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2021 m. gruodžio 4 d., šeštadienis

Elon Musk Needs China. China Needs Him.


"With the U.S. tightening technology exports to China in 2018, President Xi Jinping defiantly pledged to make China the world's future innovation and industrial center. Key to his plan was Elon Musk.

Mr. Xi viewed the South African-born entrepreneur as a technology utopian with no political allegiance to any country, according to officials involved in policy-making, and saw his Tesla Inc. as a spearhead that could make China a power in new-energy cars.

Mr. Xi rewrote the rulebook to allow foreign companies sole ownership of auto ventures so Mr. Musk would open an electric-vehicle factory in Shanghai. Authorities showered him with cheap land, low-interest loans and tax incentives, expecting in return that Tesla would groom local suppliers and bolster lagging Chinese electric-vehicle players, say people with knowledge of the talks between Beijing and the company.

Today Tesla likely makes more than half its vehicles in China, suggest calculations based on the company's third-quarter production and delivery figures and China Passenger Car Association data. Chinese sales helped propel Tesla to its first full year of profitability in 2020 and provided roughly a fourth of Tesla's revenue in the first nine months of 2021. Mr. Musk, meanwhile, has cemented his place as the world's wealthiest person.

But Tesla is facing an increasingly difficult business environment in China now. It has drawn wrath from domestic rivals over what they see as preferential treatment, suffers criticism of its vehicle quality from drivers and Chinese officials, and has been caught up in the government's sweeping crackdown on big tech.

China is pressing foreign companies to meet an ever-more-stringent policy on data security. Tesla now must retain inside the country all digital records gathered from local customers, and it must ask authorities for approval before updating certain software on cars in China.

Mr. Musk's response to the pressure has been to become a high-profile cheerleader of China's ruling Communist Party, in sharp contrast to his renegade persona in the U.S., where he has clashed with the Securities and Exchange Commission and mocked President Biden in tweets, once calling him a labor union sock puppet.

"The economic prosperity that China has achieved is truly amazing, especially in infrastructure!" Mr. Musk tweeted when the party celebrated its centenary on July 1.

Mr. Musk has hailed China's toughened data laws, and his company issued a humbling apology in April. A driver at an auto show publicly blamed Tesla brakes for an accident, after which China's top legal-affairs agency chimed in, calling the company arrogant. A short time later, Tesla said on China's Twitter-like Weibo platform: "We apologize for failing to resolve the problem of the car owner in time. We will try our best to learn the lessons of this experience."

Tesla thus finds itself falling within a familiar historical pattern, in which Beijing uses a grant of access to its vast market to advance China's own industrial capability.

After Apple Inc. brought its iPhone supply chain to China years ago, many of the Chinese companies Apple trained also became suppliers to Chinese smartphone manufacturers, which now lead the world in sales.

Apple has a healthy 11% market share in China. But another Western tech giant, Microsoft Corp., which first opened a China office in 1992, now finds itself hamstrung by the country's nationalism in areas such as cloud storage. Microsoft recently said it would shut down the localized version of its LinkedIn platform in China, citing the challenging operating environment.

"China's game isn't to let Tesla win," said Bill Russo, founder of Automobility, a Shanghai-based consulting firm. "China's game is to make the domestic industry compete."

The Information Office of the State Council, China's top government body, didn't answer questions for this article. Mr. Musk and Tesla didn't respond to requests for comment. Microsoft said it would continue to have a strong presence in China. Apple didn't respond to a request for comment.

From the outset, officials in Beijing made clear they wanted something in return for throwing open the country to Tesla, according to the people with knowledge of the parties' 2018 talks.

Chinese leaders had grown frustrated with domestic electric-vehicle companies' performance and saw Tesla as an opportunity to reset the country's auto industry. Tesla would be expected to localize its supply chain and groom Chinese manufacturers, steps that could accelerate the domestic industry.

Miao Wei, who negotiated on the deal with Mr. Musk, openly discussed how Tesla could propel underachieving local EV startups. He likened it to lobbing a predatory catfish into a pond full of sluggish fish. Representatives for the Ministry of Industry and Information Technology, which Mr. Miao then led, didn't respond to questions.

Mr. Musk long expressed interest in a plant in China that would help Tesla sell cars for less in the world's largest auto market, but he didn't want to take on a Chinese partner in a joint venture as other foreign auto makers had.

In July 2018, Tesla signed a deal to build a factory in Shanghai. Chinese authorities lauded the deal for the jobs it would create and for the roughly $345 million in annual taxes Tesla is expected to start generating at the end of 2023, according to regulatory disclosures. Beijing's embrace of Mr. Musk was so warm that at a meeting in 2019, Premier Li Keqiang offered to give him a "Chinese green card." Mr. Musk let the premier take a Tesla for a spin within the gated Zhongnanhai leadership compound.

Some at Tesla bristled at aspects of the push into China, concerned about issues including a risk of intellectual-property theft, a person familiar with the matter said.

