Where is all the warp speed gone?

"The Trump administration's Operation Warp Speed delivered three Covid-19 vaccines in record time. Yet liberals are giving the program its due only now, amid President Biden's Covid-19 stumbles. Some, including former Biden adviser Ezekiel Emanuel, are even calling for another Operation Warp Speed to boost therapies. Operation Warp Speed also delivered the two monoclonal antibody treatments. More such treatments would have been available this winter had the Biden team not abandoned the program.

Early in the pandemic, the government struggled to persuade drugmakers to invest in vaccines and therapies. Many companies lost money during previous public-health emergencies when treatments they developed turned out not to be needed. "I'm not like a drug company fan, but there's no question that a lot of them lost a lot of money trying to produce an Ebola vaccine," said Ron Klain, now White House chief of staff, in February 2020.

Operation Warp Speed shifted the financial risk to government by placing orders for vaccines and therapies before they were authorized by the Food and Drug Administration or even shown to be effective. This encouraged pharmaceutical companies to expand manufacturing capacity so vaccines and therapies were ready to be distributed once they had the FDA's green light.

Three Operation Warp Speed leaders explained the strategy in a September 2020 commentary for the New England Journal of Medicine. "Predicting drug performance in a new disease is difficult," Moncef Slaoui, Shannon E. Greene and Janet Woodcock wrote. "Many candidates may fail to demonstrate efficacy or have safety problems. It's necessary, however, to take a financial risk early to scale up manufacturing in order to have drug supplies on hand if the results are positive. If we wait for clinical trial readouts before initiating large-scale manufacturing, developing an adequate supply could take months or years."

In July 2020, Operation Warp Speed announced a $450 million manufacturing and supply agreement with Regeneron for up to 300,000 doses of its experimental monoclonal antibody. A few months later, it ordered 300,000 doses of Eli Lilly's experimental antibody. The FDA granted emergency-use authorization to both treatments in November 2020.

Supply of both monoclonals exceeded demand last winter because many people were unaware of the treatments. Still, during the final two months of the Trump presidency, Operation Warp Speed ordered another 1.25 million doses of Regeneron's and 650,000 of Eli Lilly's antibody treatments, leaving the Biden administration well supplied.

When the Biden team took over, they dismissed Mr. Slaoui, announced they were "phasing in a new structure," and retired the Operation Warp Speed name. Cases and hospitalizations fell as vaccines rolled out. President Biden prematurely declared success last Fourth of July and failed to prepare for another wave by stockpiling treatments and investing in new ones.

The Biomedical Advanced Research and Development Authority, or Barda, did announce in June 2021 that it would pay $1.2 billion for 1.7 million courses of Merck's investigational antiviral pill molnupiravir, but only if the FDA granted emergency-use authorization. That meant Merck had to put its own money at risk to expand manufacturing in advance, which may have reduced the supply that was available once the drug was authorized in December.

When the Delta variant slammed the South in July, GOP governors promoted the Regeneron and Eli Lilly monoclonal treatments. Supplies had to be rationed as demand surged. As the Delta wave crested in mid-September, the Pentagon and the Health and Human Services Department ordered 1.4 million more doses of Regeneron's antibody and 388,000 doses of Eli Lilly's.

Florida Gov. Ron DeSantis sought to circumvent the feds by ordering a monoclonal antibody treatment from GlaxoSmithKline and Vir. The antibody binds to a target on Covid-19 that is shared with the SARS virus, making it more difficult for variants to evade. It was authorized by the FDA in May, but the Biden administration then declined to add it to its meager treatment arsenal. This was a colossal mistake, since it was the only monoclonal treatment for infected patients that turned out to be effective against the Omicron variant.

The administration couldn't have anticipated that, but Operation Warp Speed's strategy was to diversify its bets expecting some to fail. The Biden team relied almost exclusively on Regeneron and Eli Lilly antibodies, even though scientists had warned that new variants might be able to evade them. The additional doses that Barda ordered in September were helpful for a couple of months until Omicron arrived.

Only in November did GSK and Vir announce a $1 billion contract with Barda. Around the same time Barda reached a $5.3 billion agreement with Pfizer for 10 million courses of its oral antiviral Paxlovid. Had it ordered these treatments earlier, much more supply would have been available this winter.

