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Nobel Winner Katalin Karikó Shared mRNA Vaccine Story with GEN, Mid-Pandemic
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Nobel Winner Katalin Karikó Shared mRNA Vaccine Story with GEN, Mid-Pandemic
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Segment:0 .
[AUDIO LOGO]
JULIANNA LEMIEUX: Hello, everyone and welcome to this Women in Science event, the first in a three-part series co-produced by Genetic Engineering and Biotechnology News, or GEN, and the Rosalind Franklin Society. I'll be your host. I'm Julianna LeMieux, science writer at GEN. Thank you so much for joining us today. It's a pleasure and honor to have Dr. Kate Karikó here to talk about her work in the field of mRNA and how it has been harnessed to fight the COVID-19 pandemic.
JULIANNA LEMIEUX: Before we get started, I'll pass it over to the executive director of the Rosalind Franklin Society, Karla Shepard Rubinger who will tell us a little more about RFS and the Vilcek Foundation. Karla, over to you.
KARLA SHEPARD RUBINGER: Thank you, Julianna. The Rosalind Franklin Society is, again, so pleased to be hosting this Women in Science series with our colleagues at GEN. The mission of the society is to showcase and promote the careers of women scientists worldwide. Many, like, Rosalind Franklin work tirelessly without recognition but with an uncommon passion and commitment for their work. Dr. Franklin's now famous Photograph 51 was the cornerstone of the discovery of DNA but was given little recognition during her lifetime.
KARLA SHEPARD RUBINGER: Our speaker today so clearly fits this model. She is passionate about her work and has always been quite optimistic about her pioneering research on the mRNA technology. In a recent interview, she claimed, I never doubted it would work. This is confidence not bravado. Given the profound impact of her work, the Vilcek Foundation has just honored her with the 2022 Vilcek Prize for Excellence in Biotechnology ahead of schedule.
KARLA SHEPARD RUBINGER: We are excited to hear more about her work followed by a brief follow-up interview with Juliana and, hopefully, time for audience questions at the end. Thank you so much for all-- for being here, back to you, Julianna.
JULIANNA LEMIEUX: Thanks, Karla. Today's presentation is also being sponsored by TriLink. TriLink Biotechnologies, a part of Maravai Life Sciences is a CDMO helping life science leaders and innovators overcome challenges in the synthesis, and scale up of nucleic acids, NTPs, and mRNA capping analogs with scaleup expertise, and unique mRNA production capabilities, including its proprietary CleanCap, mRNA capping technology. TriLink continues to expand its CGMP, and general mRNA oligonucleotide, and plasmid manufacturing capacity at its new global headquarters in San Diego, California to support therapeutic vaccine and diagnostic breakthroughs so thank you to TriLink.
JULIANNA LEMIEUX: Lastly, I want to mention that we welcome your questions for Kate. So please just drop them into the Q&A of the Zoom. And we'll try to take as many as we can at the end of her talk. So it's likely that you hadn't heard of Kate Karikó before last year unless maybe you work in the field of RNA. It's probably, equally, as likely that you have heard of her before today. You may even have seen her on CNN.
JULIANNA LEMIEUX: Kate is the senior vice president at BioNTech. For her entire career, she has focused on mRNA, the molecule that has been thrust into the limelight because it sits at the center of two highly successful COVID-19 vaccines. Today, Kate will talk about her pioneering research in mRNA and how it provided the tools necessary to develop those vaccines. But her story goes far beyond her work in the lab.
JULIANNA LEMIEUX: It is also a story of perseverance, dedication, and a love of science. Kate, the floor is yours.
KATALIN KARIKO: Thank you very much for inviting me. And today, I will talk about development of mRNA for therapeutic. And it's not warp speed, actually, added by the organizer. But this is very true. It was not that fast that the vaccine itself was developed. So the RNA-- messenger RNA history has been 60 years. So it started in the 1961, discovering the mRNA.
KATALIN KARIKO: And through the years-- through the last 60 years, a lot of things happened. And although the first one, the date, '61-- I do not remember. But the rest of it, I was witnessing and participating in it. And because I don't have the whole afternoon to talk about all of these years, what happened, I'll just try to give you some-- how I witnessed all of these years.
KATALIN KARIKO: And since it was said also by Steve Jobs that only we can connect the dots looking back, so I try to connect those dots in my-- the past. And so how I started it is as a student, undergraduate student in Hungary. And I joined a lipid lab. And I spent the summer collecting specimen, fish fats just to try to understand how the fat composition is changing depending on what kind of chew they eat.
KATALIN KARIKO: And I collected these specimens. And in the fall, I went back and to the lab and analyzed that. And this was the time when two of the colleague also came, [? Erno ?] and Eva. And they decided that they want to use, and generate phospholipids, and use it for delivering plasmid to the cell. And of course, I was an undergraduate. Everything was new for me. This was also very exciting.