As in the West, Tesla's arrival whetted people's interest in electric vehicles. The 2019 launch of the made-in-China Tesla Model 3 helped convince consumers such vehicles were a viable alternative to gasoline cars.

Tesla proved an effective "catfish," too: Its Chinese-made cars restored the confidence of Chinese investors in the electric-vehicle market, helping supercharge domestic startups that had struggled.

NIO Inc., for instance, was close to collapse but secured investment in April 2020 and saw a revival in its share price that led to further fundraising. It has thrived in Tesla's slipstream, as have two Chinese peers that sell premium electric vehicles, Li Auto Inc. and XPeng Inc. The three companies' electric-vehicle sales are likely to total more than 270,000 this year, up from around 12,000 in 2018, according to a forecast by consulting firm ZoZo Go LLC.

"Pre-Tesla, nobody believed that a Chinese brand could be riveting," said Michael Dunne, chief executive of ZoZo Go and a former General Motors Co. executive. ZoZo Go expects overall sales in China of new-energy vehicles -- including electric and plug-in hybrid vehicles -- to be roughly 3.1 million this year, more than double last year's.

A spokeswoman for NIO said the company appreciates Tesla's efforts to spur the development of the electric-vehicle industry.

The Tesla effect also lifted the supply chain, meeting a key goal of China's leaders. Tesla has sent engineers to train workers, help with design and research and impart know-how at firms ranging from a battery maker to die-casting processors.

In early 2021, Tesla said it had reached a "domestic supply sourcing ratio" of over 90% at its Shanghai factory. Tom Zhu, its top China executive, has said Tesla is on track to source all of its vehicle components locally by year-end.

"There were previously a ton of parts that were made in other parts of the world that were being shipped to Shanghai," Mr. Musk said in a July 2020 earnings call. "Just locally sourcing those components makes a massive difference to the cost of the vehicle."

Tesla engineers worked with Chinese battery maker Contemporary Amperex Technology Co. Ltd., known as CATL, to tailor products to Tesla's needs. A 2020 supply deal with Tesla affirmed the company's place as a top-tier battery maker.

A supplier of housings for components and hydraulic systems relies on Tesla for roughly half its business. Ningbo Xusheng Auto Technology Co. said in its 2020 annual report that through its cooperation with Tesla, it has "accumulated technologies relating to the design, R&D and production of electric-vehicle parts," helping it "occupy a top position in the electric-vehicle parts industry." Ningbo's 2020 revenue tripled its 2016 level.

Rival electric-vehicle companies in China are now taking aim at Tesla, many of them unhappy about what they perceive as officials' preferential treatment of a foreign car maker. Some rivals have done so by leveraging Beijing's broader clampdown on how data is handled by tech behemoths.

They include a company called 360, which started out as a cybersecurity firm, and state-owned vehicle giant SAIC Motor Corp. The two companies in March urged China's legislature to address national-security concerns associated with foreign electric-vehicle makers. Their target was Tesla, according to people with knowledge of the discussions between the companies and officials.

Zhou Hongyi, 360's founder, suggested that China adopt laws and regulations limiting the collection of geographic information from users of electric vehicles, according to state media reports. State media also said Chen Hong, SAIC's Communist Party secretary and chairman, proposed that the collection, storage and commercial use of data collected by these vehicles be filed and managed by the Chinese government.

Media representatives at 360 and SAIC didn't respond to inquiries.

Beijing restricted the use of Tesla cars on military bases and other sensitive government premises. Aided by a public backlash against Tesla, triggered by the driver's complaints in April, the government in May proposed strict regulations on automotive data collection, limiting the kind of data electric-car makers could collect and forbidding them to transfer outside China any information gathered from users on China's roads and highways.

These proposals became final in August, as per formal guidelines issued by the Ministry of Industry and Information Technology then. A personal-data protection law that took effect on Nov. 1 could further restrain the company's ability to gather digital information from Chinese consumers.

The new requirements likely will make it harder for Tesla to develop and deploy autonomous vehicles in China, because these rely on an array of sensors that collect vast amounts of data, according to analysts and current and former industry executives. Tesla's current driver-assistance features don't make vehicles autonomous.

"The sweeping data regulation was intended, at least in part, to address escalating public debate about Tesla," said Paul Triolo, head of global technology policy at Eurasia Group, a New York-based consulting firm, who consults with Chinese officials.

A sore point for local rivals of Tesla is a government policy aimed at encouraging auto makers to produce more electric vehicles. Companies that don't build enough must purchase credits from those that do. Tesla has been one of the chief beneficiaries of this rule.

"A lot of Chinese companies are very upset by the system," said Scott Kennedy, a China expert at the Center for Strategic and International Studies, a Washington think tank.

Tesla has used savings from having domestic suppliers to hold vehicle prices low enough for buyers to qualify for Chinese government subsidies. In July, Tesla launched a Model Y compact sport-utility vehicle that costs less than 300,000 yuan (about $47,000), enabling buyers to get these subsidies.