Why did the new administration abandon the successful Operation Warp Speed playbook? Most likely because progressives loathe pharmaceutical companies. Recall how congressional Democrats attacked Mr. Slaoui, a former GSK executive, without evidence, accusing him of profiting off his public service. Or maybe the Biden team believed their own cynical 2020 campaign line that Operation Warp Speed "lacks sound leadership, global vision, or a strategy."

Asked by New York Times columnist Ezra Klein last week whether the government should adopt OWS's strategy for other technologies, Mr. Klain, White House chief of staff under President Joe Biden, replied: "I think we have to be careful about the level of government intervention in the economy and make sure that we're not putting our judgment in the place of private-sector thoughts and consumer demand and whatnot. I think vaccines are a very, very special case, a public good we wanted everyone to get."

He's right, but life-saving Covid-19 therapies are also a special case.

At the same time, the Biden administration wants to spend hundreds of billions of dollars intervening in the economy to support green energy technologies that consumers largely don't want and are unlikely to do much public good." [1]

Voters usually severely punish those who cause many deaths unnecessarily. We’ll see how it happens this time soon. Including Lithuania. 

1.  Operation Warp Speed Slowly Gets Its Due
Finley, Allysia. Wall Street Journal, Eastern edition; New York, N.Y. [New York, N.Y]. 01 Feb 2022: A.15.

Apsaugoti genai: prie evoliucijos vairo

"Gamtą valdo atsitiktinumas, yra biologijos dogma. Vokietijos augalų genetikai dabar įrodė, kad mutacijos genome nesikaupia nekontroliuojamai, o organizmas tikslingai saugo kai kuriuos genus.

 

Nuo pat Charleso Darwino laikų evoliucinė biologija pagerbė atsitiktinumą ir formuluoja tokius sakinius, kaip: „Evoliucija nieko nenori, nieko neplanuoja ir neturi tikslo“. Mutacijos – pagal vieną iš svarbiausių dogmų – atsiranda atsitiktinai ir nesirūpina jų sukeliamomis pasekmėmis. Tik jų priešininkė – natūrali atranka – nusprendžia, kurie genai keičiasi greičiau, o kurie lėčiau. Todėl tokios kategorijos, kaip atsitiktinumas ir bekryptiškumas laikomos pagrindinėmis evoliucinio biologinio mąstymo prielaidomis. Šį mąstymą sutvirtino 1969 m. Nobelio medicinos premija, skirta Salvadorui Luriai ir Maxui Delbrückui. Prieš dvidešimt šešerius metus mokslininkai įrodė, kad bakterijų populiacijose visada yra ir bakterijų, kurios jau yra atsparios virusams, su kuriais tos bakterijų populiacijos dar nebuvo susidūrusios. Todėl mutacijos, tarpininkaujančios atsparumui, turėjo atsirasti be šių virusų pagalbos – tiesiog atsitiktinai ir netyčia.

 

Detlefo Weigelio, Grey Monroe ir kitų kolegų publikacija žurnale „Nature“ dabar pakerta šias pagrindines prielaidas. Weigelis yra Maxo Plancko biologijos instituto Tiubingene direktorius ir Monroe profesorius Kalifornijos universitete Davise. 

 

Mokslininkai sugebėjo parodyti, kad piktžolės Arabidopsis thaliana, vieno iš svarbiausių mokslinio modelio augalų, genomo mutacijos jokiu būdu nėra taip atsitiktinai paskirstytos visame genome, kaip manyta anksčiau. Greičiau genetiniai pokyčiai kai kur vyksta dažniau, o kitur – rečiau. Mutacijų dažnis koreliuoja su genų svarba augalo gebėjimui išgyventi ir daugintis. Mutacijų greitis yra mažesnis ten, kur yra esminiai piktžolės genai, ir didesnis regionuose, kuriuose yra mažiau esminių genų.

 

Mutacijos taip pat nevienodai pasiskirsto vadinamuosiuose koduojančiuose ir nekoduojančiuose geno regionuose. 

 

Koduojančios DNR sekos, t. y. tos, kurios yra tiesiogiai atsakingos už baltymo sintezę, buvo mutuojamos tik perpus dažniau, nei nekoduojančios sekcijos, esančios prieš ir po atitinkamų genų.

