Penn mRNA scientists Karikó and Weissman win Nobel Prize

The Nobel Prize in medicine was awarded Monday to two University of Pennsylvania scientists, Katalin Karikó and Drew Weissman, who discovered how to harness the power of messenger RNA — the genetic linchpin of the first vaccines against COVID-19.

The Moderna and Pfizer vaccines based on their research are credited with preventing millions of hospitalizations and deaths. The Penn duo’s discoveries, the first of which was published in 2005, also form the basis of potential treatments for cancer and autoimmune diseases.

Yet three decades ago, when Karikó began to study RNA for its possible uses in medicine, the concept struck many scientists as science fiction. Among other issues, the delicate molecules were quick to degrade and caused harmful inflammation in lab animals. Karikó struggled to secure federal funds for her work, and a result, in 1995 she was turned down for a tenure-track position at Penn.

Yet she stuck with it, and upon joining forces with Weissman, the two eventually cracked the code.

At a news conference hosted by Penn, Weissman credited Karikó with having the inspiration to push back against the naysayers.

“Kati lit the match,” he said.

Still, others were slow to appreciate their findings. In an interview Monday with a Nobel official, she described being “kicked out” of Penn in late 2012 and “forced to retire.” She then got a job at the German drugmaker BioNTech, which collaborated with Pfizer a decade later to make the COVID vaccine.

Not only did her ideas ultimately win out, she is now a trailblazer in a field where women have been sorely underrepresented. Karikó is the 25th woman to win a Nobel in the sciences out of the 640 winners since 1901, representing just 4% of the total. At the news conference, she was all smiles.

“We worked hard,” she said of her collaboration with Weissman. “But we enjoyed.”

When prize administrators called from Sweden on Monday with the news, Karikó was asleep at her Abington home. Her husband answered, and handed the phone to her, she said.

Before hanging up, she gave Thomas Perlmann, the secretary general of the Nobel committee, Weissman’s cell phone number — as the committee had been unable to reach him that morning.

During Monday’s news conference, Weissman described the cryptic message he received from Karikó around 4 a.m., asking if a man named Thomas had called.

When he asked for more detail, Karikó wrote back: “Nobel Prize.”

Initially, they thought it might be a joke, Weissman said at Penn’s news conference. Weissman believed they’d won only after watching the Nobel committee’s press conference from bed with his wife and cat, who was mewing impatiently for breakfast.

While Nobel recognition often comes years, if not decades, after a discovery, the Nobel committee wanted to “be more current” in honoring world-changing research, Weissman recalled the committee’s secretary general explained.

“It’s a lifetime dream, and this is coming from somebody who doesn’t work for or look forward to awards,” he said in an interview with a Nobel official Monday morning. “But the Nobel is the ultimate recognition of work.”

» READ MORE: How the COVID-19 vaccines work: A step-by-step tutorial with guidance from Drew Weissman

The pair met at the copy machine the late 1990s, while waiting to make copies of scientific journal articles, and took an interest in each other’s findings. They agreed to work together. It was a fruitful match between two areas of scientific expertise — RNA for her, the immune system for him — and two very different personality types.

In 2021, when the pair won another award, Karikó, 68, described herself as “talkative and bubbling” in contrast to Weissman’s quiet, methodical approach.

“You are coming from A to B in a straight line. And I am A to B like that,” she told Weissman in a Penn Medicine video, spinning her finger around in a circle. “You told me that. But we try to go to the same place.”

Conceptually, their goal was straightforward. DNA is the master blueprint for life, holding the recipes for all the enzymes and other proteins in the body. Messenger RNA is a temporary copy of that blueprint, used in the process of actually making the proteins.

The pair hoped that they could deliver their own temporary RNA blueprints inside human cells, coaxing them to make customized proteins without needing to interfere with the person’s master blueprint — the DNA.

But inflammation, provoked when RNA was administered to lab animals, was a stumbling block. The solution, which Karikó and Weissman published in 2005, was a slight tweak to the chemical structure supporting one of RNA’s “bases.” The inflammation all but disappeared. And as a bonus, the cells made 10 times as many of the desired proteins.

Later, they and many other scientists would make headway against the other main issue: the fragility of the genetic molecules. They learned to package the RNA inside tiny droplets of oil, called lipid nanoparticles, protecting them for safe delivery through the membrane of human cells.

“We were both completely open-minded,” said Weissman, 64. “Any data that we didn’t understand, and there was a lot of it, we sat down. We kept doing experiments. We kept getting results. We kept getting excited by the results.”

A key advantage of mRNA-based vaccines is speed. In January 2020, when Chinese officials published the genetic code of the coronavirus, scientists used it to make prototype mRNA vaccines in a matter of days.

The vaccines contained just a small portion of that overall genetic code for the virus: the recipe for its external “spike” protein. When injected into the body, these blueprints prompted the recipient’s cells to make the spike, giving the immune system a harmless taste of the virus without the risk of infection.

Elliot Barnathan, a cardiologist who worked with Karikó at Penn before leaving for an industry job in 1997, said it took uncommon foresight for her to map out all the technical hurdles. And extreme perseverance for her and Weissman to clear them, one by one.

“It’s sort of like a staircase, like a pyramid,” Barnathan said. “It was a huge undertaking to go from the ground floor to the top. She saw the top, and said: ‘OK, I’m going to have to find all these stones and schlep them. It’s a lot of time and sweat, but I can see what it’s going to look like in the end.’”

» READ MORE: Research behind COVID-19 vaccines reaps close to $1 billion in royalties for Penn

At Penn’s Perelman School of Medicine, Weissman is now working on RNA-based vaccines that would protect against multiple coronaviruses, including those that have yet to jump from animals to humans. He and Karikó both have continued to study the use of mRNA to combat other diseases.

One possible target is autoimmune diseases such as lupus. For that project, Weissman is collaborating with another prominent scientist, cell therapy pioneer Carl June.

Karikó's and Weissman’s work “changed the course of history,” said J. Larry Jameson, the dean of Penn’s Perelman School of Medicine, at a news conference hosted by Penn on Monday.

“Their pioneering work has opened the door to a new era of medicine,” he said.

It also has earned Penn a lot of money. University officials have not provided an exact total, but public databases indicate the school has reaped more than $1 billion in royalties from patents on the work by Karikó and Weissman.

The two scientists will receive their awards in a Dec. 10 ceremony in Stockholm, along with the winners of Nobels in other categories to be announced this week.