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March 8, 2022

The Karikó problem: Lessons for funding basic research

By Stuart Buck

New scientific institutes are springing up all over the place these days: Arcadia Science, New Science, Arc Institute, Activate, Actuate, Astera, Convergent Research, and more. They’re usually funded by Silicon Valley and have bold ambitions to advance scientific progress more quickly.

Why this flurry of activity? After all, the National Institutes of Health spent nearly $43 billion on biomedical research in 2021, and the National Science Foundation spent nearly $8.5 billion on other areas of science. Why would anyone want to bother with funding a small fraction of 1% of that?

Because they are convinced that the current system of science funding is uncreative and inflexible.

One common argument is that we need to “fund people not projects,” meaning we need to find the smart and visionary scientists and give them funding that isn’t tied to narrow projects.

As much as I like these efforts, I worry about a different problem, one that none of the new initiatives to date would necessarily fix. I call it the Karikó problem.

Katalin Karikó is the now-celebrated scientist who, along with a colleague, published a key paper in 2005 on messenger RNA. Her discovery ultimately formed the basis for two Covid-19 vaccines, including one made by Pfizer and BioNTech, where Karikó now works, and one made by Moderna.

But Karikó wasn’t always celebrated. Far from it.

She earned her PhD in biochemistry at the University of Szeged in Hungary, currently ranked by US News as the 712th best university globally.

She emigrated to the U.S. in 1985 with her husband and then-young daughter to take a postdoc position at Temple University in Philadelphia, and eventually got a job as a non-tenure track research assistant professor at the University of Pennsylvania. But in 1995, she got demoted because no matter how many times she applied for NIH funding for her mRNA research, she never got a grant for it.

As one of her former colleagues wrote, “by the time I joined the lab, Karikó’s history was still only discussed in hushed tones as a cautionary tale for young scientists.” Karikó herself has said that usually after such a demotion, “people just say goodbye and leave because it’s so horrible.”

Yet she persisted. A couple of years after her embarrassing demotion, she ran into immunologist Drew Weissman at the office copy machine and struck up a conversation about mRNA. Weissman was intrigued, and asked Karikó to come work in his lab. Eventually, the pair figured out how to modify mRNA just enough that it would still work but without triggering the body’s immune system to kill off the molecule first. That led to their groundbreaking 2005 paper (which, by the way, was recognized as groundbreaking only in retrospect…it was “summarily rejected” by the prestigious Nature and Science journals at the time, with Nature commenting that it was just an “incremental contribution” ).

It is a miracle that Karikó stuck in academia for so long after being treated this way.

That’s why we should worry about the invisible Karikós: the people with good ideas that weren’t popular at the time and who dropped out of academia. It’s unlikely that she was the only person in the world who had an interesting idea in 1985 that could have turned into a groundbreaking discovery over the next few decades.

We’ll never know what we missed.

That makes me think about the “fund the person, not the project” approach. To be clear, this could be a great idea, and it is well worth experimenting with. But would Karikó herself have done any better with that approach?

It’s hard to imagine. At Karikó’s demotion in 1995, no one would have said, “Here’s a 40-year-old Hungarian scientist who went to a fairly obscure university, who has zero well-known mentors vouching for her, who has spent some 10 years working on a problem that no one thinks is solvable, and who started in a non-tenure track position only to get demoted from there. Let’s give her a few million dollars in unrestricted funding over the next 10 years.”

So here’s the Karikó problem in a nutshell: Anyone can identify Karikó in retrospect, given her persistence and her eventual discoveries. But what do we do right now to find the 2022 versions of Karikó, who simply don’t (yet) look like the “visionaries” or “geniuses” who would be eligible for “person not project” funding?

My answer? Bend over backward to fund a more diverse range of people and ideas, even deliberately including ideas that are currently perceived as unpopular, unworkable, obscure, and the like. After all, many scientific discoveries can be traced back to origins that didn’t seem promising — like CRISPR, which can be traced to a Spanish study on salt-loving archae bacteria in 1993 — or even to ideas that were actively opposed by the establishment at the time.

To be sure, the success rate of this approach might be low. But if we funded 10,000 people who looked like a younger Karikó, and only one of them did something with the impact of mRNA research, that would be well worth it.

This article was originally published in STAT.

UPDATE: Since this article was originally published, I noticed that the suggested approach at the end might come across as scattershot. To the contrary, I suspect there might be ways of doing a better job to identify the characteristics of someone with brilliant ideas and the persistence to see them through. More to come on that point.

Stuart Buck is the executive director of the Good Science Project and a senior advisor to the Social Science Research Council.