Batatu batsindiye igihembo cyitiriwe Nobel cya 2019 muri Physiology cyangwa Medicine, William G. Kaelin, Jr., Gregg L. Semenza na Sir Peter J. Ratcliffe bari bamaze kwegukana igihembo cya Lasker 2016 mu buvuzi bw'ibanze kubera akazi kabo kerekana uko ingirabuzimafatizo zumva kandi zimenyera kuri hypoxia, ntabwo rero byari bitangaje cyane. Bavumbuye kandi bamenya molekile yingenzi hypoxia-idashoboka ikintu 1 (HIF-1). Uyu munsi turashaka gusubira ku nkomoko yubushakashatsi, aribwo erythropoietin, cyangwa EPO, molekile yigitangaza.

Nibintu byingenzi mubikorwa byamaraso atukura

Utugingo ngengabuzima dutukura ni ubwoko bwinshi bw'uturemangingo tw'amaraso mu maraso, kandi ni bwo buryo nyamukuru bwo gutwara ogisijeni na dioxyde de carbone binyuze mu maraso y'intangangabo. Erythrocytes ikorwa mumagufa yamagufa: Hematopoietic stem selile yabanje kwiyongera no gutandukanya progenitori yingirabuzimafatizo zitandukanye, kandi progenitori ya erythroide irashobora kurushaho gutandukanya no gukura muri erythrocytes. Mubihe bisanzwe, umusaruro wa erythrocyte wabantu ni muke cyane, ariko mugihe uhangayitse nko kuva amaraso, hemolysis, na hypoxia, umuvuduko wumusaruro wa erythrocyte ushobora kwiyongera inshuro zigera ku munani. Muriyi nzira, erythropoietin EPO nimwe mubintu byingenzi.

EPO ni imisemburo ikomatanya cyane cyane mu mpyiko. Imiterere yimiti ni proteyine ya glycosilated cyane. Kuki mu mpyiko? Hafi ya litiro y'amaraso anyura mu mpyiko buri munota, kugirango zishobore kumenya vuba kandi neza impinduka zurwego rwa ogisijeni mumaraso. Iyo urugero rwa ogisijeni mu maraso ruri hasi, impyiko zisubiza vuba kandi zikabyara EPO nyinshi. Iyanyuma ikwirakwira mu maraso igana mu magufa, aho iteza imbere ingirabuzimafatizo za erythroid progenitor mu ngirabuzimafatizo zitukura. Utugingo ngengabuzima dutukura dukuze turekurwa mu magufa tujya mu mikorere y'amaraso kugira ngo umubiri wongere imbaraga za ogisijeni. Iyo impyiko zumva kwiyongera kwa ogisijeni mu maraso, bigabanya umusaruro wa EPO, ari nako bigabanya urugero rw'uturemangingo tw'amaraso atukura mu magufa.

Ibi bikora neza. Nyamara, abantu batuye ahantu hirengeye hamwe nabarwayi bamwe na bamwe bakunze kubura amaraso make bahura nubuzima bwikigereranyo cyo hasi cyamaraso ya ogisijeni ikomeza kuba mike, idashobora kurangiza kuzenguruka hejuru kandi igatera impyiko guhora isohora EPO, kugirango amaraso ya EPO arenze kubantu basanzwe.

Byatwaye hafi imyaka 80 kugirango tuyivumbure

Kimwe nibintu byinshi byavumbuwe, abahanga mu bya siyansi basobanukiwe na EPO ntabwo byigeze bigenda neza, hamwe nibibazo nibibazo murugendo. Byatwaye hafi imyaka 80 uhereye kubitekerezo bya EPO kugeza kugena kwanyuma kwa molekile yihariye.

Mu 1906, abahanga b'Abafaransa Carnot na Deflandre bateye urukwavu rusanzwe hamwe na serumu y'inkwavu zidafite amaraso maze basanga umubare w'amaraso atukura muri plasma y'inkwavu zisanzwe wiyongereye. Bizeraga ko ibintu bimwe na bimwe bisetsa muri plasma bishobora gutera imbaraga no kugenzura imikorere ya selile zitukura. Nibwo bwa mbere prototype ya EPO. Kubwamahirwe, ibisubizo ntabwo byigeze byigana mumyaka mirongo yakurikiyeho, cyane cyane ko kubara ingirabuzimafatizo nshya zitukura zitari ukuri.

