• Thu. Sep 23rd, 2021


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An mRNA Pioneer Discusses How Her Work Led to the COVID Vaccines

Researchers often toil away for years in a lab without any promise that their research will result in anything meaningful for society. But sometimes this work results in a breakthrough with global ramifications. Such was the case for Katalin Karikó, who, along with her colleague Drew Weissman, helped develop the messenger RNA (mRNA) technology that was used to produce the highly effective COVID vaccines made by Pfizer and Moderna.

Karikó, who is now senior vice president and head of RNA protein replacement therapies at BioNTech (the company that co-developed a COVID vaccine with Pfizer), and Weissman, a professor of vaccine research at the University of Pennsylvania’s Perelman School of Medicine, have just been awarded a $3 million Breakthrough Prize in Life Sciences for their work on modifying the genetic molecule RNA to avoid triggering a harmful immune response. The Breakthrough Prizes, founded by Sergey Brin, Priscilla Chan, Mark Zuckerberg, Yuri and Julia Milner, and Anne Wojcicki, honor groundbreaking discoveries in fundamental physics, life sciences and mathematics. Karikó spent years on this research despite skepticism and a lack of funding. Ultimately, however, her efforts paid off—laying the groundwork for the overwhelmingly effective vaccines that are likely the world’s surest way out of the COVID pandemic.

Karikó was born in Hungary to a family of modest means. She started her work on modifying RNA during her Ph.D. studies and—convinced of the promise of RNA-based therapies—came to the U.S. to pursue postdoctoral research. She later ended up as a professor at the University of Pennsylvania. Interest in mRNA therapies declined, and she was told to pursue other research directions or risk losing her position, but she persisted. Over a conversation at the Xerox machine she got to know Weissman, who was interested in developing vaccines at the time. They started collaborating.

When foreign mRNA is injected into the body, it causes a strong immune response. But Karikó and Weissman figured out a way to how to modify the RNA to make it less inflammatory by substituting one DNA “letter” molecule for another. Next they worked on how to deliver it. After testing many different delivery vehicles, they settled on lipid nanoparticles as the delivery vehicle. These turned out to work incredibly well: the nanoparticles acted as an adjuvant, a substance that enhances the desired immune response to a vaccine.

Weissman and his colleagues had been working on an mRNA vaccine for influenza when word spread of a mysterious pathogen causing pneumonia in people in Wuhan, China, in late 2019. Weissman quickly realized this virus was a perfect candidate for an mRNA vaccine, and Pfizer-BioNTech and Moderna soon pivoted to work on one. The rest is history.

Scientific American spoke with Karikó about how she came to work on mRNA, why it was well suited for COVID vaccines and what other exciting medical applications it could have.

[An edited transcript of the interviews follows.]

What was your initial reaction to winning the prize? Were you surprised, or did you expect this?

KARIKÓ: No, I never expected any kind of prize. For many decades, I never got anything. I was very happy with doing the work. Getting a letter from a New York elderly home where they celebrated that, with the vaccine, nobody died when they got the infection—for me, those are the real prizes. I was aware of this Breakthrough Prize—it’s very famous. But, you know, I never thought about any kind of prize. So it was a very, very pleasant surprise.

Did you ever expect this technology to have such a global impact, in terms of the COVID vaccines? Or was it just something you were working on at the right place and time for this pandemic?

KARIKÓ: I never wanted to actually develop a vaccine. I was making this modification in the RNA because I always wanted to develop it for therapies. And when, in 2000, we learned that adding messenger RNA (which I made) to humans, they made inflammatory molecules—cytokines—I thought that I had to do something. I tried to make sure that when we are using it for a therapy—you know, such as treating a patient who has had a stroke—we don’t add some extra inflammatory molecules. At the beginning, it was thought that the immune form of this RNA would be a good vaccine. In 2017 the first paper was published showing that the modification we discovered that makes the mRNA noninflammatory could lead to a good vaccine, and the Moderna and BioNTech-Pfizer vaccines both have this modification.

