The Joe Walker Podcast - Katalin Karikó — Forging the mRNA Revolution

Episode Date: August 1, 2023

Katalin Karikó is a Hungarian-American biochemist. She is one of the inventors of mRNA technology. Full transcript available at: thejspod.com. Episode recorded on 15 February 2023.See omnystudio.com/listener for privacy information.

Ladies and gentlemen, boys and girls, swagmen and swagettes, welcome back to the show. This is an historic episode. For not only do I have a very special guest, it is also that guest's first and so far only properly long form podcast conversation. My guest is Katalin Kariko. Katalin or Kati is a Hungarian American biochemist and one of the few people instrumental to the development of mRNA technology. Now, mRNA technology obviously became famous with the coronavirus vaccines, but it has a long history, which we discuss in this episode. mRNA technology also promises a new era in medicine,

with vaccines on the cards for a panoply of viruses, as well as the tantalizing prospect of cancer vaccines. Like any scientific breakthrough, mRNA vaccines were built on a bunch of smaller innovations, each of which was necessary but not sufficient to the overall technology. Many people contributed their piece to the puzzle in the case of mRNA. Among them are Robert Malone, who first realized it might be possible to treat RNA as a drug. Then there was Paul Krieg and Doug Melton, who championed the use of synthetic RNA. There was Derek Rossi, one of the earliest scientists to recognize the

therapeutic potential of Cati's work, who also co-founded Moderna. There was Peter Cullis, whose revolutionary use of lipid nanoparticles facilitated the delivery of mRNA into cells. And of course, there's Drew Weissman, Katalin Kariko's longtime collaborator. But in this constellation of contributors, the star that shines brightest, I dare say, is Katalin Kariko herself. If slash when a Nobel Prize is awarded for mRNA, Kati is the strongest contender to be among the laureates. Kati's story is exceptional, not just for the scientific achievement, but also the adversity she battled along the way.

You may or may not be shocked to learn her grant applications were repeatedly rejected to the point where she was demoted and given a pay cut by her university in 1995. And yet Kati is even more remarkable for the way she handled these setbacks. And this conversation gives you an insight into her optimism and resilience. This episode is a little different in style to my typical approach, as this is Kati's debut in the long-form podcast arena. About half the conversation is biographical in nature. I traveled to Philadelphia to record the conversation with Kati in person. As always, if you have questions, comments, or suggestions for future guests, you can reach me on Twitter. My handle is at Joseph N Walker or by email. My address is joe at the jspod.com.

Please enjoy my conversation with Katalin Kariko. Katalin Kariko, welcome to the podcast. Thank you. Thank you for everything. So today I have three goals. I firstly want people to hear your story because it's unique and inspiring. Secondly, I want to talk about mRNA technology because it's fascinating and important. And thirdly, I want to talk about some meta-scientific issues as well. But let's start with your background.

So you were born in Hungary. Tell me what life was like growing up there in the Soviet era. From Soviet era, you know, you don't feel that. You have your family, you have your neighbors, your school, your local environment, and you just go to school. You do whatever you are doing as kids and in the family. And I have a very happy childhood. So we had a small house. We had two rooms, but we used just one during the winter because it was, you know, one you could afford to heat up. And we had a big garden.

We had animals like pigs and chickens, and we had vegetable garden. I have an older sister. She's three years older, and we had our little garden. We could put the seed ourselves, and we attended those gardens. We had flower gardens. So it was like Aden there. I was very happy growing up. And my father was butcher.

My mother, she worked at home, and then later she was bookkeeper. And we had a simple life. We didn't have running waters. We had to run to the street to get drinking water, and so we carried home. And, you know, we did not have refrigerators. You know, we put everything in the well to cool it down. And so it was, but everybody in the neighborhood was like that. And you, we didn't

have television set. So, you know, it first, at least the first 10 years in my life, so that it was a little adobe house with a reed roof. And so I went to school and I enjoyed that and it was, I was very happy. I didn't realize this until I started researching for this conversation, but the word stress wasn't applied to humans until the 1930s. Previously, it was only used by physicists. And it was first applied to humans by the Hungarian endocrinologist Hans Selye. Selye. Selye.

Thank you. And in high school, you read a book about stress by Hans Selye. Can you tell me how that influenced your thinking? Why was it so impactful? So, indeed, we actually wrote a letter to him. And he responded and we get so excited. And because he was born in Hungary, so his book about stress was translated to Hungarian. And so in the 60s, you could read his book.

And we discuss in the biologic class. And so we did understand that stress can kill you, but only how you perceive. So you have to learn to handle the stress. And what he said also in the book that without stress, life is meaningless. You wouldn't get up this morning if you don't have this anticipation, excitement that we will talk today. So you need that kind of happiness and happy. This is also stress, but it is a good stress. And how you would, you know, when you are kicked out from your job to see the good goodness of it, you know, but you have to learn.

And this is a practice. So we practice and we talk in the school about how we can focus on things that we can do. So that's what the problem with people that, you know, they focus things that they cannot change. And they also was important that the conversation has to be about what I can do, not blame others. And so it is, it was very helpful. Without reading that book, would you have been as good at handling stress? I mean, I feel like your personality is very optimistic, naturally. Yeah, I wouldn't be here.

I wouldn't talk to you. I would not reach that because it was so critical. What I can see even today that people are comparing themselves to the others immediately. Don't do that. Don't worry about that other person works less and promoted and get higher. You cannot

change that. But the people paying attention to this, they get distracted and they are not focusing what they can change, you know, doing the research. And they are not focusing what they can change, you know, doing the research. And they are blaming. They blame their children, their husband, wife, neighbors, somebody. And then you cannot change those people.

You know, they wish that they would do that and that. No, you have to always end every conversation in your mind is that what I can do. So that's very helpful. And if people would learn this, they would live a much better life. For example, the grudge that people have against somebody. So many people ask how I feel now that, you know, no, I can't tell those people who were not nice to me. I mean, I thank people who were not nice to me because I mean, I thank people who were not nice to me because without

them, I wouldn't be here because hardship and those things is forming your personality much better than if somebody, you know, prepare yours and you just have to walk and easy way. So if you struggle, you learn, you know, many things. And, and so that, um, this, uh, also people, you know, that who were not nice to me made me, you know, work harder what I have. And then that's how you have to process. So even in actually in school, in high school, we are talking about reading this book. My high school teacher told me he didn't like me. And he told me after I graduated, get to the highest mark, he said that he knows somebody at the university and he will make sure that I will not be accepted. So it is, at first you could see that, oh, this is a mean and bad news. Yeah. But if you say that, okay, how I perceive it, that's important.

I perceive that I have to work harder. So I have to be the number one. So no question about that. I will be accepted. If he says, I will arrange that you will be accepted. I, you know, sit back and work less harder. Yeah. So that you have to see in that, okay, he made me work harder.

Yeah. And then you also learn every time you learn that not everybody's rooting for me. And that was, you know, your last of the life is there. So not everybody wants you to succeed. And you have to think about that so that all of these things you have to practice to think about, okay, what did I learn from it? Because even the meanest person to tell you anything, you learn, I won't do that. I won't say to anybody else because it's hurtful. So I learn and then you move on.

So that's the simple philosophy. I don't know, maybe there is such philosophy exists, but that's if you live your life that you are so much happier. Yeah. It sounds a little bit like stoicism, which is a bit of a podcast cliche, but I won't go into that. But it's a beautiful perspective. Why was that teacher so mean to you?

Was he just a bad guy or did you do something to piss him off? You know, there are always people that, you know, they don't like if somebody too successful. Because even in elementary school, I already competed nationally in Hungary in a biology competition. And came third. Yeah, I was third best. In the whole country. Yes, exactly yes i was third best in the country it was a whole week compass competition for example and and so i was in high school i was

writing different essays i always were very uh inspired and competitive and know, not everybody likes that. And some people have a power that they can, you know, crush you and they try to use it, you know. But you just don't have to think about it too much. So if that book was so important to you, I guess I'm wondering why you didn't go to study psychology or something like that um you know i i like biology and um so it is also very important in science that you you focus on something try to solve the problem and um i know that we might talk about later about what is in in science but what i could see is that as long as I am focusing on that science part and try to solve it, you know, me and the problem and then solving it.

And that's how it is. But then you want to have more people. So you apply for more money, grants, and other things. And then you are moving away because now that if you get promoted, you get even more position to get more colleagues and more money. And then finally the goal is this promotion to get bigger team. And then what was originally the goal to understand something became a tool to reach that goal, to get this promotion and the tenure position and whatnot.