Ubushakashatsi bwa parabiose ya Reissmann na Ruhenstroth-Bauer mu 1950 bwatanze ibimenyetso bifatika. Babaga bahuza sisitemu yo kuzenguruka yimbeba ebyiri nzima, bashyira imwe mumiterere ya hypoxic indi ihumeka umwuka usanzwe. Kubera iyo mpamvu, imbeba zombi zabyaye selile nyinshi zitukura. Ntagushidikanya ko hariho imisemburo mumaraso itera kubyara ingirabuzimafatizo zitukura, aho EPO ikura izina. Kurundi ruhande, EPO yunvikana cyane na hypoxia.

EPO ni iki? Byatwaye umuhanga wumunyamerika Goldwasser imyaka 30 kugirango amaherezo asobanure ikibazo kurwego rwibinyabuzima. Niba umukozi ashaka gukora akazi keza, agomba kubanza gukarisha ibikoresho bye. Imikorere ya EPO ni ugukangura selile nshya zitukura, arikokubara ibya nyuma ntabwo aribyo. Molekile ikora cyane mumasemburo yamaraso atukura ni hemoglobine irimo heme, irimo ion ferrous hagati yayo. Itsinda rya Goldwasser rero ryanditseho uturemangingo tw'amaraso atukura akivuka hamwe na radiyo isotopi ikora kandi ikora uburyo bworoshye bwo kumenya ibikorwa bya EPO. Ibi bituma bishoboka gutandukanya no kweza ibintu bike cyane bya EPO (nanogramu kuri mililitiro) kuburugero rwamazi yinyamaswa. Ariko kwigunga kwa EPO byari bigoye cyane. Bahinduye impyiko bajya muri plasma yintama zidafite amaraso, bajya mu nkari z’abarwayi bafite ikibazo cy’ibura ry’icyuma kubera kwandura inzoka, hanyuma, mu 1977, bahanagura miligarama 8 za poroteyine y’abantu EPO kuri litiro 2,550 z’inkari ku barwayi b’Abayapani bafite ikibazo cyo kubura amaraso make.

Mu 1985, urukurikirane rwa poroteyine hamwe na gene ya EPO yabantu yararangiye. Gene ya EPO igizwe na polypeptide hamwe n’ibisigisigi 193 bya amine, bihinduka poroteyine ikuze igizwe n’ibisigisigi bya aside amine 166 nyuma ya peptide yerekana ibimenyetso mu gihe cyo gusohora, kandi ikubiyemo ibibanza 4 byo guhindura glycosylation. Mu 1998, hasesenguwe imiterere ya NMR igisubizo cya EPO hamwe na kristu ya kristu ya EPO hamwe na reseptor yayo. Kuri ubu, abantu bafite ubushishozi bwimbitse kuri EPO.

Kugeza ubu, kuvura amaraso make byasabwaga guterwa amaraso kugirango huzuzwe ibura ry'uturemangingo dutukura. Mugihe abantu biga byinshi kuri EPO, kuyitera kugirango itume umusaruro wamaraso utukura mumitsi yabo yorohereza ikibazo. Ariko kweza EPO mumazi yumubiri, nkuko Goldwasser yabigenje, biragoye kandi umusaruro ni muke. Kugena poroteyine ya EPO hamwe na gene bikurikirana byatumye bishoboka kubyara EPO ya recombinant abantu benshi.

Byakozwe na societe yibinyabuzima yitwa Applied Molecular Genetics (Amgen). Amgen yashinzwe mu 1980 ifite abanyamuryango barindwi gusa, yizeye gukora biofarmaceuticals hamwe nubuhanga bwavutse bwa biologiya ya biologiya. Interferon, imisemburo ikura irekura, urukingo rwa hepatite B, icyorezo cya epidermal yari mu mazina ashyushye kurutonde rwabo, ariko ntanumwe wagerageje gutsinda. Kugeza mu 1985, Lin Fukun, umuhanga mu Bushinwa ukomoka muri Tayiwani, mu Bushinwa, yakoresheje gene ya EPO y'abantu, hanyuma amenya ko hakorwa EPO ikora hakoreshejwe ikoranabuhanga rya ADN.