The Shanghai plant now is Tesla's main export hub and helped the company introduce its Model Y to Europe, Chief Financial Officer Zachary Kirkhorn told investors in October. The factory makes more vehicles than Tesla's plant in Fremont, Calif., Mr. Musk said in October, and underpinned the company's record global deliveries in the third quarter.

Long term, Tesla is likely to lose ground in China to domestic competitors, industry analysts say. Earlier this year, Morgan Stanley analysts forecast that Tesla would make up roughly 15% of China's all-electric vehicle market this year but that this would fall below 7% by 2030 as homegrown companies gain traction.

"Tesla's position in the domestic Chinese market will be substantially diluted over time through competition and policies to encourage local players," the analysts said.

Mr. Musk remains personally popular in China, where people accustomed to conformity admire his maverick behavior in the U.S. Aspiring Chinese tech entrepreneurs look to him for inspiration, tracking moves of the "Silicon Valley Iron Man." Some Chinese businesses have even trademarked products using the Chinese translation of his name, Ma Si Ke.

Mr. Musk may have to settle for a sizable, though not dominant, position in the Chinese market, some analysts suggest. Tesla sold more than 73,000 vehicles in China in the three months ended in September, not including exports, a record quarterly performance, China Passenger Car Association data show. Yet in a recent survey of roughly 1,600 Chinese consumers, Tesla ranked among the top auto brands to avoid, signaling that the company could be hitting a ceiling on market share, Bernstein Research analysts said.

Mr. Musk has maintained his deferential tone. In September, when China held an internet conference aimed at pushing its alternative version of the web -- at a time when the government was pressing a regulatory crackdown on tech -- not many of the country's tech stars attended.

Mr. Musk spoke via video, describing how Tesla had set up a data center in China to store the digital records gathered from its production, sales, service, charging and other activities in the country.

"At Tesla, we're glad to see a number of laws and regulations that have been released to strengthen data management," Mr. Musk said." [1]

 

Where is Landsbergis' place in this story? We have one such person wandering around Vilnius thinking he is Napoleon the First. 


1. EXCHANGE --- Elon Musk Needs China. China Needs Him. The Relationship Is Complicated. --- To attract Tesla, the Chinese government rewrote its rules for foreign auto businesses and offered tax incentives and cheap land. Now, the auto giant is entering bumpier terrain.

Wei, Lingling; Elliott, Rebecca; Moss, Trefor.  Wall Street Journal, Eastern edition; New York, N.Y. [New York, N.Y]. 04 Dec 2021: B.1.

Nuostabi informacinės RNR technologijos istorija ir įspūdingos informacinės RNR technologijos perspektyvos

"Ar vakcinos nuo Covid-19 nesėkmingos? Toks požiūris yra kai kuriose žiniasklaidos priemonėse, plintant proveržio infekcijoms ir naujiems viruso variantams. Tai taip pat yra klaidinga. Paskiepyti žmonės yra labiau linkę į lengvas infekcijas, nei iš pradžių tikėjosi visuomenės sveikatos priežiūros institucijos. Tačiau skiepai ir toliau rodo stiprią apsaugą nuo rimtų ligų, o ypač informacinės RNR (iRNR) vakcinos – Pfizer/BioNTech ir Moderna – yra lengvai pritaikomos naujiems variantams.

 

Dar svarbiau, kad drama dėl vakcinų užmaskavo didesnę ir nuostabią istoriją, kuri yra didžiulis iRNR technologijos pažadas. Informacinė RNR parodė didžiulį medicinos pritaikymo potencialą, ne tik Covid, bet ir kitoms infekcinėms ligoms, taip pat vakcinoms ir gydymui nuo vėžio iki išsėtinės sklerozės. Jos raida yra pasakojimas apie mokslinį atkaklumą ir nuoširdumą, kuris nusipelno daugiau dėmesio, o svarbų vaidmenį atlieka amerikiečių imigrantė iš komunistinės Vengrijos.

 

Omikron variantas yra iRNR pažado ir prisitaikymo pavyzdys. Omikron turi apie 30 smailių baltymų mutacijų, dėl kurių vakcinos sukeltiems antikūnams gali būti sunkiau atpažinti ir neutralizuoti virusą. Tačiau iRNR vakcinos gali būti lengvai pakeistos naujam variantui.

 

„BioNTech“ ir „Pfizer“ teigia, kad gali pradėti gabenti vakcinas, skirtas omikron, per 100 dienų, jei apsauga nuo esamų vakcinų iš esmės sumažės prieš naująjį variantą. „Moderna“ jau pradėjo testuoti stimuliuojančius skiepus, skirtus numatytoms mutacijoms. Ji taip pat teigia, kad greitai patobulins specifinį „omikron“ stiprintuvą, kuris galėtų būti prieinamas kitų metų pradžioje.

 

Toks greitas posūkis būtų neįmanomas, naudojant įprastines vakcinų technologijas, kurių gamyba ir pristatymas paprastai trunka nuo šešių iki 36 mėnesių. Vakcinų kūrimas gali užtrukti dar daug metų. 