So that, but there, you know, you are not in control because somebody will decide. And I think that many people who gave up job during the pandemic, those who were tenured position, what they realized that, oh, I am just a manager. I am in the desk writing grants, writing papers, and those are having fun in the lab, you know, and they missed that. Yeah. I have lots of questions about that, which, which I'll ask you a bit later, but so you became interested in science at school you did exceptionally well in

that that week-long biology competition you mentioned and then you graduate high school um you go to university uh you study biology at university and then um you start your PhD program in 1978 and you start work on RNA that same year. But that kind of happened by chance, right? Could you tell me that story? Yes, yes. So I might mention also to getting the university was very difficult because the whole country just like they invited for the oral exam 300 and invited 30 and then accepted 15. So, you know, it is, was very difficult. And then because my parents had, you know, just elementary school education, I get a chance to, during the summer to participate at

the university in a program for the underprivileged children so that it was not first time in my life I entered a university, but during the summer. And it was very important, you know, the university initiated this kind of program for the children. Because your dad did six years of elementary, your mom did eight years. Yes. And so nobody was high school educated in our family.

And so it was important, this kind of action. And so at the university, I went to Szeged. It is a southern part of Hungary, this university city, because the biological research center was planned to be there and started or opened in 1972. So in 1973, I decided that I will go to this city because there is the biological research center. And that was my dream to work at that place and so when I started at the university I I mean we had a early morning like seven o'clock started in the morning and then eight o'clock we had so many different classes and even Saturday we had classes so that it was like analytical chemistry physical chemistry chemistry, biochemistry,

and all of this microbiology and all of, we learn everything. It is not like here in the United States. But then I went also to the research center, the biological research center as a student, and I ended up in the lipid team, which, you know, seems like a boring thing. And then I spent the summer actually in a fishery institute collecting fat from fish to identify when we feed them with different material that what their fat looks okay and so this working with lipids what happened is one day two colleagues from this biochemistry section of this biological resource center wanted to make liposome and they needed phospholipids and and they came to our lipid team to help. And then I participated when we isolated this phospholipid. We needed phospholipid, but we were behind the iron curtain.

And that fraction, which you can buy for 10 Deutschmark, it was not available for us. So we had to isolate. We looked at an old recipe and we, 1942, how to isolate this phospholipid from cold brain. So it came handy that my father was butcher. And, you know, when I look at the brain, I wouldn't say, oh, this is disgusting. And we did like five days, you know, when different fraction we took away with using different kind of organic supplement, acetone, ether, chloroform and so on. And we get this fraction of this phospholipid. And I was so excited. And I work later on with this Eva Kondoroshe and Ernő Duda. And we work

to make liposomes. And we put DNA in it and delivered to the cells. They have done this in the end of the 70s, you know, when they delivered like a viral particle to a cell which otherwise you couldn't infect because there were no receptor on it and delivered. And they did so many interesting things. And it, you know, was was for me, was very exciting. And just one day, Janu Thomas walked in and then my supervisor mentioned that Kati is finishing and she,

she wants to make her PhD. And Janu said, oh, okay, I am in the RNA lab. She can come and work with me. That's how it was. So then, okay, I am in the RNA lab. She can come and work with me. That's how it was. So then, okay, RNA. When you got interested in RNA, PCR hadn't been discovered yet. That wasn't discovered until the mid-1980s. And maybe in a moment you can explain what PCR is. But without PCR, you couldn't create synthetic RNA. So why were you so excited about RNA at that stage before synthetic RNA had been created?

I started to work in the RNA lab in 1978. And the prior year, 77, Ian Kerr in London discovered that there is a short RNA molecule which might be responsible for the interferon mediated antiviral effect the interferon is a cytokine which was known that interferes with the viral replication and Januk came actually

from the pharmaceutical industry to this research center and he thought that we need an antiviral compound and he had connection to the industry and they sponsored our research. So we will develop an antiviral compound. This was a three nucleotide containing short RNA molecule linked with a two prime, five prime, which is unusual linkage. And we have to make it enzymatically. We made it chemically. And I also set up the antiviral testing lab there.

And it is interesting that even later in my life, I always work with colleagues who are not experts what I had to do. Everybody was here, organic chemist, and I was the biologist, had to set up the essays, had to understand what making, you know, this small molecule biologically, and later on life also, everybody was expert on a different field. And maybe, maybe this is how, you know, invention is coming and novelty because you educate each other and then you come up with something that you wouldn't as individual would think about. So anyway, this RNA molecule was an exciting thing and we did a good progress.

The problem was the delivery so that in animal study it was not feasible. We couldn't wrap it up, this small molecule to deliver inside the cell and we lost our support from the industry. But, you know, when you work with RNA in the, you know, beginning of, you know, in the, I mean, end of seventies, yeah, and beginning eighties, I mean, you learn how to label, how to different enzyme you work with. And it was just a lot of knowledge you gather with this and that it stays with you. You know, that this molecule, which makes this 2-prime, 5-prime molecule,

you know, this is an enzyme we have in our bodies. This is also important for the COVID. They identified that those children who get seriously sick, they had a problem. They did not have enough of that enzyme. They had mutation in it. So, you know, from, I follow all of this field, I ever worked, what is going on today? And so I can see that those important molecules and understanding is very critical. But anyway, I enjoyed working with these RNA molecules.

And of course, when I learned that I cannot work further in this institute, I tried to find another place where they are working with these molecules. First in Europe, but, you know, they couldn't get a stipend as a postdoc, and then finally ended up here in Philadelphia. Professor Suhadornik was also interested to work in this two-prime, five-prime linked antiviral molecule. I'll come back to your move to the US, but I guess I have another question about what you were thinking during your PhD program. So you were originally interested in using RNA to develop therapies. Had you begun thinking about vaccines at that stage? No, no, I was not that visionary. I was just excited that, you know, learning biology.

I mean, every time I read this book, David Baltimore wrote it, and I said, oh, my God, these viruses are so smart. Of course, you know, it is just because evolution, you know. Not they figure out how to get around our immune system, but because they evolved this way. But, you know, I learned a lot of biology. I work with working with RNA. And so it was, that was exciting for me. So tell me about the big move to America in 1985. Yes.

So at my 30th birthday, I learned that I have to leave. I have six months left and then I have to leave the institute. And I have six months to find another job. This was my first time when I was kicked out. And so again, every time I say that several times later it happened, if I wouldn't be kicked out that many times, I wouldn't be here. Because it is important that, you know, don't take personally, don't take that, you know, somebody is deciding on that, that you are, you know, a loser. What is important, what you do next.

So that's how I came to America. And it was not easy because in 85, we are in still a communist Hungary and to prevent defection, so they only allow my family, my two and a half years old daughter, my husband and me to move to America to have a $50 for Susan, my family, my two and a half years old daughter, my husband and me to move to America to have $50 for Susan, my daughter, 50 for my husband and me. They said, ask from your employer

money. So with $100, a small family would leave Hungary and to come America and next day, how we will live. You know, they try to this way to limit movement. And so that's how we started. And you actually came over with a little more cash than that because you were able to sell your car on the black market. How does that work? Yeah. I mean, we had a Russian car, which we could sell.

Officially, we just have to change the money of the black market because there were students from Arabic countries that I could exchange. Actually, he didn't have a dollar, he had a pound. And so I exchanged and we got something, $1,000 and 800 pounds. And it was like $1,200 equivalent. And, you know, in Hungary, you were not, the Hungarian currency was not convertible. And you couldn't go and purchase freely from your foreign Hungarian currency to dollar. And you are not, if somebody would give you money, currency, foreign currency,

like a dollar, you have to go to the bank and give it to them. And they will give you whatever Hungarian currency. You are not allowed to have it. And so it was against the law. But we have to live somehow. And so this $1,000 was like a lot of money. Later when, you know, it turned out that how we hide it to the teddy, Susan teddy bears, because it was, you know, smuggled.

She smuggled out. So it was Susan's know, smuggled. She smuggled out. So it was Susan. We can blame Susan. Yeah, Susan smuggled them on. Other Hungarians also sent me letters and emails that how did, where did they hide? Everybody had to come out with some extra money, you know. You just cannot come to a family to America with $100.

So did you sew it into the teddy bear? So I put in and wrapped it up and then I stitch it back. And then we watched her that, you know, at the airport. Don't let go of that bear. Don't leave that bear there. Did she know the money was in it or was she too young? No, she was two and a half years old. Yeah, yeah.

So at this point, I actually to um kind of digress from your story and talk a little bit about the science because i think people will need some basic understanding to then follow the rest of the the discoveries that happen over the next few decades from when you land in america and maybe i don't Kati, but I, by the way, people in America say Katie, but Hungary, you would say Kati, right? Yes. I'll say Kati. So maybe a nice framework to kind of frame this, you know, microbiology 101 section of the conversation would be Jim Watson's central dogma of molecular biology, which is that DNA makes RNA makes protein and the information is unidirectional. So it flows in that direction only. DNA and proteins never actually meet, and that's why they need messenger RNA,

which is a particular type of RNA. There are actually other types of RNA. Why don't we, and I apologize because I know this is like so basic, but maybe it would be helpful if we just quickly go through each of those things. So firstly, could you explain DNA? DNA is a storage of information in our body. Every cell in our body has it, and all free-living organisms and even viruses can have DNA. And it contains information and composed from four basic nucleotides and the order of it defined that what kind of protein they are coding for. And the DNA is quite stable.