Recombinant muntu EPO ifite urutonde rumwe na proteine ​​ya endogenous EPO, kandi ifite na glycosylation ihinduka. Mubisanzwe, recombinant yumuntu EPO nayo ifite ibikorwa bya endogenous EPO. Muri Kamena 1989, ibicuruzwa bya mbere bya Amgen, recombinant muntu erythropoietin Epogen, byemejwe na FDA yo muri Amerika kuvura amaraso make yatewe no kunanirwa kw'impyiko zidakira ndetse no kubura amaraso mu kuvura ubwandu bwa virusi itera SIDA. Epogen yagurishijwe hejuru ya miliyoni 16 z'amadolari mu mezi atatu gusa. Mu myaka 20 yakurikiyeho, Amgen yiganjemo isoko rya EPO yateranijwe. Epogen yazanye Amgen miliyari 2.5 z'amadorari yinjira muri 2010 honyine. Muri 2018, isoko ry’imigabane rya Amgen ryari miliyari 128.8 z’amadolari y’Amerika, rikaba ari iya munani mu bya farumasi nini ku isi.

Twabibutsa ko Amgen yabanje gukorana na Goldwasser kugirango batange poroteyine zabantu za EPO zisukuye kugirango zikurikirane, ariko Goldwasser na Amgen bahise bagwa kubera itandukaniro ryibitekerezo. Goldwasser na kaminuza ye ya Chicago, bakoze ubushakashatsi bwibanze, ntabwo bigeze batekereza gutanga imisemburo yavumbuye, bityo bakaba batabonye igiceri na kimwe kugirango EPO igere ku bucuruzi bukomeye.

Ni - ni gute bitera imbaraga

Iyo duhumeka, ogisijeni yinjira muri selile ya mitochondriya kugirango itware urunigi rw'ubuhumekero kandi itange urugero runini rwa ATP, isoko nyamukuru y'ingufu mu mibiri yacu. Abantu bafite amaraso make ntibafite ingirabuzimafatizo zitukura zihagije, kandi ingaruka zihuse nuko badafata ogisijeni ihagije, bigatuma bumva bananiwe, bisa nibibazo byo guhumeka mugihe kirekire. Iyo batewe inshinge za EPO zabantu, imibiri yabarwayi ba anemia itanga selile nyinshi zitukura,gutwara ogisijeni nyinshi, kandi ukabyara ingufu nyinshi za molekile ATP, ukuraho neza ibimenyetso.

Ariko, bamwe mubakora siporo nabo batangiye gutekereza kuri recombinant muntu EPO. Niba imisemburo ya recombinant artificiel yo mu bwoko bwa EPO ikoreshwa mugukangura umubiri wabakinnyi kubyara selile nyinshi zitukura, birashoboka kuzamura ubushobozi bwabakinnyi bwo kubona ogisijeni no kubyara molekile zingufu, zishobora no kunoza imikorere yabakinnyi mukwihangana ibyabaye nko gusiganwa ku magare, kwiruka intera ndende no gusiganwa ku maguru. Urupapuro rwo mu 1980 mu kinyamakuru cyitwa Applied Physiology rwerekanye ko ibitera amaraso (erythropoietin, abatwara ogisijeni ya artile ndetse no guterwa amaraso) bishobora kongera kwihangana 34%. Niba abakinnyi bakoresha EPO, barashobora kwiruka kilometero 8 kuri podiyumu mumasegonda 44 mugihe gito ugereranije na mbere. Mubyukuri, gusiganwa ku magare na marato byabaye bibi cyane kubitera EPO. Muri Tour de France 1998, umuganga wikipe ya Espagne mu ikipe ya Festina yafatiwe ku mupaka w’Ubufaransa afite amacupa 400 ya recombinant EPO! Igisubizo, byanze bikunze, nuko ikipe yose yirukanwe muri Tour ikabuzwa.

Komite mpuzamahanga y'imikino Olempike yongeyeho EPO ku rutonde rwabujijwe mu mikino ya Barcelona yo mu 1992, ariko kuvugurura ibizamini bya muntu bya EPO byari bigoye ku buryo mbere y'imikino yo mu 2000 nta buryo bwo kumenya neza niba abakinnyi babikoresha. Hariho impamvu nyinshi: 1) Ibiri muri EPO mumazi yumubiri biri hasi cyane, kandi EPO kuri ml yamaraso kubantu basanzwe ni nanogramu 130-230; 2) Aminide acide igizwe na artificiel recombinant EPO ihwanye neza neza na proteine ​​ya endogenous muntu ya EPO, gusa uburyo bwa glycosylation buratandukanye cyane; 3) Igice cya kabiri cyubuzima bwa EPO mumaraso ni amasaha 5-6 gusa, kandi mubisanzwe ntibishobora kumenyekana nyuma yiminsi 4-7 nyuma yo guterwa bwa nyuma; 4) Urwego rwa EPO kugiti cye ruratandukanye cyane, biragoye rero gushiraho igipimo cyuzuye cyuzuye.

