落尘小说

Chapter 7 Cellular therapy（第1页）

Chapter7Cellulartherapy

Mostdiseaseshavecellulariybetraplebiochemicalimbalabecorrectedbydrugs。Thecellsreturntoanear-normalstateafeelsbetter。Someplexdiseasesstartwithgepreventaparticularproteinbeingexpressedetheproteinstrusuchawaythatitsfunisalteredoriive。Evenwiththedbalaernalrepairorcellsuiegenegesesd，whehefualcellprocesses，theyhaveadevastatiohorfuncreasedgrowthcausedbygeotheslipperyslopeofcerwherethese‘outoftrol’cellsfurthergetheirgeiddeveloptheabilityforlimitlessdivisionand，insomecases，gaiytoiissues。Ireatingsuchdiseasesrequiresthattheerrantcellsareremoved，corrected，oreveerreplayotherdiseasesarelylifethreateningbutotbecorrectedbydrugtreatmeheirplexbioature。Theidealsolutiothediseaseatitsrthefaultycells。Thisprocessiscalledcellulartherapyandbedividediforms。Themostfamiliaristhetransplantationofmaturefunalcells，asinabloodtransfusion，andstemcellsasiransplaillawaitastandardtherapyfortheintroduodifiedhumanorareplacearequiredsubstance，susulin-produgcellsfordiabetics。

MaheSwissphysidalchemistPhilippusAureolusParacelsusasthefirstpersoheceptofcelltherapyinhisbrossenWuSurgeryBook’）publishedin1536ie:‘thehearthealstheheart，luheluhespleen;likecureslike’。Thisremarkhistheorythateatihyanimalanswouldrebuildaalizetheparticularageingorfaultyaritionistdoethanoneofamoderherapist。Aslongagoas1667，Jean-BaptisteDenis，wintheroyallaboratoryofLouisXIV，attemptedtotransfusebloodfromaentallyillpatiere-bloodtransfusiono1912hysistriedtotreatsufferingfromuivethyroidlahyroid1931，aSwissPaulhe‘fatherofcelltherapy’byatwheroduethyroidtissueintoarapidlydeteripatienteriencedseveredamagetlandsdurihepatientredlivedforafurther30years。Niehansbeownedforhiscellulartreatments，andhispatientsincludedmembersofvariousRoyalfamilies，PopePiusXII，politidfamousfilmstars。Hisnameaments，especiallyskiyprocesses，liveonatthePaulNiehansidedinSwitzerlandbyhisdaughter。The20thturyislitteredwithstoriesofso-calledcellulartherapies。JohnBrinkley，knowglanddoctor’，reportedlydid16，000operationsiedmenwithtissuefromthetesticlesofyounggoats，assertingthatthisprocedurewaseffectiveagainstimpotendcouldditifromasanity。Hislicewasrevokedonthegroundsofimmoralityandunprofessionalduct。JamesWilsoheuseofboviissuecells。Heclaimedthatsuchcellularpreparatioh‘havetheabilitytomigratetoanytissueinneedofrepairahesite，takeoeristicsofthehealthycellitassociateswith’。Otherattemptsalongsimilarlinesdredsofdeathsbyvioleionstobacterialorviraliionsingtwomenwhodiedofgasgangrenefollowiioalsheepcells。Other，eveionableembryoransplanttherapieswerepioneeredbyNiehansinSwitzerland。Inthe1970s，hisstudentWolframKuhupaMexico，wheretherewereions，usingembryonicbluesharkcellspurchasedofflocalfishermenandwithadubiousnumberoflivecells，to‘treat’patientsforawiderangeofdiseases。Asaresultofthis‘quadthebadpressitreceived，itisherewasahighdegreeofscepticismaboutcell-basedtherapiesasroachedthe21sttury。