 

Naudojant iRNR, vakcinos gamintojams tereikia maždaug šešių savaičių, kad pritaikytų skiepą, o tada paimtų jį iš laboratorijos į gamybą.

 

Informacinė RNR pateikia genetinį kodą, nurodantį žmogaus ląstelėms, kaip sukurti baltymą – šiuo atveju koronaviruso smaigalį, kuris prisijungia prie žmogaus ląstelių ACE2 receptorių. Informacinė RNR yra apgaubta lipidų nanodalelėmis, kurios yra riebalinės dėmės, apsaugančios genetinę motininę apkrovą nuo skilimo ir palengvinančios jos patekimą į ląsteles. Kai iRNR suleidžiama į raumenis, žmogaus ląstelės tampa mažomis vakcinų gamyklomis, kurios išskiria pseudoviruso daleles, kurios savo ruožtu skatina imuninę sistemą gaminti antikūnus, kurie reaguoja, kai susiduria su tikruoju dalyku. Vakcinos taip pat indukuoja T ląsteles, kurios užtikrina atsarginę apsaugą nuo antikūnų. Jei virusas mutuoja, mokslininkai gali lengvai pakeisti naują genetinį kodą  iRNR molekulėje.

 

„Moderna“ ir „Pfizer/BioNTech Covid“ vakcinos yra pirmieji komerciškai patvirtinti iRNR produktai, tačiau jie tapo įmanomi dėl dešimtmečius trukusių eksperimentų, naujovių ir ryžto. Genetikai nustatė iRNR egzistavimą septintojo dešimtmečio pradžioje. 

 

Informacinė RNR reguliuoja genų ekspresiją ir yra vienos grandinės molekulė, panaši į dvigubos spiralės DNR. Informacinė RNR neša instrukcijas iš DNR į baltymų gamybos mechanizmus ląstelėse, žinomus, kaip ribosomos.

 

Čia istorijoje atsiranda Katalin Kariko. 66 metų Vengrijoje gimusi biochemikė, dabar „BioNTech“ mokslininkė, pirmą kartą pradėjo dirbti su RNR, būdama septintojo dešimtmečio pabaigoje Segedo universiteto magistrantė. Mokslininkai buvo suinteresuoti manipuliuoti vadinamąja maža RNR, kad būtų sukurtas antivirusinis poveikis. 1985 m. biologijos centrui, kuriame ji dirbo mokslininke, pritrūko finansavimo, todėl jos postdoktorantūros pareigos buvo nutrauktos.

 

Ji pateikė paraiškas dėl trijų mokslinių tyrimų pozicijų Europoje, bet negalėjo gauti finansavimo. Tada ji gavo postdoktorantūrą Temple universitete. Ji su vyru pardavė savo automobilį už 900 funtų sterlingų (apie 1200 dolerių), įsiuvo kupiūras į savo 2 metų dukters meškiuką – Vengrija neleido piliečiams išsivežti grynųjų iš šalies – ir persikėlė į Filadelfiją.

 

Po daugelio metų Pensilvanijos universitetas pasamdė ją docente. Tuo metu ji numatė naudoti iRNR, kad sukurtų terapinius baltymus, kurie galėtų pakeisti vaistus. Tačiau kadangi jai nepavyko gauti grantų, ji buvo palikta nepaaukštinta pareigose. Vyriausybė, ne pelno institucijos ir investuotojai skeptiškai vertino iRNR, nes buvo laikoma, kad genetinė medžiaga yra trapi ir gamina per mažai baltymų, kad būtų veiksminga. „Dvejus metus kiekvieną mėnesį teikdavau paraišką grantui ir jo negavau“, – interviu sako M. Kariko. iRNR tyrimai „buvo užsistovėjusi bala“.

 

Pasikliaudama vyresniaisiais fakulteto dėstytojais, kurie parėmė jos mokslinius tyrimus, ji buvo pasiryžusi parodyti, kad iRNR gali būti naudojama medicininiam gydymui. Kurį laiką ji bendradarbiavo su kardiologu, kurdama iRNR, koduotą baltymams, kurie galėtų užkirsti kelią kraujo krešuliams po širdies šuntavimo operacijos. Vėliau ji dirbo su neurologu, kad sukurtų iRNR, kuri nurodytų ląstelėms sukurti fermentą, gaminantį azoto oksidą, kuris galėtų išplėsti smegenų kraujagysles ir palengvinti insulto gydymą.

 

Vieną dieną ji atsitrenkė į imunologą Drew Weissman prie kopijavimo aparato. "Jis domėjosi vakcina ir sakė, kad dirbo su Anthony Fauci. Aš nežinojau, kas yra Fauci. Tuo metu jis nebuvo televizijoje", - sako ji. "Drew pasakė, kad nori sukurti vakciną, kuri būtų gydomoji ir profilaktinė."

 

Ji atliko daug eksperimentų su gyvūnais ir ląstelėmis, kultivuotomis Petri lėkštelėse. Tačiau, kai daktaras Weissmannas išbandė jos sintetinę mRNR, ji sukėlė uždegiminį atsaką tarp žmogaus imuninių ląstelių.

