Category Archives: Interesting

Iran’s Nuclear Negotiators Make the U.S. Sit at the Kiddie Table

This is just fine with the President of the ‘Free’ World. Those whom the Democrats appointed to most agencies and offices of this administration are spineless when it comes to standing up for the principles of America and the west. They are will to sacrifice it all on the altar of ??? mrossol

WSJ  11/28/2021  By Reuel Mark Gerecht adn Ray Takeyh

Arms-control talks between Iran and the great powers resume Monday with a notable absence. At Tehran’s insistence, the U.S. delegation won’t have a seat at the table—its members must wait in an antechamber to be briefed by the Europeans. The mullahs have always relished humiliating Americans, particularly those eager to prove their benevolent intentions. These negotiations will yield little, no matter how much money Washington releases or how ardently Biden administration officials describe any follow-on talks as important steps toward a diplomatic solution.

The clerical regime’s atomic ambitions will continue to progress rapidly because the U.S. administration has no intention of trying to rescind what President Obama’s nuclear deal granted: the development of high-yield, easily hidden centrifuges, the key to an unstoppable bomb program. The Islamic Republic has displayed an uncanny ability to advance its aspirations and eviscerate American red lines with impunity.

The theocracy’s nuclear diplomacy succeeds precisely because it seeks no agreement. The mullahs understand things their interlocutors don’t. The U.S. and Israel have repeatedly chosen not to disable Iran’s nuclear program by force, undermining the regime’s fear of attack and allowing the supreme leader, Ali Khamenei, more maneuvering room. All U.S. administrations have sincerely, at times desperately, wanted an accord. The United Nations and the International Atomic Energy Agency censure the Islamic Republic, and the regime ignores them. If Tehran pretends to be interested in diplomacy, Washington, always fearful of another war in the Middle East, makes more concessions.

The achievements of this diplomatic stratagem are extraordinary. Washington and the Europeans once insisted that the Islamic Republic couldn’t have a domestic enrichment capacity. This was a sensible precaution. The infrastructure required to enrich uranium for nuclear power is the same as what is needed to make a bomb. The process is costly, and most nations that use civilian nuclear power import refined uranium.

 
 

Yet today U.S. and European officials, and many nuclear experts, pooh-pooh the idea that Iran should forgo indigenous enrichment. The Joint Comprehensive Plan of Action, the nuclear deal Mr. Obama struck and President Trump abandoned, has become canonical among Democrats. It specifies not only that Iran has the right to enrich but that its enrichment capability can become industrialized. The clerical regime obtained this permissive accord by merely showing up at various conclaves and holding firm. American officials fulminated, threatened, bickered among themselves and eventually capitulated.

The Biden administration isn’t diverging from Mr. Obama’s path. A well-timed Israeli leak shows the White House is considering an interim arrangement whereby Iran would cease some of its activities in exchange for sanctions relief. It won’t be long before Washington deludes itself into believing that a threshold capability will satisfy Iran, that it can be an Islamist version of Japan—inches away from developing a bomb but with no intention to take the next step.

The ascendance of the hard-line Ibrahim Raisi to the presidency altered the economics of arms control. He subscribes to Mr. Khamenei’s “economy of resistance,” the notion that Iran can meet its needs by relying on its internal market and trade with China and neighboring states. In this view, segregation from the global economy is virtuous, wise and courageous. Unlike former President Hassan Rouhani, the new crew isn’t looking for Western commerce as a means of rejuvenating the economy and the revolution. There appears to be little concern among Mr. Khamenei’s ruling elite that this scheme will lead to poverty and another lost generation.

Even more than Mr. Raisi, Mr. Trump accelerated history. According to Mr. Obama’s blueprint, we were going to see a nuclear Iran and a much richer clerical regime. Freed from sanctions, the ruling clergy and the Islamic Revolutionary Guards would have had time to build up their armed forces, as well as the nuclear-weapons program. Thinking that renewed and improved sanctions would give him a “good” nuclear deal (always a dubious proposition), Mr. Trump collapsed 15 years of Western diplomacy and the JCPOA’s envisioned decade of sun-setting restrictions into clear and irrevocable choices.

Mr. Biden can’t turn back the clock. Diplomacy and extortion—the two are synonymous for the Islamic Republic—may have had their day. Mr. Khamenei is going to make the president pony up a huge amount of money for the fleeting relief of his nuclear anxiety—assuming the supreme leader still even wants to play such games with the U.S. For Mr. Biden, the only question is whether he wants to endure this humiliation in return for so little.

Mr. Gerecht, a former Iranian-targets officer in the Central Intelligence Agency, is a senior fellow at the Foundation for Defense of Democracies. Mr. Takeyh, the author of “The Last Shah,” is a senior fellow at the Council on Foreign Relations.

https://www.wsj.com/articles/iran-nuclear-jcpoa-tehran-enrichment-islamic-republic-11638129541?mod=hp_opin_pos_3#cxrecs_s

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German Fisherman Catches Ultra-Rare Bright-Yellow Catfish That Looks Like Giant Banana

By Epoch Inspired Staff   November 9, 2021

A professional angler from Germany reeled in a rare bright-yellow wels catfish—like a giant, writhing banana with gills—while fishing with his twin brother on a lake in the Netherlands.

The fisherman from Duisburg, Martin Glatz, on Oct. 4 was testing out a new lure, and at first thought he’d hooked a fish “comparable to a 47-inch pike,” he said, judging by the fight being put up.

