izindaba

Umsebenzi wokwenza umuthi wokugoma uvame ukuchazwa njengokungabongi. Ngokusho kukaBill Foege, omunye wodokotela bezempilo yomphakathi abakhulu emhlabeni wonke, “Akekho oyokubonga ngokubasindisa esifweni abengazi ukuthi unaso.”

Kodwa odokotela bezempilo yomphakathi baphikisa ngokuthi imbuyiselo yokutshalwa kwezimali iphezulu kakhulu ngoba imigomo ivimbela ukufa nokukhubazeka, ikakhulukazi ezinganeni. Pho kungani singenzi imithi yokugoma yezifo ezivikeleka kakhulu ngomjovo? Isizathu siwukuthi imithi yokugoma kufanele isebenze futhi iphephe ukuze isetshenziswe kubantu abanempilo, okwenza inqubo yokwakhiwa komgomo ibe yinde futhi ibe nzima.

Ngaphambi kuka-2020, isikhathi esimaphakathi kusukela ekukhulelweni kokuqala kuya ekunikezweni kwelayisense yemithi yokugoma kwakuyiminyaka eyi-10 kuye kweyi-15, kanti isikhathi esifushane kakhulu kwaba iminyaka emine (umuthi wokugoma). Ukwakha umuthi wokugomela i-COVID-19 ezinyangeni eziyi-11 ngakho-ke kuyisenzo esimangalisayo, esenziwe senzeka iminyaka yocwaningo olubalulekile ezisekelweni zokugoma ezintsha, okugqame kakhulu i-mRNA. Phakathi kwabo, iminikelo ka-Drew Weissman kanye noDkt. Katalin Kariko, abamukeli be-2021 Lasker Clinical Medical Research Award, ibaluleke kakhulu.

Umgomo wemigomo ye-nucleic acid usekelwe emthethweni omaphakathi ka-Watson no-Crick wokuthi i-DNA ibhalwa ku-mRNA, futhi i-mRNA ihunyushwa ibe amaprotheni. Cishe eminyakeni engu-30 edlule, kwaboniswa ukuthi ukwethula i-DNA noma i-mRNA engqamuzaneni noma kunoma iyiphi into ephilayo kungaveza amaprotheni anqunywa ukulandelana kwe-nucleic acid. Ngokushesha ngemva kwalokho, umqondo wokugomela i-nucleic acid waqinisekiswa ngemva kokuba amaprotheni avezwe yi-DNA yangaphandle akhonjiswe ukuthi enze impendulo yokuzivikela yokuzivikela. Kodwa-ke, ukusetshenziswa komhlaba wangempela kwemijovo ye-DNA kunqunyelwe, ekuqaleni ngenxa yokukhathazeka kokuphepha okuhlobene nokuhlanganisa i-DNA ku-genome yomuntu, futhi kamuva nangenxa yobunzima bokukhuphula ukulethwa okuphumelelayo kwe-DNA ku-nucleus.

Ngokuphambene, i-mRNA, nakuba isengozini ye-hydrolysis, ibonakala ilula ukuyisebenzisa ngoba i-mRNA isebenza ngaphakathi kwe-cytoplasm futhi ngakho-ke ayidingi ukuletha ama-nucleic acid ku-nucleus. Amashumi eminyaka ocwaningo oluyisisekelo olwenziwa u-Weissman noKariko, ekuqaleni elebhu yabo futhi kamuva ngemva kokuthola ilayisense ezinkampanini ezimbili ze-biotechnology (i-Moderna ne-BioNTech), kuholele ekutheni umgomo we-mRNA ube ngokoqobo. Sasiyini isihluthulelo sempumelelo yabo?

