How Scientists Drew Weissman (MED’87, GRS’87) and Katalin Karikó Developed the Revolutionary mRNA Technology inside COVID Vaccines
Drew Weissman (MED’87, GRS’87) and Katalin Karikó pioneered the mRNA technology that is fundamentally reshaping the landscape of vaccine development and the future of gene therapies. Photo by Peggy Peterson/Courtesy of Penn Medicine
How Scientists Drew Weissman (MED’87, GRS’87) and Katalin Karikó Developed the Revolutionary mRNA Technology inside COVID Vaccines
It started with a chance encounter, and led to worldwide acclaim for the two researchers
An astonishing number of world-changing medical breakthroughs have come to humanity by way of serendipity. Mishaps and lucky breaks gave us X-rays, insulin, and, most famously, penicillin, discovered in 1928, when a Scottish biologist returned from a summer holiday to find the bacteria cultures in his lab destroyed by a peculiar mold. Modern medicine was transformed in an instant.
But the story of how scientist Drew Weissman (MED’87, GRS’87) and his research partner Katalin Karikó developed the revolutionary mRNA technology that powers the world’s most effective COVID-19 vaccines was a much slower burn—one that easily could have flickered out. Their decades-long crusade has been marked by rejection, crushing setbacks, and dogged perseverance. Chance had nothing to do with it. Except, perhaps, for how they met.
It was 1998. Weissman, an immunologist with a PhD in microbiology, had recently accepted a position at 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 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 realized 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.”
efficacy of mRNA vaccines in preventing COVID-19 infection.
What followed was a partnership that has lasted for more than two decades. During that time, they pioneered the mRNA technology that is fundamentally reshaping the landscape of vaccine development and the future of gene therapies. Not only have the new mRNA vaccines proven to be more effective and safer than traditional vaccines, they can be developed and reengineered to take on emerging pathogens and new variants with breathtaking speed. Using mRNA technology, Pfizer-BioNTech designed its coronavirus vaccine in a matter of hours.
Now, Weissman and Karikó are being hailed for their work. Earlier this year, Brandeis University and the Rosenstiel Foundation honored the scientists with the Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research. In September, they won a Breakthrough Prize in Life Sciences from the Breakthrough Prize Foundation. And Columbia University awarded them the Louisa Gross Horwitz Prize, bestowed annually for groundbreaking work in medical science. Of the 106 previous Horwitz Prize winners, nearly half have gone on to receive Nobel Prizes.
Cracking mRNA’s Code
From the start, Weissman and Karikó believed mRNA was the key to unlocking a new generation of vaccines and therapeutics. Theoretically, it could instruct any cell in the body to make any desired set of proteins. But practically, there were many obstacles. Synthetic mRNA was notoriously unstable and tended to break down before it could do its job. The closest attempt came in 1990 when researchers from the University of Wisconsin showed that injected mRNA could generate proteins in mice. Many scientists, however, were skeptical that this process could be replicated in humans.
For her part, Karikó had been captivated by mRNA since the earliest days of her career. She left her native Hungary in 1985, when funding dried up for her lab, taking a low-level postdoctoral position at Temple University. Four years later, Karikó moved to Penn, where she would spend the next decade making sporadic discoveries with mRNA but consistently failing to win grants. She was forced to move from lab to lab, going wherever she could find someone willing to fund her research.
By the time she met Weissman, at the copy machine, Karikó had been demoted and was adrift without funding or a lab. But Weissman didn’t care about her lack of grants or credentials. “I never say no to anything,” he says. “RNA had been tried by others and didn’t work very well, but I wanted to try it.”
Karikó brought her synthetic mRNA to his lab. Weissman injected it into mice. Then he waited to see what would happen. The results were unexpected and discouraging. The mRNA set off a harmful inflammatory immune response in the mice. They grew sick, and some died. “Kati got depressed because it meant that mRNA couldn’t be used as a therapeutic,” Weissman recalls. “You can’t give something that makes people sick.”