But when he peered down and saw the sunny-hued catfish “glowing” from about three to four meters below the surface, he started to panic a bit. “We fell into a state of shock,” Glatz told The Epoch Times. “And [I] yelled at my brother to have the landing net ready.”

Epoch Times Photo
(Courtesy of Martin Glatz)

He and his brother Owen netted and boated the extravagant, lemon-hued catfish. After measuring and snapping a few photos with the specimen, following regulations, they released it, so as to let it grow “very big.” He said the fish measured 1.19 meters and described it as “uniformly bright-orange” and “beautiful.”

“I have never seen such a catfish before,” Glatz told Live Science. “I am still overwhelmed by it.”

The catfish’s unusual yellow hue is probably caused by a genetic disorder called leucism, which, like albinism, is a pigmentation deficiency occurring in animals, but unlike albinism, does not affect the eyes. The disorder can affect mammals, birds, reptiles, and fish, causing them to appear lighter than normal—making them an easy target for predators.

Epoch Times Photo
(Courtesy of Martin Glatz)
Epoch Times Photo
(Courtesy of Martin Glatz)

Wels catfish, endemic to much of Europe, according to Field & Stream, can grow to be 9 feet long and weigh almost 300 pounds. Typical specimens are dark greenish-black, with some exhibiting mottled yellow spots, according to NOAA.

Some luck is involved boating a rare fish such as this one, of course, though Glatz, a devoted professional of the sport who wets his line two to three days a week, has ample opportunity. He’s been fishing since the age of 13, he said, and was introduced to the sport by his grandfather. Glatz’s favorite fishing spot is in Duisburg Harbor.

“It’s in our family,” he told the newspaper. “My twin brother is fishing, my wife is fishing, and hopefully our sons will discover the hobby for themselves as well.”

https://www.theepochtimes.com/german-fisherman-catches-ultra-rare-bright-yellow-catfish-that-looks-like-giant-banana_4085439.html?utm_source=News&utm_medium=email&utm_campaign=breaking-2021-11-21-1&est=ulKkVi2M9qoMlvElhB9QoHB80Sy9J3KP6lz2rCLnZ3zgTJWFq5ODUmGMiG6vYA==

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The tangled history of mRNA vaccines

This article from NATURE is provides a good history of the long road to mRNA development. Quite long, but interesting. mrossol

 
 
Illustration that shows the mRNA code used in the Pfizer–BioNTech vaccine, with a syringe containing a lipid nanoparticle.

The RNA sequence used in the COVID-19 vaccine developed by Pfizer and BioNTech (Ψ is a modified form of the uridine nucleotide, U).Credit: Nik Spencer/Nature

In late 1987, Robert Malone performed a landmark experiment. He mixed strands of messenger RNA with droplets of fat, to create a kind of molecular stew. Human cells bathed in this genetic gumbo absorbed the mRNA, and began producing proteins from it1.

Realizing that this discovery might have far-reaching potential in medicine, Malone, a graduate student at the Salk Institute for Biological Studies in La Jolla, California, later jotted down some notes, which he signed and dated. If cells could create proteins from mRNA delivered into them, he wrote on 11 January 1988, it might be possible to “treat RNA as a drug”. Another member of the Salk lab signed the notes, too, for posterity. Later that year, Malone’s experiments showed that frog embryos absorbed such mRNA2. It was the first time anyone had used fatty droplets to ease mRNA’s passage into a living organism.

Those experiments were a stepping stone towards two of the most important and profitable vaccines in history: the mRNA-based COVID-19 vaccines given to hundreds of millions of people around the world. Global sales of these are expected to top US$50 billion in 2021 alone.

But the path to success was not direct. For many years after Malone’s experiments, which themselves had drawn on the work of other researchers, mRNA was seen as too unstable and expensive to be used as a drug or a vaccine. Dozens of academic labs and companies worked on the idea, struggling with finding the right formula of fats and nucleic acids — the building blocks of mRNA vaccines.

Today’s mRNA jabs have innovations that were invented years after Malone’s time in the lab, including chemically modified RNA and different types of fat bubble to ferry them into cells (see ‘Inside an mRNA COVID vaccine’). Still, Malone, who calls himself the “inventor of mRNA vaccines”, thinks his work hasn’t been given enough credit. “I’ve been written out of history,” he told Nature.

Inside an mRNA COVID vaccine: infographic that shows the innovations used in the mRNA and nanoparticle of the vaccine.

Nik Spencer/Nature; Adapted from M. D. Buschmann et al. Vaccines 9, 65 (2021)

The debate over who deserves credit for pioneering the technology is heating up as awards start rolling out — and the speculation is getting more intense in advance of the Nobel prize announcements next month. But formal prizes restricted to only a few scientists will fail to recognize the many contributors to mRNA’s medical development. In reality, the path to mRNA vaccines drew on the work of hundreds of researchers over more than 30 years.

The story illuminates the way that many scientific discoveries become life-changing innovations: with decades of dead ends, rejections and battles over potential profits, but also generosity, curiosity and dogged persistence against scepticism and doubt. “It’s a long series of steps,” says Paul Krieg, a developmental biologist at the University of Arizona in Tucson, who made his own contribution in the mid-1980s, “and you never know what’s going to be useful”.

The beginnings of mRNA

Malone’s experiments didn’t come out of the blue. As far back as 1978, scientists had used fatty membrane structures called liposomes to transport mRNA into mouse3 and human4 cells to induce protein expression. The liposomes packaged and protected the mRNA and then fused with cell membranes to deliver the genetic material into cells. These experiments themselves built on years of work with liposomes and with mRNA; both were discovered in the 1960s (see ‘The history of mRNA vaccines’).