Banqoba izithiyo eziningana. I-mRNA ibonwa ngama-innate immune system pattern recognition receptors (FIG. 1), okuhlanganisa namalungu omndeni wama-Toll-like receptor (TLR3 kanye ne-TLR7/8, ezwa i-RNA enemicu ephindwe kabili ne-single-stranded, ngokulandelana) kanye ne-retinoic acid ingenisa indlela yeprotein yofuzo I (RIG-1), yona ibe yiphethini yokufa kwe-RIG. i-recognition receptor, Ibona i-RNA emifushane ephindwe kabili futhi isebenze uhlobo I-interferon, ngaleyo ndlela isebenze amasosha omzimba aguquguqukayo). Ngakho, ukujova i-mRNA ezilwaneni kungabangela ukushaqeka, okusikisela ukuthi inani le-mRNA elingasetshenziswa kubantu lingase libe nomkhawulo ukuze kugwenywe imiphumela engemihle engamukeleki.

Ukuhlola izindlela zokunciphisa ukuvuvukala, u-Weissman no-Kariko baqala ukuqonda indlela ama-receptors okuqaphela iphethini ahlukanisa ngayo phakathi kwe-RNA etholakala ku-pathogen kanye ne-RNA yabo. Baqaphele ukuthi ama-Rna amaningi angaphakathi kweseli, njenge-ribosomal Rnas ecebile, ashintshwe kakhulu futhi aqagela ukuthi lezi zinguquko zivumele ama-Rna awo ukuba abaleke ekuqashelweni kokuzivikela komzimba.

Impumelelo ebalulekile yeza lapho u-Weissman noKariko bebonisa ukuthi ukulungisa i-mRNA nge-pseudouridine esikhundleni se-ouridine kunciphisa ukusebenza kwamasosha omzimba kuyilapho kugcinwa amandla okuhlanganisa amaprotheni. Lokhu kuguqulwa kwandisa ukukhiqizwa kwamaprotheni, kufika izikhathi ezingu-1,000 kune-mRNA engashintshiwe, ngenxa yokuthi i-mRNA elungisiwe ibalekela ukubonwa yi-protein kinase R (inzwa ebona i-RNA bese i-phosphorylates bese ivula isici sokuqalisa ukuhumusha i-eIF-2α, bese ivala ukuhumusha kwamaprotheni). I-Pseudouridine modified mRNA iwumgogodla wemithi yokugomela i-mRNA enelayisensi eyakhiwe ngabakwaModerna kanye ne-Pfizer-Biontech.

Ukuphumelela kokugcina kwaba ukunquma indlela engcono kakhulu yokupakisha i-mRNA ngaphandle kwe-hydrolysis kanye nendlela engcono kakhulu yokuyiletha ku-cytoplasm. Ukwakhiwa kwe-mRNA okuningi kuhlolwe ezinhlobonhlobo zemithi yokugomela amanye amagciwane. Ngo-2017, ubufakazi bomtholampilo obuvela ezivivinyweni ezinjalo bubonise ukuthi ukuhlanganisa nokulethwa kwemigomo ye-mRNA ene-lipid nanoparticles kuthuthukisa ukuzivikela komzimba ngenkathi kugcinwa iphrofayili yokuphepha elawulekayo.

Ucwaningo olusekelayo ezilwaneni lubonise ukuthi ama-lipid nanoparticles aqondise kumaseli e-antigen-presenting ekukhipheni ama-lymph node futhi asize impendulo ngokwenza kusebenze izinhlobo ezithile zama-follicular CD4 helper T cell. Lawa maseli e-T angakhuphula ukukhiqizwa kwe-antibody, inani lamaseli e-plasma aphila isikhathi eside kanye nezinga lokuphendula kwamaseli e-B avuthiwe. Imithi yokugomela emibili enelayisense ye-COVID-19 mRNA okwamanje isebenzisa ukwakheka kwe-lipid nanoparticle.