Transplantationofbloodcells

Bloodtransfusionusinganimalbloodstartedihturybutwasunsuccessfulbecauseofbloodgroupinpatibilityaions。SuchwasthedeathtollthattransfusionwasbahroughoutEuropeforover150years。Arouurhtury，KarlLandsteinerdisanbloodgroups（A，B，AB，O），forwhichhereceivedtheNobelPrizein1930。Mixingbloodfromindividualswithinpatiblegroupsleadstobloodglutination。Landsteinerdiscoveredthatthisprocesswasduetoanimmunologicalreabetweendissimilarbloodgroups。Theclassifiofbloodgroupsisbasedonthepresenceorabsenheritedantigens，ingproteins，carbohydrates，andlipids，onthesurfaceoftheredbloodcells。Ifinpatiblebloodisiibodiesi’sbloodplasmaattaewredbloodddestroythemiioncalledhaeminrenalfailureandcirculatoryshock。Bloodtransfusionisnowaroutineprodmostblooddonatioioheirpoheseincluderedbloodcells，platelets，whitebloodcells，plasma，andvariousproteinssutibodiesandgfactors（seeChapter5）。Seleposallowforspeeios，auseofaunitofblood。Forexample，plateletshelprestoretheblood’sgabilitywheopeoplewithtoofewplatelets（thromboia），aleadingtosevereandspontaneousbleedingandwhiesasideeffeotherapy。Whilethetransfusionofwhitecellsisrarefiions，ithasbeeherapywhenthecellshavebeeiipulatedtoeliti-tumourcellactivity。

Inthe1970s，EdwardDonnallThomasdemobonemarrowfusedintravenouslyrepopulatethebonemarrorodualbloodcells，workforwhichhereceivedtheNobelPrizein1990。Theactivetheserepopulatiiobloodstemcells。Cytsrequiredforcertreatmeroyalldividingdtlydonotdisatebetweentumourdbloodstemcells。Replagthepatient’sstemcellsfollowiherapyreplehebonemarrowcellpopulationaheresumptionofnormalbloodcellproduarrolantationhasbeenusedinawiderangeofcertherapiesingleukaemiaandlymphomatorepairbecausedbychemotherapy。Boransplantshavealsobeensuctreatingiaandotherdiseaseswherestemcellsaredamagedorabsent。

Autologousbloodstemcelltherapyusesthepatient’sownstemcells，whichareremovedaotreatmeagesofautologoustransplaheyarerelativelyfreeofiionandthereuionismorerapidaologoustransplaalossibleandsoothersourcellsareneeded。Allogeneisplantsihydoissuesmustbeaclosetissuematchtothoseofthepatiehedoive）isgeothepatiehematchofspecificcell-surfas，calledthehistopatibilityplex。EvenasingleDNAbasepairdiffereinginagedaminoaeofthefivehistopatibilityproteiinamismatgboraresareabletosequeheDNAofallfivehistopatibilitygeopatibility。Owilymatchedstemcellsbutueddonorsneedasmanymatismatcreasestheriskofgraftrejeraftversushostdisease。Graftrejeothebodyrejeelantedcellswhilegraftversushostdiseaseothenewcellsrejectthebody。Botheffectsresultinanimmunologicalreathatbefatal。

&reatments，bonemarrowwastakenfreboypicallythepelvis，throughareachesthetreoftheboeiqueisreferredtoasabonemarrowharvestandisperformedundergehesiawithalltherequirementsofhospitalizingthedonor。Nowadaysstembesourgblood。Thismethodedfromahatgstemcreaseddramaticallyfollowiionsofablrowthfarowthfadtheirstemcellsarecollectedbyameicalseparator，afterwhichtheredcellsarereturhedonor。

Itisalsopossibletoisolateusefulamountsofbloodstemniotidtheumbilicalcord。Cordbloodhasahightrationofstemcells，butonlyenoughforbloodstemsplantsinyoung。Usingbinationsofgrowthfactors，itispossibletoamplifytheemtheumbilicalcordallowingpossibleuseinadulttransplants。Umbilicalstemerallyproducelowlevelsofgraftversushostdisease。Steofone’sownumbilicellsforpossiblefutureuseinadultlifehasdevelopedintoanexpandiissuestepanies。

aherapy

Intheearly1960s，mouseembryoniaeshavingstemcellcharacteristicswerederivedfromateratoa。Thiscertissueismadeupofgermcellsthatarederivedfromtheovarydiredirectlyduetobirthdefectsresultingfrembryodevelopmehesecellswashinderedbyproblemsofgeioability。TheisolationofESesfromnormalembryos（seeChapter6）overcamethesedefedbegananewareaofresearch，explthepossibilitiesofisolatingandmanipulatinghumanembryoniccellsforpossibleuseasstemcelltreatmentsinadults。

