Conversation with Nobel laureate Katalin Karikó: Walking in the no-man's-land of mRNA for 40 years, I have always believed that what I am doing is something of great importance.

When the entire world turned its attention to mRNA vaccines and hailed them as the saviors against the COVID-19 pandemic, the woman who laid their scientific cornerstone behind the scenes had already walked alone on a little-trodden, widely questioned path for 40 years.

Katalin Karikó, the 2023 Nobel Laureate in Physiology or Medicine, does not have a typical, linear "genius success story". Her story began in a small Hungarian village with no running water or stable electricity. "What truly shaped me was that simple family life closely connected to nature," Karikó recalled in an exclusive interview with Edu Guide. The childhood curiosity of watching chicks break out of their shells became the first sprout of her scientific intuition.

Her scientific career was a long tussle against the stubborn consensus of mainstream academia. When the molecular biology community was obsessed with studying DNA and plasmids, Karikó focused on messenger RNA (mRNA), which was then regarded as "tricky" and "hopeless". After joining the University of Pennsylvania in the 1990s, her path did not become smoother. Instead, she faced demotion, difficulty in securing funding, and widespread pessimism from her peers. "I always felt that what I was doing was important. It was just that no one else understood it," she said. What sustained her was not the expectation of immediate success, but a Stoic belief: "Focus on the things you can change."

Her key breakthrough — the discovery that replacing the natural components of mRNA with modified nucleosides (such as pseudouridine) could drastically reduce the harmful immune reactions it triggers — was not an instantaneous epiphany either. "In the field of science, there is never a moment where you go 'wow, I just discovered this'," she described to Edu Guide. It was a slow, arduous process full of self-doubt, requiring countless days and nights in the lab, including New Year's Eve and New Year's Day, to rule out countless possible interfering factors and conclusively prove the causal relationship.

This tenacity partly stemmed from her unique philosophy of dealing with adversity. From the time when her high school teacher threatened to block her access to university to the many setbacks in her career, she learned to turn "negative pressure" into motivation. "I am always grateful to those who tried to make my life miserable, because they made me a better person." She attributed this attitude partly to the influence of her father, who remained optimistic and never complained even in the face of difficult life.

Even after making foundational achievements in science, Karikó's attitude towards science itself remains so pure that it is almost unconventional. "It is always science that drives the progress of knowledge," she said. She criticized some peers for putting career advancement above scientific discovery, and warned students: "They are not working for their superiors, but for driving the progress of science."

Today, mRNA technology has risen from an overlooked niche to a revolutionary platform in biomedicine, with applications in a wide range of fields from vaccines to cancer treatment and protein replacement therapy. Looking back on this journey, Karikó's definition of success is completely different from the recognition that the outside world chases. She shared with Edu Guide, "Success is actually that I am still the same person I was 60 or 50 years ago, honest and natural, nothing more."

What changes the world is often not the most sought-after trend, but the persistent belief that chooses to stay true to curiosity and focus on the matter at hand even through the long unseen years. In this noisy era, the very existence of Katalin Karikó is a quiet declaration on how to face difficulties and stick to your beliefs.

Below is the full (abridged) conversation between He Peikuan, founder of Edu Guide, and scientist and Nobel laureate Katalin Karikó, enjoy:

On Childhood and Curiosity

He Peikuan: You grew up in a small cottage in Hungary with no running water or stable electricity. Do you think this materially deprived environment actually helped you develop better on your scientific path?

Scientist Katalin Karikó: I don't think deprivation itself is necessary. What truly shaped me was that simple family life closely connected to nature. We had animals, plants and a garden, which helped me observe things. We saw chicks hatch out of eggs, and you would be curious about how they got there. This kind of curiosity could also be experienced by a child from a wealthy family who explores nature on a farm or somewhere else. I think all children are curious about something.

He Peikuan: There is a discussion now that people from stable, wealthy families with no financial pressure are more suitable for a scientific research career. What do you think of this view?

Katalin Karikó: I studied in public schools all the time, and the conditions were very simple. But that's not necessarily a bad thing. I think when you have more resources and the ability to help your children, you may deprive them of the opportunity to learn how to fight for themselves and how to achieve things. All parents want the best for their children, but maybe they are not doing it right, because they stop their children from fighting for something, so the children cannot experience the feeling that "yes, I made it".

For me, a stable family is reflected in simple life: my parents loved each other, never shouted at each other, and they never spoke ill of others in front of people. This helps shape a child's character more than having all the money and similar things.