KATALIN KARIKO: So I joined them and participated in that study. Of course, phospholipid fraction, which actually they wanted to use was not available. We were behind iron curtain, and it was under embargo. And we went to the slaughter house and came back with a cold brain. And we spent the whole week isolating the required fraction phosphatidylserine ethanolamine fraction, and then wrapped it up the plasmid, and delivered to mammalian cells.
KATALIN KARIKO: So delivering nucleic acid with lipids was not novel, not new even in that time. Actually in the mid-'70s, Papahadjopoulos already described how to make liposome. And for me, the first paper really when mRNA was delivered into mammalian cells and primary mammalian cells was published in 1978, [? Dimitriadis. ?] And this RNA was not in-vitro transcribed because we don't know how to.
KATALIN KARIKO: At that time, we didn't know how to synthesize. But he isolated this from reticulocytes. And it was globin mRNA. So that was my work in the lipid lab as an undergraduate. And for my PhD, I went to the RNA Lab. I didn't know at that time that RNA and lipid were always so close to each other. But I stayed in the same institute.
KATALIN KARIKO: And my supervisor was [? Yanou ?] Thomas. And he made a cap analogs. And of course, today you can order cap analogs. But he made it for Aaron Shatkin and Furuichi who discovered in '75 that the messenger RNA has a cap. And to identify the molecules they needed reference material. And they needed a good organic chemists like Yanou who would synthesize and then send it to them. And it was interesting.
KATALIN KARIKO: I might mention that here all of my colleague, Janusz Ludwig and all of the others were organic chemists. And I was a biologist. And it was in all in my subsequent years-- I always worked with people who had a very different expertise than what I had or what I supposed to do. But here, actually, we didn't make mRNA. We were in the '70s. But we were interested to make a very interesting molecule, the two-prime five-prime link oligoadenylate.
KATALIN KARIKO: This was just discovered in 1977-- Ian Kerr in London. And it was assumed that when double-stranded RNA activates oligoadenylate synthetase enzyme, this molecule is formed. And this two-prime, 5-prime link small trinucleotide is activating an enzyme, which is responsible for antiviral effects. So we were in these '70s.
KATALIN KARIKO: And we needed so badly an antiviral molecule. We needed-- also today and it seemed that if we can synthesize that and deliver, maybe we have some very good antiviral compound. And the pharmaceutical company supported this activity. It is also-- I might mention here that whenever I subsequently work, I always kept my eye on all of those molecules I started with in my career.
KATALIN KARIKO: And then for example, the OAS just recently identified how important it is for those who have a COVID infection and SARS-CoV-2 infected people who had low level of for some genetic reason. They are very in serious trouble and serious disease form. So we were doing this. But the delivery was difficult although with this liposome, which we already did in the lipid unit-- could give a solution.
KATALIN KARIKO: But it was quite tedious to make with this film method and the wrapping of molecules. And so we ran out of funds. And I ended up in Philadelphia in Professor Suhadolnik's laboratory. He was the-- he wrote the textbook on modified nucleosides. And he was mainly interested in different kind of analogs. And all of this had some cytotoxic effect.
KATALIN KARIKO: And one of them actually, cordycepin, which I already used in Hungary because it was easy to make two-prime, five-prime because it was three-prime doxy molecule. And the professor also discovered that pseudouridine could be made some microorganism as a de novo nucleosides. But I learned here that all of these nucleosides is quite toxic.
KATALIN KARIKO: But here, again, my responsibility was to focus on this two-prime, five-prime nucleotides. And we did so many different modification introduced into nucleotide linkage, and nucleobase, and the five-prime. And we also changed the sugar in it. And of course, we would have needed very much a antiviral compound because here now we are in the '80s.
KATALIN KARIKO: HIV was a very serious problem. And there were no cure for those patients who'd get infected. Although we couldn't use this molecule, but because we set up all of the assay, which was related to this interferon induced mechanism, we participated in 1985-'86 in a clinical trial run by Hahnemann University where double-stranded RNA was used to treat HIV patients.
KATALIN KARIKO: These were mismatched double-stranded RNA. It is like the poly I:C. But there were some mismatches there and it was less toxic. Actually, double-stranded RNA was-- early '70s already was a clinical trial, and even today is not approved because when too little is not enough, and too much is too toxic. And interestingly is that time, we didn't know how double-stranded RNA-- in using their furan.
KATALIN KARIKO: And we had to wait up until 2001 when the first molecule, the first receptor was identified that it was toll-like receptors. But this time we didn't know. And I was always curious how a double-stranded RNA could induce interferon. I have to leave, again, the laboratory. And I ended up at the tour in Uniformed Services University of Health Sciences where I learned a lot of basic molecular mechanism.
KATALIN KARIKO: Although the plasmid isolation was we still did a very tedious caesium chloride ultracentrifugation. But many things I learned there, which was just introduced. And one of them was the triazole, which was John-Chomsky-introduced. And it made RNA isolation so easy. The TARC polymerase was the molecule of the year in '89. And T7 and SP6 phage polymerases were introduced to make RNA. And for me, it was important that-- one day a student from [INAUDIBLE] lab walked in with a lipofectamine.
