Dialogue with Nobel laureate Katalin: On the road less traveled, I've always believed that I'm doing something important.

When the whole world turned its attention to mRNA vaccines and hailed them as the saviors in the fight against the COVID-19 pandemic, the woman who laid the scientific foundation for them behind the scenes had already been walking alone on a little-traveled and much-questioned path for forty years.

Katalin Karikó, the winner of the 2023 Nobel Prize in Physiology or Medicine, her story is not a typical, straight-up narrative of a genius. It began in a small Hungarian village without running water or a stable electricity supply. "What really shaped me was the simple family life closely connected with nature," Karikó recalled in an exclusive interview with Edu Guide. The childhood curiosity of watching chicks hatch became the first sprout of her scientific intuition.

Her scientific research career was a long struggle against the stubbornness of the mainstream scientific community. While the field of molecular biology 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 obtaining funding, and the general pessimism of her peers. "I always felt that what I was doing was important. It's just that others didn't understand," she said. What supported her was not the expectation of immediate success but a Stoic belief: "Focus on what you can change."

Her key breakthrough - the discovery that replacing the natural components in mRNA with modified nucleosides (such as pseudouridine) could greatly reduce the harmful immune responses it triggered - was not an instant epiphany either. "In the field of science, there's never a situation where you go 'Wow, I've discovered this,'" she described to Edu Guide. It was a slow, arduous process filled with self-doubt, requiring countless days and nights in the laboratory, including New Year's Eve and New Year's Day, to rule out countless possible interfering factors and conclusively prove the causal relationship.

Part of this perseverance stems from her unique philosophy of dealing with adversity. From the threat of her high school teacher to prevent her from going to college to the many setbacks in her career, she learned to turn "negative pressure" into motivation. "I always thank those who tried to make my life miserable because they made me better." She partly attributed this attitude to the influence of her father, who remained optimistic in difficult life and never complained.

Even after making foundational achievements in science, Karikó's attitude towards science itself remains pure to an almost unusual degree. "It's always science that drives the progress of knowledge," she said. She criticized some of her peers for putting career advancement above scientific discovery and admonished students: "They're not working for their superiors but for the advancement of science."

Today, mRNA technology has leaped from an overlooked corner 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 very different from the recognition pursued by the outside world. She shared with Edu Guide, "Success is actually being the same person as I was 60 or 50 years ago, honest and natural, that's all."

What changes the world is often not the most popular trends but the persistent beliefs of those who, in the long years when no one is watching, still choose to be true to their curiosity and focus on their work. In this era of hustle and bustle, the very existence of Katalin Karikó is a quiet declaration of how to face difficulties and stick to one's beliefs.

The following is the full text (with deletions) of Edu Guide's conversation with scientist Katalin Karikó. Enjoy:

On Childhood and Curiosity

He Peikuan: You grew up in a cottage in Hungary without running water or a stable electricity supply. Do you think this materially deprived environment actually helped you develop better on the scientific path?

Katalin: I don't think deprivation itself is necessary. What really shaped me was the simple family life closely connected with nature. We had animals, plants, and a garden, which helped me observe things. We saw chicks hatching from eggs, and you'd wonder how they got there. This kind of curiosity could also be experienced by a child from a wealthy family exploring nature on a farm or somewhere else. I think all children are curious about something.

He Peikuan: There's a current discussion that people from stable and wealthy families without financial pressure are more suitable for a scientific research career. What do you think of this view?

Katalin: I always went to public schools with very basic conditions. But it's not necessarily a bad thing. I think when you have more resources and the ability to help your children, you might deprive them of the opportunity to learn how to fight for themselves and achieve something. Parents all want the best for their children, but maybe they're doing it wrong because they don't let their children strive for something, and then the children can't experience the feeling of "Yes, I did it."

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

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

Katalin: When you're doing research, you can see progress. If I couldn't see anything, I wouldn't believe so firmly. In this process, I made progress in obtaining more proteins from RNA, and I would deliver them into cells. Then I thought about the application in cells like bone marrow. And then the possibility in animals and in the treatment of certain diseases. This always gave me a glimmer of hope. That's what gave me strength.

And it's also important to have at least one person supporting you. You need someone, at least one person, to always encourage 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's complaining about, you can't concentrate.

I later realized that this is a Stoic philosophy. That is, you should always focus on what you can change. Don't waste your time on things you can't influence. When you've made a decision, don't waste time thinking about what would have happened if you had done it differently. If you've made a decision, just look forward and think about how to make progress. That kind of philosophy helped me and gave me guidance.

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

He Peikuan: You mentioned in your autobiography that you turn stress into positive energy. In your daily scientific research life, how do you actually deal with stress?

Katalin: I started doing this in high school. When I graduated, my teacher said he would make sure I wouldn't be admitted to college because he knew people. That was negative stress. But how can you turn it into something positive? So you have to understand that the decision is up to you. I could say, forget it, I won't be admitted anyway; or I could say, okay, I'll learn a lot. I'll be the best, and they have to admit me.

So I turned it into something positive. That's why I always thank those people who tried to make my life miserable because they made me better. If that teacher had said he would make sure I got admitted, wouldn't I have learned less? Now, I've learned more instead.

Your happiness and peace in life should never depend on others. Whether you're fired or not, you must focus on what to do next. Your future shouldn't depend on this decision. It will depend on what you do next. So it's simple. But you have to practice.

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

Katalin: I wonder about this myself. My father was unemployed by any organization or individual for four or five years because he was punished for his activities. But he was always in a good mood. He didn't complain. I didn't really understand it when I was a child. So maybe there are some genetic factors, and you'll naturally have a positive outlook. But at the same time, because of 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's always optimistic. When I encounter setbacks, he always tells me, it's okay, it will pass. Try harder, and you'll make it. His optimism has also been passed on to me.

