"Katalin Kariko and Drew Weissman won the Nobel Prize in medicine on Monday for an idea that pushed them to the fringes of the scientific establishment before it saved millions of lives during the pandemic.
Kariko, a molecular biologist, and Weissman, an immunologist, realized during a chance encounter at a University of Pennsylvania photocopy machine in the 1990s that they could combine their work to explore how messenger RNA might produce effective drugs or vaccines.
Their collaboration was met with skepticism by their colleagues and indifference in the scientific community. Kariko struggled to secure funding for her work. Penn demoted her and sent her to work in an office on the outskirts of campus.
"People wondered, 'What the hell is wrong with her,' there must be some reason she's not on the faculty," Kariko has said.
Years later, as drugmakers raced to develop vaccines against Covid-19, it was mRNA technology that powered widely used shots from Pfizer-BioNTech and Moderna. The Nobel committee credited Kariko's and Weissman's work with saving millions of lives.
"The laureates contributed to the unprecedented rate of vaccine development during one of the greatest threats to human health in modern times," the committee said in awarding Kariko, 68 years old, and Weissman, 64, the annual prize in physiology or medicine. Kariko is the 13th woman among 227 people to win the prize.
"We focused on doing the science," Kariko said Monday. "That's why we persevere, we are resilient."
Kariko, a gregarious and outspoken scientist with a Ph.D. in biochemistry, had tried for nearly a decade to convince colleagues that mRNA could deliver desired proteins to the body. Then she met Weissman.
Weissman, a medical doctor with a Ph.D. in immunology and microbiology, hardly smiled around campus, even for photos. His wife once joked that he was so taciturn he set a self-imposed word limit each day. He was eager to help other researchers, though.
Like most scientists at the time, Weissman was originally wary of mRNA, a molecule deemed too short-lived and difficult to make in the lab to provide much value. Kariko convinced him to use mRNA in his experiments.
"If you make it, I'll try it," Weissman remembered telling her, halfheartedly.
Before mRNA technology, vaccines were made from inactive or harmless viral material. Such therapies can take more than 10 years to develop because of the laborious cell culturing required to grow the viruses. Kariko and Weissman wanted to find ways to inject mRNA into the body without setting off the body's defenses.
"We knew from the beginning that RNA had incredible potential, we just didn't know when," Weissman said on Monday, after he learned he had won the Nobel in a 4 a.m. phone call.
In the 1980s, researchers discovered a method of producing mRNA without cell culture called in vitro transcription. But mRNA made by that method triggered immune responses that caused inflammation and it didn't result in efficient protein production in the body. Discoveries by Kariko and Weissman helped overcome those roadblocks.
They proved they could modify mRNA, a kind of molecular worker bee that carries instructions encoded in DNA, so it could be used safely and effectively. Researchers are now testing mRNA vaccines to target other diseases including influenza and some cancers.
Weissman had been working with part of the immune system called dendritic cells, and Kariko had been experimenting with injecting mRNA into cancer cells. The two decided to inject mRNA into dendritic cells to see if the mRNA would cause the production of certain proteins. It did. The results were "off the wall," Weissman once said. But the mRNA triggered an inflammatory response because the cells treated it as a foreign intruder, negating any benefit.
The duo figured out that if they modified the base components, or nucleosides, of mRNA, they could avert the inflammatory response [1].
The modifications effectively rendered mRNA "immune silent," allowing it to get into cells to do its work. The scientists also discovered that modified mRNA significantly increased protein production.
After publishing a breakthrough paper in 2005, Kariko and Weissman thought they would be inundated with interest from biotechnology companies and other scientists. That didn't happen. The pair's startup didn't get far. They kept at it anyway.
Bart Anderson, who worked with Kariko and Weissman at Penn as a Ph.D. student in the 2000s, remembers Kariko saying her ambition was to see at least one person helped by mRNA therapies in her lifetime.
"They had the foresight and determination to see the value of therapeutic mRNA, regardless of what the wider scientific community thought," said Anderson, who is developing RNA-based medicines for pain at Grunenthal, the German pharmaceutical company.
A few years after Kariko and Weissman published their seminal work, a stem-cell scientist at Harvard University, Derrick Rossi, built on it in his own research, leading him to become a co-founder of Moderna.
"It is rare that a fundamental discovery makes such an enormous clinical impact," Rossi said on Monday.
Penn patented their mRNA technology, and the Philadelphia-based university later licensed it to Moderna and BioNTech. Moderna and BioNTech pay a portion of their mRNA vaccine sales as royalties to Penn.
Kariko was a senior vice president at BioNTech from 2013 until 2022, and now advises the company. She is also a professor at University of Szeged in her native Hungary and an adjunct professor at Penn. Weissman is a professor at Penn.
Winners of the Nobel Prize in physiology or medicine receive 11 million Swedish kronor, the equivalent of around $1 million.
"It's a great privilege to belong to all of those scientists who have received this prize," Kariko said." [2]
1. Kariko noticed that her control, transport RNA, did not cause a strong immune reaction in the body. While trying to understand why, she found that the main cause was most common modification of uridinenucleotide in nature is when a sugar residue is attached to a base with a C-Cbond, resulting in pseudouridine, instead of a C-N bond in uridine. Such a modification is enough to keep in the body the mRNA we have synthesized long enough to produce enough of the protein we want to synthesize.
2. Pair Met With Doubts, Now Win Nobel Prize. Mosbergen, Dominique; Loftus, Peter; Zuckerman, Gregory. Wall Street Journal, Eastern edition; New York, N.Y.. 03 Oct 2023: A.1.
Komentarų nėra:
Rašyti komentarą