The history of mRNA vaccines: A timeline that shows the key scientific innovations in the development of mRNA vaccines.

Nik Spencer/Nature; Adapted from U. Şahin et al. Nature Rev. Drug Discov. 13, 759–780 (2014) and X. Hou et al. Nature Rev. Mater. https://doi.org/gmjsn5 (2021).

Back then, however, few researchers were thinking about mRNA as a medical product — not least because there was not yet a way to manufacture the genetic material in a laboratory. Instead, they hoped to use it to interrogate basic molecular processes. Most scientists repurposed mRNA from rabbit blood, cultured mouse cells or some other animal source.

That changed in 1984, when Krieg and other members of a team led by developmental biologist Douglas Melton and molecular biologists Tom Maniatis and Michael Green at Harvard University in Cambridge, Massachusetts, used an RNA-synthesis enzyme (taken from a virus) and other tools to produce biologically active mRNA in the lab5 — a method that, at its core, remains in use today. Krieg then injected the lab-made mRNA into frog eggs, and showed that it worked just like the real thing6.

Both Melton and Krieg say they saw synthetic mRNA mainly as a research tool for studying gene function and activity. In 1987, after Melton found that the mRNA could be used both to activate and to prevent protein production, he helped to form a company called Oligogen (later renamed Gilead Sciences in Foster City, California) to explore ways to use synthetic RNA to block the expression of target genes — with an eye to treating disease. Vaccines weren’t on the mind of anyone in his lab, or their collaborators.

Diptych of portraits of Paul Krieg and Douglas Melton

Paul Krieg (left) and Douglas Melton (right), who worked on ways to synthesize mRNA in the laboratory.Credit: University of Arizona; Kevin Wolf/AP Images for HHMI

“RNA in general had a reputation for unbelievable instability,” says Krieg. “Everything around RNA was cloaked in caution.” That might explain why Harvard’s technology-development office elected not to patent the group’s RNA-synthesis approach. Instead, the Harvard researchers simply gave their reagents to Promega Corporation, a lab-supplies company in Madison, Wisconsin, which made the RNA-synthesis tools available to researchers. They received modest royalties and a case of Veuve Clicquot Champagne in return.

Patent disputes

Years later, Malone followed the Harvard team’s tactics to synthesize mRNA for his experiments. But he added a new kind of liposome, one that carried a positive charge, which enhanced the material’s ability to engage with the negatively charged backbone of mRNA. These liposomes were developed by Philip Felgner, a biochemist who now leads the Vaccine Research and Development Center at the University of California, Irvine.

Diptych of portraits of Philip Felgner and Robert Malone

Philip Felgner (left) and Robert Malone.Credit: Steve Zylius/UCI; Robert Malone

Despite his success using the liposomes to deliver mRNA into human cells and frog embryos, Malone never earned a PhD. He fell out with his supervisor, Salk gene-therapy researcher Inder Verma and, in 1989, left graduate studies early to work for Felgner at Vical, a recently formed start-up in San Diego, California. There, they and collaborators at the University of Wisconsin–Madison showed that the lipid–mRNA complexes could spur protein production in mice7.

An excerpt from Robert Malone’s lab notebooks, describing the 1989 synthesis of mRNA for injection into mice

An excerpt from Robert Malone’s lab notebooks, describing the 1989 synthesis of mRNA for injection into mice.Credit: Robert Malone

Then things got messy. Both Vical (with the University of Wisconsin) and the Salk began filing for patents in March 1989. But the Salk soon abandoned its patent claim, and in 1990, Verma joined Vical’s advisory board.

Malone contends that Verma and Vical struck a back-room deal so that the relevant intellectual property went to Vical. Malone was listed as one inventor among several, but he no longer stood to profit personally from subsequent licensing deals, as he would have from any Salk-issued patents. Malone’s conclusion: “They got rich on the products of my mind.”

Verma and Felgner categorically deny Malone’s charges. “It’s complete nonsense,” Verma told Nature. The decision to drop the patent application rested with the Salk’s technology-transfer office, he says. (Verma resigned from the Salk in 2018, following allegations of sexual harassment, which he continues to deny.)

Malone left Vical in August 1989, citing disagreements with Felgner over “scientific judgment” and “credit for my intellectual contributions”. He completed medical school and did a year of clinical training before working in academia, where he tried to continue research on mRNA vaccines but struggled to secure funding. (In 1996, for example, he unsuccessfully applied to a California state research agency for money to develop a mRNA vaccine to combat seasonal coronavirus infections.) Malone focused on DNA vaccines and delivery technologies instead.

In 2001, he moved into commercial work and consulting. And in the past few months, he has started publicly attacking the safety of the mRNA vaccines that his research helped to enable. Malone says, for instance, that proteins produced by vaccines can damage the body’s cells and that the risks of vaccination outweigh the benefits for children and young adults — claims that other scientists and health officials have repeatedly refuted.

Manufacturing challenges

In 1991, Vical entered into a multimillion-dollar research collaboration and licensing pact with US firm Merck, one of the world’s largest vaccine developers. Merck scientists evaluated the mRNA technology in mice with the aim of creating an influenza vaccine, but then abandoned that approach. “The cost and feasibility of manufacturing just gave us pause,” says Jeffrey Ulmer, a former Merck scientist who now consults with companies on vaccine-research issues.