 

Galiausiai ponia Kariko ir daktaras Weissmanas eksperimentuodami atrado, kad pakeitus uridiną, vieną iš mRNR komponento „raidžių“, į chemiškai panašų junginį, vadinamą pseudouridinu, uždegiminis atsakas susilpnėjo. "Tai pagamino 10 kartų daugiau baltymų", - sako ji. Nuo 2005 m. jie paskelbė straipsnių, aprašančių jų atradimą, seriją.

 

Tyrimai patraukė kamieninių ląstelių biologo Derricko Rossi dėmesį, kuriam kilo mintis panaudoti iRNR suaugusiųjų žmogaus kamieninėms ląstelėms perprogramuoti. Savo idėja jis pasidalijo su Harvardo medicinos mokyklos kolega imunologu Timothy Springeriu. J. Springeris turėjo dar ambicingesnių minčių komercializuoti iRNR ir kreipėsi į Robertą Langerį, Masačusetso technologijos instituto biomedicinos inžinerijos profesorių, turintį patirties vaistų pristatymo ir audinių inžinerijos srityse. Finansuojant biotechnologijų rizikos kapitalo investuotojams, „Moderna“ buvo įkurta 2010 m.

 

Tuo tarpu Ugur Sahinas ir Ozlem Tureci, vyro ir žmonos imunologų komanda iš Vokietijos, taip pat dirbo su iRNR. Pora numatė naudoti iRNR imunoterapijai, kuri mobilizuoja imuninę sistemą kovai su vėžiu. 2008 m. jie pristatė „BioNTech“.

 

„BioNTech“ ir „Moderna“ licencijavo „Kariko-Weissman“ naujovę ir jai kūrė pritaikymus daugiau, nei dešimtmetį. Be genetinės sekos, koduojančios baltymą, iRNR taip pat apima elementus, kurie pateikia žmogaus ląstelių mechanizmų instrukcijų vadovą.

 

Kiekviena ląstelė turi galimybę gaminti baltymus, sako Dr. Sahinas, BioNTech generalinis direktorius. „Tačiau „vertimo“ reguliavimas yra sudėtingas procesas. Vertimu jis vadina procesą, kurio metu iRNR paverčiama baltymu. "Turite įsivaizduoti, kad ribosoma, kurioje verčiama iRNR, yra privilegijuota vieta ląstelėje. Ne kiekviena iRNR gali ten patekti", - sako jis; iRNR reikia "paso, kad pasiektų ribosomą. Ląstelė gamina daug kitų iRNR. Taigi, vyksta konkurencija, kiek laiko iRNR gali išlikti ribosomoje ir būti panaudota baltymo sintezei. Ir tai daro skirtumą, ar iRNR išlieka pakankamai ilgai, kad padarytų penkias baltymo kopijas, ar 20 ar 100 baltymų kopijų.

 

Mokslininkai turi ne tik sukurti genetinę seką baltymams, kuriuos nori sukurti ląstelės. Jie taip pat turi sukurti „pasą“, kad lieptų ląstelės mechanizmams sukurti daugiau ar mažiau baltymų.

 

BioNTech dirba su „savaime amplifikuojančia“ iRNR, kuri gali pagaminti didelį kiekį baltymų iš nedidelio iRNR kiekio. Tai galėtų nepaprastai pagerinti gamybos efektyvumą – efektyviai perkelti daugiau iRNR gamybos iš laboratorijos į žmogaus ląsteles – ir būsimų vakcinų bei gydymo būdų veiksmingumą.

 

2018 m. BioNTech kartu su Pfizer sukūrė gripo vakciną. Įprastais skiepais nuo gripo virusai suleidžiami į apvaisintus vištų kiaušinius. Mokslininkai surenka skystį, kuriame yra viruso, ir jį inaktyvuoja – tai sudėtingas procesas, trunkantis mažiausiai šešis mėnesius. Mokslininkai turi atspėti, kokios padermės gali vyrauti, likus mažiausiai aštuoniems mėnesiams iki gripo sezono. Tai yra viena iš priežasčių, kodėl gripo vakcinos vidutiniškai 50% veiksmingos, užkertant kelią ligoms.

 

Informacinės RNR vakcina nuo gripo galėtų pagerinti šį veiksmingumą, nes geriau suderinama su apyvartoje esančiomis padermėmis. Ir iRNR sukuria stipresnį imuninį atsaką nei inaktyvuoti virusai. „Pfizer“ ir „BioNTech“ pradėjo gripo vakcinos bandymą rugsėjį, o „Moderna“ – liepą.

 

Moderna taip pat tobulina vakcinas nuo kitų infekcinių ligų, įskaitant Zikos, ŽIV, Epstein-Barr, CMV, žmogaus metapneumovirusą, paragripo virusą ir kvėpavimo takų sinklininį virusą. Paskutiniai trys yra kvėpavimo takų virusai, galintys sukelti sunkias ligas vaikams ir vyresniems, nei 65 metų žmonėms. „Moderna“ siekia vienu metu sujungti vakcinas nuo sezoninio gripo, RSV ir Covid-19.

