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Ntchito yopanga katemera nthawi zambiri imafotokozedwa kuti ndi yosathokoza. M’mawu a Bill Foege, mmodzi wa madokotala odziŵa bwino za umoyo wa anthu padziko lonse, “Palibe amene angayamikire chifukwa chowapulumutsa ku matenda amene sanawadziwepo.”

Koma madotolo azaumoyo akutsutsa kuti kubweza ndalama ndikwambiri chifukwa katemera amalepheretsa kufa ndi kulumala, makamaka kwa ana. Nanga ndichifukwa chiyani sitikupanga katemera wa matenda omwe angathe kupewedwa ndi katemera? Chifukwa chake ndi chakuti katemera ayenera kukhala ogwira mtima komanso otetezeka kuti athe kugwiritsidwa ntchito mwa anthu athanzi, zomwe zimapangitsa kuti chitukuko cha katemera chikhale chotalika komanso chovuta.

Chaka cha 2020 chisanafike, nthawi yapakati kuyambira pa kubadwa koyambirira mpaka kupereka chilolezo cha katemera inali zaka 10 mpaka 15, ndipo nthawi yayifupi kwambiri inali zaka zinayi (katemera wa mumps). Kupanga katemera wa COVID-19 m'miyezi 11 ndiye chinthu chodabwitsa, chotheka ndi zaka za kafukufuku wofunikira pa nsanja zatsopano za katemera, makamaka mRNA. Pakati pawo, zopereka za Drew Weissman ndi Dr. Katalin Kariko, omwe adalandira 2021 Lasker Clinical Medical Research Award, ndizofunikira kwambiri.

Mfundo ya katemera wa nucleic acid idakhazikitsidwa mu lamulo lapakati la Watson ndi Crick loti DNA imalembedwa mRNA, ndipo mRNA imasinthidwa kukhala mapuloteni. Pafupifupi zaka 30 zapitazo, zidawonetsedwa kuti kubweretsa DNA kapena mRNA m'selo kapena chamoyo chilichonse kumatha kuwonetsa mapuloteni opangidwa ndi nucleic acid. Posakhalitsa pambuyo pake, lingaliro la katemera wa nucleic acid lidatsimikiziridwa pambuyo poti mapuloteni omwe amafotokozedwa ndi DNA yachilendo adawonetsedwa kuti amapangitsa kuti chitetezo cha mthupi chitetezeke. Komabe, ntchito zenizeni za katemera wa DNA zakhala zochepa, poyamba chifukwa cha chitetezo chokhudzana ndi kuphatikizira DNA mu jini la munthu, ndipo pambuyo pake chifukwa cha vuto la kukulitsa kutulutsa bwino kwa DNA mu mtima.

Mosiyana ndi zimenezi, mRNA, ngakhale kuti imatha kugwidwa ndi hydrolysis, ikuwoneka kuti ndi yosavuta kugwiritsira ntchito chifukwa mRNA imagwira ntchito mkati mwa cytoplasm choncho sifunikira kupereka nucleic acids mu nucleus. Zaka makumi angapo za kafukufuku wofunikira wa Weissman ndi Kariko, koyambirira mu labu yawo ndipo pambuyo pake atapereka zilolezo kumakampani awiri asayansi yazachilengedwe (Moderna ndi BioNTech), zidapangitsa kuti katemera wa mRNA akwaniritsidwe. Kodi chinsinsi cha kupambana kwawo chinali chiyani?

Anagonjetsa zopinga zingapo. mRNA imazindikiridwa ndi ma innate immune system pattern recognition receptors (FIG. 1), kuphatikizapo mamembala a banja la Toll-like receptor (TLR3 ndi TLR7/8, omwe amamva kuti RNA yokhala ndi zingwe ziwiri ndi imodzi, motsatira) ndi retinoic acid imayambitsa njira ya jini I protein (RIG-1), yomwe imapangitsa kuti maselo a imfa awonongeke. recognition receptor, Imazindikira RNA yaifupi iwiri yozungulira ndikuyambitsa mtundu wa I interferon, potero kuyambitsa chitetezo cha mthupi). Choncho, kubaya mRNA mu nyama kungayambitse mantha, kutanthauza kuti kuchuluka kwa mRNA komwe kungagwiritsidwe ntchito mwa anthu kungakhale kochepa pofuna kupewa zotsatira zosavomerezeka.

Kuti afufuze njira zochepetsera kutupa, Weissman ndi Kariko adayamba kumvetsetsa momwe ma receptors amasiyanitsira pakati pa RNA yochokera ku tizilombo toyambitsa matenda ndi RNA yawoyawo. Iwo adawona kuti ma Rna ambiri a intracellular, monga ma ribosomal Rnas olemera, adasinthidwa kwambiri ndipo amalingalira kuti zosinthazi zidalola ma Rna awo kuthawa kuzindikirika ndi chitetezo chamthupi.

Kupambana kwakukulu kudabwera pomwe Weissman ndi Kariko adawonetsa kuti kusintha mRNA ndi pseudouridine m'malo mwa ouridine kumachepetsa mphamvu ya chitetezo chamthupi kwinaku ndikusunga mapuloteni. Kusintha kumeneku kumawonjezera kupanga mapuloteni, mpaka nthawi za 1,000 za mRNA yosasinthika, chifukwa mRNA yosinthidwa imathawa kuzindikira ndi protein kinase R (sensor yomwe imazindikira RNA ndiyeno phosphorylates ndikuyambitsa kumasulira koyambirira kwa eIF-2α, motero kutseka kumasulira kwa mapuloteni). Pseudouridine modified mRNA ndiye msana wa katemera wa mRNA wovomerezeka wopangidwa ndi Moderna ndi Pfizer-Biontech.