You know that you can isolate DNA from dinosaurs. There's still, you know, sequences are there. And so this is a storage, the information. So when people, you know, when paleontologists excavate dinosaur bones, sometimes they can recover the DNA, but they can never recover the RNA, which is very unstable, it self-destructs. So talk a little bit about that. So there is a very small difference between

DNA and RNA. The major one is that the DNA is double-stranded, the RNA is single-stranded. But beside that, the chemical composition is just the hydroxyl and extra hydroxyl is present on the sugar part of this RNA, which makes it very labile. You don't even need an enzyme to cut it up. If you just store in a room temperature, sooner or later your RNA is degraded. And so this is the role also in the body. And that was the reason. Actually, from the 50s,

they already were looking for this messenger RNA and they couldn't find it because it was so labile. So when 1961, two papers published in Nature, the word labile was in the title in both of those papers, labile. And the messenger RNA is, as we said, a particular type of RNA. You also have like tRNA and then you have some... Ribosomal RNA actually. Ribosomal RNA, 80-90% in our RNA in our body is ribosomal and they are part of the protein synthesis machinery. So yeah, there is DNA. The process is making an RNA is transcription and those are performed by RNA polymerases, enzymes which can polymerize,

makes RNA. And the RNA is going to the ribosomes. And this is the protein synthesis factory. And then the tRNAs, the transfer RNAs carrying the amino acid, and then they are reading the sequence and they putting one amino acid after the other as the sequence dictates, and you have the protein. So proteins are putting one amino acid after the other as the sequence dictates and you have the protein. So proteins are made of amino acid and DNA is made of, and RNA is made of nucleic acid. Very good. Thank you. Proteins are, as you said, manufactured in the ripe zones, which sit in a particular

part of the cytoplasm in the cell. It can... Float around. A lot of places it can be. Oh, okay, okay. And DNA is located only in the nucleus? If it is eukaryotic cells, yes, it is in the nucleus. Yeah.

And there are, correct me if I'm wrong, but there are upwards of me if I'm wrong, but there are upwards of about 30,000 types of protein in our cells. I don't know. Many. Many, because there are, you know. Yeah. And I guess the key point is that protein is like the functional unit of the cell. Yes, yes.

The different proteins, because those proteins could be enzymes, generate lipids and other components of our bodies. So over the years, people have tried to create therapies at the kind of the beginning and the end of that chain. So we've had like gene-based therapies focused on DNA. We've had, well, I guess like Genentech pioneered protein-based therapies from the 1980s. I have to say that even before, because a hundred years ago was insulin was introduced. That was,

you know, the protein replacement because there were, you know, the type 1 diabetes patient were, and those proteins were isolated. At the beginning, so 100 years ago, they isolated from animal tissue or different kind of, different sources, and then this is what they used. And in the 1982, you know, come the recombinant protein. When they could make human protein by bacteria or different cell factories, those were recombinant protein. And that started in 1982. Okay, I see.

So people had tried things with DNA-based therapies, protein-based therapies, but RNA-based therapies were very, very difficult, maybe even considered impossible when you were working on RNA. Even the DNA started, listen, 1980, 1990 started the Human Genome Project. And when they started to identify

the genes and the mutation in it and identify that responsible for certain disease, the thought was in the 1990s that oh, we just deliver the correct genes and everything will be fine. So that was the focus on, I mean, the Human Genome Project was 13 years, 1990. You remember Bill Clinton denounced that we know the human genome.

And so they tried to focus on that, but it was not easy. They thought that we need permanent changes back to normal. Interestingly, maybe in these days it seems now that the promise of the gene therapy based on DNA actually may be fulfilled by RNA because came the CRISPR-Cas9 technology, and you could change the genome with very simple enzymes, which will recognize certain area of the genes, and that is delivered as an mRNA. It is critical that it will be short-lived and just make the change and everything disappears. So that's an exciting time what we have now.

Yeah. Okay, so to return to your story, so you arrive in the US in 1985, and you're still obviously really excited about RNA. When did you become excited about mRNA in particular? At Temple University, I've worked three years and we work different kind of RNA there. Actually, we did a human trial together with Hahnemann University and we used double standard RNA to treat HIV patient. Because you know that 1986, that was a major viral problem, that infection and then was no assay, no test. It was very difficult at that time. But then we used double-stranded RNA. And then I worked one year in Bethesda, very basic molecular biology I did. And then when I was reading there day and night because my family was lived in Philadelphia and I worked in Bethesda

and I was entertained this thought that people try to use anti-sense RNA and I said why not using the sense RNA and the liver as a therapy and I start to read about that, what can be done. And it came very handy one day. This guy walked in and he said he has this lipofectin. They just developed and it can deliver easily nucleic acid to the cell. And then I said, oh, that's what I need. Because this liposome, what I did in Hungary was very tedious, you know, the somes and very complicated and very fragile. And so I thought, oh, that's it. I need this lipofectin.

And then I applied for the new job at the University of Pennsylvania. And then I proposed to my colleague who hired me that we will use messenger RNA and we will do it because I was reading that we can make mRNA and because we are in 89 and 84, 85 was to publication came out from Harvard University and Douglas Melton and Paul Krieg, they described that you can use phage RNA polymerase, which has very high fidelity, very efficient, very simple way to generate RNA. And so I said, OK, we are set. Love it. So in 89, you got the position at the University of Pennsylvania. So you wanted to make RNA, put it into a cell,

instruct the cell to make proteins that it wouldn't otherwise make. Yeah. And you set up an experiment with a machine called a gamma counter to detect the protein? I mean, so I went to cardiology. Yeah. So my colleague, Elliot Barnett, and he was going to the seeing patient and catheterizing and so on again. And then I was trying to educate him about RNA and he tried to educate me about the blood vessel and coagulation and what problem we have there, what problem we have to solve.

And so his interest was in this urokinase receptors, which can bind to a molecule. This is used to solve the clots, which unintentionally form in our blood vessel and cause heart attack and other. And then if we would have more of these molecules there, let's say, when they do bypass surgeries, because that's what they also did there. And so they have a blood vessel in hand, and then they try to insert and then we can have some RNA put through on it and what this RNA should be this urokinase receptor that would be beneficial.

So I cloned and made RNA for urokinase receptor and my colleague made radiolabeled urokinase to test whether this mRNA, which calls for urokinase, I deliver to the cell, whether they make functional receptor. And to measure it, we had to use this radioactive material and to see whether it binds or not. Why it is so critical, this urochialis receptor? Because it had to be, this is a protein, had to be so much modified. So many things had to happen to be functional. And voila, you deliver the RNA and somehow the cell knew what to do. Put there all of these sugars in it which needed, process the other end of the carboxy terminal,

end of this protein and linked and it was functional. We were, you know, watching this gum counter that, you know, printed out slowly this result and we could see that, okay, it works. So at that time we thought that, oh, okay, we can use ex vivo, like on a blood vessel, on cells, deliver RNA, and get beneficial protein overexpressed for a short period of time. So that's when you first realized you could use mRNA to get cells to create protein. But after that, you kind of were in the, I guess I'm sort of exaggerating here, but in the wilderness for many years, you suffered a series of career setbacks. Could you talk about some of those stories?

So we were doing this progress. And I have to say from 1989, in the first two years I worked at University of Pennsylvania, every month I wrote a grant to get money to establish myself. I had a faculty position as a research assistant professor, which is non-tenured position, but, you know, I could have my own lab, but I didn't get any of those. I tried to propose the RNA, how I would use circular RNA. Actually in these days, they think it is a new thing. In 92 or 93, I already had Grant, which was rejected. I proposed that and I did a circular RNA. Anyway, so I was working hard to do the experiments, generating more data, but, you know, it was not sufficient. They were critical about that RNA is labile, it wouldn't be useful, and I don't have enough data. Sometimes they question that I don't have enough knowledge

to do these experiments. So that, you know, I was always listening because, you know, share what I can do. Not that they should accept my proposal. That's otherwise you would think they are done. No, they don't understand how great idea is. If I conclude that they don't understand, I have is if they if I conclude that they don't understand I have to say yes because maybe I did not explain well and so that I improve my writing

my colleagues look at there you know and and did more experiments and but at the university there was a rule that if five years you are not establishing yourself in a faculty, you don't get money, then you have to be promoted or kicked out and demoted, removed from the faculty. And that's what happened to me in 1995. And that was a difficult time for a couple of other reasons. You were diagnosed with cancer. Your husband got stuck in Hungary with his visa. Yeah, I really, I had lumps in my breast. And then the same time when

we went to the hospital, we get this, that my husband had to go back to for his green card. And we didn't read carefully. And two days later he left, I was here and then, uh, um, he couldn't return because, um, what happened is that when I was in age visa, he was still working and paid the tax and they looked at that. He was not supposed to work. And so if we wouldn't pay the tax, they wouldn't see it, but we were always honest. And so he was stuck in Hungary for five months and he came back in May. He left in January and, you know, we just purchased the house. We had to pay the mortgage and it was like, I just couldn't rest. I had to, you know, find a new job and And it was a very difficult time. And that's what

happened that one of the students who was a student prior in the lab, medical student, by that time he worked in a resident in neurosurgery. And he could convince, his name is David Langer, convinced the chairman that neurosurgery needs a molecular biologist. You know, it was just so unbelievable how he could convince him, but he said, okay. And they gave me laboratory, they gave me salary. And that's how 17 years i worked on this bench there yeah because i was surprised reading some of your papers it has you as um being in pens yeah department of neurosurgery yeah yeah even the famous 2005 yes yeah 17 years 17 years i worked there. And so, again, with David Langer, we try to solve different problems. And now I am working with somebody who's going there every day, operating on patient and comes back with what kind of problem facing, what he can do and what I can do and what we can do together.