Researchers at a small biotech firm in Strasbourg, France, called Transgène, felt the same way. There, in 1993, a team led by Pierre Meulien, working with industrial and academic partners, was the first to show that an mRNA in a liposome could elicit a specific antiviral immune response in mice8. (Another exciting advance had come in 1992, when scientists at the Scripps Research Institute in La Jolla used mRNA to replace a deficient protein in rats, to treat a metabolic disorder9. But it would take almost two decades before independent labs reported similar success.)

Portrait of Pierre Meulien

Pierre Meulien.Credit: IMI Joint Undertaking

The Transgène researchers patented their invention, and continued to work on mRNA vaccines. But Meulien, who is now head of the Innovative Medicines Initiative, a public–private enterprise based in Brussels, estimated that he needed at least €100 million (US$119 million) to optimize the platform — and he wasn’t about to ask his bosses for that much for such a “tricky, high-risk” venture, he says. The patent lapsed after Transgène’s parent firm decided to stop paying the fees needed to keep it active.

Meulien’s group, like the Merck team, moved to focus instead on DNA vaccines and other vector-based delivery systems. The DNA platform ultimately yielded a few licensed vaccines for veterinary applications — helping, for example, to prevent infections in fish farms. And just last month, regulators in India granted emergency approval to the world’s first DNA vaccine for human use, to help ward off COVID-19. But for reasons that are not completely understood, DNA vaccines have been slow to find success in people.

Still, the industry’s concerted push around DNA technology has had benefits for RNA vaccines, too, argues Ulmer. From manufacturing considerations and regulatory experience to sequence designs and molecular insights, “many of the things that we learned from DNA could be directly applied to RNA”, he says. “It provided the foundation for the success of RNA.”

Continuous struggle

In the 1990s and for most of the 2000s, nearly every vaccine company that considered working on mRNA opted to invest its resources elsewhere. The conventional wisdom held that mRNA was too prone to degradation, and its production too expensive. “It was a continuous struggle,” says Peter Liljeström, a virologist at the Karolinska Institute in Stockholm, who 30 years ago pioneered a type of ‘self-amplifying’ RNA vaccine.

“RNA was so hard to work with,” says Matt Winkler, who founded one of the first RNA-focused lab supplies companies, Ambion, in Austin, Texas, in 1989. “If you had asked me back [then] if you could inject RNA into somebody for a vaccine, I would have laughed in your face.”

The mRNA vaccine idea had a more favourable reception in oncology circles, albeit as a therapeutic agent, rather than to prevent disease. Beginning with the work of gene therapist David Curiel, several academic scientists and start-up companies explored whether mRNA could be used to combat cancer. If mRNA encoded proteins expressed by cancer cells, the thinking went, then injecting it into the body might train the immune system to attack those cells.

Curiel, now at the Washington University School of Medicine in St Louis, Missouri, had some success in mice10. But when he approached Ambion about commercialization opportunities, he says, the firm told him: “We don’t see any economic potential in this technology.”

Another cancer immunologist had more success, which led to the founding of the first mRNA therapeutics company, in 1997. Eli Gilboa proposed taking immune cells from the blood, and coaxing them to take up synthetic mRNA that encoded tumour proteins. The cells would then be injected back into the body where they could marshal the immune system to attack lurking tumours.

Gilboa and his colleagues at Duke University Medical Center in Durham, North Carolina, demonstrated this in mice11. By the late 1990s, academic collaborators had launched human trials, and Gilboa’s commercial spin-off, Merix Bioscience (later renamed to Argos Therapeutics and now called CoImmune), soon followed with clinical studies of its own. The approach was looking promising until a few years ago, when a late-stage candidate vaccine failed in a large trial; it has now largely fallen out of fashion.

But Gilboa’s work had an important consequence. It inspired the founders of the German firms CureVac and BioNTech — two of the largest mRNA companies in existence today — to begin work on mRNA. Both Ingmar Hoerr, at CureVac, and Uğur Şahin, at BioNTech, told Nature that, after learning of what Gilboa had done, they wanted to do the same, but by administering mRNA into the body directly.

Diptych of portraits of Ingmar Hoerr and Eli Gilboa

Ingmar Hoerr (left) founded CureVac, and cancer immunologist Eli Gilboa (right) founded the first mRNA therapeutics firm.Credit: Sebastian Gollnow/dpa/Alamy; Eli Gilboa

“There was a snowball effect,” says Gilboa, now at the University of Miami Miller School of Medicine in Florida.

Start-up accelerator

Hoerr was the first to achieve success. While at the University of Tübingen in Germany, he reported in 2000 that direct injections could elicit an immune response in mice12. He created CureVac (also based in Tübingen) that year. But few scientists or investors seemed interested. At one conference where Hoerr presented early mouse data, he says, “there was a Nobel prizewinner standing up in the first row saying, ‘This is completely shit what you’re telling us here — completely shit’.” (Hoerr declined to name the Nobel laureate.)

Eventually, money trickled in. And within a few years, human testing began. The company’s chief scientific officer at the time, Steve Pascolo, was the first study subject: he injected himself13 with mRNA and still has match-head-sized white scars on his leg from where a dermatologist took punch biopsies for analysis. A more formal trial, involving tumour-specific mRNA for people with skin cancer, kicked off soon after.