 

Prieš pandemiją „Moderna“ ir „BioNTech“ dirbo naudodami iRNR terapiniais tikslais. „Moderna“ kartu su „AstraZeneca“ naudojo iRNR terapiją, siekdama atkurti širdies nepakankamumu sergančius pacientus. Jų iRNR koduoja baltymą, vadinamą kraujagyslių endotelio augimo faktoriumi A, kuris skatina naujų kraujagyslių augimą. 1 fazės tyrimas, baigtas 2019 m. pradžioje, parodė, kad iRNR, suleista į žmonių odą, sukėlė lokalizuotą baltymo gamybą be rimto šalutinio poveikio. Praėjusį mėnesį jie pranešė apie teigiamus ankstyvuosius 2 fazės tyrimo rezultatus.

 

Kaip prieš dešimtmetį pripažino J. Rossi, iRNR taip pat suteikia galimybę perprogramuoti ląsteles. „Mes parodėme, kad iRNR gali būti naudojama generuoti iš kraujo ląstelių kamienines ląsteles“, – sako dr. Rossi. "Tai   padidina potencialą kovoti su įvairiomis ligomis, įskaitant senėjimą ir audinių atstatymą." Būsimas iRNR naudojimas galėtų apimti kremzlės gamybos stimuliavimą, kad palengvintų artritą, o kolageno - raukšlių mažinimui.

 

Autoimuninės ligos, kai imuninė sistema atakuoja kūno dalis, yra dar viena perspektyvi tyrimų sritis. BioNTech šiais metais paskelbė tyrimą, kuris parodė, kad iRNR vakcina gali gydyti išsėtinę sklerozę, neslopindama imuninės sistemos, kaip tai daro esami gydymo būdai.

 

BioNTech pagrindinis dėmesys skiriamas vėžiui. Klinikinėje rinkoje yra 21 iRNR produktas, kuris naudoja 11 skirtingų vėžio ląstelių naikinimo metodų. Vienas iš pirmųjų M. Kariko projektų bendrovėje BioNTech buvo susijęs su citokinus – imuninį atsaką kontroliuojančius baltymus – koduojančios iRNR injekcija į naviko paviršių. Dėl to „šaltas auglys įkaista, todėl imuninės ląstelės ten migruoja, kad galėtų surasti metastazavusį naviką ir jį nužudyti“.

 

Kitas būdas yra vėžio imunoterapija, pritaikyta pacientui. Daktaras Sahinas paaiškina, kaip tai veikia: paėmę biopsiją „mes nustatome mutacijas“ ir naudojame mašininį mokymąsi „atrinkdami tas mutacijas, kurios geriausiai tinka paciento augliui aptikti. Tada paruošiame pacientui iRNR. Tai yra ką galime padaryti per mažiau, nei šešias savaites“.

 

Tada pacientui suleidžiama iRNR, kuri koduoja „neoantigenus“ ant naviko, o tai suaktyvina imuninę sistemą, kad naviką atakuotų. BioNTech jau pradėjo 2 fazės individualizuoto melanomos ir storosios žarnos vėžio gydymo bandymus, o pirmųjų rezultatų tikimasi kitais metais. Ji taip pat stengiasi naudoti iRNR, kad būtų išvengta atkryčių, skatinant T ląsteles patruliuoti visame kūne ir naikinti paslėptas vėžio ląsteles, kurios metastazuoja.

 

Nors „Moderna“ ir „BioNTech“ buvo iRNR pionieriai, stambūs vaistų gamintojai, įskaitant „Pfizer“, „Sanofi“ ir „Merck“, dabar daug investuoja į šią technologiją, o tai reiškia, kad didesnė pažanga gali įvykti dar greičiau. Rizikos kapitalistai pila pinigus į iRNR startuolius, tokius, kaip „Strand Therapeutics“ ir „Kernal Biologics“.

 

Ne visi eksperimentiniai iRNR produktai bus sėkmingi. „Daug kartų maniau, kad kažkas yra gera idėja, o paskui supratau, kad tai neįgyvendinama“, – pripažįsta M. Kariko. Tačiau, kaip rodo jos karjera, „yra galimybių langai šalia uždarų durų“ [1]

1. The Vast Promise of mRNA Technology

Finley, Allysia.  Wall Street Journal, Eastern edition; New York, N.Y. [New York, N.Y]. 04 Dec 2021: A.11.

The Vast Promise and Amazing History of mRNA Technology


"Are Covid-19 vaccines a failure? That's the view in some media quarters amid breakthrough infections and new virus variants. It's also false. Vaccinated people are more prone to mild infections than public-health authorities initially anticipated. But the shots continue to provide strong protection against serious disease, and the mRNA vaccines in particular -- Pfizer/BioNTech's and Moderna's -- are adaptable to new variants.