So maybe innovation is coming this way. So sometimes you have a huge lab and you can investigate a problem in many different directions and then you advance knowledge, science, but also that you are talking to maybe just the person and you talk to each other and then realizing that together what you can accomplish. So that sounds like an extremely difficult period. Yes. So that people usually say that you, Kati, you suffer so much. I have to say that I was always very happy.

In the laboratory, I was at the bench all the way. I was 58 years old. I did my own experiments. I cultured the bacteria, isolated plasmid, made RNA, cultured the cells, transfected, measured. I did every part. So put the gels, a lot of gels, and analyzed the data, came home, reading, writing, doing all of these things. And I felt that I was in full control. I control, I was in the laboratory, I know what to do. I was reading something in the evening at home, I realized, oh, maybe this provides explanation of what I am seeing and okay, I can do it. Oh, I can do it. And

next day I went in and then I was just doing that experiment. And so it is very empowering and the discovery that many technical problems I am solving, it is a success. You know, I didn't get the grants, which, you know, the basic R01 grant in the United States. You can establish a laboratory, but I had a lot of happiness. These discoveries and the full control over the experiments, you know, is very empowering and exciting. And you have an understanding of how things are. And then you are reading articles. Not like, you know, you start to read an article

and after the second sentence, you don't even know what I am doing, why I am doing, why I am doing this, but you are looking for something. And that is so exciting, you know, that this hunt, because you have a hunch that something is happening. Have you ever calculated what percentage of your grant applications were successful? No, it has to be 0.0 something because I had one grant when we established after our discoveries. We established the company and then the first grant we submitted for small business That was the only time I was a PI on a grant.

So fast forwarding to 1998, this was a big kind of turning point or moment in your career because you're standing at a Xerox machine photocopier at the University of Pennsylvania, and you made Drew Weissman. Can you tell me that story? Yeah, 1997 or 1998 or something like that. Maybe it was 1997. No, we don't remember either that it was 1997 or 1998. I don't know. It is critical because from 2002, I never went to the Xerox machine.

I downloaded everything digitally. So thanks God that progress was not that great in certain fields, because otherwise I never meet him. Because, of course, digitally is much easier to download papers. But that time, I have science, nature, you know, I paid for. And then I went and Xeroxing, you know, and archiving the papers and system set up for that and so on, so on. So, and then I noticed this new guy on the floor there that he's also occupying that Xerox machine, my favorite one. And in the 97, 98, I already work in neurosurgery,

but they don't have their Xerox machine. So I still went back to Department of Medicine, which is just the fourth floor up. Probably I knew the password for the Xerox machine and I used that. So I started to talk to this new guy. I asked him, you know, what he was doing. And, of course, I always brag about what I am doing and so on. And so, but he's a much more quiet person. And he told me that he was working at Antoni Fauci's lab, which told me nothing because Antoni Fauci was not in the television set like in the last two years or prior to that. And he was working in HIV research and he wants to develop a vaccine, a prophylactic or a therapeutic. I never even heard of therapeutic vaccine.

But and so that's when we started actually educating each other because I told that I am making RNA and I can do anything. And then so he said, oh, he would be interested to test out mRNA as a vaccine. And I made the RNA. And meanwhile, I learned the immunology from Drew, Drew Weissman. Because when I learned, we understood that what our system is, how our immune system is working, that recognize that something is foreign. Oh no. Drew told me, oh, bovine serum albumin you would inject, your body is doing nothing. He said that you need a danger signal. That's not always understood. You need an adjuvant. You need to tell something to your immune system, hey, that's dangerous. You have to make

immune response against that. And so that's how we slowly educate or sometimes not that slowly educated each other. You know, I learned immunology and I learned RNA. I made the RNA and he was very happy. In 2000, we published about this Gag HIV specific protein that we deliver to the human dendritic cells, which was discovered not long before that. And this is the most professional human immune cells, which he could make a culture and test out. And this he delivered, and then everything was great

because not only you delivered the protein, protein generated from this mRNA, but also this activated everything he wanted. And a lot of inflammatory molecule was made. And that made me, you know, sad that when I realized he was happy with all of these activities, but I was not happy because I did not want to have any inflammatory molecule. My goal was to make therapeutic protein coding RNA. And so then we started to think together, why the RNA I am making is different than what is inside the cell or not different at all. The reason why it's so inflammatory is because we are putting

from outside to immune cells and this RNA is not supposed to be outside, you know, outside the cell. And so that suggested the idea that, oh, we should test out. We should isolate RNA from our, you know, human cells and see that when we put on this special immune cells, human identity cells, whether they respond the same way when we put our in vitro made, the RNA made in the tube. And we never thought that we will identify something is not immunogenic. We, at that point, we thought that maybe we expected that all of them will activate this and generate immune response and isolated, you know, transfer RNA and ribosomal RNA,

bacteria, different bacterial RNA, and then we just put on the cells. And then we found that this transfer RNA did not induce any immune response. And that made us thought that, could it be that this transfer RNA, which is very well known, the most, contain the most modified nucleosides,

maybe that makes them non-immunogenic? So that was the thought generated. And of course, you know, the next question immediately was how the hell we will prove that, how we will make RNA containing modification, nucleoside modification. So to summarize, so you and Drew met in 97, 98, whenever it was, and that kind of represents the marriage of immunology with mRNA. And then the bit, so this is a very important, this is like the most important collaboration in your career. This is the collaboration that leads to the mRNA-based vaccines. And the big problem or obstacle that you and Drew

are trying to overcome is the immune response problem. So the body basically rejects the synthetic mRNA. It's immunogenic, causes inflammation. And so you're trying to work out how to basically mask the synthetic mRNA so that the cells accept it. We just want to understand how this immune response, where it is coming from. We didn't set out a goal to make a non-immunogenic RNA. We had no idea that we can, there is such, such thing exists.

We just want to understand that, is it the RNA I make synthetically? Is any different what is inside the cell? And the way to prove that, to isolate out from the cell, make one in the tube, put on the cell and see that, did they respond the same way? And of course we found that most of the RNA did induce the immune response. Our RNA, of course, in our body, our RNA inside the cell. But when you have an injury, it comes out. You also get inflammatory reaction from that.

So after a few experiments, you and Drew discover that all you had to do was modify the mRNA. And the way to do that was by just adding one molecule called pseudouridine. Uridine. Uridine. Uridine. Can you tell me about this discovery? So when we discovered that transfer RNA, which has a heavily modified number of modified nucleoside present,

like 25% of the nucleoside in a tRNA is modified, we thought that we have to make an mRNA, see that whether we can have a translatable product which is not immunogenic. We already knew at that point that more than 100 modifications exist in the RNA. And we didn't know which one is important in the tRNA. Do we need all or one? cyst in the RNA. And we didn't know which one is important in that day RNA. Do we need all or one? And the enzymes which incorporates it, which makes the changes is not known.

So we just couldn't call up a company to send that enzyme. So we thought that we have to maybe purchase these building blocks and try to see that whether we can incorporate. And we insisted just purchasing kind of modification, which is not naturally present in the human body and nothing foreign, just human body present kind of modification, concentrated. Anyways, we purchased 10 that was only available and five of them incorporated. So we could make RNA, the other five not incorporated. And then when we looked at these five, we looked at these RNAs containing five different modification, we found that as long as the uridine was changed in this mRNA, then it was not inflammatory. And what we found is that when pseudo-uridine was present, we could have 10 times more protein

from that RNA. So it was like, you know, an icing on the cake. Right. The double whammy. yeah not only was it non-inflammatory but now we have so much more protein right right that's cool so i i really wanted to there was a question i really wanted to ask which was whether you had like a causal hypothesis as to whether pseudo-uridine would work or whether you were just kind of spraying and praying and you discovered it by trial and error? So, you know, that you have to understand that when you have RNA from the DNA, there are hydrogen bounding sequence information, the sequence order, you know, that you have a hydrogen

bounding needed. When you have an RNA and it reads by the tRNA, again, you have a certain interaction between the messenger RNA and the tRNA. And then you have to make sure that when we made the mRNA, those which require to make this interaction is not blocked by different modification. So that it was obvious that only those which we couldn't synthesize RNA is the reason is because these bonding couldn't form. And so that we expected that all of them, what we could make could be translatable. And so it was expected that all of them would be translate. It was surprised that two of them would not, we couldn't make any protein from it. And so you have to understand that we changed all of the nucleoside in those mRNA. And naturally, actually, we learned 10 years later,

our messenger RNA also have pseudo-uridine. We just didn't know at that time. In 2002, 2003, we didn't know. 2014, they described and they could identify because the pseudo-uridine and the uridine is actually the same wall weight. The base is both of them is uracil. Only the link, how it's the base linked to the sugar

is different. So very similar and they couldn't identify because the weight was the same. I see, I see. I see. Okay, so this discovery was published in a paper in 2005, which is now a very famous paper. But the kind of reaction from the scientific community was lukewarm.

