When Katalin Karikó’s phone rang at 3:40am on October 2, her husband, Bela Francia, grabbed it and quickly passed it to her. “It’s for you,” he told her.
With no number showing up and the person on the line unveiling the seemingly improbable news that she had just won a Nobel Prize, the adjunct professor of neurosurgery at the University of Pennsylvania assumed it was a prank. As did her collaborator Dr Drew Weissman, the Roberts Family Professor of Vaccine Research at the university’s Perelman School of Medicine. “Kati texted me this cryptic message at four in the morning: ‘Did Thomas call?’” Weissman recounted at a press conference on Penn’s campus. “I texted her back and said, ‘No, who’s Thomas?’ She says: ‘Nobel Prize.’” Karikó, 68, told Weissman the Nobel team couldn’t reach him because they had the wrong number for him. “And we said, this has to be a prank,” said Weissman, 64. So, they decided to wait for the official announcement at the 5:45am press conference in Sweden. He told the audience he just sat in bed, “and I was looking at my wife, and my cat was begging for food, and the press conference started and it was real. Then we really became excited about this”.
Messenger RNA (mRNA) pioneers Karikó and Weissman―whose years of scientific partnership unlocked an understanding of how to modify mRNA to make it an effective therapeutic, enabling a platform used to rapidly develop lifesaving vaccines amid the Covid-19 pandemic―were named winners of the 2023 Nobel Prize in Physiology or Medicine. The award comes nearly three years after the rollout of mRNA vaccines across the world.
How they met
It was 1997. Weissman, an immunologist with a PhD in microbiology from Boston University, had recently moved from Dr Anthony Fauci’s lab, where he was studying HIV, to the University of Pennsylvania and was trying to figure out how to make a better vaccine. Most traditional vaccines work by injecting an inactive, weakened or small fragment of a pathogen―called an antigen―to trigger an immune response that the body remembers and can jump-start if the invader returns. But developing such vaccines can take years, and live pathogens pose health risks to those with compromised immune systems.
Weissman was especially intrigued by a single-stranded molecule called 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?
Biochemist Karikó had always been fascinated with what she calls the “fragile molecule”―the RNA (ribonucleic acid). She had been researching synthetic mRNA for more than 30 years. But her path was not easy. She left her native Hungarian town of Kisújszállás in 1985 and settled in the US. The daughter of a butcher and a bookkeeper in postwar communist Hungary, Karikó grew up in an adobe home without running water, television or refrigerator; her family grew its own vegetables. It was from her parents that she learnt that hard work was part of life, and also to make sausages. A curious kid, she saw the wonders of nature all around her and was determined to become a scientist. She did her PhD at the University of Szeged and postdoctoral fellowship at its Biological Research Center. When the university’s research programme ran out of money, Karikó, Francia (whom she met as a student) and their then two-year-old daughter Susan moved to Philadelphia with $1,200 sewn into Susan’s teddy bear. She had moved to the US on an invitation from a biochemist professor at Temple University. A few years in, she got another job offer, which upset the professor. He reportedly told immigration officials that Karikó was living illegally in the US. Karikó had to hire a lawyer to fight deportation. Owing to legal issues, she lost the job offer.
Her recently released memoir Breaking Through: My Life in Science is a revelation about the persistence of this extraordinary woman who believed that someday mRNA would transform ordinary cells into tiny factories capable of producing their own medicines on demand. She sacrificed nearly everything for this dream, but the obstacles she faced only motivated her, and eventually she succeeded.
The hurdles kept coming even after she joined University of Pennsylvania in 1989 as adjunct professor and researcher. While she landed teaching positions, her grant applications to study mRNA were repeatedly turned down. But Karikó kept her focus on mRNA, exploring how the single-stranded molecules of genetic code could treat a wide range of conditions―from strokes to cancer―and also protect against influenza, among other ailments. Her luck turned in 1997, when she met Weissman and the two formed a research partnership.
“I came to Penn 25 years ago and met Katalin Karikó at a copy machine,” said Weissman. At Penn’s press conference, Karikó joked that Penn should perhaps invest in more copy machines, so researchers have the opportunity to stand around, chitchat, and share their ideas. She added that she and Weissman worked in different buildings and departments, so the meeting was purely luck.
But the duo was as different as chalk and cheese. Weissman has always claimed that “Kati and I are very different people. Kati is very emotional and reactive; I’m very quiet, even-keeled, non-emotional”.
