Dr. Katalin Kariko, Insights Into mRNA

The Research & Discoveries Guarding Humanity From Covid-19

In a series of interviews covering the most significant scientific discoveries, Param Malik and Dr. Kariko's conversation discusses remarkable advancements in mRNA science, vaccines, and her inspiring journey in research. Featured below is a selected segment of the full interview.

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Param: Dr. Kariko, thanks for your time. Your work has been such an inspiration, and it's not often that scientists can see such a direct translation of their work in the way you have. Before we talk about your research, could you reflect on your beginnings in the field and what inspired you to be more involved with scientific discovery?

Dr. Kariko: You know, even in high school I was doing little experiments (i.e. using seeds to trace the process of germination). I was a student in Hungary, where after high school you have five years of university. And during these college years I often went to the laboratory (in our research institute) and really wanted to be more involved. We have a research center there called the Hungarian Academy of Science, with a research center branch in Szeged called the Institute of Biochemistry, Biological Research Centre. That was in the southern part of Hungary where I was studying. And the chief of the lab told me to go to the Fishery Institute [in another city] during the summer and learn their process, analyze lipids and do other things. So I broke into the field with lipids and that’s how I started.

Param: Reflecting on your early path, what lessons would you want to share with aspiring scientists?

Dr. Kariko: One thing I find very important is that you must enjoy what you do. Science is not for everybody. If you like to just keep thinking about the way things are and are always trying to find reasons, if you enjoy this investigative process, then that's who you are. Yes, I get in the spotlight these days, but the spotlight is not on the scientists usually. You have to be very interested in your work.

One problem, I find, is that many students are not as informed. You know, you are now writing this article to spread awareness and this is important because my disappointment is that if you ask others whether they can name a scientist who is alive, will you get any response? People know all of these celebrities and sports people and not the scientists. So that’s a major problem. It’s also important for people to remember not to compare themselves with others professionally, you just have to focus on solving the problems you're trying to solve.

Param: When you were starting research, what obstacles and challenges did you face?

Dr. Kariko: Oh, so, you know, as a scientist, you always run into problems with your experiments or with grants, you might be disappointed if some experimental results did not align with what you would have liked. The key to success is that even after every failure you can get up and keep doing things with the same enthusiasm. That's how it is.

So in Hungary, we were behind the Iron Curtain. Many chemicals and crucial things for our experiments were not available. For instance, when I needed ethyl acetate for the lipid work, I had to read how I could make it, get the ethanol and the glacial acetic acid and other ingredients together, and then distil it and spend half a day to get the acid. Another was when I needed phospholipids to formulate a substance and it was available in Germany, but it was behind the Iron Curtain so we had to read in 1942 how you can isolate these phospholipids from a core brain. But what is important is that you learn science with what you have and you must be resourceful.

Param: You’ve worked extensively with mRNA. Could you explain why you were interested in mRNA and your work in the space?

Dr. Kariko: It's important to know that mRNA is not what we invented. Every living organism, every cell has mRNA, because that's part of the information flow in the cell. Messenger RNA (mRNA) is a part of that flow of genetic information to make a protein. So this mRNA, the advantage, which I was thinking when I told others why we should use RNA for therapy is because it was more like a conventional drug. You know, it codes for something. It is programmed and set to produce this protein, and then the RNA degrades, the protein degrades, and if it sees good results, you can reply, you give more, then there will be more protein buildup. So it was more like a conventional drug. You could program a cell to produce a particular protein or molecule or antibody, and then it could help you activate an immune response or help cure a disease.

Param: How did you collaborate with Dr. Drew Weissman in developing the COVID-19 vaccine and applying mRNA in that context?

Dr. Kariko: I met Drew Weissman in 1998 at Penn. He wanted to make a vaccine, and so I learned all of this immunology and vaccinology from him and we did a lot of work together there. When I left Penn in 2013, and when I came here [BioNTech] in 2015, we started to hear about the prospects of using and developing messenger RNA vaccines for infectious disease. It was already used for cancer vaccines, and the clinical trials were running at the time. And in 2018 Pfizer approached BioNTech to collaborate on the development of an mRNA- based vaccine for the prevention of influenza. So we started to work two years before the pandemic emerged. We were all already prepared to quickly put the mRNA technology to use for this case. All of the testing was done and it was ready for human trials.

Param: You mentioned before if the pandemic had happened a few years earlier, it would not have been possible to make the vaccine as fast as it was made now.

Dr. Kariko: More like 20 years ago, I would say, because that is when the information was scarcely available, reagents and genes were difficult to find and expensive to order, and the high through-put sequencing demand was very complex for the machinery and apparatus at the time. Technological advancements over time have helped us make very significant discoveries in this space.

Param: Can you share how the mRNA vaccine works and the mechanisms behind it?

Dr. Kariko: Yes. So this messenger RNA, because it is very fragile, has to be wrapped up in something when we deliver it into an organism. In this case, the vaccine utilizes lipid nanoparticles that are responsible for covering up and protecting the RNA as it enters the cell, and helping it overcome multiple extracellular and intracellular barriers. When it is injected, there are different component lipids that help it aggregate and so on. You have the adjuvant stimulant, which would tell the immune system, listen, listen, you have to watch it, you have to do something.

Your muscle tissue is actually full of immune cells. When the mRNA is injected, the dendritic cells, which are the most professional immune cells, and macrophages, pick up some and the rest goes to the nearby lymph nodes. These immune cells make the protein translated from the mRNA once it successfully reaches the target cells, and that protein in this case is the antibody that binds to the SARS-Cov2 virus and blocks it from binding to your cells. Your B cells are activated as well to produce more of these antibodies, and your cytotoxic T cells will directly disable any detectable viruses. So the vaccine is very advantageous in helping us generate an effective immune response.