So that when we first wanted to publish in Nature that we also included the translation. But then we reorganized because they rejected immediately. They said that it is an incremental improvement. And I had to look up the word incremental. I didn't know. I started to learn English when I was 18 and incremental was not part of it. And then we took out the translation part and then we just had the immunological part. And the translation part was published in 2008 because by that time we generated data in animals.

We demonstrated that in animals also it's not immunogenic, the RNA. We demonstrated it can be translated there, so we put more data on it. But in 2005, Drew, who is a very quiet person, he told me that our telephone will ring and people will call us, but nobody called. I get to, he said that we will be invited to give talks and other things, but we get to invitation 2006.

Right. And then fast forwarding, 2013, you give a lecture, you meet the founder and CEO of BioNTech at the lecture. He offers you a job. You start at BioNTech. Not long after that, so about 2015, Pfizer and BioNTech partner to try and make... 18.

Right. Okay. Yes, sorry. So 2018, they signed the partnership to collaborate on making an mRNA-based flu vaccine. And were you directly working on that mRNA-based flu vaccine? Yes, on a collaboration with Pfizer and signing the agreement here in Pearl River in New York state.

We were there. And because I presented there also the modified nucleoside, because my colleagues here, Norbert Pardee, Drew Weissman, they already working on formulation and getting better and better data so that I was involved and tried to help that project. And the way that partnership works is BioNTech does the science and Pfizer does the manufacturing and distribution. And they did also, you know, it's collaboration science. It was, you know, that we will hand over the

production and whatnot. So it was, you know, we met the scientists there, they did experiments also, you know, animal experiments. And yeah, so it was such, such way. I have some specific questions about how mRNA technology works. But actually before those, I wanted to ask about this incredible partnership with Drew. So I've heard Drew say in some interviews I was watching in preparation for this that it was kind of your interaction, the chemistry you had that made the project work. And, you know, without each other's knowledge,

the technology might have taken like another five, 10 years to develop, if at all. And so your interaction is what helped kind of push the field forward. I'm really interested in the idea of partnerships. There are obviously some famous scientific partnerships that came before yours with Drew. You know, Watson and Crick comes to mind. I was wondering, so you and Drew couldn't get funding

in the early days of your partnership, so you couldn't add more people to the team. Was that a blessing rather than a curse? Because it meant that you could only work together as a pair and maybe there's something more productive about pairs. You know, because we couldn't play the movie to see that what would happen if we would have money, what would happen if they don't kick me out, you know, from cardiology and so on.

We don't know that if more people would work on it, that whether we could advance faster and better or whether it would be more destruction or different direction. But when we looked at the data, Drew just gets so excited as I was. And, you know, we cut each other words, whereas, you know, he's very quiet. But then, no, maybe this is this way. We should do that. You know that.

And also when we were working, you know, he keep submitting grants and for using as a vaccine, I was submitting grants for therapeutic purposes. And, you know, in the middle of the night, you know, just email him something about, and he respond because three o'clock he was still up and he's also working. And you feel that, you know, we try to do something together. And immediately when we looked at the data that modification is important, if we don't have modification, we have a lot of interferon in use. You know, he as a physician think differently. And he think about, oh, maybe the lupus patient, maybe, maybe they don't have modification.

And then immediately goes out, get samples from lupus patient. And we try to isolate back the RNA, see that whether their RNA is not modified. So, you know, his mind is a different direction. And I am a basic scientist. I, you know, I add to that part to the story. And you have to respect your colleagues, you know, the same way and then come together to develop something and get excited. And so it is, yeah, it is important.

Although, you know, we never work even in the same department, not in the same building, neighboring building. But, you know, we did great work together. Some specific questions about how mRNA technology works. Could you just explain how mRNA vaccines work? So mRNA vaccine, the mRNA, we did not invent it. Nature invented. And actually, it was invented for the pathogens. The virus has 29 different protein encoding sequences.

Now that we are selecting just one, and actually the virus also contains mRNA, so that we are selecting one of the 29 protein encoding sequences, and this we are using as a vaccine. Why? Because it goes for a protein which is on the surface of the virus and that could be recognized by the immune system and can neutralize it, eliminate that kind of virus. So actually, instead of, you know, like all time, that when they try to attenuate the virus,

we are just selecting, eliminating all others, just selecting the critical RNA part, which can code for the protein that can be neutralized. I don't know whether it was good. That was perfect. No, no, that was perfect. Thank you. Something that, like, I guess this is more of a kind of historical or sociological question about the community of researchers. But something that's been puzzling me is, you know, if we go back to that central dogma of molecular biology, DNA makes RNA, which makes protein. You've essentially got three kind of playgrounds there to experiment with therapeutics, although I'm sure that's simplifying it because it's not as if the opportunities within each of those three are necessarily equal. But it's fair to say that at least one of the big playgrounds is RNA. And, and moreover, there's something very intuitive about using mRNA to develop vaccines

because like conceptually, it's almost like the mirror image of how a virus works. And so, because the virus hijacks cells using mRNA and then, and then replicates. And so like I get that the immune response problem seemed really difficult, maybe intractable, but the history of science is just like filled with problems that seemed intractable. And so maybe there was only like a really small chance of solving that problem. But given that the payoff was so large, like the positive

benefits that could come from it was so large, like surely in expected value terms, like if you multiply that very small probability by the massive positive benefit, it was still worth dedicating a lot of research to. So like what's the answer here? Like why were people so dismissive, so skeptical? Was it like the academia and the funding system distorted the incentives of other scientists? Or did RNA just genuinely seem like a delusional thing to be working on? Like why were people so skeptical?

I don't understand. Skeptic, vaccine skeptic or skeptic about the mRNA possibility to explore? The mRNA possibility to explore. I have to say, Joe, that recently more paper is about me than I ever published. And those are trying to identify why I never get the money, why they didn't give this proposal money. And one interesting thing was published about that there is a central

where is the money, the fame, the most likely that your proposal gets funded because this is the most favorable topic. Maybe today the RNA is. If you are working with mRNA, maybe that's the central there. And then there are people in the periphery that they don't have. There is no fame. There is no money, no nothing there. You know, the only thing is the periphery is freedom. You can do what you like to do,

what you feel that it is important. And so that's what proposal is that why they should give me money, and they questioned that. She came from a university nobody knew about. She never had a mentor who was famous. And somehow this gravitates always the same people, same circle. They get published there, they get the money. And that's another explanation is that, you know, was not famous enough or didn't have anybody who would, you know, support me in a way that somebody's famous and well established scientist stand behind and says, oh, look at this, good.

You know, our paper had to be discovered by scientists at Harvard in 2011. They published, that's what people started to pay attention, you know, when they used to generate induced pluripotent cells, stem cells. Yeah. So the idea is sort of maybe difficult to evaluate or it seems a bit crazy. And so then people need to, I guess, look at your background or your pedigree to decide whether to award the grant.