But neither scientist was ready to give up on the promise of mRNA. They spent years investigating the cause of the inflammation and years more experimenting with how to prevent it.
In 2005, they had a breakthrough.
By altering one of mRNA’s four building blocks, known as nucleosides, Weissman and Karikó found that their modified mRNA could fly under the radar of the body’s immune system, no longer causing inflammation. It was a game changer, and they both knew it.
With this hurdle cleared, the clinical applications for synthetic mRNA seemed infinite. Custom-tailored mRNA, once injected into the body, could order cells to produce any desired sequence of proteins.
There were “enormous possibilities,” Weissman says. The scientists believed their technology had the potential to transform medicine, opening the door to countless new vaccines, therapeutic proteins, and gene therapies.
The idea may have been too radical to grasp. Several leading medical journals turned down their report of their findings before it was published, in 2005, by the journal Immunity. The researchers braced for the shock waves their study would generate in the scientific community.
“I told Kati our phones are going to ring off the hook,” Weissman recalls. “But nothing happened. We didn’t get a single call.”
The researchers were deeply frustrated at the lack of interest. Still, they secured patents, and in 2006 launched a company called RNARx that focused on developing mRNA therapeutics for a wide range of diseases. But eventually funding ran out and the company shut down.
The pair forged ahead, and five years after they published their groundbreaking findings, their discovery caught the attention of two biotech newcomers, Moderna of Cambridge, Mass., and Germany’s BioNTech. Both companies eventually licensed Weissman and Karikó’s patents. (Karikó was hired by BioNTech in 2013, and the company would later partner with US pharmaceutical giant Pfizer on vaccine development. The two companies also now support Weissman’s lab.)
By the time ominous reports of a mysterious virus began emerging from Wuhan, China, in late 2019, Moderna and BioNTech had been working on developing mRNA influenza vaccines and other therapies for years. As soon as China released the genome sequence for the new coronavirus, both companies began racing toward a vaccine.
Would mRNA Vaccines Work in People?
The Pfizer-BioNTech and Moderna vaccines deployed the same clever mechanism. A shot of specially coded mRNA would instruct certain cells to manufacture the notorious COVID-19 spike protein, enabling the cells to briefly masquerade as the virus and teach the immune system to recognize it. Within weeks of injection, the mRNA would break down naturally without a trace, leaving in its wake a powerful immunity against the coronavirus.
Although Weissman was confident in the science—he had worked on 20 different vaccines in animal models with great success—he was anxious to see the results of the human trials. “In science, we know that what works in mice rarely works in humans, and what works in [monkeys] sometimes works in humans,” Weissman says. “So I was very nervous [about] whether it would work in people.”
Results from the human clinical trials showed the vaccines to be remarkably safe, with 95 percent efficacy in preventing COVID-19 infection. Weissman was elated. In December 2020, he and Karikó received their first vaccine shots together at the University of Pennsylvania.
“It was an emotional moment,” he says, reflecting on their long struggle to show the world the promise of this extraordinary molecule. “There were a lot of down times, a lot of soul-searching, a lot of figuring out why things weren’t working. But we never lost hope because we both saw the incredible potential that mRNA had.”
Since COVID vaccines were first granted emergency use authorization from the Food and Drug Administration in December 2020, nearly 219 million Americans have been immunized, with the vast majority receiving either the Pfizer-BioNTech or Moderna vaccines.
There were a lot of down times, a lot of soul-searching, a lot of figuring out why things weren’t working. But we never lost hope.”
Columbia’s David Ho, one of the country’s leading virologists, calls their research “an essential precursor” to the COVID vaccines “that have made a huge impact on the pandemic.” Others in the scientific community believe Weissman and Karikó deserve the Nobel Prize for their groundbreaking discoveries with mRNA.
Weissman takes it all in stride. “We knew from the beginning that what we were doing had huge potential,” he says, “but every scientist’s work isn’t like that. If RNA had not worked, no one would have heard of Kati and me, and we would’ve retired and gone off to our nursing homes.”