Kupambana komaliza kunali kudziwa njira yabwino yopangira mRNA popanda hydrolysis ndi njira yabwino yoperekera mu cytoplasm. Mapangidwe angapo a mRNA ayesedwa m'makatemera osiyanasiyana motsutsana ndi ma virus ena. Mu 2017, umboni wazachipatala kuchokera ku mayesero oterowo udawonetsa kuti kutsekeredwa ndi kutumiza kwa katemera wa mRNA wokhala ndi lipid nanoparticles kumathandizira chitetezo chamthupi ndikusunga mbiri yachitetezo chotheka.

Maphunziro othandizira nyama awonetsa kuti ma lipid nanoparticles amayang'ana ma antigen-presenting ma cell pakukhetsa ma lymph nodes ndikuthandizira kuyankha poyambitsa kuyambitsa mitundu ina ya follicular CD4 wothandizira T cell. Maselo a T awa amatha kukulitsa kupanga ma antibodies, kuchuluka kwa maselo a plasma omwe amakhala nthawi yayitali komanso kuchuluka kwa kuyankha kwa ma cell a B okhwima. Katemera awiriwa omwe ali ndi zilolezo za COVID-19 mRNA onse amagwiritsa ntchito lipid nanoparticle formulations.

Mwamwayi, kupita patsogolo kumeneku pakufufuza koyambira kudachitika mliriwu usanachitike, kulola makampani azamankhwala kuti apitilize kuchita bwino. Katemera wa mRNA ndi wotetezeka, wothandiza komanso wopangidwa mochuluka. Mlingo wopitilira 1 biliyoni wa katemera wa mRNA waperekedwa, ndipo kukulitsa kupanga mpaka 2-4 biliyoni mu 2021 ndi 2022 kudzakhala kofunikira pankhondo yapadziko lonse lapansi yolimbana ndi COVID-19. Tsoka ilo, pali kusagwirizana kwakukulu pakupeza zida zopulumutsa moyozi, ndi katemera wa mRNA womwe panopa umayendetsedwa makamaka m'mayiko omwe ali ndi ndalama zambiri; Ndipo mpaka kupanga katemera kukafika pachimake, kusalingana kumapitilirabe.

Mokulirapo, mRNA imalonjeza mbandakucha watsopano pankhani ya katemera, kutipatsa mwayi wopewa matenda ena opatsirana, monga kukonza katemera wa chimfine, komanso kupanga katemera wa matenda monga malungo, HIV, ndi chifuwa chachikulu chomwe chimapha odwala ambiri ndipo sagwira ntchito ndi njira zanthawi zonse. Matenda monga khansa, omwe poyamba ankawoneka ovuta kuthana nawo chifukwa cha mwayi wochepa wa chitukuko cha katemera komanso kufunikira kwa katemera waumwini, tsopano akhoza kuganiziridwa kuti apange katemera. mRNA sikuti ndi katemera chabe. Miliyoni mabiliyoni a Mlingo wa mRNA womwe tabaya odwala mpaka pano atsimikizira chitetezo chawo, ndikutsegulira njira zochiritsira zina za RNA monga kusintha kwa mapuloteni, kusokoneza kwa RNA, ndi CRISPR-Cas (magulu okhazikika a interspaced short palindromic kubwereza ndi zogwirizana ndi Cas endonucrenases) kusintha kwa majini. Kusintha kwa RNA kunali kutangoyamba kumene.

Zimene Weissman ndi Kariko achita pa sayansi zapulumutsa miyoyo ya anthu mamiliyoni ambiri, ndipo ulendo wa ntchito ya Kariko ukuyenda bwino, osati chifukwa chakuti ndi wapadera, koma chifukwa chakuti ndi wapadziko lonse. Munthu wamba wochokera kudziko la Kum'mawa kwa Europe, adasamukira ku United States kuti akakwaniritse maloto ake asayansi, koma kuti avutike ndi dongosolo laulamuliro la US, zaka zandalama zovutirapo zofufuza, komanso kutsika. Adavomeranso kuti achepetse malipiro kuti labu igwire ntchito ndikupitiliza kafukufuku wake. Ulendo wa sayansi wa Kariko wakhala wovuta, womwe amayi ambiri, othawa kwawo komanso ochepa omwe amagwira ntchito ku maphunziro amawadziwa. Ngati munachitapo mwayi wokumana ndi Dr. Kariko, akuyimira tanthauzo la kudzichepetsa; Zitha kukhala zovuta zakale zomwe zimamupangitsa kukhala wokhazikika.

Kugwira ntchito molimbika komanso kuchita bwino kwambiri kwa Weissman ndi Kariko kumayimira mbali zonse zasayansi. Palibe masitepe, palibe mailosi. Ntchito yawo ndi yayitali komanso yovuta, yomwe imafunikira kulimbikira, nzeru ndi masomphenya. Ngakhale sitiyenera kuiwala kuti anthu ambiri padziko lonse lapansi alibebe mwayi wopeza katemera, ife omwe tili ndi mwayi wolandira katemera wa COVID-19 ndi othokoza chifukwa cha chitetezo cha katemera. Tithokoze asayansi awiri oyambira omwe ntchito yawo yabwino yapangitsa kuti katemera wa mRNA akhale weniweni. Ndimagwirizana ndi anthu ena ambiri posonyeza kuyamikira kwanga kosatha kwa iwo.