Karikó would agree. “Once Drew showed me, ‘You know, Kati, from A to B, you zigzag, zigzag, zigzag! And I am just like, straight.’ But I told him that when I zigzag, I learn so much,” she told Adam Smith, who was interviewing her on behalf of the Nobel Prize Committee after she got the award. She describes herself as “talkative and bubbling”; Drew, on the other hand, has a daily word quota, according to his wife Mary Ellen, daughters Rachel and Allison and other family members. But despite their differences, the two have maintained a two-and-a-half-decade partnership. “When you would see us looking at the data, we cut each other’s words,” Karikó told Smith. “What it means, you know, we are very ‘alive’.”
For over a decade since they first met, Weissman and Karikó worked to chemically modify mRNA so it could be used safely and effectively in vaccines. In 2005, they published a key discovery: mRNA could be altered and delivered effectively into the body to activate the body’s protective immune system. The mRNA-based vaccines elicited a robust immune response, including high levels of antibodies that attack a specific infectious disease that has not previously been encountered. Unlike other vaccines, a live or attenuated virus is not injected or required at any point.
Cracking the mRNA Code
Many vaccines stimulate immunity and prepare the body to fight against a specific virus by using a weakened or dead version of the actual virus. mRNA vaccines, however, carry a genetic code that causes the body’s cells to produce proteins that the immune system recognises as the virus. The immune system then builds up the necessary defenses against the viral proteins to protect against future infection and severe disease.
Prior to Weissman’s and Karikó’s breakthrough research, mRNA vaccines being developed to prevent infectious diseases did not effectively and safely elicit protective immune system responses in animal models. Weissman and Kariko changed the way the mRNA was made by including specific naturally occurring mRNA modifications that make the mRNA safer, more stable and effective for prophylactic and therapeutic purposes.
Every strand of mRNA is made up of four molecular building blocks called nucleosides. But in its altered, synthetic form, one of those building blocks, like a misaligned wheel on a car, was throwing everything off by signalling the immune system. So Karikó and Weissman simply snubbed it out for a slightly tweaked version, creating a hybrid mRNA that could sneak its way into cells without alerting the body’s defenses. Hence, base modifications in the mRNA almost eliminated the inflammatory response, a discovery that shed light on how cells recognise and respond to the nucleic acids.
Pausing the pandemic
Scientists and investors were quick to see the therapeutic promise of the technology. BioNTech set up shop in 2008, followed two years later by Moderna.
When the Covid-19 pandemic struck, the true value of the pair’s lab work was revealed in the most timely of ways, as companies worked to quickly develop and deploy vaccines to protect people from the virus. Both Pfizer-BioNTech and Moderna utilised Karikó’s and Weissman’s technology to build their highly effective vaccines to protect against severe illness and death from the virus.
Arguably few Nobel winners had a hand in saving more lives than Karikó and Weissman. One study estimates that in the US alone, the vaccines prevented over 3 million deaths and 18 million hospitalisations and saved more than $1 trillion. Worldwide, of course, the effect was even larger.
Gunilla Karlsson Hedestam, a professor at the Karolinska Institutet and a member of the Royal Swedish Academy of Sciences’ Covid-19 expert group, discussed the impact of Karikó’s and Weissman’s findings on the pandemic at a press conference to disclose the 2023 winners. “What's important here, I think, is that vaccines could be developed so fast. And this was… largely due to improvements in the technology, and this basic discovery that allowed this. So, I think in terms of saving lives, especially in the early phase of the pandemic, it was very important,” said Hedestam.
The prize illustrates the pace at which mRNA went from a highly promising but unproven technology to a modality used in almost entire populations. At the press conference, Thomas Perlmann, a Karolinska professor, relayed what Karikó said on hearing the news, explaining how she has undergone “a dramatic change in her circumstances” from losing a job 10 years ago to being a Nobel winner today.
“In order for our society to move forward, we need science,” Weissman said at the press conference. “Everything that’s moved our society forward in the past thousands of years has been science-based: the invention of the round wheel, the invention of transportation, the invention of antibiotics. We need to encourage our children, our grandchildren, and our neighbours, everybody, that science is what moves the world forward. That’s why it’s important and it needs to be supported.”
Karikó echoed that sentiment, while noting that science does not necessarily offer immediate results or praise. “You have to learn how to handle failure,” she said, because more often than not the experiments don't reveal what you hoped. “But you can learn from that …we work hard but we enjoy.” Karikó is the 13th woman to be awarded the Nobel Prize in Physiology or Medicine since 1901.
We nearly missed out on this huge line of research
Karikó was hired by the University of Pennsylvania in a role that put her on track to become a full tenured professor. But she struggled to get grant funding for her work on mRNA. And in roles like Karikó’s, bringing in grant funding was everything. In 1995, Penn demoted her. Anyone of less grit and determination would have just given up long before the groundwork for today’s vaccines was laid. But Karikó persevered. She had to hop from lab to lab at Penn and eventually joined Weissman’s lab, which was working on an HIV vaccine. Together, they ended up taking a closer look at a key barrier to creating mRNA vaccines: the body’s strong immune response to mRNA.