But at the same time, not everyone can think so optimistically. Sometimes they might be a little negative when facing setbacks.

Katalin: I'll try to tell people, for example, scientists receive all kinds of letters saying that their work or applications have been rejected. But blaming the people who rejected you won't help. Instead, look for the reasons. Maybe it's because I didn't explain clearly. So that's something I can and should do right away, right? Or explain it more clearly. But if you blame others and complain, it won't help. But that's what people like to do. I'm saying that everyone can lead a happier life if they look at life from a different perspective.

He Peikuan: Yes, looking at life from a different perspective can be great. Moreover, your scientific research career was full of setbacks. You were demoted at the University of Pennsylvania. This was not only a professional setback but also related to your identity and dignity to some extent. Why did you never consider leaving? Was there something more important that made you think it was worth persevering?

Katalin: You know, I always felt that what I was doing was important. It's just that others didn't understand. Because they hated working with RNA. In the field of molecular biology, everyone was working with plasmids. When you isolate plasmids, you first add RNase. The students splash it everywhere, and everything in the whole laboratory is contaminated with that RNA-degrading enzyme. When they try to look at the results, there's no worthwhile progress to observe. But actually, it's because of the contamination. And I knew I could handle it. Others concluded that the situation was bad because they didn't have good laboratory practices. So, I simply ignored all these naysayers. They didn't know anything.

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

On Scientific Research: There's No "Eureka Moment" for Breakthroughs

He Peikuan: On the day you made the famous "breakthrough" - realizing that nucleoside modification could solve the immunogenicity problem of mRNA, was it like a sudden flash of inspiration, or was it a long process that needed subsequent experiments to confirm?

Katalin: In the field of science, there's never a situation where you go "Wow, I've discovered this." You do the experiment, and then you'll understand what's going on. You think maybe I missed something. Maybe I got confused. I have to repeat it. And it all came very slowly.

I remember when I realized the significance of pseudouridine, there was no Internet to look it up at that time. I went to look at a biochemistry book to see what this pseudouridine looked like and why it was like that. What was 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: Was its synthesis efficiency higher? Was it really non-immunogenic? These results emerged slowly.

The next question was: Why? Why did nature design it this way? How could I prove it? Was it really the pseudouridine itself that was working? No one had ever made messenger RNA containing pseudouridine before. I had to figure out whether the triphosphate form of pseudouridine could really be incorporated into RNA.

At this stage, you'll be completely submerged in work. You vaguely feel that you've discovered something important, but the tasks are overwhelming. No one has done this before. Maybe it's simply impossible. You can't run out naked shouting, "I've discovered something!" - you have to have evidence. You have to prove it's a direct causal relationship.

He Peikuan: It still takes some process to conduct experiments again to prove it's correct and useful.

Katalin: Yes. So I continued. Even when I successfully synthesized mRNA containing pseudouridine and later found it was "cleaner" - with less double-stranded RNA - I still had to ask: Was it really because of the pseudouridine that it worked better? Or was it just because there were fewer contaminants? To rule out this possibility, I had to purify the RNA containing uridine and the RNA containing pseudouridine to the same extent to ensure that the levels of double-stranded RNA were exactly the same.

The problem was that there was no literature describing how to do this. So we tried all kinds of methods. I clearly remember spending one New Year's Eve and New Year's Day in the laboratory just to find a way to completely purify RNA. Because I had to prove: Even in the absence of double-stranded RNA, would pseudouridine still perform better? I didn't know the answer at that time.

There were so many questions and so many possible explanations throughout the process. You constantly observe some phenomena and then keep asking: What's the real reason behind this? This is the scientific process - difficult but exciting. Searching for the truth itself is an extremely arduous but fascinating task.

On the Groundbreaking Significance of mRNA Nucleoside Modification

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

If I were to use a simple analogy to explain, I'd say this: The RNA in our bodies is made up of four kinds of "building blocks." We found that if you just change one of these building blocks a little bit, this molecule - which is messenger RNA, the one that originally triggers an inflammatory response, carries genetic information, and directs protein synthesis - can become non-immunogenic and thus produce the correct proteins more stably and efficiently in cells.

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

Katalin: Yes. This year, we have a deeper understanding of the mechanism. Now we know that there are some enzymes in the endosomes of immune cells that will cut and degrade RNA at the places where it contains uridine. But once the uridine is modified, these enzymes can't cut the RNA. In this way, the RNA can escape intact into the cytoplasm and be translated into proteins.

Since the endosome is where the immune sensors are highly concentrated, when the uridine can't be cut and no signal can be released, the immune system won't be activated. This is the fundamental reason why nucleoside modification makes mRNA "non-immunogenic."

He Peikuan: You've also been keeping an eye on the latest and most cutting-edge scientific discoveries until now, right?

Katalin: I focus on what I'm doing, which isn't mRNA. But I just came back from an mRNA therapy conference. We've had an RNA therapy conference since 2013. We organized this non-profit event, and many students participated. One year it's in Europe, and the next year it's in the United States. So we'll select interesting topics to present to the audience. More than 600 people participated in this conference. We also care about what's exciting in this field and whether people will do experiments in different ways when they get back to the laboratory.

On Passion: Pure Scientific Pursuit

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

Katalin: There were several times. For example, in 2016, I could have retired because I was sick and hospitalized. At least for me, I felt like I had to act unusually. So at that time, half of my face was paralyzed, and saliva kept flowing down. But I had to put on a show. I went back to work one week after the surgery, even though everyone expected me to go home and rest. But I wanted to feel that I was okay, that I could think and do things. You might think, well, I'm vulnerable, I'm sick, I should restrain myself, or I have to think these things are devastating. But at least I felt normal. So I