Kuva mu 2000, WADA yakoresheje gupima inkari nkuburyo bwonyine bwo kugenzura siyanse yo kumenya neza EPO recombinant. Bitewe nuko itandukaniro rito riri hagati yuburyo bwa glycoylated ya artificiel recombinant EPO nubwa EPO yumuntu, imitungo yashizwemo ya molekile zombi ni nto cyane kandi irashobora gutandukanywa nuburyo bwa electrophoreis bwitwa isoelectric kwibanda, aribwo buryo nyamukuru kuri gutahura mu buryo butaziguye ibihangano bya recombinant EPO. Nyamara, bamwe ba recombinant EPO bagaragazwa ningirabuzimafatizo zikomoka ku bantu bagaragaje ko nta tandukaniro riri hagati ya glycosylation, bityo abahanga bamwe bavuga ko EPO idasanzwe na EPO endogenous EPO igomba gutandukanywa nibintu bitandukanye bya karubone isotope.

Mubyukuri, haracyari imbogamizi muburyo butandukanye bwo gupima EPO. Kurugero, Lance Armstrong, umunyamerika wamamaye ku magare, yemeye ko yafashe EPO n’ibindi bitera imbaraga mu gihe yatsindiye irushanwa rya Tour de France irindwi, ariko mu byukuri ntabwo yari yemejwe ko ari mwiza kuri EPO mu kizamini icyo ari cyo cyose cya doping icyo gihe. Tugomba gutegereza tukareba niba ari "ikirenge kimwe hejuru" cyangwa "ikirenge kimwe hejuru".

Nigute ikora igihembo cyitiriwe Nobel

Ijambo ryanyuma kubyerekeye isano iri hagati ya EPO nigihembo cyitiriwe Nobel cya 2019 muri Physiology cyangwa Medicine.

EPO nikibazo gisanzwe cyimyumvire yumubiri wumuntu hamwe nigisubizo cya hypoxia. Kubwibyo rero, Semenza na Ratcliffe, babiri bahawe igihembo cyitiriwe Nobel, bahisemo EPO nk'intangiriro yo kwiga uburyo bwo kwiyumvisha ingirabuzimafatizo no kurwanya hypoxia. Intambwe yambere kwari ugushaka ibintu bya gene ya EPO ishobora gusubiza ihinduka rya ogisijeni. Semenza yerekanye urufunguzo 256-shingiro rudakurikiranwa kuri 3 'kumanuka wanyuma wa gene irimo kodegisi ya EPO, yitwa hypoxia element element. Niba ibi bintu bikurikiranye byahinduwe cyangwa byasibwe, ubushobozi bwa proteine ​​ya EPO bwo gusubiza hypoxia buragabanuka cyane. Niba ibi bintu bikurikiranye byahujwe no kumanuka 3 'iherezo ryizindi genes zidafitanye isano na hypoxia, izi gen zahinduwe nazo zerekana ibikorwa bya EPO bisamubihe bya hypoxia.

Ratcliffe nitsinda rye bahise bavumbura ko iki kintu gisubiza hypoxic kitagaragara gusa mumpyiko cyangwa umwijima ushinzwe kubyara EPO, ahubwo no mubundi bwoko bwinshi bwakagari bushobora gukora mubihe bya hypoxique. Muyandi magambo, iki gisubizo kuri hypoxia ntigishobora kuba umwihariko wa EPO, ahubwo ni ibintu byakwirakwiriye muri selile. Izi selile zindi, zidafite inshingano zo gukora EPO, zigomba kuba zifite molekile (nkibintu byandikirwa mu nshingano zoguhindura imvugo ya gene) byumva impinduka ziterwa na ogisijeni kandi bigahuza na hypoxic reaction kugirango zifungure genes nka EPO.