The Message of Messenger RNA

They all laughed at Christopher Columbus when he said the world was round, Ira Gershwin reminded us. But that was nothing compared to the experience of Giordano Bruno, the Danish astronomer. They burned him at the stake for saying this round world of ours revolves around its sun, just one of many in a vast universe. The folks at the Inquisition just couldn’t abide that.

Pushing the boundaries of knowledge has never been for the faint of heart.

Drew Weissman and Katalin Kariko know this well. Luckily for the rest of us they didn’t end up like Giordano Bruno. But for thirty years their life-saving idea was scoffed at by the powers that be in medical research.

Now, you may not recognize their names. But you certainly know their work. In fact, you are likely to be among the 6,710,513 New Yorkers who have had their work product jabbed into your arm of late.

Drs. Weissman and Kariko, you see, are the researchers who figured out how to use a molecule called messenger RNA, known familiarly to you as mRNA, to create vaccines and therapeutics.

For most of us, the COVID-19 vaccines arrived almost by magic, at “warp speed” as former President Donald Trump, understandably but unfortunately, termed it.

Yet for Weissman and Kariko these vaccines were anything but sudden. They came not out of the blue, but out of their labs. Weissman and Kariko are the proverbial “overnight successes” who had been laboring in relative obscurity for years.

Repeatedly Rebuffed

Obscurity doesn’t actually do justice to their persistence.

Their insight, or call it a scientific instinct, if you prefer, was repeatedly rebuffed by the institutional leaders of American research, including, among others, Anthony Fauci and the National Institutes of Health.

“If the pandemic had not happened nobody would know I ever existed,” Kariko said the other day in Manhattan. “But I knew always that what I was doing is important and one day, maybe not my lifetime, somebody will pick it up and do something.”

Kariko made these remarks as she and Weissman accepted the Ross Prize in Molecular Medicine, bestowed by the Feinstein Institutes of Medical Research, a part of Northwell Health, New York’s largest hospital network, and the science journal, Molecular Medicine.

The prize is given annually, with a missed year for the pandemic, “to motivate and cultivate promising careers in the fields of science and research,” according to the organizers.

Motivation, of course, can include telling the truth about how hard things can get, as Kariko illustrated in the lecture she gave as part of receiving the award.

Her subject was the history of mRNA research. As far back as the 1990s researchers had published papers showing the potential of mRNA to create vaccines for influenza and even cancer. But they were having trouble keeping the mRNA stable long enough to do its medical work.

“We Just Have to be Braver”

Kariko, a refugee from Hungary, wanted to pursue this work at her adopted research home, the University of Pennsylvania. But in May 1994 she received two nearly identical letters from two parts of the university rejecting her proposal. “We received many more meritorious proposals than we could possibly fund,” the letters both said.

We know this because, dramatically, she included these rejection letters in her slide show on the history of mRNA research. Not to gloat, she says, but to give hope to other researchers struggling to win support for their work.

“We just have to be braver,” Kariko said.

Kariko persisted and found other allies, including Weissman. They met in 1997 while running research papers through a copying machine, an enabler of serendipity that Kariko notes would shortly be eliminated by the march of technology.

It took them another decade, but Kariko and Weissman succeeded in modifying and packaging the mRNA so it could reach the right part of the body to trigger immune responses.

She continued this research at the company that became BioNTech and was actually testing an mRNA-based cancer vaccine when the pandemic broke out.

That is where most of us became aware of Kariko’s work. BioNTech teamed up with Pfizer to use the mRNA technology to create the COVID-19 vaccine. Moderna, working independently, did much the same thing.

So the idea that the COVID-19 vaccine was developed in record time is true, if you start from the start of the pandemic, but wildly wrong if you go back to those rejection letters.

Unwillingness to Listen

Early in the pandemic, a prominent public health officer at the World Health Organization, the Canadian Bruce Aylward told me that one of the biggest challenges to bringing the pandemic under control was the unwillingness of people to listen to good ideas from others.

He was thinking particularly in that moment of how places like Taiwan and Hong Kong had successfully used lockdowns, distancing and masking to curb the spread of the virus.

But when Aylward’s observation was mentioned to Weissman he immediately connected it to his own and Kariko’s experience.

“That’s the definition of the NIH,” Weissman said. “When you submit a grant to the NIH only very particular types of grants get approved. Typically, they’re by senior people who are well know in the field and the idea might not be that interesting or novel but they like to fund people who have been funded before.

“When you come to them with a brand new idea that’s completely different from what they are used to they don’t like it. They say, ‘oh well, there’s not enough support that says its going to work.’ And that’s what Katy and I went through for ten years of submitting grants and having them say no. Finding the right people to listen to potential new ideas is difficult.”

They are listening now. Weissman and Kariko say they appreciate the honors and invites they are now receiving, but long to get back to their labs. Kariko worries she doesn’t have time to read all the research papers in her field. The Nobel Prize in Medicine is even mentioned.

Weissman says he has been pitched by pharmaceutical companies and biotech startups to come do his mRNA thing for them.

Does he ever want to just say, “Where were you thirty years ago?” he is asked.

“I’m not a vindictive person,” he replied. “I don’t think that way.”