Şahin and his immunologist wife, Özlem Türeci, also began studying mRNA in the late 1990s, but waited longer than Hoerr to start a company. They plugged away at the technology for many years, working at Johannes Gutenberg University Mainz in Germany, earning patents, papers and research grants, before pitching a commercial plan to billionaire investors in 2007. “If it works, it will be ground-breaking,” Şahin said. He got €150 million in seed money.

Diptych of Özlem Türeci walking through a laboratory and Ugur Sahin working at a fume cupboard in a laboratory

Özlem Türeci (left) and Uğur Şahin (right) co-founded the mRNA vaccine firm BioNTech.Credit: BioNTech SE 2021

The same year, a fledgling mRNA start-up called RNARx received a more modest sum: $97,396 in small-business grant funding from the US government. The company’s founders, biochemist Katalin Karikó and immunologist Drew Weissman, both then at the University of Pennsylvania (UPenn) in Philadelphia, had made what some now say is a key finding: that altering part of the mRNA code helps synthetic mRNA to slip past the cell’s innate immune defences.

Fundamental insights

Karikó had toiled in the lab throughout the 1990s with the goal of transforming mRNA into a drug platform, although grant agencies kept turning down her funding applications. In 1995, after repeated rejections, she was given the choice of leaving UPenn or accepting a demotion and pay cut. She opted to stay and continue her dogged pursuit, making improvements to Malone’s protocols14, and managing to induce cells to produce a large and complex protein of therapeutic relevance15.

Portrait of Katalin Kariko looking through a window

Katalin Karikó helped to show that chemical modifications to RNA can smuggle the molecule past the body’s immune defences.Credit: Hannah Yoon/Bloomberg/Getty

In 1997, she began working with Weissman, who had just started a lab at UPenn. Together, they planned to develop an mRNA-based vaccine for HIV/AIDS. But Karikó’s mRNAs set off massive inflammatory reactions when they were injected into mice.

She and Weissman soon worked out why: the synthetic mRNA was arousing16 a series of immune sensors known as Toll-like receptors, which act as first responders to danger signals from pathogens. In 2005, the pair reported that rearranging the chemical bonds on one of mRNA’s nucleotides, uridine, to create an analogue called pseudouridine, seemed to stop the body identifying the mRNA as a foe17.

Drew Weissman

Drew Weissman worked with Karikó, and co-discovered the advantages of modified mRNA.Credit: Penn Medicine

Few scientists at the time recognized the therapeutic value of these modified nucleotides. But the scientific world soon awoke to their potential. In September 2010, a team led by Derrick Rossi, a stem-cell biologist then at Boston Children’s Hospital in Massachusetts, described how modified mRNAs could be used to transform skin cells, first into embryonic-like stem cells and then into contracting muscle tissue18. The finding made a splash. Rossi was featured in Time magazine as one of 2010’s ‘people who mattered’. He co-founded a start-up, Moderna in Cambridge.

Moderna tried to license the patents for modified mRNA that UPenn had filed in 2006 for Karikó’s and Weissman’s invention. But it was too late. After failing to come to a licensing agreement with RNARx, UPenn had opted for a quick payout. In February 2010, it granted exclusive patent rights to a small lab-reagents supplier in Madison. Now called Cellscript, the company paid $300,000 in the deal. It would go on to pull in hundreds of millions of dollars in sublicensing fees from Moderna and BioNTech, the originators of the first mRNA vaccines for COVID-19. Both products contain modified mRNA.

RNARx, meanwhile, used up another $800,000 in small-business grant funding and ceased operations in 2013, around the time that Karikó joined BioNTech (retaining an adjunct appointment at UPenn).

The pseudouridine debate

Researchers still argue over whether Karikó and Weissman’s discovery is essential for successful mRNA vaccines. Moderna has always used modified mRNA — its name is a portmanteau of those two words. But some others in the industry have not.

Researchers at the human-genetic-therapies division of the pharmaceutical firm Shire in Lexington, Massachusetts, reasoned that unmodified mRNA could yield a product that was just as effective if the right ‘cap’ structures were added and all impurities were removed. “It came down to the quality of the RNA,” says Michael Heartlein, who led Shire’s research effort and continued to advance the technology at Translate Bio in Cambridge, to which Shire later sold its mRNA portfolio. (Shire is now part of the Japanese firm Takeda.)

Although Translate has some human data to suggest its mRNA does not provoke a concerning immune response, its platform remains to be proved clinically: its COVID-19 vaccine candidate is still in early human trials. But French drug giant Sanofi has been convinced of the technology’s promise: in August 2021, it announced plans to acquire Translate for $3.2 billion. (Heartlein left last year to found another firm in Waltham, Massachusetts, called Maritime Therapeutics.)

CureVac, meanwhile, has its own immune-mitigation strategy, which involves altering the genetic sequence of the mRNA to minimize the amount of uridine in its vaccines. Twenty years of working on that approach seemed to be bearing fruit, with early trials of the company’s experimental vaccines for rabies19 and COVID-1920 both proving a success. But in June, data from a later-stage trial showed that CureVac’s coronavirus vaccine candidate was much less protective than Moderna’s or BioNTech’s.

In light of those results, some mRNA experts now consider pseudouridine an essential component of the technology — and so, they say, Karikó’s and Weissman’s discovery was one of the key enabling contributions that merits recognition and prizes. “The real winner here is modified RNA,” says Jake Becraft, co-founder and chief executive of Strand Therapeutics, a Cambridge-based synthetic-biology company working on mRNA-based therapeutics.