More important, the drama over vaccines has masked a bigger and untold story, which is the vast promise of mRNA technology. Messenger RNA has shown enormous potential for medical applications beyond Covid to other infectious diseases, as well as vaccines and treatments for conditions from cancer to multiple sclerosis. Its development is a tale of scientific perseverance and serendipity that deserves more attention, with a prominent role by an American immigrant from communist Hungary.

The Omicron variant is an example of mRNA's promise and adaptability. Omicron has some 30 mutations on its spike protein that could make it harder for vaccine-induced antibodies to recognize and neutralize the virus. But mRNA vaccines can be reformulated for the new variant.

BioNTech and Pfizer say they could begin shipping vaccines that target Omicron within 100 days if protection from their existing vaccines declines substantially against the new variant. Moderna has already started testing booster shots designed to anticipate mutations. It also says it would rapidly advance an Omicron-specific booster shot, which could be available early next year.

That quick pivot would be impossible with conventional vaccine technologies, which usually take between six and 36 months just to manufacture and deliver. It can take many more years to design vaccines. With mRNA, vaccine makers only need about six weeks to adapt a shot and then take it from the lab to production.

Messenger RNA delivers the genetic code instructing human cells how to create a protein -- in this case, the coronavirus spike, which binds to the ACE2 receptor on human cells. The mRNA is enveloped in lipid nanoparticles, which are fatty blobs that protect the genetic motherload from degradation and facilitate its entry into cells. Once the mRNA is injected into the muscle, human cells become vaccine mini-factories that churn out pseudovirus particles, which in turn prompt the immune system to produce antibodies that respond when confronted with the real thing. The vaccines also induce T cells, which provide a backup defense to antibodies. If a virus mutates, scientists can easily swap new genetic code into the mRNA.

The Moderna and Pfizer/BioNTech Covid vaccines are the first commercially approved mRNA products, but they were made possible by decades of experimentation, innovation and determination. Geneticists established the existence of mRNA in the early 1960s. RNA regulates how genes are expressed and is a single-stranded molecule similar to the double-helix DNA. Messenger RNA carries the instructions from DNA to the protein-making machinery in cells, known as ribosomes.

That's where Katalin Kariko comes in. The 66-year-old Hungarian-born biochemist, now a scientist at BioNTech, first began working with RNA as a graduate student in the late 1970s at the University of Szeged. Researchers were interested in manipulating what is known as small RNA to generate antiviral effects. In 1985 the biological center where she was a researcher ran out of funding, and her postdoctoral position was terminated.

She applied for three research positions in Europe but wasn't eligible for funding. Then she landed a postdoctoral position at Temple University. She and her husband sold their car for GBP900 (about $1,200), sewed the notes into their 2-year-old daughter's teddy bear -- Hungary didn't allow citizens to take cash out of the country -- and moved to Philadelphia.

Years later the University of Pennsylvania hired her as an adjunct professor. At the time, she envisioned using mRNA to create therapeutic proteins that could substitute for medications. But because she failed to obtain grants, she was passed up for promotions. Government, nonprofit institutions and investors were skeptical about mRNA since the genetic material was considered fragile and produced too little protein to be effective. "For two years every month I submitted for a grant and got none," Ms. Kariko says in an interview. Research on mRNA "was a backwater."

Relying on senior faculty to support her research, she was determined to show that mRNA could be used for medical treatments. For a time she collaborated with a cardiologist on designing mRNA coded for proteins that could prevent blood clots after heart-bypass surgery. Later she worked with a neurologist to design mRNA that would instruct cells to create an enzyme that produces nitric oxide, which could dilate the brain's blood vessels to relieve a hemorrhage.

One day she bumped into the immunologist Drew Weissman at a copy machine. "He was interested in doing a vaccine, and he says he was working with Anthony Fauci. I didn't know who Fauci was. He was not in the television at the time," she says. "Drew said he wanted to make a vaccine that can be therapeutic and prophylactic."

She performed many experiments in animals and on cells cultured in Petri dishes. Yet when Dr. Weissmann tested her synthetic mRNA, it triggered an inflammatory response from human immune cells.

Eventually, Ms. Kariko and Dr. Weissman discovered by experimentation that swapping out uridine, one of mRNA's component "letters," for a chemically similar compound called pseudouridine blunted the inflammatory response. "This produced 10 times more protein," she says. Starting in 2005 they published a series of papers describing their discovery.

The studies caught the attention of stem-cell biologist Derrick Rossi, who had the idea of using mRNA to reprogram human adult stem cells. He shared his idea with his Harvard Medical School colleague Timothy Springer, an immunologist. Mr. Springer had even more ambitious ideas to commercialize mRNA and approached Robert Langer, a Massachusetts Institute of Technology biomedical engineering professor with expertise in drug delivery and tissue engineering. With funding from biotech venture capitalists, Moderna was founded in 2010.

Meantime, Ugur Sahin and Ozlem Tureci, a husband-and-wife immunologist team from Germany, were also working on mRNA. The couple envisioned using mRNA for immunotherapies, which mobilize the immune system to fight cancer. In 2008 they launched BioNTech.