One thing is, for example, I was not faculty. And the other thing is that, you know, those who are evaluating, those already have big lab to run, to write the papers. And they have like, I don't know, 10 grants. And they read it. They have limited time. And then when they see something which they similar what they are doing, and those people who evaluate who already get money. That's why I always get the same kind of field the money because it's read quickly and oh that's

interesting this makes sense because they immediately understand because they are on the field and if something comes out so unusual you know they just can't stand behind one proposal and then that would be which they understand quickly because this is similar what they are doing i do have some questions about how we can improve science but as i said i'll save those to the end because i want to come back to the object level questions about mrna technology so something that i've been thinking about which which i think i mean as you know is very important is the delivery mechanism and so we use polar lipid nanoparticles to or lipid nanoparticles uh to to deliver the mrna into the cell um and they they're quite like a crude delivery mechanism so i was wondering whether there are there are ways of delivering mRNA without polar lipid

nanoparticles. Like can we get delivery mechanisms to be more targeted? Could you use antibodies which are more direct or like Galnax, which don't hurt the liver? So the lipid nanoparticles actually contains four different components, lipids. And one of the components is actually the adjuvant for the vaccine. So they are not inert, just wrapping material. They have function also. And not only lipid nanoparticles, there are other lipoplexes are used, for example, what we use for cancer therapy, for vaccines, as well as we use for polarization induction, then you don't have these kind of components. You have different kind of lipids in it. And when you deliver, IV injected goes to the spleen or in the other case, you know, that it could lipid nanoparticle goes to the liver,

or if it is, uh, inject locally to intramuscularly, most of the time is, uh, um, macrophages and other immune cells will pick it up because that's their role to pick up things. And, um, and of course you can, uh, um, deliver an RNA by a targeted way, because if it is delivering to the wound, you just put on the surface, you can deliver. Of course, you try to reach certain cell types and or certain organ. And then for this, you need some targeting. And of course, there are publications about that using antibody to target that particles, but you know, you cannot freeze them together or you cannot, you have to create a bedside because you have the particle frozen and then you put the antibody. If

you freeze the antibody, you know, they mix up and then they won't function. So there are technical hurdles there. But you can also put on the surface, and they did actually, a ligand, which you are targeting the cell which has the receptor, and when the ligand reaches the receptor, that it takes in the whole cargo together with the RNA. And so there are different tricks what people are using and this, you know, is a very intensive

field right now that people try to improve delivery methods to reach certain places. One of them is the bone marrow because editing there for certain diseases like sickle cell anemia or others maybe is critical to reach that or for treating HIV patient. Which new potential delivery method are you most excited about? I mean, these all, the targeted one is a different way to target is very important and very intensively used right now. And I am also interested to see when it is not used as a vaccine, as a therapeutics. And some of the therapeutics, when it codes for editing enzyme, it will be

using for gene therapy or using like what I also worked at BioNTech, when the messenger RNA goes for cytokines and we inject it to the tumors and then making a cold tumor hot so that all of the immune cells will run there and recognize which kind of epitope they have to look for. And when they circulate, they can find already distantly located tumors and they can eliminate that. This is clinical trial ongoing with Sanofi. Once you've got messenger RNA that's been delivered into a ribosome, that's been turned into a protein, that's really only like the beginning of the story because you still need to consider the protein's tertiary structure. And as you know, Kati, if the protein's folded in a certain way, it may or may not be able to interact with a particular receptor. And so post-translational modifications are really important in regulating a protein's function.

Certain amino acids can have a phosphate group added to them. That can have a big effect on protein. It can become linear rather than bent. Sugars can also be added and affect the protein's function. So the way in which the protein is decorated is important to how it goes on to function. And so my question is like, once you've decided, say with the coronavirus vaccine, once you've decided to deliver the spike protein into the cells, how did you think about engineering it so that the spike protein would be folded in the correct way and presented to the cells in the correct way. Because obviously if it wasn't folded in the right way, maybe our immune system wouldn't have produced antibodies

that were the exact right fit for the virus. I was not participating in generating the corona vaccine, but the cells know how to do this kind of decoration. It is interesting what you are saying, because at the beginning, so when our first project was using erythropoietin, we tried to show the biological effect. Erythropoietin is made by kidney cells. But of course, we injected the mRNA to the muscle or sub-Q or to the skin.

A protein is made. And the erythropoietin, half of the weight is sugar. And it can function. Only those sugars are there. And interestingly, it didn't matter where we injected and where this mRNA was translated. We always had functional protein. So the cells, even if they normally not making that kind of protein, they know what to do. There are very unique cases where really you need a certain chaperone

present in the cell to make it the fold properly, but it's very, very rare. So any cell can do. And when they was made for the vaccines, of course, in that case, big advantage was that already knowing certain amino acid change is required to have the conformation. And so that was incorporated in the vaccines. And when you inject, the cell knows what to do because certain amino acid presence will say that what kind of sugar,

what kind of modification is had to be happened there. And that's why, you know, because we are mammalian, you know, and it was a problem when they try to make a human protein in the bacteria because they don't glycosylate and you couldn't make a certain recombinant protein in the bacteria. And when we are talking about, you know, the therapy, you mentioned that sometimes, you know, the protein or you can deliver the protein, deliver the RNA or DNA. You have to understand that the protein therapy is only working for extracellular protein. If you want the protein in your nuclei,

and that's what should be there, if you just inject that protein, it never find that way. How we would know that where to go? But when you deliver the mRNA, it can have the signal on it to where to go. But when you deliver the mRNA, it can have the signal on it to where to go. So it had to be translated inside the cell. So that opens up that with RNA, not just you can replace all of these,

most of this protein therapy, which is very expensive because you had to figure out how to modify the protein and purify. And that's why all of the recombinant protein product antibodies are very expensive. With the RNA, you don't have, you no need that. You just deliver the RNA, the cell will know how to decorate, how to do those things. You don't have to purify, yeah. But you can also generate intracellular proteins, which will be work inside the cell. Of course, for that one, you have to reach that specific cells, that neurons or that heart cells or whatever cells.

And that's the challenge. But otherwise, for targeting, if you have just the extracellular protein you don't need target any cell can do i see i guess um that that actually raises one of the benefits of rna-based therapies it can do both intra and extracellular stuff yes yeah protein you can generate yeah yeah i know you didn't work directly on the COVID vaccines, but I guess I just had some, like coming to COVID now, some questions about that. So COVID comes around in 2020, scientists sequence the coronavirus's genome in January, Pfizer and BioNTech and Moderna vaccines enter clinical testing in April of 2020, so very shortly thereafter, the vaccines start going into the arms of patients in December 2020. I guess there may be like a couple of reasons why this could happen so rapidly. One is just like the nature of mRNA technology itself. But the other is that you'd already been working on that mRNA-based flu vaccine from about

2018. And so there was almost like a template that they could just redeploy for COVID. So I guess a few questions, and feel free to pass on any of these if you just don't feel like you have the best kind of, you're well well positioned to answer them. But so why do vaccines normally take so long to be developed? You can develop a vaccine, but if there is no virus around, that it is difficult to evaluate. So that's what happened several times already, you know, that they develop a vaccine

and, you know, you have to test. And then if the virus disappears, then you cannot measure that how good your vaccine is. And, you know, at the beginning, vaccine was developed by the virus was passaging, passaging until it was less dangerous, you know, to get this, where viral protein was delivered, which was generated as recombinant protein together with some kind of adjuvant. And again, this, you know, technically also generating recombinant protein was not easy. And so I am not an expert on this one, definitely, but that's what I can see, that major reason. So there are currently about three variants of COVID circulating.

There are like two previous variants which are functionally extinct. If there are three variants circulating, does that mean you can only get sick three times at the moment? Yeah. So I have to say that when I have any kind of vaccine related questions, I ask Drew Weissman. And he said that, you know, if we wouldn't have new variants, we would be fine. And he also told me that none of the vaccine is, you know, 100% protective. You get, you know, you don't get a different kind of infection because the virus is not around.

But if it would be around, you might get, even if you would vaccinate it. So that this is just thinking that, oh, we don't get any of these disease. Yeah, because the, you know, the pathogen is not around. But I don't know that if, you know, definitely when messenger RNA coding for this spike protein is injected and repeatedly they found is that repertoire of antibodies increasing. So different part of the spike protein is recognized by antibodies and you generate those. So it is why even if you get a new variant,

it is not deadly for those who get vaccinated already. Why aren't the current mRNA COVID vaccines, why don't they seem to be infection blocking? Again, I mentioned that I'm not an expert. My understanding is that when you have in your blood high level of antibodies because you just get vaccinated, then actually in your mucus and also in the milk, they can show. People send me pictures showing that in their milk they can see, detect antibodies, so that you will have antibodies in other area. And then when you already, you know, the antibodies level dropping, then you might have less in your mucus or in the nose and other places to capture it. So, but again, better if you don't use these things

because I am not an expert. Okay. And I don't try to pretend. I don't know the viruses. I left BioNTech because, you know, I want to concentrate on something which excited me for many years. Yeah. Yeah.

Fair enough. Okay. Let's go let's uh so we'll finish on covid so i i really want to ask you about meta scientific issues so thinking about how we can improve how science is done and we've spoken about some of the issues and how they kind of intersect with your own personal story. Generally, there are a lot of problems, like one of them, which is relevant here, is that very talented scientists need just a lot of luck. They have to be in the right university at the right time to get grants and set themselves up with a faculty position and

then there's like a chicken and egg problem where you need grants to get the faculty position but then the faculty position helps with the grants you have to convince your seniors that you'll be able to bring grants in so um those are all challenges i'd like to discuss. But actually, firstly, Kati, I'd like to ask, so you're someone very remarkable in that you just kept persisting, you maintained your optimism, you didn't let things affect you. Not only did you not let them, it's probably not even accurate to say you didn't let them affect you, you tried to reinterpret them positively and use them to drive you. Not only did you not let them, it's probably not even accurate to say you didn't let them affect you. You tried to reinterpret them positively and use them to drive you. Did you see any colleagues though, who just like weren't as tenacious and who simply gave up?