 

 Esminiai genai parodė net dviem trečdaliais mažiau mutacijų, nei neesminiai genai. 

 

„Atrodo, tarsi evoliucija būtų žaidžiama su pakrautais kauliukais“, – sako Weigelis. „Augalai akivaizdžiai sukūrė būdą, kaip apsaugoti svarbiausius savo genus nuo mutacijų, kad jie galėtų geriau išgyventi. Tai visiškai naujas požiūris į tai, kaip atsiranda mutacijos ir kaip veikia evoliucija.

 

Kuo pagrįstos šios išvados? Weigelis ir jo kolegos atliko vadinamuosius mutacijų kaupimo eksperimentus su šimtais Arabidopsis augalų, kurių metu natūrali atranka buvo beveik visiškai pašalinta, ir ištyrė daugiau, nei milijoną naujai atsiradusių mutacijų. Pašalinus natūralią atranką, mokslininkai sugebėjo išanalizuoti visas mutacijas, įskaitant kenksmingąsias, kurios paprastai greitai išnyksta, veikiant atrankos spaudimui. Šis žygdarbis buvo įmanomas tik todėl, kad Arabidopsis turi palyginti nedidelį genomą su 120 milijonų bazinių porų. Kaip atsiranda netolygus mutacijų pasiskirstymas piktžolių genome?

 

Devyniasdešimt procentų dispersijos gali būti paaiškinta skirtingais epigenetiniais ženklais ir skirtumais DNR pakavimo baltymuose. Šie genomo pokyčiai – taip sakant apsauginiai dangteliai – lemia, kiek atvira ir prieinama genetinė medžiaga yra jos įtakos sferoje, taigi, kaip gerai DNR gali būti atkurta, įvykus mutacijai, nes remonto fermentai negali atlikti savo darbus be tiesioginės prieigos prie DNR grandinės. 

 

„Svarbiausia mūsų išvada yra ta, kad akivaizdu, kad ląstelėje yra genų klasė, kuri yra pažymėta kitaip, nei kiti genai ir kurie dėl šių ženklų yra ypač gerai ir efektyviai pataisomi“, - sako Weigelis. – Tai mus nustebino.

 

Kas išlaiko Arabidopsis labiau subalansuotą – netolygus mutacijų pasiskirstymas ir efektyvus esminių genų taisymas, ar neigiama arba gryninanti atranka, pašalinanti kenksmingas ir žalingas genų versijas? 

 

Weigelis ir jo kolegos sugebėjo parodyti, kad evoliucijai (bent jau Arabidopsis) daugiau įtakos turi efektyvus esminių genų taisymas, o mažiau – gryninimo atranka. Kadangi esminiai piktžolės genai toleruoja nedidelį kintamumą, augalas akivaizdžiai nelaukia, kad atranka pašalintų pažeistą alelį, bet iš karto ir tiksliai ištaiso klaidą.

 

Augalų veisimo galimybės

 

„Nepaisant to, esminiai genai, laikui bėgant, taip pat keičiasi, – sako Weigelis, – nors ir lėčiau, nei kitos genomo dalys.“ Regionai, kuriuose yra mažiau svarbių genų, toleruoja didesnį kintamumą. Čia atrankai suteikiama daugiau galimybių pasirinkti naujus ir naudingus variantus. Rezultatai yra nuostabūs keliais aspektais. Viena vertus, jie pakeičia evoliucinės biologijos jėgų, slypinčių natūralų kitimą, vaizdą. Kita vertus, jie turi ir labai praktinių pasekmių.

 

Jei Arabidopsis apsaugo savo svarbiausius genus nuo mutacijų specialiais genomo ir baltymų žymenimis, žmogaus genomas taip pat gali būti geriau apsaugotas, pavyzdžiui, nuo mutacijų, sukeliančių vėžį.

 

 Tačiau augalų selekcija taip pat gali būti naudinga. Jei žinote, kurie genomo regionai yra ypač jautrūs mutacijoms, o kurie mažiau, natūralią variaciją galima geriau kontroliuoti. Bet kuriuo atveju atsitiktinumas nėra vienintelis evoliucijos variklis."

 

Protected genes : At the wheel of evolution

"Chance rules nature, is a dogma of biology. German plant geneticists have now shown that mutations do not accumulate in the genome in an uncontrolled manner, but rather that the organism protects some genes in a targeted manner.