Not everyone is so certain. “There are multiple factors that may affect the safety and efficacy of an mRNA vaccine, chemical modification of mRNA is only one of them,” says Bo Ying, chief executive of Suzhou Abogen Biosciences, a Chinese company with an mRNA vaccine for COVID-19 now in late-stage clinical testing. (Known as ARCoV, the product uses unmodified mRNA.)

Fat breakthrough

As for linchpin technologies, many experts highlight another innovation that was crucial for mRNA vaccines — one that has nothing to do with the mRNA. It is the tiny fat bubbles known as lipid nanoparticles, or LNPs, that protect the mRNA and shuttle it into cells.

This technology comes from the laboratory of Pieter Cullis, a biochemist at the University of British Columbia in Vancouver, Canada, and several companies that he founded or led. Beginning in the late 1990s, they pioneered LNPs for delivering strands of nucleic acids that silence gene activity. One such treatment, patisiran, is now approved for a rare inherited disease.

Pieter Cullis standing and smiling in a laboratory

Pieter Cullis.Credit: Paul Joseph for UBC

After that gene-silencing therapy began to show promise in clinical trials, in 2012, two of Cullis’s companies pivoted to explore opportunities for the LNP delivery system in mRNA-based medicines. Acuitas Therapeutics in Vancouver, for example, led by chief executive Thomas Madden, forged partnerships with Weissman’s group at UPenn and with several mRNA companies to test different mRNA–LNP formulations. One of these can now be found in the COVID-19 vaccines from BioNTech and CureVac. Moderna’s LNP concoction is not much different.

The nanoparticles have a mixture of four fatty molecules: three contribute to structure and stability; the fourth, called an ionizable lipid, is key to the LNP’s success. This substance is positively charged under laboratory conditions, which offers similar advantages to the liposomes that Felgner developed and Malone tested in the late 1980s. But the ionizable lipids advanced by Cullis and his commercial partners convert to a neutral charge under physiological conditions such as those in the bloodstream, which limits the toxic effects on the body.

What’s more, the four-lipid cocktail allows the product to be stored for longer on the pharmacy shelf and to maintain its stability inside the body, says Ian MacLachlan, a former executive at several Cullis-linked ventures. “It’s the whole kit and caboodle that leads to the pharmacology we have now,” he says.

Diptych of portraits of Ian MacLachlan and Tom Madden

Ian MacLachlan (left) and Thomas Madden (right).Credit: Ian MacLachlan; Acuitas Therapeutics

By the mid-2000s, a new way to mix and manufacture these nanoparticles had been devised. It involved using a ‘T-connector’ apparatus, which combines fats (dissolved in alcohol) with nucleic acids (dissolved in an acidic buffer). When streams of the two solutions merged, the components spontaneously formed densely packed LNPs21. It proved to be a more reliable technique than other ways of making mRNA-based medicines.

Once all the pieces came together, “it was like, holy smoke, finally we’ve got a process we can scale”, says Andrew Geall, now chief development officer at Replicate Bioscience in San Diego. Geall led the first team to combine LNPs with an RNA vaccine22, at Novartis’s US hub in Cambridge in 2012. Every mRNA company now uses some variation of this LNP delivery platform and manufacturing system — although who owns the relevant patents remains the subject of legal dispute. Moderna, for example, is locked in a battle with one Cullis-affiliated business — Arbutus Biopharma in Vancouver — over who holds the rights to the LNP technology found in Moderna’s COVID-19 jab.

An industry is born

By the late 2000s, several big pharmaceutical companies were entering the mRNA field. In 2008, for example, both Novartis and Shire established mRNA research units — the former (led by Geall) focused on vaccines, the latter (led by Heartlein) on therapeutics. BioNTech launched that year, and other start-ups soon entered the fray, bolstered by a 2012 decision by the US Defense Advanced Research Projects Agency to start funding industry researchers to study RNA vaccines and drugs. Moderna was one of the companies that built on this work and, by 2015, it had raised more than $1 billion on the promise of harnessing mRNA to induce cells in the body to make their own medicines — thereby fixing diseases caused by missing or defective proteins. When that plan faltered, Moderna, led by chief executive Stéphane Bancel, chose to prioritize a less ambitious target: making vaccines.

Diptych of portraits of Derrick Rossi and Stephane Bancel

Moderna’s Derrick Rossi (left) and Stéphane Bancel (right).Credit: Derrick Rossi; Adam Glanzman/Bloomberg/Getty

That initially disappointed many investors and onlookers, because a vaccine platform seemed to be less transformative and lucrative. By the beginning of 2020, Moderna had advanced nine mRNA vaccine candidates for infectious diseases into people for testing. None was a slam-dunk success. Just one had progressed to a larger-phase trial.

But when COVID-19 struck, Moderna was quick off the mark, creating a prototype vaccine within days of the virus’s genome sequence becoming available online. The company then collaborated with the US National Institute of Allergy and Infectious Diseases (NIAID) to conduct mouse studies and launch human trials, all within less than ten weeks.

BioNTech, too, took an all-hands-on-deck approach. In March 2020, it partnered with New York-based drug company Pfizer, and clinical trials then moved at a record pace, going from first-in-human testing to emergency approval in less than eight months.

Both authorized vaccines use modified mRNA formulated in LNPs. Both also contain sequences that encode a form of the SARS-CoV-2 spike protein that adopts a shape more amenable to inducing protective immunity. Many experts say that the protein tweak, devised by NIAID vaccinologist Barney Graham and structural biologists Jason McLellan at the University of Texas at Austin and Andrew Ward at Scripps, is also a prize-worthy contribution, albeit one that is specific to coronavirus vaccines, not mRNA vaccination as a general platform.