Here at BioNTech, I am in charge of the protein replacement program. We use modified mRNA for cancer treatment. And this is not a vaccine. This is mRNA coding for cytokines and injecting them into tumors to make the tumor “hot” so that immune cells will learn what to see and can eliminate metastatic tumors. We did not know that there would be a pandemic, but I was aware that this is a very good way to make a vaccine because, with my colleagues at the University of Pennsylvania, we had already used it not just for Zika virus but for influenza, HIV, herpes simplex—it was already demonstrated in animal studies that it is such an excellent vaccine.

So when the pandemic started, was it immediately clear to you that this could be a useful technology to develop COVID vaccines?

KARIKÓ: From 2018 we had worked with Pfizer to develop a vaccine for influenza. And we were already ready to start a clinical trial for that. But switching over to COVID, it was just a technical thing. And so it was already ready.

If the pandemic had happened 20 years ago, you would need to have, physically, in your hands, a piece of the virus. So that would be a big delay. But commercial gene synthesis started about 20 years ago. Now you can just order a gene. You order DNA, and then you insert it into a [typically circular molecule of DNA called a] plasmid, and then you make RNA. But making the nanoparticle to deliver the mRNA is kind of challenging.

The lipid nanoparticles were a key part of the technology to make it useful for vaccines, right?

KARIKÓ: In my view, yes. The lipid nanoparticle protects the mRNA outside the cell because, in the blood and everywhere, there is a lot of human RNA. Second, it helps it to enter because the cell will pick up the particle. And then it is in the endosome [a membrane-bound compartment] in the immune cells, and then this lipid nanoparticle helps escape from the endosome to the cytoplasm [the solution inside cells] so the protein can be made. It is a very smart particle.

Do you see this technology being useful for many other types of applications, such as the cancer treatment you mentioned earlier?

KARIKÓ: It is already. What I started here at BioNTech, injecting messenger RNA coding for cytokines…, the human trial had already been going on for years. And then the other program with the nucleoside-modified mRNA was already ongoing. For example, Moderna is producing antibodies for chikungunya virus. [In a collaboration with AstraZeneca] they already have a phase II trial [led by the latter company] injecting mRNA into the heart [that] codes for [a protein that] generates new blood vessels. And they are also running a clinical trial for wound healing. So the data were out there—you already saw these ongoing trials for mRNA therapy—and it was just people who are not in the field who were not aware. They thought, “Oh, this is the first use.” No, there are many, many other applications.

Has all this new interest in mRNA changed this field? Do you think it will accelerate the development of mRNA vaccines for other diseases, such as influenza?

KARIKÓ: Yeah, if you read the Wall Street Journal article [interviewing] Albert Bourla, CEO of Pfizer, you know, he said that Pfizer will pursue mRNA vaccines for other diseases. They will do autoimmune disease. We published this year, at BioNTech, that we use tolerization [exposing someone to an antigen, or substance that provokes an immune response, until they can tolerate it]. We use an animal model for multiple sclerosis, and we showed that you can use tolerization against an autoimmune disease if the mRNA codes for the autoantigen. Before, it was like CureVac, Moderna, BioNTech—these were smaller companies working with RNA. And now, all of the sudden, you can see that Sanofi is buying into other companies, Pfizer is doing it, and so the large companies are realizing that they can get many products in their pipeline very quickly.

Do you think that this mRNA technology could be a good candidate for a universal coronavirus vaccine?

KARIKÓ: I think that it could work for all vaccines except those against bacterial diseases. [It could work for vaccines against] viruses and parasites, such as [those that cause] malaria and, of course, for cancer—but we have to understand better what to target.

What do you plan to do with the prize money?

KARIKÓ: Probably, I will use it for research. I will make a company. When I got a smaller award, I gave it back to those who needed it more—for the education of underprivileged children. I am 66 years old and not used to having a car. I never had a new car, and I don’t think I would have one now.