BioNTech and Moderna both licensed the Kariko-Weissman innovation and have spent more than a decade building on it. Beyond a genetic sequence that encodes a protein, mRNA also includes elements that provide an instruction manual to the human cell machinery.

Every cell has the ability to make proteins, Dr. Sahin, CEO of BioNTech, says. "But the regulation of the 'translation' is a complex process." By translation, he means the process by which mRNA is converted into a protein. "You have to imagine that the ribosome where the mRNA is translated is a privileged place in the cell. Not every mRNA can go there," he says; mRNA needs "a passport to reach the ribosome. And when it is in the cell, there are many other mRNAs produced by the cell. So there's a competition for how long the mRNA can stay at the ribosome and be translated. And it makes a difference whether the mRNA stays long enough to make five copies of a protein or 20 or 100 copies of a protein."

Scientists don't only have to design the genetic sequence for the proteins they want cells to create. They also have to create the "passport" to tell the cell's machinery to create more or less of a protein.

BioNTech is working on "self-amplifying" mRNA that can produce large amounts of protein from a small amount of mRNA. This could enormously improve manufacturing efficiency -- effectively moving more mRNA production from the lab into human cells -- and the efficacy of future vaccines and treatments.

In 2018 BioNTech paired with Pfizer to develop a flu vaccine. With conventional flu shots, viruses are injected and fertilized in chicken eggs. Scientists harvest the fluid containing the virus and inactivate it, a cumbersome process that takes at least six months. Scientists have to guess the strains likely to be predominant at least eight months before flu season. That's one reason flu vaccines are only 50% effective at preventing illness on average.

An mRNA flu vaccine could improve that efficacy by better matching the strains in circulation. And mRNA generates a stronger immune response than the inactivated viruses. Pfizer and BioNTech started a flu-vaccine trial in September, and Moderna launched one in July.

Moderna is also advancing vaccines for other infectious diseases, including Zika, HIV, Epstein-Barr, CMV, human metapneumovirus, parainfluenza virus and respiratory synclinal virus. The last three are respiratory viruses that can cause severe illness in children and people over 65. Moderna aims to combine vaccines for seasonal flu, RSV and Covid-19 into a single shot.

Before the pandemic, Moderna and BioNTech were each working on using mRNA for therapeutic purposes. Moderna paired with AstraZeneca on an mRNA therapy to regenerate heart tissue patients with heart failure. Their mRNA encodes a protein called vascular endothelial growth factor A, which promotes new blood-vessel growth. A phase 1 trial completed in early 2019 showed the mRNA, after being injected into the skin of men, caused a localized production of the protein without severe side effects. Last month they reported positive early results from a Phase 2 trial.

As Mr. Rossi recognized a decade ago, mRNA also offers the potential to reprogram cells. "We have shown that mRNA can be used to take a blood cell and generate a stem cell," Dr. Sahin says. "This opens up the potential to address various diseases including aging and tissue repair." Future mRNA uses could include stimulating the production of cartilage to ease arthritis and collagen to reduce wrinkles.

Autoimmune diseases, in which the immune system attacks parts of the body, are another promising area of research. BioNTech this year published a study that showed an mRNA vaccine has potential to treat multiple sclerosis without suppressing the immune system like existing therapies do.

BioNTech's main focus is cancer. It has 21 mRNA products in its clinical pipeline that use 11 different approaches to killing cancer cells. One of Ms. Kariko's first projects at BioNTech involved injecting mRNA coding for cytokines -- proteins that control the immune response -- into the surface of a tumor. That makes "the cold tumor hot, so that immune cells migrate there so they can see the metastatic tumor there and kill it."

Another approach is cancer immunotherapy personalized for the patient. Dr. Sahin explains how it works: After taking a biopsy, "we identify the mutations" and use machine learning "to select those mutations that are the best suited to detect the patient's tumor. And then we prepare mRNA for the patient. This is something we can do in less than six weeks."

The patient is then injected with mRNA that codes for "neoantigens" on the tumor, which turbocharges the immune system to attack it. BioNTech has already begun Phase 2 trials for personalized melanoma and colon-cancer therapies, with initial results expected next year. It is also working on using mRNA to prevent relapses by inducing T cells to patrol throughout the body and kill hidden cancer cells that metastasize.

While Moderna and BioNTech were pioneers in mRNA, large drug makers including Pfizer, Sanofi and Merck are now investing heavily in the technology, which means more advances may come even sooner. Venture capitalists are pouring money into mRNA startups such as Strand Therapeutics and Kernal Biologics.

Not all experimental mRNA products will succeed. "There are many times I thought something was a good idea and then I realized it was not feasible," Ms. Kariko concedes. But as her career shows, "there are windows of opportunities from closed doors."” [1]

1. The Vast Promise of mRNA Technology

Finley, Allysia.  Wall Street Journal, Eastern edition; New York, N.Y. [New York, N.Y]. 04 Dec 2021: A.11.