This year’s Nobel Prize in Physiology or Medicine has been jointly awarded to Katalin Karikó and Drew Weissman for discoveries enabling the creation of a new kind of vaccine, including some of the first ones that protected against COVID-19, the Nobel Assembly announced today.
The prize recognizes the pair’s pioneering research on messenger RNA (mRNA), the genetic strands that carry the proteinmaking instructions encoded by DNA to assembly sites within cells. Working together at the University of Pennsylvania (UPenn), Karikó and Weissman showed in the early 2000s that it was possible to dampen the body’s inflammatory responses to labmade mRNAs by making specific chemical changes to the component bases of the molecules—findings that allowed future groups to deliver mRNA into human cells to make viral proteins, such as the spike molecule on SARS-CoV-2.
“Karikó and Weissman made fundamental discoveries of [the] importance of base modifications in mRNA, which eliminated a major obstacle to mRNA-based clinical applications,” says Rickard Sandberg, a member of the Nobel Assembly. “Building upon this mRNA technology, as well as research by others on stabilized spike protein and mRNA delivery using lipid nanoparticles, two highly effective mRNA vaccines against COVID-19 were developed and approved in record time.”
“This is a wonderful choice of Nobel Prize,” says Anthony Fauci, former director of the U.S. National Institute of Allergy and Infectious Diseases, who had Weissman as a fellow in his lab. “[It’s] the classic example of a years and years–long collaboration on a very, very difficult problem. … They doggedly kept at it and made a discovery that has already transformed many areas of biomedical research.”
Whereas traditional vaccines typically contain a weakened or killed version of a pathogen, key pathogen proteins made in labs, or viruses genetically engineered to make those proteins in the body, mRNA by itself can instruct cells to make particular proteins that trigger immune responses. The seed for the mRNA vaccine idea was planted in the 1980s, following the development of techniques to generate the genetic strands in the lab. But lab-made mRNA molecules triggered potentially harmful immune responses.
Karikó, born in Hungary in 1955, and Weissman, born in Massachusetts in 1959, began collaborating on the problem at UPenn in the late 1990s, combining Karikó’s background in RNA biochemistry with Weissman’s expertise in immunology. They realized the immune reaction was linked to a fundamental difference between mRNAs made within mammalian cells and those being made by scientists in the lab: Whereas natural mRNAs have various chemical modifications tacked on them, labmade mRNAs didn’t.
The researchers tried reproducing some of these modifications in mRNA in the lab and then presenting the resulting molecules to immune cells called dendritic cells. In 2005, they reported in the journal Immunity that replacing an mRNA base called uridine with naturally occurring, modified bases such as pseudouridine could greatly reduce the inflammatory response. Over the next few years, they developed the work further, showing in 2008 that the use of pseudouridine could increase the amount of protein made by cells that took up the mRNA. They also unraveled the cellular mechanism behind their results.
The work was picked up by several companies in the 2010s, with focus falling initially on vaccines against Zika virus and MERS-CoV, the coronavirus that causes Middle East respiratory syndrome. Such research was key to the rapid development of vaccines to deliver the spike protein of another coronavirus, SARS-CoV-2, into human cells soon after the outbreak of COVID-19 began: The first regulatory authorizations for mRNA vaccines were given in December 2020 to Pfizer and BioNTech (which employed Karikó as senior vice president until recently) and to Moderna. (Science profiled Moderna, and much of the early mRNA work, in 2017.) Since the start of the pandemic, these and other types of shots against SARS-CoV-2 have been administered more than 13 billion times globally.
Aside from honoring a discovery that opened a new research avenue, the Nobel Prize might have a practical impact on uptake of COVID-19 vaccines, suggests Olle Kämpe, vice chair of the committee that chose the winners of this year’s award. Although Kämpe believes it’s unlikely that people who are firmly against vaccines will have second thoughts, he expects “giving a Nobel Prize for this COVID-19 vaccine can make hesitant people take the vaccine and be sure that it’s very efficient and it’s safe.”
Although manufacturing large amounts of mRNA vaccines is complex, they’re still faster and simpler to make than vaccines based on other strategies. In those cases, giant bioreactors are used to grow huge batches of viruses, bacteria, or the cells that are synthesizing the key pathogen protein. The mRNA approach simply biochemically synthesizes the genetic sequence for the desired protein and encases it in a lipid nanoparticle to protect the strand from destruction.
Despite the significance of their mRNA advance, Karikó and Weissman struggled to find the resources to develop the work clinically, only recently receiving recognition through awards such as the 2022 Breakthrough Prize. Karikó, now a professor at the University of Szeged as well as an adjunct professor at UPenn’s Perelman School of Medicine, tells Science that in the early 2000s, she didn’t even have a research team when she was doing the key work. “I am so unlikely a person to win the Nobel Prize,” she says, noting that she did the biochemistry experiments with her own hands.
One of the most promising avenues for mRNA vaccines is the possibility that they can trigger immune responses that attack tumors. Jessica Foster, an oncologist at the Children’s Hospital of Philadelphia, has long worked on this potential application with Karikó. “This prize is so well deserved,” Foster says. “[Her] grit and determination to follow the science, despite many telling her she could not succeed, are an inspiration to all. She is a brilliant scientist, an incredible mentor, and a role model to female scientists across the world. The advances in mRNA biology she uncovered will change our lives for centuries to come.”
Although no mRNA-based drug has yet been approved to treat a disease—rather than prevent illness, as vaccines do—Moderna, other companies, and academic labs have candidates in clinical trials. They’re designed to produce therapeutic proteins in the body for conditions ranging from cystic fibrosis to heart disease.
Thomas Perlmann, secretary general for the Nobel Assembly and Nobel Committee, remarked at today’s press conference that Karikó “never received an R01 one grant from [the U.S. National Institutes of Health] which is a clear sign that she struggled and didn’t get recognition for the importance of her vision. … And maybe this tells something about the funding situation and also being a female, being a foreigner, and so forth.” Karikó becomes just the 13th woman to be awarded the Nobel Prize in Physiology and Medicine in its more than 120-year history.
“The Nobel Prize today recognizes decades of painstaking research and a belief that mRNA technology would have useful applications one day,” says Soumya Swaminathan, who served as chief scientist at the World Health Organization until 2022 and now chairs a foundation in Chennai, India. “The success of mRNA vaccines against COVID has now opened up a whole research enterprise with potential therapeutics and vaccines for both communicable and noncommunicable diseases.”
