapoptosis，aoe　c（aproteinalfunyprodu）whichexitsthroughthenewlyformedpores。Thisinformatioasaresultofsomesintotidriawereioperfectlyhealthycells，resultinginapoptosis。Thereleasede　dstoseveralotherproteioplasmtoformaplexcalledtheapoptosomewhiturn，activatesacascadeof‘exees’whilykillthecellbutcausefragmentationofthenudintobite-sizepiecesreadytobephagocytosedbyneighbcells。

&rihoccursaspartofadevelopmentalprogramme，itseemedlikelythattherewereactuallygenesforapoptwith　orhabditiselegans（amuchstudiedodeworm），whereitisknowly131ofthetotalof1090cellsdiebyapoptdevelopment，BobHorovitzfreintheUSAframmedcelldeathgeudiesledtothearizein2002，sharedwithJohnSulstonandSydneyBrennerfreintheUK。

&hese‘celldeath’gehosegewereroutiedinmanymammalianceringthatapoptosiswasameismtodeletecellswithdamagedDNA。Mutationsihgeosis，allowihdamagedormutatedDNAtodevelopabnormallyaumours。DavidLane，wholosthisfathertohewasoedhisresearcheffortstoexplorethegesthatonormale1979，hefoundp53，aproteinthatisinactivatedordefialmostallcercells。Ifnormalp53ispreselevelsindividingdacellhasdamagedDesitsDNAiheriggersapoptthat，ihwaytoseingalldivision，henspiriionasatumoursuppressorandthe‘guardianofthegeotiestcellsarereizedbyuem（seeer）andremovedbyphagocytosis。Thus，evenatadvaagesofcer，arestorationofthe‘p53response’willbringpowerfuldefensesintoplaytoshrinktumoursandstrowth。Uingnormalp53intocerotasimpleprodseveralmicalstrategiesaretlyuion。Thepromiseofgeheaiplediseaseshasstilltoberealized，largelybecausethepracticalitieseheirprodutotherightamountsaimewithoutuablesideeffectsarestillproviremelydiffiterestingly，aappearstohavemadethemressiments，withadrugdigbeenapprovedforheadandne2003，whereastheUSFoodandDrinkAdministrationby2010hadnotapprovedanyp53-basedtreatments。