MouseEScellshavebeeehegeiehesegeiiceareextremelyuseful，astheyactasamodeltostudythefunsofindividualgenesiohumans。Transgenicmicearecreatedbytransferringagene（forexampleahumaedgeoculturedEScells。Alternatively，individualgenesockedout’byintrodugafeenadrugresistaeuhesegenemanipulatiooriouslyi，ahetreatedeedtobegrownindselectedfeheselectedcellsarethenmijetotheinnercellmassofanormalembryobeforeimplantatioerusofafostermothermouse。Thehaveacopyoftheintroduepreseheirpairedes（i。e。theyareheterozygous）aherbredtogainhomozygousstrainsinwhiewgene（orkgene）hasaates，sotheeffectarentiheahegeneisexpressedinaparticulartissueorcelltypewilldependonitsgenomiehatusuallybedirectedattheEScelllevelbycarefulmolecularsele。Therearenowthousandseraihaspeealterationandtheyhavegreatlyenhanderstandingofmanyplexbiologicalprocesses。Wheheoverexpressionehemajorcauseofadisease，transgeniimalsactasamodelfordevelopingnewdrugsorpharmaceutiterventiohesegeiipulationsintrodugesthatresultiuses，esbe‘resdgrownincultureforusefulresearch。

ThereareanumberofpossiblesouranEScells:（i）cadaverfoetaltissue，（ii）embryafterireatments，（iii）embryosmadesolelyforresearchpurposesusingIVF，and（iv）embryosmadeusiraoeggs（theteiqueusedtocreateDollythesheep）。AllhumanEScellsourcesraiseethidreligiousquestions。trybytry，pulationusuallyrefiectsthepredomihidreligiousviews，withmanytriespletelyprohibitingallworkonembrystrictregulations，whilesomehavefew，ifaiosofhumaemcellresearchbelievethatahumanlifebeginsassoonasaneggisfertilized。Thedestrubryoisdeemedmorallyasmurder。TheyalsuethatESologiesareafirststeptoreproduing，whidamentallyviolatesahesanctityoflife。Propuethatiuralreproduaeilizedbutfailtoimplaerus。Afertilizedegg，whileitmaybeinghumabesideredahumailithasbeensuccessfullyimplantedinawomahemethodsrequiredforIVFroutiemorehumahanarehecourseofafertilitytreatment，leavingexcessembryosthatareoftensimplydisditismorallypermissibletousesuchembryosforpotentiallylife-savingbiomedicalresearch。ESesfromearly1990sexperimentshavebeeeduseinicaltreatments。

Oneexampleofusireathumaniheapprovalin2009forthefirstphaseoficaltrialsfortransplantationofhumahebrainandspinalcodeorcells），derivedinculturefromhumaopatientswithinjuredspinalcords。ThefirstpatieedinOctober2010byHaeamattheUyofia，IrvineandspohebiotepanyGerosinratshadpreviouslyshownthattherehadbeehereentinanimalswithspinaljuriesafteraseveransplantationofhumahadbeeooligodendroeageihisnewongoingstudytotreatparaplegicswilllastforatleastfiveyears。Whileitisthistreatmentwillpletelycuretheinjury，itishopedthatitwillshowsuffitrepairoftheobeworthwhile。ThisisapistudypromisingabrightfuturefortheuseofEScellsfspinalinjuries。

&hical，religious，andpolitistraintsofisolatingembryoniantherapyhasdriventheresearchdream，ayofindugorde-differentiatingadultbryo-likepluripotecouldbeusediherapy。In2006，ShinyaYamanakaproduducedpluripotentousefibroblastcellsbyftheexpressioneroviruses（aDNAvirusfamilythatissequehehostDoiheexpressioifiedasimportantformaintaiheadultfibroblastcells。Earlyattemptsdidallysuccessfulastheexpressionofsenesceraftertransplantationintothemouseembryo。Thisproblemwasoverein2008byusienes。Uroviruses，thisvirusdoesnotisowhehoste。SeveralgroupsmirroredthesemouseexperimentsinadulthumahefollDingandcolleaguesfounditossibletoatitopluripotehoutoionbutusimentwithtwosmallchemithesizedproteins。Themanipulationofanindividual’sadultcellstoproduic-likecellscapabletheiransandtissuesisprediajoricaltreatmeure。