 

Some of the furore in discussions of credit for mRNA discoveries relates to who holds lucrative patents. But much of the foundational intellectual property dates back to claims made in 1989 by Felgner, Malone and their colleagues at Vical (and in 1990 by Liljeström). These had only a 17-year term from the date of issue and so are now in the public domain.

Even the Karikó–Weissman patents, licensed to Cellscript and filed in 2006, will expire in the next five years. Industry insiders say this means that it will soon become very hard to patent broad claims about delivering mRNAs in lipid nanoparticles, although companies can reasonably patent particular sequences of mRNA — a form of the spike protein, say — or proprietary lipid formulations.

Firms are trying. Moderna, the dominant player in the mRNA vaccine field, which has experimental shots in clinical testing for influenza, cytomegalovirus and a range of other infectious diseases, got two patents last year covering the broad use of mRNA to produce secreted proteins. But multiple industry insiders told Nature they think these could be challengeable.

 

“We don’t feel there’s a lot that is patentable, and certainly not enforceable,” says Eric Marcusson, chief scientific officer of Providence Therapeutics, an mRNA vaccines company in Calgary, Canada.

Nobel debate

As for who deserves a Nobel, the names that come up most often in conversation are Karikó and Weissman. The two have already won several prizes, including one of the Breakthrough Prizes (at $3 million, the most lucrative award in science) and Spain’s prestigious Princess of Asturias Award for Technical and Scientific Research. Also recognized in the Asturias prize were Felgner, Şahin, Türeci and Rossi, along with Sarah Gilbert, the vaccinologist behind the COVID-19 vaccine developed by the University of Oxford, UK, and the drug firm AstraZeneca, which uses a viral vector instead of mRNA. (Cullis’s only recent accolade was a $5,000 founder’s award from the Controlled Release Society, a professional organization of scientists who study time-release drugs.)

Some also argue that Karikó should be acknowledged as much for her contributions to the mRNA research community at large as for her discoveries in the lab. “She’s not only an incredible scientist, she’s just a force in the field,” says Anna Blakney, an RNA bioengineer at the University of British Columbia. Blakney gives Karikó credit for offering her a speaking slot at a major conference two years ago, when she was still in a junior postdoc position (and before Blakney co-founded VaxEquity, a vaccine company in Cambridge, UK, focusing on self-amplifying-RNA technology). Karikó “is actively trying to lift other people up in a time when she’s been so under-recognized her whole career”.

Although some involved in mRNA’s development, including Malone, think they deserve more recognition, others are more willing to share the limelight. “You really can’t claim credit,” says Cullis. When it comes to his lipid delivery system, for instance, “we’re talking hundreds, probably thousands of people who have been working together to make these LNP systems so that they’re actually ready for prime time.”

“Everyone just incrementally added something — including me,” says Karikó.

Looking back, many say they’re just delighted that mRNA vaccines are making a difference to humanity, and that they might have made a valuable contribution along the road. “It’s thrilling for me to see this,” says Felgner. “All of the things that we were thinking would happen back then — it’s happening now.”

Nature 597, 318-324 (2021)

https://www.nature.com/articles/d41586-021-02483-w?utm_source=pocket-newtab

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How Steven Weinberg Transformed Physics and Physicists | Quanta Magazine

Aug 12, 2021 by Nima Arkani-Hamed

Steven Weinberg, who died on July 23, towered over theoretical physics in the second half of the 20th century. He strongly believed that, armed only with the fundamental principles of relativity and quantum mechanics, the theoretical physicist can examine all phenomena in the universe — from the smallest to the largest scales. His work transformed our understanding of every aspect of fundamental physics in startlingly deep and original ways.

Weinberg was a master of quantum field theory, a branch of physics born from applying the rules of quantum mechanics to the electromagnetic field, which sees a particle — the photon —as a “quantized” excitation of the field. He was instrumental in propelling quantum field theory to astonishing new heights in the description of nature.

The themes of unification and symmetry drove all of Weinberg’s work and led to his famous breakthrough on electroweak unification, which revealed a hidden unity between two of the universe’s four fundamental forces. At first sight, the electromagnetic and weak interactions seem utterly different: We see electromagnetic waves as light in everyday life, while the weak force — responsible for radioactivity — operates on subnuclear scales. Weinberg realized that at very high energies, the two forces should be intertwined, described by what’s known as Yang-Mills theory, whose equations have a special property called gauge symmetry. But this essential commonality is hidden by the so-called Higgs mechanism, which generates masses for elementary particles such as the electron and the W and Z particles (which mediate short-range weak interactions), all the while leaving the long-range photon massless. The model he proposed in 1967 for realizing this vision made many detailed predictions and has been triumphantly confirmed by experiments beginning in the 1970s and ’80s, capped off by the 2012 discovery of the Higgs particle. Weinberg shared the 1979 Nobel Prize in Physics with Sheldon Glashow and Abdus Salam for this work, a pillar of the Standard Model of particle physics.

But ironically, this effort was in many ways uncharacteristic of Weinberg’s oeuvre, as he tended to be more concerned with general properties of the laws of nature rather than specific models. He had an unmistakable style, beginning any discussion from general principles and developing a systematic chain of arguments, one step following another with seeming inevitability. While he loved mathematics, he focused squarely on using it as a tool to describe the world. Weinberg asked simple and deep questions. Why is nature described by quantum field theory? Why are there so few possibilities for describing the properties of elementary particles and their interactions?