Like how many, generally, how many talented scientists do you think we lose because they just feel defeated by the system and the politics of science yes so definitely it's very very so it is not easy to be scientist but the other field is similar i have to say one issue is i am a woman yeah and know, and then if 1982 in Hungary, there would not be rules that, you know, affordable, high quality childcare where my daughter was four't afford, I had to stay home. And then if you stay home for two years, then you are so out of knowledge that it is almost impossible to catch up. So there are many, many things, you know, we might, you didn't mention the women issue, but that's what you can see that more female students at the universities, but you know, that position when they But even for men it would be good if affordable child care would be there because they also take part of child care and then their responsibility to put bread on the table. And then they have to give up sometimes through this field. Interestingly, in Drew Weissman's lab was a student

and he wanted to be a scientist, but when he realized that what happened to me and in the medical field, you have to bring in the money. It's not in other fields but in a medical science you have to as a scientist you have to cover your salary and and he decided that he will be md phd because as a doctor still he can function and help the family so so that's difficulties in our field to be scientists. And definitely men will give up because, you know, they have to, if they don't get enough money, then, you know, they cannot support their family. And I have to say that I don't have hobbies, my hobby is science. So that's also

easy that I don't get too much money, you know, as a salary and but that's enough, we can get by. But how could improve how we could see that something is a good idea is difficult because, you know, there could be great idea, but I don't have expertise on it. Just like we talk about viruses. I did a lot of work with viruses, but still I wouldn't say that I am expert on it. And to judge other work, that whether it is reasonable or not. So when people ask me many times, I say that, you know, I would be the last person to tell you that this is not feasible because so many times I heard that.

So that I don't have enough information, but the people would not acknowledge that, you know, they would make judgment and say, no, it's not good. And yeah, so people think that, you know, if they would give everybody for their idea to develop some money, then if from thousand people, one would come up with something would be already worse. And, you know, we know that failure is always there.

I mean, this is why we call it not, I am not a searcher. I am a researcher. Research, because re, re, redoing, retesting. I like that. Because, you know, to make sure that things happen on that way. And then for me, although it is a basic science, but from day one, when I started to work, even if the Fisher Institute to understand that how the food we give to the fish would influence the fat and, and then work with Yano in developing antiviral compound, you know. So there was always there,

the usefulness, it will be good for something, you know, and that was the same when I was here at Penn, when we could deliver the cell, the RNA, and we could express the protein, oh, it will be good for some cell therapy and thinking, oh, maybe for bone transplantation, maybe even older people can give bone marrow because now that we can extend the tip of the chromosome. And so always it was in my mind that, oh, usefulness. And now that people are doing it with mRNA, I am so happy because actually I also tested that and many ideas which I have. So

that now that many people are trying, more money is coming to the RNA field, I am sure that many new product will be developed. And because even if the final product would be a protein, but accelerates the search, the research, the development of a product. Because with RNA, it is so easy. If I have an, we are here, you know, I have a template. Actually, without PCR also, you can have in vitro transcription. So you can have a genes and plasmid, and then you can make an RNA. I mean, it takes, you know, 30 minutes, you already have the RNA.

I put on the cell, 10 minutes later, I can see the protein. That's unbelievable powerful to think that how quickly you can do anything, and then you see the outcome. And so I am very optimistic about the future because it will accelerate the science, the discoveries, and the medicine should be cheap also because the RNA is cheap to make. Yeah, yeah. Yeah, it's the magic.

There are many good things about it. Okay, so putting aside simply giving everything more money, how should we reform how the biosciences are funded? So if you could wave a magic wand and change how the biosciences were funded, what would you do? But it can't just be giving more money. I don't know. I don't know. I don't know what should be done. I don't know.

But do you have any opinions based on your experience? So many things is changing how it happened before. I was just reading yesterday that no more we can review every paper which get published. There is not enough people who would do that, critically reading something that it was a peer-reviewed paper. No, there is not enough scientists. The scientists had to do the research.

They don't have time to zillions of paper to read. It is, everything is difficult. So there are, you know, venture capitalists are you know venture capitalists you know who are risking their money and believing that some ideas is good but

I don't know. Many things right now is going to produce. I would bet that it won't work, but I wouldn't say. I don't know. I don't know that how you should, even if you would say more money will be there,

that what should be done. Yeah, I don't know there's an interesting question about ego so ego has kind of been a theme of this conversation you're you know i get the sense that you're not someone who's driven by ego or seeking recognition but obviously many scientists are and i wonder whether we view that as a problem or potentially like an opportunity that we should harness. So do you think we should be celebrating scientists more? I have to say that at the Gardner Award ceremonies, part of it was that I had to talk to high school students. There were 300 of them. And each of them could name a hockey player.

But when I asked just one living Canadian scientist, they could name. There was no name. They couldn't. So one question is why we don't know about all of these discoveries, all of the scientists discovering things? In the morning, people are taking their pills, saving their life. They never ask, who come up with, who's saving my life? Who is this person I want to know?

James Ellison and Honjo, they did this checkpoint inhibitors. These scientists, they get, you know, this checkpoint inhibitors. These scientists, you know, they get the Nobel Prize for it. But do you know that the people who are getting and with lung cancer and surviving and other cancer, they get this checkpoint inhibitors that they would know? These are the guys. They saved my life. No. And when I ask reporters, why you are not writing about them? Why about the celebrities? Why it is more important that who is breaking up or marrying or whatnot, you know, famous? This is what the people want to hear.

But I said that they read about because that's what you are writing. You write about the science. The science could be so important. You know, looking at the Super Bowl and running with the ball, running at the gel and getting the example or some result is get just as excited and why we don't know about all of these discoveries what is happening in these days and my daughter was

checked out for this non-invasive pregnancy test when they can identify from her blood that whether her child has Down syndrome. And, you know, I met the guy, Dennis Lowe, we get the Lasker Award together. You know, he discovered this is so important thing.

Do you know that the people who are getting this test so non-invasively, they appreciate? Do they know about him? Where we should start this? You know, I will in April, I get the breakthrough prize, which is supposed to be, you know, the Oscar of science because, you know, red carpet events. But yes, I think, you know, scientists should be recognized the achievement

and the people's interest, you know, writing about, or we are talking about right today, so you are doing your part, so that they would know what what did they discovered. Yeah. And is that that that will then incentivize more brilliant people to become scientists? Exactly. Yeah. So so I mean, I guess that kind of implies that that like ego is a useful thing because we're kind of playing to their egos yes of course you have to have the desire but when it gets the goal to be recognized and i think that the goal should be that you should

discover and understand and then present and then get some solution for for diseases or something and that's so many disease we don't even know We don't even know what is the reason and the cause for those symptoms. And without it, we don't know how to treat, so that we need more scientists and more women, because the women think differently. They multitasking, and we need all of the young mind to come. And then I can see that less and less people want to come to science. They want to be, I don't know, influencer or something.

Ego is the number one thing. I, personally, I never had that desire to be recognized. Again, I can imagine how people could be doing all of this work and then they are not recognized. They get called crazy. But this Shaya thing, who cares? I thought, you know, 100 years, nobody knows I ever existed. I am doing this. I can do that.

And I not crave that. But there are people who are not like that. And they are not, they are miserable. So anyway, and for me also, I was so on the other side, you know, being very humble, the very background, you know, nobody. I mean, coming to America, you could imagine I had no classmate. I have not a single person I ever seen in my life who would be here. And there is no credit card. That's what makes the immigrant great.

Because then no matter what, I have to survive. I have my family here with me. I get them here and then what we will do. And then you will be fearless. And you are, because the whole thing is gambling coming here with that kind of, even $1,000 is not much. You understand? So it completely changes you. Because people ask, why you couldn't do this in Hungary?

Can you imagine? I was working nine months in Bethesda and I had no street address. I slept in the office under the desk. We couldn't afford to leave two different places. We didn't live in this house. We just rented. But my daughter went to school here and I am 200 miles away and weekly coming and going. Do you think in Hungary I would do that? No, I would ask my somebody, classmates, somebody to help me out. But here was nobody. Yeah. It's a difficult thing being an immigrant, but so many people have become so successful because you don't have

a choice. Because hardship is forming your character much better than when somebody is arranging for you to walk because you don't learn how to and you appreciate more everything what you have than if it is given to you oh yeah okay they accepted me okay i got this one yeah yeah absolutely my last meta-scientific question. So as we've discussed, you and Drew Weissman met at a photocopier, which is like pretty close to the classic water cooler conversation, just with a different machine. Has the COVID-induced shift to working from home reduced the number of those serendipitous conversations. Is there a chance that you and Drew may never have collaborated

if you'd both been working from home? And what has been the net impact of working from home on scientific research? Do you think overall it's a positive or a negative? That is definitely important that scientists should talk to each other. You know, that's why I go to the meetings and so on. And some pharmaceutical company, they don't let, take out the coffee from the cafeteria. You have to drink there.

