iindaba

Umsebenzi wokwenza isitofu sokugonya udla ngokuchazwa njengongenambulelo. Ngokwamazwi kaBill Foege, omnye woogqirha abakhulu bempilo yoluntu kwihlabathi, “Akukho mntu uya kukubulela ngokubahlangula kwisifo ebengazi ukuba banaso.”

Kodwa oogqirha bempilo yoluntu bathi imbuyekezo kutyalo-mali iphezulu kakhulu kuba izitofu zokugonya zithintela ukufa kunye nokukhubazeka, ngakumbi ebantwaneni. Ke kutheni singenzi izitofu zokugonya ngakumbi izifo ezinokuthintelwa ngogonyo? Isizathu sesokuba izitofu zokugonya kufuneka zisebenze kwaye zikhuseleke ukuze zisetyenziswe kubantu abasempilweni, nto leyo eyenza inkqubo yophuhliso lwesitofu sokugonya ibe nde kwaye ibenzima.

Phambi kuka-2020, ixesha eliphakathi ukusuka ekukhawulweni kokuqala ukuya kunikezelo lwelayisensi yogonyo yayili-10 ukuya kwi-15 leminyaka, elona xesha lifutshane yiminyaka emine (ugonyo loqwilikana). Ukuphuhlisa isitofu sokugonya se-COVID-19 kwiinyanga ezili-11 ke ngoko yinto engaqhelekanga, eyenziwa yiminyaka yophando olusisiseko kumaqonga okugonya amatsha, eyona nto ibalulekileyo i-mRNA. Phakathi kwabo, iminikelo kaDrew Weissman kunye noDkt Katalin Kariko, abafumana i-2021 Lasker Clinical Research Award Award, kubaluleke kakhulu.

Umgaqo-siseko emva kokugonya kwe-nucleic acid umiliselwe kumthetho ophakathi kaWatson kunye noCrick wokuba iDNA ibhalwe kwi-mRNA, kwaye i-mRNA iguqulelwe kwiiprotheni. Phantse kwiminyaka engama-30 eyadlulayo, kwaboniswa ukuba ukwazisa i-DNA okanye i-mRNA kwiseli okanye nayiphi na into ephilayo ingabonisa iiproteni ezigqitywe ngokulandelelana kwe-nucleic acid. Kungekudala emva koko, ingcamango yokugonya i-nucleic acid yaqinisekiswa emva kokuba iiprotheyini ezichazwe yi-DNA yangaphandle zaboniswa ukuba zenze impendulo yokukhusela i-immune. Nangona kunjalo, usetyenziso lwehlabathi lokwenyani lwezitofu zokugonya ze-DNA zikhawulelwe, okokuqala ngenxa yeenkxalabo zokhuseleko ezinxulumene nokudibanisa i-DNA kwigenome yomntu, kwaye kamva ngenxa yobunzima bokunyusa ukuhanjiswa okusebenzayo kwe-DNA kwinucleus.

Ngokwahlukileyo koko, i-mRNA, nangona ichaphazeleka kwi-hydrolysis, ibonakala ilula ukuyisebenzisa kuba i-mRNA isebenza ngaphakathi kwe-cytoplasm kwaye ke ayidingi ukuhambisa i-nucleic acids kwinucleus. Amashumi eminyaka ophando olusisiseko olwenziwa nguWeissman noKariko, ekuqaleni kwilebhu yabo kwaye kamva emva kwelayisensi kwiinkampani ezimbini zebhayoloji (iModerna kunye neBioNTech), ikhokelele kwisitofu sokugonya se-mRNA ukuba yinyani. Yintoni eyona nto yayiphambili kwimpumelelo yabo?