A key scientific hurdle to mRNA vaccination had been cleared. But the hurdles that were a product of our broken academic science system remained.
“We couldn’t get funding. We couldn’t get publications. We couldn’t get people to notice RNA as something interesting,” Weissman said in an interview. “Pretty much everybody gave up on it.”
They tried working toward mRNA vaccination outside academia, founding a small company called RNARx. That too ran into problems. In 2006, Penn applied for and received two patents for Karikó’s and Weissman’s work. But RNARx struggled to come to a licensing agreement with Penn for the patents.
So, according to a 2021 report in Nature, Penn sold the patents for $300,000 to a small lab-reagents supplier in Madison. When the funder backing Moderna called Karikó to ask to license the patents, she had to tell them she didn’t have them. They were eventually sublicensed to both Moderna and BioNTech (which partnered with Pfizer), for hundreds of millions of dollars.
In 2013, Karikó joined BioNTech as vice president. She had to leave Penn and was forced to retire. So in other words, a researcher with a world-changing discovery was for so long unable to get sustained funding to do further research―a clear failure of our institutions for deciding what merits funding.
It’s hard to guess exactly what went wrong in Karikó’s case, but there are some obvious possibilities. Researchers have long complained that a single objection on the committee considering a grant can effectively kill it, making the process highly subjective and leading it to strongly favour incremental, conservative research rather than bold ideas. Even worse, it can end up favouring work that is already halfway done.
One of the best strategies to get a grant is to not apply until you already have very impressive results data, but this strategy highly rewards having a well-funded lab. That makes it very difficult for new researchers to break in―like Karikó, who immigrated to the US at age 30, without financial resources.
It is a fate many scientists are deeply afraid of, and which therefore discourages them from doing work that may not get grants―even if they know it has important, world-changing potential. And she wasn’t able to get other institutional jobs. Thankfully, Karikó had a supportive husband who could enable her commute to BioNTech in Germany to continue her work at a company that saw its potential.
“I think about all of the young girls who may become inspired by my story and want to become scientists. To them I say: stay curious, adopt the right attitude and stay on the track no matter how long and winding that road may be,” remarked Karikó when she was awarded the Lasker-DeBakey Clinical Medical Research Award in 2021.
It is important to note here that mRNA vaccines were the work of countless people, and that no new vaccine is developed by a lone hero―that’s simply not how modern biology works. Many, many other people have worked on mRNA vaccines, and there are probably other routes around the immune system response problem. But if the technology had been even a few years delayed, millions of lives would have been lost, which means that Karikó’s and Weissman’s work, employed in both the Moderna and Pfizer vaccines, was indeed a huge deal.
According to Dr Elena Atochina-Vasserman, member of The Weissman Lab at Penn and adjunct assistant professor of medicine, Karikó’s and Weissman’s technology was like showing someone with a rotary phone the new iPhone―it was a device that didn’t just improve how calls were made; it fundamentally changed how someone moved through the world. “Somebody takes the walnuts from the fire, but you enjoy them all,” said Atochina-Vasserman, who is originally from Russia and is working on a vaccine against the stomach bug norovirus.
Both Karikó and Weissman have received countless emails and letters thanking them for their work. For Karikó, the recognition has been a long time coming. She recounted how till a few years ago, she was known as Susan’s mom―Susan is a two-time Olympic champion in rowing. “And now that my daughter came several times to the awards ceremony with me, she was introduced as ‘Kati’s daughter’,” she said.
Future of mRNA technology
Weissman once said that he does not rest on his laurels and always wants to move forward. “My family and, I am sure, my lab are mad at me… I did not celebrate when the phase 3 clinical trials came in,” he said. “I had already moved on to something new.”
Weissman has now set his sights on a more ambitious target: a pan-coronavirus vaccine. He is now working on a vaccine that will protect against every Covid variant that will likely appear. “Our thinking is that we will use it as a way to immunise the world―and prevent the next pandemic from happening in the future.” Weissman is hardly stopping with coronaviruses. He is working on about 20 other vaccines for diseases from malaria to HIV, with several moving into clinical trials. His lab is also exploring new gene therapies to treat immune deficiencies like cystic fibrosis and genetic liver diseases. One of the most promising projects focuses on curing sickle cell anaemia, a chronic genetic disorder that disproportionately affects people of African descent. In time, he believes mRNA gene therapies can bring hope to research on devastating neurological diseases such as Alzheimer’s and Parkinson’s that have seen disappointingly few advances. ¨