He Peikuan: Mm-hmm, many things are more important than superficial material possessions. You also mentioned your firm belief in the potential of mRNA many times in your autobiography. Looking back, when the research prospect seemed completely hopeless, how did you distinguish between correct scientific belief and stubborn delusion?

Katalin Karikó: When you do research, you can see progress. If I couldn't see anything, I wouldn't have believed in it so much. In this process, I made progress in getting more protein from RNA, which I would deliver into cells. Then I thought about applications in cells like bone marrow cells. Then I thought about the possibilities in animals and in the treatment of certain diseases. This always gave me a glimmer of hope. That's what gave me strength.

It is also important that at least one person supports me. You need one person, at least one person who keeps encouraging you. My parents, my husband and my daughter. That's what drives scientific progress. For example, if you have to worry about what your husband is doing and what he is complaining about, you can't concentrate.

I later realized that this is a Stoic philosophy. You should always focus on the things you can change. Don't waste your time on things you can't influence. Once you make a decision, don't waste time thinking about what would have happened if you had done that. If you have made the decision, just look ahead and think about how to make progress. That philosophy helped me and guided me.

On Optimism and Belief: I Always Felt That What I Was Doing Was Important

He Peikuan: You mentioned in your autobiography that you turn pressure into positive power. In your daily scientific research life, how did you actually cope with pressure when you faced it?

Katalin Karikó: I started doing this back in high school. When I was about to graduate, my teacher said he would make sure I wouldn't be admitted to university, because he knew people in the admissions office. That was negative pressure. But how do you turn it into something positive? You have to understand that the decision is in your own hands. I could say, forget it, I won't get admitted at all; or I could say, okay, I will learn a lot, I will be the best, and they have to admit me.

So I turned it into something positive. That's why I am always grateful to those people who tried to make my life miserable, because they made me a better person. If that teacher had told me, "I'll make sure you get admitted", wouldn't I have learned much less? Now, I ended up learning far more.

Your happiness and the peace in your life should never depend on other people. Whether you get fired or not, you have to focus on what to do next. Your future should not be determined by that decision. It will be determined by what you do next. So it's very simple. But you have to practice it.

He Peikuan: Do you think you were born with an optimistic attitude, or did you learn it after experiencing some setbacks?

Katalin Karikó: I wonder about that myself. My father went four or five years without being hired by any organization or individual, because he was punished for his activities. But he was always in a good mood, and he never complained. I didn't really understand that when I was little. So maybe there is some genetic factor that makes you naturally positive. But it also comes from his upbringing: his childhood was full of hardships, and he never complained.

So I think it might be hereditary, but I also think everyone can practice it.

He Peikuan: My father is the same, he is always optimistic. When I encounter setbacks, he always tells me, "It's okay, it will pass. Try harder, you can make it." His optimism has also passed on to me.

But at the same time, not everyone can think optimistically like that, and sometimes when they face setbacks, they might be a little negative.

Katalin Karikó: I try to tell people, for example, scientists receive all kinds of letters saying that their work or application has been rejected. Blaming the person who rejected you doesn't help you. Instead, find out the reason, maybe I didn't explain it clearly enough. That's something I can do right away, something I should do, right? Explain it more clearly. But if you blame others and complain, it does you no good. But that's what people like to do. I want to say that everyone can live a much happier life if they look at life from a different angle.

He Peikuan: Yeah, looking at life from a different angle can be great. Besides, your scientific career is full of setbacks, and you were demoted at the University of Pennsylvania. That was not just a professional setback, but to some extent related to identity and dignity. Why did you never consider leaving? Was there something more important that made you think it was worth sticking to?

Katalin Karikó: You know, I always felt that what I was doing was important. It was just that no one else understood it. Because they hated working with RNA. In the field of molecular biology, everyone was working with plasmids. When you isolate plasmids, the first thing you add is RNase. Students splatter it around, and everything in the entire lab gets contaminated with that RNase that degrades RNA. When they try to look at the results, there is no progress worth observing. But that's only because of the contamination. And I knew I could handle it. Other people concluded that the situation was bad just because they didn't have good lab practices. So I just ignored all those naysayers who didn't know anything.

So I was very optimistic that one day it would be useful, but I didn't expect to live to see the day when people use it. Scientists have to be optimistic, because we believe in things that have never been done before, and imagine that they are possible.

On Scientific Research: There is No "Eureka Moment" for Breakthroughs

He Peikuan: On the day you made your famous "breakthrough" — realizing that nucleoside modification could solve the mRNA immunogenicity problem — was it an instantaneous inspiration, or a long process that required subsequent experiments to confirm?

