The lifesaving, Nobel Prize-winning discovery that almost didn’t happen

S E E D E D   C O N T E N T

The Nobel Prize for Medicine was awarded on Monday to Katalin Karikó and Drew Weissman, for discoveries that led to the development of mRNA vaccinations, including those developed during the Covid-19 pandemic.

Arguably few Nobelists 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 hospitalizations and saved more than $1 trillion . Worldwide, of course, the effect was   even larger .

By far the most effective vaccines against Covid-19 were the mRNA vaccines developed by Pfizer and Moderna, and both companies benefited from the discoveries of Weissman and Karikó about how to change the body’s immune response to mRNA. Their Nobel Prize, obviously, is richly deserved.

It’s also a bit of a warning sign.

In hindsight, little medical research was of more importance than Karikó’s work at Weissman’s lab on making mRNA vaccines a reality. But at every stage, the research community that should have embraced this research instead stymied it, because of powerful incentives in science toward work that is more fundable and more publishable.

It’s hard to escape the impression that mRNA vaccines reached production despite the system, rather than because of it. And that raises the question: What other extraordinary, world-changing research programs are our current research lab system not equipped to nourish?

We nearly missed out on this huge line of research

Karikó was hired by the University of Pennsylvania in 1989 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. “She was too committed to the promise of mRNA to switch to other, perhaps more easily fundable projects,” David Scales, a junior researcher who worked in her lab at Penn,   told WBUR .

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,” Scales said.

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. mRNA would be unusable for vaccines if the body identified it as a foreign agent and destroyed it. Together, they worked out a way of altering the chemical bonds in mRNA in a way that appeared to allow it to escape the immune system’s notice.

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 on Monday . “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 2021 reporting in   Nature , Penn sold the patents for $300,000 to a small lab-reagents supplier in Madison. When the funder backing the vaccine company 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.

“I was kicked out, from Penn, was forced to retire,” Karikó   told   Adam Smith, interviewing her on behalf of the Nobel Prize committee after she got her award. She eventually found a place at BioNTech, which required her commuting to and from Germany.

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 favor incremental, conservative research rather than bold ideas. Even worse, it can end up favoring 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 many financial resources.

Then, because of Karikó’s struggle to get grants, she was demoted by her institution. It’s 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 should 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 and Weissman’s work, employed in both the Moderna and Pfizer vaccines, was indeed a huge deal.)

What we may be missing

This is not a triumphant story about the successful functioning of our systems for R&D and scientific discovery. Those systems appear to have basically failed. This is a story about how through sheer stubbornness, and a few strokes of luck, the mRNA technology made it to market, where it saved millions of lives and trillions of dollars. That makes it a great fit for a Nobel Prize, which celebrates individuals who made extraordinary contributions that changed the face of their fields. But it also makes it a cautionary tale.

How many people like Karikó and Weissman are out there, confident that they’re on to something world-changing and yet unable to get the funding to keep researching it? How many scientists quietly change careers toward something more fundable?

There are a lot of different ideas for how we could make scientific funding more flexible and responsive, and let scientists pursue projects without immediate payoffs. I’ve written about   the Arc Institute, a philanthropic effort to do just that , as well as about zany-but-legitimately-valuable ideas like   allocating some funding by lottery . But while we can debate the best solution, I don’t think we can debate any longer that there’s a problem.

There’s too much at stake in scientific research for us to set grant and tenure policies that systematically fail our researchers and then hope they overcome adversity and succeed anyway. Karikó’s untouchable conviction and decades-long labor in obscurity until she was at last vindicated is a beautiful story of the triumph of the human spirit, and it should never happen again.