&ialofusiorepairdiseasedanddamagedanswithouttheriskaionorothersideeffeendpointthatisdrivingmuchresearch。Stemcelltherapiesexistbut，sofar，oalmedicaltreatments。Themainareasressareiingofdmuscledamage，diabetes，liver，Parkinson’sdisease，andHuntingdon’sdisease。

Cardiovasculardisease—inghypertension，aryheartdisease，stroke，aiveheartfailure—isthemajorcauseofdeathinmanytriesaroundtheworld。Whendeprivedofoxygen，cardiacmusclecells（yocytes）dieandthistriggerstheformationofscartissue，theoverloadofbloodfloressure，agofviablecardiaccellsleadifailureah。Usi，andpigmodels，varioustypesofstemgembryonidothelial，andnaturallyheartstemcellshavebeensheedamagedhearttissues。Afewstudiesinhumans，usuallyundergery，haveshownthatstemtroduceddirectlytotheheartortrahebloodcirhavegivenimproveddiionofne>

Musculardystrophyisagroupofgeicdisordersicausesthemusclestoweakenwithtimeauallyleadstoprematuredeath。Theiscausedbytheproteindystrophinwhiaiyofmusgmouseanddogmodels，stemcellscalledmesoangioblasts（programmedtodiffereomusclecells）withacorrecteddystrophingeransplanted。Normaldystrophinlevelsahwereregainedinfouroutofsixdogs，suggestiherapymaybethewayaheadfortreatmentofthisgeicdisease。

In2008，EScellsweretodevelopingintoimmaturebetacellscapableinsulin，whichwereabletoreversediabetesihesameyear，adulthumanskincells，firstiopluripotentcells，rogrammedtoprodu。Amoreexgaspectwasthatthesecellssesulioglucose（astheydonormallyihinthepaisonlyamatteroftimebeforetransplantationofinsulin-produgcellswillreplaeedforalifetimespeinginsulininpeoplesufferingfromtype1diabetes。Similarprogresshasbeeuringliveristemmigliverregeionadistinctpossibility。

ThegraduallossofdnerveareasofthebraisinParkinson’sdisease。Earlycellulartreatmeraalbraintissue。Afewindividualsshorovementandprovidedageneralproofofprifromthetioustissuesource，theseicaltrialsdidhighlightseveralissuesingtheneedfequantitiesofpuredthatthefoetaltransplaedthemselvesbytransmissionofParkinson’sdisease。In2008，induitorstemcellswerecreatedfromskinfibroblastsofmidthenfurtherdiffereoneuronalprecursorcellswhich（follolantatioedintbrain。Thisapproachhasbeeendedinananimalmodelwhichmimison’sdiseasebykillingoffthenormaldcellswithatoxin。Transplantationofiemcellsgaveamarkedimprovemeoedanimals。ThemajeisnowtouandhowParkinson’sdiseasedevelopsaemcellmodelstodeveltreatments。

Huntington’sdiseaseisaivediseasethatischaracterizedbythedeathofhebrainthatproduitterchemical（gammaaminobutyricaicaltreatmentusingstemcellsfton’shasmirroredthatofParkinsoaltissueastemcellsgraftedibrainincreasebrainactivity，ingmions。Stemcellsmayhe‘magicbullet’forthisdiseasebutajorpartofitseffeagement。

Mesenchymalstemcells，foundinthebonemarrow，ducartilage，boendonas，mus，fat，aheyareeasytoisolatefromsmallquantitiesofbonemarrowandarereadilygrowsransplantatioocksareviableandcouldbeusedfor‘offtheshelf’therapies。Theyarealsofoualpulp，thesofttissueih。Wisdomteethareaparticularlyrichsourdthisopeingpossibilityofvisitiforastemsplant。Embryonichymalstemcellshavebeentrahejawbomieofthese‘trewintofullyfunalhardteethcapabletopaiooth-derivedstembepersuadedtehremaianIndianbiotepaheworld’sfirstdentalstemk。