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mRNA pioneer discusses how her work led to the COVID vaccine

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Researchers often struggle in the lab for years without the promise that their research will bring something meaningful to society. But sometimes this work can lead to breakthroughs that have a global impact. This is the case with Katalin Kariko, who, along with her colleague Drew Weissman, helped develop the messenger RNA (mRNA) technology used to produce the highly effective COVID vaccine produced by Pfizer and Moderna.

Kariko, senior vice president and head of RNA protein replacement therapy at BioNTech (a company that co-developed the COVID vaccine with Pfizer), and Weissman, a professor of vaccine research at the University of Pennsylvania’s Perelman School of Medicine, are currently inducing a detrimental immune response. He was awarded the Breakthrough Prize in Life Sciences of $ 3 million for his work on modifying gene molecular RNA to avoid this. Founded by Sergey Brin, Priscilla Chan, Mark Zuckerberg, Yuri and Julia Milner, and Anne Wojcick, the Breakthrough Prize celebrates breakthroughs in basic physics, life sciences, and mathematics. Kariko spent years on this study, despite skepticism and lack of funding. But in the end, her efforts paid off. The COVID pandemic has laid the foundation for an overwhelmingly effective vaccine that is likely to be the most reliable method in the world.

Kariko was born in Hungary to a family of modest means. She began her research on RNA modification while she received her PhD. Convinced of the research and the potential of RNA-based therapies, I came to the United States to pursue postdoctoral research. She later became a professor at the University of Pennsylvania. Interest in mRNA therapy diminished and she was told to pursue other research directions or risk losing her position, but she persisted. During a conversation on a Xerox machine, she became acquainted with Weissman, who was interested in developing vaccines at the time. They started to cooperate.

When foreign mRNA is injected into the body, it causes a strong immune response. However, Kariko and Weissman have come up with a way to modify RNA to reduce inflammation by replacing the “letter” molecule in one DNA with another. Then they worked on how to deliver it. After testing many different delivery media, they settled on lipid nanoparticles as the delivery medium. These turned out to work incredibly well. Nanoparticles acted as an adjuvant, a substance that enhances the desired immune response to the vaccine.

Weissman and his colleagues were working on an influenza mRNA vaccine in late 2019 when the mysterious pathogen that causes pneumonia spread to the Wuhan people in China. Weissman soon realized that the virus was a perfect candidate for an mRNA vaccine. BioNTech and Moderna quickly pivoted to work on one. The rest is history.

Scientific American She talked to Calico about how she started working on mRNA, why she is suitable for the COVID vaccine, and other exciting medical uses.

[An edited transcript of the interviews follows.]

How was your first reaction to winning? Are you surprised or expected of this?

KARIKÓ: No, I didn’t expect any kind of award. For decades I didn’t get anything. I was very happy with the job. I received a letter from the Elderly Housing with Care in New York congratulating that no one died when infected with the vaccine. For me, these are real prizes. I knew this Breakthrough Prize — it’s very famous. But as you know, I have never thought of any kind of award. It was a very nice surprise.

Have you ever expected this technology to have such a global impact on COVID vaccines? Or was it working in the right place and time for this pandemic?

KARIKÓ: I didn’t really want to develop a vaccine. I was making this change to RNA because I always wanted to develop it for treatment. And in 2000, when I learned that adding the messenger RNA I made to humans produced cytokines, which are inflammatory molecules, I thought I had to do something. When used for treatment, such as in the treatment of patients with stroke, we avoided adding inflammatory molecules. Initially, the immune form of this RNA was thought to be a good vaccine. The first paper was published in 2017, showing that changes that make mRNA non-inflammatory may lead to better vaccines. Also, both the Moderna vaccine and the BioNTech-Pfizer vaccine have this change.

Here at BioNTech, I am in charge of the protein replacement program. Modified mRNA is used to treat cancer. And this is not a vaccine. It is the mRNA that encodes cytokines that inject them into the tumor to “heat” the tumor, learning what immune cells should see, and allowing them to eliminate metastatic tumors. I wasn’t sure if a pandemic would occur, but I realized that this was a very good way to make a vaccine because I had already used it for influenza as well as Zika virus with a colleague at the University of Pennsylvania. was doing. , HIV, Herpes Simplex-Animal studies have already proven that this is a very good vaccine.

So, when the pandemic began, was it immediately clear to you that this could be a useful technique for developing a COVID vaccine?

KARIKÓ: Since 2018, we have been working with Pfizer to develop an influenza vaccine. And we were already ready to start clinical trials for that. However, switching to COVID was technical. And it was already ready.

If the pandemic happened 20 years ago, you would physically need to have some of the virus in your hands. So that’s a big delay. However, commercial gene synthesis began about 20 years ago. Now you can just order the gene. Order DNA and order it [typically circular molecule of DNA called a] A plasmid, and you make RNA. However, creating nanoparticles to deliver mRNA is a challenge.

Lipid nanoparticles were an important part of the technology to make them useful for vaccines.

Kariko: In my opinion, that’s right. Lipid nanoparticles protect extracellular mRNA. This is due to the presence of many human RNAs in the blood and everywhere. Second, as the cells pick up the particles, it helps them enter.And it’s in endosomes [a membrane-bound compartment] In immune cells, and these lipid nanoparticles help escape from endosomes to the cytoplasm [the solution inside cells] You can make protein. It’s a very smart particle.

Do you think this technology will be useful for many other types of applications, such as the cancer treatments mentioned above?

Kariko: That’s right. What I started here at BioNTech was to inject messenger RNA that encodes cytokines … human clinical trials have already been going on for years. And other programs using nucleoside-modified mRNA were already underway. For example, Moderna produces antibodies against the chikungunya virus. [In a collaboration with AstraZeneca] They are already in Phase II trials [led by the latter company] Inject mRNA into the heart [that] Code [a protein that] Creates new blood vessels. We are also conducting clinical trials for wound healing. Therefore, the data were there — you have already seen these ongoing trials for mRNA therapy — and it was only unaware of those who were not in the field. They thought, “Oh, this is my first use.” No, there are many other applications.

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

Kariko: Yeah, if you read The Wall Street Journal paper [interviewing] Pfizer CEO Albert Bourla, you know, he said Pfizer pursues mRNA vaccines for other diseases.. They develop autoimmune disorders.This year, BioNTech announced the use of tolerances. [exposing someone to an antigen, or substance that provokes an immune response, until they can tolerate it].. Using an animal model of multiple sclerosis, we have shown that tolerance to autoimmune disease can be used when mRNA encodes an autoantigen. Previously it was like CureVac, Moderna, BioNTech. These were small businesses dealing with RNA. And now, suddenly, you can see that Sanofi has acquired another company and Pfizer is doing it. As a result, large companies are finding that many products are available in the pipeline very quickly.

Do you think this mRNA technology is a good candidate for a universal coronavirus vaccine?

KARIKÓ: I think it is effective for all vaccines except bacterial infections. [It could work for vaccines against] Viruses and parasites [those that cause] In the case of malaria and, of course, cancer, we need to better understand what we are targeting.

What are you going to do with the prize money?

KARIKÓ: Perhaps I will use it for my research. I make a company. When I received a small prize, I returned it to those in need more for the education of underprivileged children. I’m 66 years old and I’m not used to having a car. I’ve never had a new car and I don’t think I have one now.

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