Nobel for Pioneers in Covid Vaccine

THE COVID PANDEMIC is historic not just because a new virus showed humanity how vulnerable it is to unexpected dangers from the microscopic world, but also for how this danger was met in entirely novel ways. A technology that will change the nature of medicine got the biggest clinical trial ever, entrenching it for further use. This is the mRNA vaccine that, while India itself saw not much of, was what a large part of the Western world relied on. Moderna and Pfizer are the two pharmaceutical companies that pioneered it and, with the assistance of governments, manufactured billions of doses in record time. But these end products were the result of research that went back decades, and two of the scientists whose work was crucial in making mRNA technology real have just been awarded the Nobel Prize in Physiology or Medicine 2023. The press release of the Nobel Prize awarding it to Katalin Karikó and Drew Weissman says: “The discoveries by the two Nobel Laureates were critical for developing effective mRNA vaccines against COVID-19 during the pandemic that began in early 2020. Through their groundbreaking findings, which have fundamen­tally changed our understanding of how mRNA interacts with our immune system, the laureates contributed to the unprec­edented rate of vaccine development during one of the greatest threats to human health in modern times.”

About a quarter of a century ago, Karikó and Weissman ran into each other at a photocopying machine in the University of Pennsyl­vania where they were both working. Weissman, an immunologist, was researching on ways to make more efficient vaccines. A Boston Univer­sity alumni magazine Bostonia article of 2021 says: “Weissman was espe­cially intrigued by a single-stranded molecule called messenger RNA, or mRNA, which brings our cells the DNA blueprint for making proteins so that the body can function. If we could manipulate those instructions, could mRNA be harnessed to create an entirely new kind of vaccine— one that could generate immunity without ever bringing a pathogen into the body? One day, while waiting at the office to photocopy ar­ticles from a research journal, Weissman struck up a conversa­tion with Penn biochemist Karikó. The two scientists realised they shared a particular interest. “I had always wanted to try mRNA,” Weissman says, “and here was somebody at the Xerox machine telling me that’s what she does.” What followed was a partnership that has lasted for more than two decades.”

Vaccines are traditionally made using viruses that have been weakened to the point of being harmless, or inactivated. They are then introduced into the body, which creates antigens. When the real virus eventually strikes, the body’s immune system is ready and quickly destroys it because it already knows it. The mRNA vaccines use an entirely different process. It does not involve the necessity to have a version of the virus. The code of the human body is held in its DNA. It tells cells the proteins that need to be manufactured for survival and growth. mRNA or messenger RNA is a molecule that carries instructions from the DNA to the cells on what to produce. If you could control mRNAs, then you can make cells produce proteins of your choosing. It is an inge­nious tweaking of the body’s own system to become medicinal factories. When it comes to Covid, the Pfizer and Moderna vac­cines sent custom-made mRNAs into cells to tell them to make the telltale spikes of the virus. The immune system recognised the spike as a foreign body and created antigens. Again, when a Covid infection happened, the body al­ready had a targeted immune response ready against the virus. The mRNA vac­cine had the advantage of being able to be made fast and in scale, precisely the requirement during a pandemic.

mRNA or messenger RNA is a molecule that carries instructions from the DNA to the cells on what to produce. If you can control mRNAs, then you can make cells produce proteins of your choosing. It is an ingenious tweaking of the body’s own system to become medicinal factories

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When Karikó and Weissman had begun working with mRNAs, there were specific problems which made the process unfeasible. For one, the cells needed to read these mRNAs to be­gin production. Instead, the immune system, recognising it correctly as a pathogen, destroyed them. Something was needed to trick the immune system into accepting the mRNAs. “For years, Dr. Weissman and Dr. Karikó were flummoxed. Mice injected with mRNA became lethargic. Countless experiments failed. They wandered down one dead end after another. Their problem was that the immune system interprets mRNA as an invading patho­gen and attacks it, sickening the animals while destroying the mRNA. But eventually, the scientists discovered that cells protect their own mRNA with a specific chemical modification. So they tried making the same change to mRNA synthesized in the lab before injecting it into cells. It worked: The mRNA was taken up by cells without provoking an immune response,” reported The New York Times. The second thing the scientists did was find a way to effectively transport the mRNA using lipid nanopar­ticles so that cells produce the instructed proteins efficiently. The importance of this finding, specifically for vaccines, was explained by Karikó in an interview to Scientific American two years ago: “The lipid nanoparticle protects the mRNA outside the cell because, in the blood and everywhere, there are a lot of human enzymes that can degrade the RNA. Second, it helps it to enter because the cell will pick up the particle. And then it is in the endosome [a membrane-bound compartment] in the im­mune cells, and then this lipid nanoparticle helps escape from the endosome to the cytoplasm [the solution inside cells] so the protein can be made. It is a very smart particle.”

But it hadn’t been easy. For most of their careers, mRNA was not a fashionable field of study. Karikó in fact had seen her pay being cut, her laboratory transferred to mofussil outskirts of the university, and even demoted. As The New York Times reported: “Unable to get a grant, she said she was told she was ‘not faculty quality’ and was forced to retire from the university a decade ago. She remains only an adjunct professor…The mRNA work was especially frustrating, she said, because it was met with indiffer­ence and a lack of funds. She said she was motivated by more than not being called a quitter; as the work progressed, she saw small signs that her project could lead to better vaccines. ‘You don’t perse­vere and repeat and repeat just to say, ‘I am not giving up’,’ she said.”

Now that the technology has been found to be effective, it has the ability to change medicine radically. After the announcement of the Nobel, the scientific journal Nature published an article looking at what the future portended by talking to experts in the field. A wide variety of viruses are being targeted to develop vaccines against including monkeypox, Nipah, Zika, respiratory syncytial virus, cytomegalovirus. But the big target is cancer. “Cancers have been a tough nut to crack because malignant cells mutate rapidly, weakening therapeutics’ power. With mRNA, researchers can develop cancer vaccines that target dozens of an­tigens on tumour cells simultaneously. Hitting several targets at once could make it harder for cancer cells to evolve ways to evade immune responses elicited by a vaccine. Clinical trials of a new class of personalized cancer vaccine are underway: these vaccines use mRNA aimed at a collection of mutated proteins that are found in an individual’s own tumour,” reported the article.

The two scientists, meanwhile, are coming to terms with the sudden attention. At a press conference organised by the university, Weissman said he had first got the news when Karikó had phoned asking if the Nobel committee had got in touch. They had contacted her but had a wrong number for him. “And we said, this has to be a prank,” said Weissman.

About The Author

Madhavankutty Pillai

Madhavankutty Pillai has no specialisations whatsoever. He is among the last of the generalists. And also Open chief of bureau, Mumbai  

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