The Future of mRNA Technology
These days, Weissman seems a bit wistful for a time when he could work in relative anonymity. “I was and still am quiet and shy and not very outgoing,” he says. “I’ve always enjoyed working in my lab alone without much attention. The reporters, awards committees, everybody imaginable wanting to talk to me—it’s been the hardest thing.”
With what little leisure time he has, Weissman likes to unwind by engineering more domestic innovations. “When he’s having trouble finding a solution to something, he builds rooms onto our house,” says his wife, Mary Ellen, a child psychologist. The couple has two daughters, Rachel and Allison.
“I build screen porches, kitchens, bathrooms, playrooms,” Weissman says. “I enjoy building. I’m sure I got that from my dad.” His father was an engineer who owned a company that designed optical mirrors for satellites. His mother was a dental hygienist.
Weissman describes a carefree childhood growing up in Lexington, Mass., “playing kickball in the streets and roaming around the neighborhood causing trouble.” In high school, his talent for science came into focus. “I was always interested in biology and took the top science classes,” he says.
He studied biochemistry and enzymology at Brandeis University and earned an MD/PhD in immunology and microbiology from Boston University in 1987. After a residency in Boston, he pursued a fellowship at the National Institutes of Health, where he worked closely with Anthony Fauci (Hon.’18), now director of the NIH’s National Institute of Allergy and Infectious Diseases, whom he describes as “one of the great drivers of my research interest.”
Weissman has been dismayed by the partisan vitriol directed at his former mentor. “I see it as very sad. I never imagined that people would attack Tony for trying to save lives and do the right thing,” he says. “The United States is absolutely ridiculous in how they’ve handled this vaccine and the pandemic itself. And the continued politicization of it is terrible.”
His frustration with how the United States is managing the pandemic has led him to focus on vaccine access for the rest of the world. Weissman is currently working with the governments of Thailand, Malaysia, South Africa, and Rwanda, among others, to develop and test lower-cost COVID vaccines.
To Weissman, the new COVID variants present a compelling challenge. The beauty of mRNA vaccines, he says, is that tweaking the code to work against Delta or other new strains “is a simple thing. It takes a few weeks to make a brand-new vaccine.”
He has set his sights on a more ambitious target: a pan-coronavirus vaccine. “There have been three coronavirus epidemics in the past 20 years,” he explains. “You have to assume there are going to be more. We’re now working on a vaccine that will protect against every variant that will likely appear. Our thinking is that we’ll use it as a way to immunize the world—and prevent the next pandemic from happening in the future.”
So far, the results in mice, which were published in the journal Nature in August, have been promising. But Weissman is hardly stopping with coronaviruses. He’s 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 anemia, a chronic genetic disorder that disproportionately affects people of African descent. The existing treatment is a labor-intensive procedure that involves removing bone marrow from the patient, treating it with an altered virus designed to deliver a healthy version of the sickle cell gene, and then putting the marrow back into the patient. “The problem with that is 200,000 people are born with sickle cell in sub-Saharan Africa every year,” Weissman says, “and it’s half a million dollars per treatment.”
Using mRNA technology, Weissman has developed a gene therapy that can treat sickle cell anemia with a single shot. “We’ve taught [the mRNA] how to target bone marrow stem cells, so they fix the gene and cure the disease,” he says. The therapy has been successful in mice and will move into monkey trials soon.
“Once we get the sickle cell therapy working, there are a couple of hundred other bone marrow genetic diseases it can be applied to,” he says, along with liver and lung genetic disorders. 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.
Meanwhile, biotech companies like Moderna and BioNTech are charging forward on a mind-bending spectrum of mRNA applications, including personalized cancer vaccines and autoimmune therapies.
Weissman generally comes across as pragmatic and self-effacing, but as he looks to the future, he sounds genuinely awed by the staggering potential of the technology he and Karikó invented: “It really is exciting. It’s limitless.”
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