Katalin Karikó: In the field of science, there is never a moment where you go "wow, I just discovered this". You do the experiment, and then you understand what's going on. You think maybe I missed something, maybe I mixed something up. I have to repeat it. And all of this came very slowly.

I remember when I realized the significance of pseudouridine, there was no internet to check back then. I went to look at a biochemistry book to see what pseudouridine actually looks like, why it is like that, what's so special about it. Then I started reading the limited relevant materials, and then I had to repeat the experiment. I needed to confirm several key questions: is its synthesis efficiency higher? Is it really non-immunogenic? These results emerged slowly.

The next question was: why? Why would nature design it this way? How can I prove that? Is pseudouridine itself really the thing that works? Back then, no one had ever made messenger RNA containing pseudouridine. I had to figure out whether the triphosphate form of pseudouridine could really be incorporated into RNA.

At this stage, you are completely overwhelmed by work. You vaguely feel that you have discovered something important, but there are so many tasks that you can barely catch your breath. No one has ever done this before. Maybe it's impossible to achieve at all. You can't run out naked and shout "I've discovered something!" — you have to have evidence. You have to prove that this is a direct causal relationship.

He Peikuan: You still need to go through the process of redoing the experiments to prove that it is correct and useful.

Katalin Karikó: Yes. So I kept going. Even after I successfully synthesized pseudouridine-containing mRNA and found that it was "cleaner" with less double-stranded RNA, I still had to ask: is it really working better because of pseudouridine? Or is it just because there are fewer contaminants? To rule out this possibility, I had to purify both uridine-containing RNA and pseudouridine-containing RNA to the same extent, ensuring that the levels of double-stranded RNA were completely consistent.

The problem was that there was no literature describing how to do that. So we tried all kinds of methods. I clearly remember that I spent New Year's Eve and New Year's Day one year in the lab, just to find a way to completely purify RNA. Because I had to prove: even without double-stranded RNA, does pseudouridine still perform better? I didn't know the answer at that time.

There were so many problems and so many possible explanations throughout the process. You keep observing phenomena, and keep asking: what is the real reason behind this? That's the process of science — hard, but exciting. The pursuit of truth itself is an extremely arduous yet fascinating task.

On the Groundbreaking Significance of mRNA Nucleoside Modification

He Peikuan: If you use a simple analogy to explain your core breakthrough — that nucleoside modification of mRNA can solve the immunogenicity problem — how would you describe it to ordinary readers so that they can better understand the importance of your work?

Katalin Karikó: I have to say, the Nobel Prize in Medicine is awarded for discoveries. We discovered that in our bodies, our RNA, all RNA, is more highly modified than RNA from bacteria or other organisms. This discovery helps reduce the inflammatory properties of our own RNA. So this is a discovery, not the invention of a vaccine.

If I use a simple metaphor to explain it, I would say: the RNA in our body is made up of four "building blocks". We found that by slightly changing one of these building blocks, this molecule — which originally triggers inflammatory reactions, carries genetic information and guides protein synthesis, namely messenger RNA — can no longer trigger immune reactions, thus producing the correct protein more stably and efficiently in cells.

He Peikuan: It helps mRNA avoid inflammatory reactions and translate to synthesize the correct proteins.

Katalin Karikó: Mm-hmm. This year we have gained a deeper understanding of the mechanism. Now we know that there are enzymes in the endosomes of immune cells that will cut and degrade RNA at positions containing uridine. But once uridine is modified, these enzymes cannot cut the RNA. In this way, RNA can completely escape into the cytoplasm and be translated into proteins.

Since endosomes are exactly where immune sensors are highly concentrated, when uridine cannot be cut and no signal is released, the immune system will not be activated. This is the fundamental reason why nucleoside modification makes mRNA "non-immunogenic".

He Peikuan: You have been paying attention to and tracking the latest, most cutting-edge scientific discoveries until now, right?

Katalin Karikó: I focus on what I am doing now, which is not mRNA. But I just came back from an mRNA therapy conference. We have had an RNA therapy conference since 2013. We organized this non-profit event, which is attended by many students. It is held in Europe one year, and in the United States the next. So we pick interesting topics to present to the audience. More than 600 people attended this conference. We also care about what is exciting in this field, and whether people will do their experiments in different ways when they go back to the lab.

On Passion and Pure Pursuit of Science

He Peikuan: During your scientific research, you were also diagnosed with cancer. Did these experiences change your views on career and life?

Katalin Karikó: Several times. For example, in 2016, I could have retired because I was sick and hospitalized. At least for me, I felt I had to behave abnormally. At that time, half of my face was paralyzed, and saliva kept dripping down. But I put on a brave face, and went back to work a week after the surgery,