 

Ever since Charles Darwin, evolutionary biology has paid homage to chance and formulates sentences like "Evolution wants nothing, plans nothing and has no goal". Mutations - according to one of their most important dogmas - occur randomly and do not care about the consequences they produce. Only its opponent, natural selection, decides which genes change faster and which change more slowly. Categories such as chance and directionlessness are therefore considered basic assumptions of evolutionary biological thinking. This thinking was cemented by the Nobel Prize in Medicine awarded to Salvador Luria and Max Delbrück in 1969. Twenty-six years earlier, the scientists had shown that bacterial populations always also contain bacteria that are already resistant to viruses that they have not yet encountered and which they therefore also not know. The mutations that mediate resistance must therefore have arisen without the help of these viruses - just randomly and undirectedly.

 

A publication by Detlef Weigel, Gray Monroe and other colleagues in the journal "Nature" now scratches at these basic assumptions. Weigel is Director at the Max Planck Institute for Biology in Tübingen and Monroe Professor at the University of California in Davis. 

 

The scientists were able to show that the mutations in the genome of the weed Arabidopsis thaliana, one of the most important scientific model plants, are by no means as randomly distributed across the genome as previously assumed. Rather, genetic changes occur more frequently in some places and less frequently in other places. The frequency of mutations correlates with the importance of the genes for the plant's ability to survive and reproduce. The mutation rate is lower where the essential genes of the weed are located, and higher in the regions where the less essential genes are located.

 

The mutations are also unequally distributed within the so-called coding and non-coding regions of a gene. Coding DNA sequences, i.e. those that are directly responsible for the synthesis of a protein, were only mutated half as often as the non-coding sections that lie before and after the respective genes. 

 

Essential genes showed two-thirds fewer mutations than non-essential genes. 

 

"It's just as if evolution were playing with loaded dice," says Weigel. "Plants have evidently evolved a way to protect their most important genes from mutations so that they can survive better. This is a whole new perspective on how mutations arise and how evolution works.”

 

What Arabidopsis in the Lot?

 

What are these findings based on? Weigel and his colleagues carried out so-called mutation accumulation experiments with hundreds of Arabidopsis plants, in which natural selection was almost completely eliminated, and examined more than a million newly occurring mutations. By eliminating natural selection, the scientists were able to analyze all mutations, including the harmful ones, which normally disappear quickly under the pressure of selection. This feat was only possible because Arabidopsis has a relatively small genome with 120 million base pairs. How does the unequal distribution of mutations in the weed genome come about?

 

Ninety percent of the variance can apparently be explained by different epigenetic marks and DNA packaging proteins. These changes in the genome – protective caps, so to speak – determine how open and accessible the genetic material is in its sphere of influence and thus how well the DNA can be repaired in the event of a mutation, because the repair enzymes cannot do their job without direct access to the DNA strand .

 

 "Our most important finding is that there is obviously a class of genes in the cell that are marked differently than other genes and that are repaired particularly well and efficiently because of these markings," says Weigel. "That surprised us."

 

Now, what keeps Arabidopsis more in balance—the uneven distribution of mutations and the efficient repair of essential genes, or the negative or purifying selection that removes harmful and deleterious gene versions? 

 

Weigel and his colleagues were able to show that evolution—at least in Arabidopsis—is more strongly influenced by the efficient repair of essential genes and less by purifying selection. Because the weed's essential genes tolerate little variability, the plant obviously does not wait for that the selection removes the damaged allele, but repairs the error immediately and precisely.

 

Opportunities for plant breeding

 

"Nevertheless, the essential genes also change over time," says Weigel, "albeit more slowly than other parts of the genome." Regions with less important genes tolerate more variability. Here the selection is given more scope to select new and useful variants. The results are remarkable in several respects. For one thing, they change the picture that evolutionary biology has had of the forces behind natural variation. On the other hand, they also have very practical consequences.

 

If Arabidopsis protects its most important genes against mutations with special markers on the genome and proteins, the human genome may also be better protected, for example against mutations that cause cancer. 

 

But plant breeding could also benefit. If you know which regions of the genome are particularly susceptible to mutations and which are less so, natural variation can be better controlled. In any case, chance is not the only engine of evolution."