Bayoyisa imiqobo emininzi. I-mRNA ibonwa yi-innate immune system recognition receptors (FIG. 1), kubandakanywa amalungu osapho lwe-Toll-like receptor (TLR3 kunye ne-TLR7 / 8, evakalelwa kukuba i-RNA ene-double-stranded kunye ne-single-stranded RNA, ngokulandelanayo) kunye ne-retinoic acid ibangela i-gene I protein (RIG-1) indlela, ethi ilandele i-plasma ye-cell (i-RIG) i-recognition receptor, Iqaphela i-RNA emfutshane ephindwe kabini kwaye isebenze uhlobo lwe-Interferon, ngaloo ndlela isebenze i-immune system). Ke, ukutofa i-mRNA kwizilwanyana kunokubangela umothuko, icebisa ukuba isixa se-mRNA esinokusetyenziswa ebantwini sinokulinganiselwa ukuze kuthintelwe iziphumo ebezingalindelekanga ezingamkelekanga.

Ukuphonononga iindlela zokunciphisa ukudumba, u-Weissman kunye noKariko baqala ukuqonda indlela i-receptors yokuqaphela ipateni eyahlula phakathi kwe-RNA ephuma kwi-pathogen kunye ne-RNA yabo. Baye baqaphela ukuba ii-Rnas ezininzi ze-intracellular, ezinje nge-ribosomal Rnas etyebileyo, ziguqulwe kakhulu kwaye zicingela ukuba olu tshintsho luvumela ii-Rnas zabo ukuba zibaleke ukuqatshelwa komzimba.

Impumelelo ephambili yeza xa u-Weissman kunye noKariko babonisa ukuba ukuguqula i-mRNA ngepseudouridine endaweni ye-ouridine kunciphise ukusebenza kwamajoni omzimba ngelixa igcina amandla okufaka iiproteni. Olu hlengahlengiso lunyusa imveliso yeprotheyini, ukuya kuthi ga kwi-1,000 ngamaxesha e-mRNA engaguqukiyo, kuba i-mRNA elungisiweyo ibalekela ukuqatshelwa yiprotein kinase R (inzwa eqaphela i-RNA kunye ne-phosphorylates kwaye isebenze i-factor initiation factor eIF-2α, ngaloo ndlela ivala ukuguqulelwa kweprotheni). I-Pseudouridine elungisiweyo ye-mRNA ngumqolo wogonyo olunelayisensi lwe-mRNA oluphuhliswe yiModerna kunye nePfizer-Biontech.

Ukuphumelela kokugqibela yayikukumisela eyona ndlela ilungileyo yokupakisha i-mRNA ngaphandle kwe-hydrolysis kunye neyona ndlela ilungileyo yokuyihambisa kwi-cytoplasm. Amachiza amaninzi e-mRNA avavanyiwe kwiintlobo ngeentlobo zezitofu zokugonya ezinye iintsholongwane. Ngo-2017, ubungqina beklinikhi obuvela kulingo olunjalo lubonise ukuba i-encapsulation kunye nokuhanjiswa kwezitofu zokugonya ze-mRNA ezine-lipid nanoparticles ziphucule i-immunogenicity ngelixa kugcinwa iprofayili yokhuseleko olulawulekayo.

Izifundo ezixhasayo kwizilwanyana ziye zabonisa ukuba i-lipid nanoparticles ijolise kwiiseli ze-antigen-presenting kwi-drain lymph nodes kunye nokuncedisa impendulo ngokubangela ukuba kusebenze iintlobo ezithile ze-follicular CD4 helper T cells. Ezi seli ze-T zinokunyusa imveliso ye-antibody, inani leeseli ze-plasma ezihlala ixesha elide kunye neqondo lokuphendula kweeseli ze-B ezivuthiweyo. Ezi zitofu zimbini zinikwe ilayisenisi ye-COVID-19 mRNA zombini zisebenzisa i-lipid nanoparticle formulations.