Ngenhlanhla, le ntuthuko ocwaningweni oluyisisekelo yenziwa ngaphambi kwalolu bhubhane, okuvumela izinkampani zemithi ukuthi zakhele empumelelweni yazo. Imithi yokugoma ye-mRNA iphephile, iyasebenza futhi ikhiqizwa ngobuningi. Imithamo engaphezulu kwebhiliyoni eyodwa yokugomela i-mRNA isinikezwe, futhi ukukhuphula ukukhiqizwa kufinyelele kumithamo eyizigidi eziyizinkulungwane ezingama-2-4 ngo-2021 nango-2022 kuzobaluleka empini yomhlaba wonke yokulwa ne-COVID-19. Ngeshwa, kukhona ukungalingani okuphawulekayo ekufinyeleleni kulawa mathuluzi okusindisa impilo, nemithi yokugomela i-mRNA okwamanje elawulwa kakhulu emazweni anemali engenayo ephezulu; Futhi kuze kube yilapho ukukhiqizwa komuthi wokugoma kufinyelela ezingeni eliphezulu, ukungalingani kuzoqhubeka.

Ngokubanzi, i-mRNA ithembisa ukuntwela kokusha emkhakheni wezokugoma, okusinika ithuba lokuvimbela ezinye izifo ezithathelwanayo, njengokuthuthukisa imithi yokugomela umkhuhlane, nokwenza imithi yokugomela izifo ezifana nomalaleveva, i-HIV, nesifo sofuba ezibulala inani elikhulu leziguli futhi ezingasebenzi kahle ngezindlela ezivamile. Izifo ezinjengomdlavuza, obekucatshangwa ukuthi kunzima ukubhekana nazo phambilini ngenxa yamathuba amancane okuthuthukiswa komgomo kanye nesidingo semithi yokugoma yomuntu siqu, manje sezingacatshangelwa ukuze kwakhiwe imithi yokugoma. I-mRNA ayigcini nje ngemigomo. Izigidigidi zemithamo ye-mRNA esiyijove ezigulini kuze kube manje ikufakazele ukuphepha kwazo, ivula indlela yezinye izindlela zokwelapha ze-RNA ezifana nokushintshwa kwamaprotheni, ukuphazamiseka kwe-RNA, kanye ne-CRISPR-Cas (amaqoqo avamile okuphindaphinda okufushane kwe-palindromic ahlanganisiwe kanye nokuhlela izakhi zofuzo ze-Cas endonucrenases). Inguquko ye-RNA yayisanda kuqala.

Izimpumelelo zesayensi zika-Weissman no-Kariko zisindise izigidi zabantu, futhi uhambo luka-Kariko lomsebenzi luyahamba, hhayi ngoba luhlukile, kodwa ngenxa yokuthi luthinta yonke indawo. Njengomuntu ovamile ovela ezweni laseMpumalanga Yurophu, wathuthela e-United States ukuyophishekela amaphupho akhe esayensi, kodwa wazabalaza nohlelo lwe-US lokuhlala, iminyaka yoxhaso oluqinile locwaningo, kanye nokudilizwa esikhundleni. Waze wavuma nokuncishiswa iholo ukuze aqhubeke nelebhu futhi aqhubeke nocwaningo lwakhe. Uhambo lwesayensi luka-Kariko belunzima, abesifazane abaningi, abokufika kanye nabancane abasebenza ezikhungweni zemfundo ephakeme abalwaziyo. Uma uke waba nenhlanhla yokuhlangana noDkt. Kariko, uhlanganisa incazelo yokuthobeka; Kungase kube ubunzima besikhathi esidlule obumgcina egxilile.

Ukusebenza kanzima kanye nezimpumelelo ezinkulu zika-Weissman no-Kariko zimelela zonke izici zenqubo yesayensi. Azikho izinyathelo, awekho amamayela. Umsebenzi wabo mude futhi unzima, udinga ukuqina, ukuhlakanipha nombono. Yize kungafanele sikhohlwe ukuthi abantu abaningi emhlabeni wonke abakakwazi ukuthola imigomo, thina esinenhlanhla yokugonyelwa i-COVID-19 siyabonga ngezinzuzo zokuvikela zemithi yokugoma. Sihalalisela ososayensi ababili abayisisekelo umsebenzi wabo omuhle owenze imigomo ye-mRNA yaba ngokoqobo. Ngihlanganyela nabanye abaningi ekudluliseleni ukubonga kwami ​​okungapheli kubo.