In this vein, Weinberg reimagined quantum field theory from a different perspective, asserting the primacy of special relativity, quantum mechanics and the notion of particles as a starting point. In his early work he studied long-range forces, such as electromagnetism and gravity, mediated by massless particles, the photon and graviton. Like all elementary particles, these have an intrinsic angular momentum, or “spin,” that comes in quantized units: Photons have spin 1 and gravitons spin 2. Weinberg showed that special relativity and quantum mechanics put striking restrictions on the interactions of massless particles. Spin 1 particles must be described by theories whose equations have gauge symmetry, while spin 2 particles must have the properties of the graviton, with a universal coupling strength to all particles. This provided a deeper derivation of the equivalence principle assumed by Albert Einstein as his starting point for developing general relativity. No other possibilities are consistent — the long-range forces we see in nature exhaust what is permitted by special relativity and quantum mechanics.

Another landmark contribution, which transformed our understanding of why quantum field theory describes the world, was his introduction of the notion of “effective field theories.” Weinberg argued that the principles of quantum mechanics and of locality — the idea that experiments performed sufficiently far apart in space-time should not affect each other — guarantee that the interactions of particles accessible at some energy scale must be described by a simple “effective” quantum field theory that involves only these particles. The dominant interactions between the particles are given by a finite number of interaction strengths, while the fingerprints of unknown physics at higher energies are systematically encoded in an infinite set of ever tinier interactions. (The ideas of effective field theory were also developed around the same time, from a complementary perspective, by Ken Wilson.)

Above all, Weinberg was a great unifier. He disliked the “Einsteinian” view of gravity as the curvature of space-time — which gives gravity a privileged position in defining the arena where all other phenomena operate — feeling that this erected an artificial barrier preventing researchers from seeing deeper connections between gravity and the rest of physics. This led him to formulate general relativity using the methods of particle physics, in the first of his many tour de force textbooks, Gravitation and Cosmology. He also realized that the seemingly disparate fields of particle physics and cosmology had to be united, since high-energy collisions between elementary particles were ubiquitous in the hot, dense conditions of the early universe shortly after the Big Bang, and he provided the theoretical tools needed to usher in a golden age of explorations in early-universe cosmology.

Weinberg’s fascination with cosmology led him to ponder the infamous cosmological constant problem. Violent quantum mechanical fluctuations, present everywhere in the vacuum, should endow empty space with an enormous energy density and cause space-time to be highly curved, in stark disagreement with the large, nearly flat universe we observe. Why is this vacuum energy, or “cosmological constant,” so small? In 1987, Weinberg proposed a radical approach to this problem using a minimal version of the “anthropic principle.” He reasoned that perhaps the vacuum energy could take on different values, and that if it were bigger than a specific minute size, an accelerated expansion of the universe would rip apart galaxies before they had a chance to form, leading to a structureless, empty universe — one devoid of people wondering about the size of the cosmological constant. Weinberg argued that this predicted a tiny but nonzero size for the vacuum energy. In 1998, astronomers discovered that the expansion of the universe is accelerating, with the simplest explanation being the presence of vacuum energy at just about the size suggested by Weinberg’s argument. Weinberg largely avoided the many boring diatribes surrounding the anthropic principle that followed, contenting himself with having pragmatically used anthropic reasoning to make a correct prediction about nature.

In addition to being one of the greatest theorists of his era, Weinberg was also the preeminent public intellectual of fundamental physics. His first popular book — The First Three Minutes, about cosmology and the Big Bang — became an instant classic and proved profoundly influential for both the general public and professional researchers. Many physicists, including me, started learning cosmology from this book. In Dreams of a Final Theory, Weinberg eloquently expounded on the notion of “beauty” in physics, stressing that it’s not a capricious aesthetic judgement, but a reflection of the incredible rigidity of physical laws and the ever greater sense of inevitability associated with the way they explain the world.

Ever since my days as a graduate student, Weinberg was the intellectual hero of my life in physics. His textbooks on quantum field theory were a godsend, and his perspectives on the inevitability of quantum field theory and on effective field theory formed the foundation of my picture of the world. I worked through his books diligently, carrying them around with me everywhere I went. Weinberg used overly detailed notation that made for crowded equations, so a casual reading of his text was impossible — all for the best, since being forced to translate his insights into my own notation really made them stick. My years of transcribing Weinberg had an interesting side effect: To this day, when I think of some fundamental aspect of field theory, I see the words from his books in my mind’s eye and hear his voice in my head. I also vividly remember reading his paper on the anthropic explanation for the cosmological constant, which had me walking around in a daze for a month. It took me many years to come to terms with this point of view, and eventually even to embrace it in my own research.

I first met Weinberg in person in the early 2000s. Although he had been kind and encouraging to me about my work, I became uncharacteristically bashful in his presence. In the midst of a technical discussion, I uttered the phrase “as you taught us” many more times than I can remember. I never entirely shook this feeling of reverence around him.

Discerning the fundamental simplicity behind nature’s inner workings is the highest goal a theoretical physicist can aspire to. No one in the past 60 years did this better than Weinberg. He was also a profound and humane thinker, who taught us all how to seek out that which, as he put it, “lifts human life a little above the level of farce and gives it some of the grace of tragedy.” His example will forever serve as an inspiration, and as a model for a life deeply lived.

https://www.quantamagazine.org/how-steven-weinberg-transformed-physics-and-physicists-20210811/?utm_source=pocket-newtab

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