Ngethamsanqa, le nkqubela phambili kuphando olusisiseko lwenziwa phambi kobhubhane, ivumela iinkampani zamayeza ukuba zakhele kwimpumelelo yazo. Ugonyo lwe-mRNA lukhuselekile, luyasebenza kwaye luveliswa ngobuninzi. Ngaphezulu kwebhiliyoni enye yeedosi zesitofu sokugonya se-mRNA, kwaye ukonyusa imveliso ukuya kwi-2-4 yezigidigidi zeedosi ngo-2021 nango-2022 kuya kubaluleka kumlo wehlabathi ochasene ne-COVID-19. Ngelishwa, kukho ukungalingani okubonakalayo ekufikeleleni kwezi zixhobo zokusindisa ubomi, kunye nogonyo lwe-mRNA okwangoku olulawulwa ikakhulu kumazwe anengeniso ephezulu; Kwaye de ukuveliswa kwesitofu sokugonya kufikelele kwinqanaba eliphezulu, ukungalingani kuya kuqhubeka.

Ngokubanzi, i-mRNA ithembisa ngokusa okutsha kwicandelo lokugonya, isinika ithuba lokuthintela ezinye izifo ezosulelayo, ezinjengokuphucula izitofu zokugonya umkhuhlane, kunye nokuphuhlisa izitofu zokugonya izifo ezifana nesifo seengcongconi, i-HIV, kunye nesifo sephepha ezibulala inani elikhulu lezigulana kwaye zingasebenzi ngendlela eqhelekileyo. Izifo ezinjengomhlaza, ebezikade zijongwa kunzima ukujongana nazo ngenxa yamathuba asezantsi ophuhliso lwesitofu sokugonya kunye nesidingo sogonyo olulolwakho, ngoku zinokuqwalaselwa kuphuhliso lwezitofu zokugonya. I-mRNA ayikho malunga nezitofu zokugonya kuphela. Iibhiliyoni zeedosi ze-mRNA esizitofe kwizigulana ukuza kuthi ga ngoku zibonakalise ukhuseleko lwazo, zivula indlela yolunye unyango lwe-RNA olufana nokutshintshwa kweprotein, uphazamiseko lwe-RNA, kunye ne-CRISPR-Cas (iqela eliqhelekileyo lokuphinda-phinda i-palindromic emfutshane edibeneyo kunye ne-Cas endonucrenases ehambelanayo) nokuhlelwa kofuzo. Inguqulelo yeRNA yayisandul’ ukuqalisa.

Impumelelo yenzululwazi kaWeissman noKariko isindise izigidi zabantu, kwaye uhambo lukaKariko lomsebenzi luyahamba, hayi ngenxa yokuba lukhethekile, kodwa ngenxa yokuba luyinto yonke. Umntu oqhelekileyo ovela kwilizwe laseMpuma Yurophu, wafudukela e-United States ukuya kufezekisa amaphupha akhe enzululwazi, kuphela ukuzabalaza nenkqubo yase-US ye-tenure, iminyaka yenkxaso-mali yophando oluyingozi, kunye nokuthotywa. Wade wavuma ukuthatha intlawulo yokugcina ilebhu iqhuba kwaye aqhubeke nophando lwakhe. Uhambo lwenzululwazi lukaKariko lubenzima, olo ninzi lwabafazi, abafuduki kunye nabancinci abasebenza kwizifundiswa baqhelene nabo. Ukuba ukhe waba nethamsanqa ngokwaneleyo lokudibana noGqr. Kariko, uqulathe intsingiselo yokuthobeka; Isenokuba bubunzima bexesha elidlulileyo obumgcina eqinile.

Umsebenzi onzima kunye nempumelelo enkulu ye-Weissman kunye ne-Kariko imele yonke inkalo yenkqubo yesayensi. Akukho zinyuko, akukho imayile. Umsebenzi wabo mde kwaye unzima, ufuna ukuzingisa, ubulumko nombono. Ngelixa kungafuneki silibale ukuba abantu abaninzi kwihlabathi liphela abakakwazi ukufikelela kumayeza okugonya, abo bethu banethamsanqa ngokwaneleyo lokugonyelwa i-COVID-19 banombulelo ngezibonelelo ezikhuselayo zezitofu zokugonya. Sivuyisana noosonzululwazi ababini abamsebenzi wabo obalaseleyo wenze ukuba ugonyo lwe-mRNA lube yinyani. Ndizibandakanya nabanye abaninzi ekuvakaliseni umbulelo wam ongapheliyo kubo.