And meanwhile, you are drinking, talking to colleagues. And you cannot go back to your office and just drink that coffee next to your computer. You have to talk to somebody. So that's important. Of course, important. I told you that all of what we try to do with Elliot Barnett and with David Langer, you know, that he was telling me about the patient

and what is causing it. And then I was telling, you know, about what RNA I can do and how it would influence, what RNA would be the best. And so that conversation is leading to, you know, new discoveries and new treatment. And yes, of course, it is important. It is good to, time to time, you know, to concentrate and stay home and, and think about and read and do other things. But definitely, I also mentioned

that I worked at the bench and I found that the working at the bench is also helpful. Many of the scientists, you know, I was 58, working still, pulling the gel, and so many things came to my mind when I was in the middle of the experiment, you know, thinking about what this molecule is doing and what could be the outcome and maybe the other outcome will be and how to explain it. And so it is, I enjoy it. And then, of course, many technical things I improved. And so it is, I found beneficial for me to work with my hands for that long. Some questions about the future, just to finish. Do you predict that pretty much all vaccines will move over to mRNA technology? You have to understand that the RNA calls for a protein.

And many bacterial vaccine, you know, the bacterial surface is sugar, complex sugar, so that might be a different situation. Yeah. But the intracellular bacteria, you know, like the tuberculosis and others, it will be similar like in a cancer vaccine because you are, you have to generate cellular immunity. A cell, a T cell had to recognize the infected cell, just like this T cell had to recognize the mutated cancer cancer cell. Yeah. But, you know, we didn't talk about,

like, at Penn, when they introduced me, they usually said that, did you know Cotty's daughter is Olympic champion? The people didn't say, did you know Cotty works

with MR&E? Nobody said that. I was the famous mother. Mom. I was the famous mother, mom. I was the mother of Suzanne Francia. And then, you know, we went to these Olympic Games and everywhere I was introduced. She's Suzanne's mom. Now that I am getting the awards, my daughter is coming with me.

And now she's recognized. She's Kati's daughter. And now she's recognized she's Cathy's daughter. Yeah. That's funny. Now it is changed. And now she works for a company, actually, TriLink, which produces the cap part of the mRNA. And now she's bragging always that her mother is me. So things change.

They do. They do, do yeah that's so funny um so so currently madonna biontech are working on mrna based vaccines for a range of different things including hiv zika a few kinds of cancer there's the flu flu one, malaria, genital herpes, tuberculosis, food allergies, sickle cell anemia, other autoimmune diseases. I'm interested in the cancer vaccines in particular. How does that work and what's the timeline on those? When do you think we could expect those? I am not expert on this one. Okay.

Yeah. You have to understand that to make a vaccine against a pathogen like a virus, you need antibody. The antibody recognizes a protein on a particular surface. Yeah. The antibody recognizes a protein on a particular surface, yeah? Now that when this pathogen enters inside the cell, the antibodies cannot see it. You need cellular immunity. The cellular immunity, those T cells, one of them, which can make cytokines

and which recognize some kind of thing presented by these infected cells, showing a little part of the virus. And then that T cells secrete things, come here, come here, problems. And then there are killer cells are coming in and they kill. So this is two type of T cells and eliminate. When you have a cancer, most of the time you don't have any protein put on the surface. You don't need antibody. The antibody is not just in some case you have a specific protein. But most of the case, the cell is just maybe, you know, have an extra chromosome. And then it just divide, divide, divide. And then it cannot fit in the bone marrow,

and they come out, and those are immature cells, and so this different kind of cancer. There is not even mutation in it. So what the hell could, how the immune cells would recognize that it is something wrong, yeah? So, but when there is a mutation, then maybe they present something and then these T cells recognize that it is something not what I'm supposed to see. You know that how the immune system works,

that how from your thymus the cells are coming out, which had the different receptors. And then here in your thymus, which is my, I am too old, but, you know, they have to go through on that, like a map, and then in your thymus, every protein in your body,

every protein in your body, even which is in your brain, is expressed. And if your T cell is coming and stick to it, they cannot come out. They die. And those who cannot stick to anything, they come out, sitting in your lymph nodes and waiting for information. And these dendritic cells, they are going around, hum, hum, hum, hum, hum, eating things, always some debris, and then on their way stop by at the lymph nodes. T-cells sitting there, and then these dendritic cells haven't seen any danger,

so it's presenting things on their surface and show, and then these T cells has the receptor, show them that if you see this, you have to tolerate because this is everything is normal. Go out, you know, and then picks up something and big bang, you know, the stimulant is there and says, this is danger. The dendritic cells next time runs to the lymph node. The T cells are sitting there and they said,

guys, you know, that's dangerous. Whatever. And then what these T cells is recognizing and trying that whether they can, their T cell receptor

fits to this little epitope when this MHC is hold up. And when it fits, they get this thing now you have to divide divide divide then you start to see your lymph node is getting big that's a good news you found your pathogen will be fighted because T cells found yeah yeah and then these T cells divide divide and running out and see that where we we can see this kind of thing that we can bind. And they find those, you know, infected cells and then they start to eliminate.

This is in space how all in your body happens. That's simple. Wow. that's simple wow what what at the moment what's the biggest constraint on developing mrna vaccines as you could see they started to work on like there is hiv moderna has to program for that but you have to know that the hiv is a virus which is covered with sugar covering so the antibody can see the protein but is covered and one part is not. And that is the part which is not important constantly mutate. So tricking and exhausting the immune response. So that's the pathogen is very critical. This SARS-CoV-2, this virus was a simple one, easy.

HIV, you know, working more than 20 years to develop vaccine is difficult because the pathogen is very tricky. And you can see that they try to develop vaccine against viruses that we don't have any vaccine against. But now that you could see that both companies, Moderna and BioNTech, announced with Pfizer that they will have a vaccine against shingles. Right now, shingrix is a very good vaccine, but in Europe it is like 800 euro or 600 euro. The vaccine is very expensive. So hopefully the RNA vaccine would be much cheaper. So there are, you know, a lot of efforts to develop new vaccines or replace some of them. Maybe good, but very expensive, or maybe not that good, so that you will see this trend. And of course, beside these infectious disease vaccine,

you know, the therapeutic application and more and more companies are formed. And even the larger companies, we talk about Moderna, BioNTech, Pfizer, but you know that Sanofi has Translate Bio purchased that RNA company and there is CureVac there, which was the first one established in 2000 that also vaccine with JSK. And so there will be more vaccine and more protein products based on mRNA. My final two questions, what was it like getting your first COVID vaccine, knowing that that couldn't have happened without all of your efforts and all of your struggle over the years? Can you tell me that story about that moment?

Yes, I have to say or correct you because i every time i think about all of the other scientists who who work of course who's uh you know my my work i established on theirs you know and also all of the scientists and the colleagues and biNTech and Pfizer and Moderna and everything. And I was, you know, together with Drew Weissman, we were getting the BioNTech-Pfizer vaccine. I was very excited and I am a little bit, can be emotional. And then when we were walking there, actually, to this room, they already camera set up that we will get officially this vaccine. In the other neighboring room already were giving to the healthcare workers

at Penn who worked in the hospital. And then my new chairman said that these are the people who invented the vaccine or something like that. And these people just started to clap. And I was just, you know, realizing so emotional we came. You know, that was overwhelming for me. And getting the vaccine, seeing that needle there and then the syringe and seeing that the vaccine is there. And I worked in biotech and very much I knew that what sequence and what structural elements were there because we worked on it.

My colleagues from day one, I went there on it, my colleagues. From day one, I went there for formulation, for example, the formulation, the lipid nanoparticle that my team, we screened different formulation and that's we zeroed in with Aquitos formulation and did many, many improvements on the construct. I love that story. That makes me so happy.

Last question, what are you working on at the moment and what's exciting you? Oh, I won't talk and I don't want to hope high because I could be wrong. I should let you go. But, um, okay. Kati, thank you so much for everything you've done. And thank you so much for your time today. It's been an honor. Oh, thank you for asking for everything you've done and thank you so much for your time today it's been an honor oh thank you for asking but again i am saying that in the name of all of those people who came before us who work with us you know i am accepting that thanks in their name also because i i so many times i was reading articles i don don't know those people, but I felt that I would hug them. Oh, my God.

Yes, thank you to those people as well. Yeah. All right. Thanks, Kati. All right. Thanks so much for listening. Two quick things before you go. First, for links, show notes, and the episode transcript,

go to my website, thejspod.com. That's thejspod.com. And finally, if you think the conversations I'm having are worth sharing, I'd be deeply grateful if you sent this episode or the show to a friend. Message it to them, email them, drop a link in a WhatsApp group. The primary way these conversations reach more people is through my listeners sharing them. Thanks again. Until next time. Ciao. Thank you.