KATALIN KARIKO: And he said that it is good for delivering nucleic acid. So it was-- a lot of progress was made. And then I learned all of this right there. And then I worked here one year and ended up in University of Pennsylvania. And my colleague, Elliot Barnett and cardiologist, he paid my salary. And then I tried to apply for grants, which is known that it was not very successful.
KATALIN KARIKO: But he had money. And then we started to use messenger RNA. And the idea was that it would be a therapeutic RNA. And we will apply for different research as well as therapeutic purposes. And so we made an mRNA. And this coded for urokinase. And that was the first success of what we had because when we delivered this receptor, actually needed post-translationally modified glycosylated and GPI anchored to the cell, all of this decoration is needed to be functional.
KATALIN KARIKO: And we were surprised that delivering the RNA cell knew all what to do. And then we get functional protein, which bind to the urokinase. Of course, prior to that, I did a lot of effort to deliver-- to treat cystic fibrosis and the receptor I delivered to cells. And it was never get the full protein. And it was-- so I was very anxious to make sure that when we deliver an RNA, certain cells has to have those things, which is needed to process properly the protein to make it functional.
KATALIN KARIKO: Anyway, that Eliot was doing bypass surgeries. And then we had blood vessels. And we tried to see how we can apply it to deliver some kind of therapeutic encoding mRNA so that the patency of that blood vessel is better. But the changes came when Eliot had to leave. And charismatic resident, David Langer convinced the chairman of neurosurgery that neurosurgery needs a molecular biologist.
KATALIN KARIKO: And they should give a lab. And then this is when I get a lab. And then I get some funding and we started to work with David. His idea was to make a eNOS-encoding mRNA because he identified a problem in subarachnoid hemorrhage, the blood vessel vasoconstriction. And he thought that if he could deliver the mRNA there. And locally, the nitric oxide is released by this and made this enzyme.
KATALIN KARIKO: Then it can have a vasodilatation. And so we did a lot of studies, looked at-- through [INAUDIBLE] in small pig. We traveled to Buffalo, looked at rabbit models. We were in Chicago and checked out in subarachnoid model system in the university. But we had to go back always and try to improve because we couldn't show that it works.
KATALIN KARIKO: So I stayed in neurosurgery and try to make mRNA for stroke treatment and with different model. But David had to leave. And then I met Drew Weissman who happened to arrive to Penn from Anthony Fauci's lab. And his main goal was to develop a prophylactic as well as therapeutic HIV vaccine.
KATALIN KARIKO: And he was experimenting with-- he used human dendritic cells. And he tried to use plasmid and other-- and peptide protein to make the dendritic cells to present this antigen. And really, we met at the Xerox machine, the copy machine. And luckily, because it was in '98-- and from 2002, I did not copy anything. I was reading all of the papers digitally.
KATALIN KARIKO: But at that time, I still had to copy and put in to the cabinet as all of us did a scientist. So we were talking. And I told Drew that, oh, I can make that mRNA that he was interested. And he used that. And he was very happy that it activated this in-vitro transcribed RNA, the dendritic cells. And he get a good immune response.
KATALIN KARIKO: And he get-- high level of antigen was produced. I was not very much worried of that result but more when his study showed that inflammatory cytokines were secreted by this RNA that was made. And that was very bad news for me as I wanted to use the mRNA to therapeutic purposes and, as I mentioned, for stroke treatment.
KATALIN KARIKO: And that is the last thing a stroke patient would need, more inflammatory cytokines to induce. So to tell you just what happened during this time in other people's laboratory, I might mention here that in the '90s-- the early '90s, other people what they did, there were one application for therapeutic use. It was vasopressin RNA for Floyd Bloom. They published at the script where they could show therapeutic benefit.
KATALIN KARIKO: And other people also use mostly for vaccination. And there were two papers here. The first one was by the French team, Pierre [INAUDIBLE] and his colleague. They delivered with liposome, actually, a nucleoprotein specific influenza encoding the RNA. And the same kind of RNA was-- same kind of encoding, the product was used by the Karolinska Scientist, [INAUDIBLE]..
KATALIN KARIKO: He used a self-amplifying RNA. And he injected it naked to vaccinate. But most of the '90s, and from '95, and later on actually focused on cancer vaccine. The messenger RNA-- in-vitro transcribed messenger RNA was used for cancer vaccine. David Curiel used the-- he also injected the animals in the RNA as naked. And Gilboa, actually, he used lipofectamine.
KATALIN KARIKO: And so the scientists already focusing on using not the mRNA coding for some kind of a lipoprotein but try to find some use for messenger RNA. And I withdrew to try to understand that why this messenger RNA in-vitro synthesizing is immunogenic. We thought that maybe because it's coming to the dendritic cells from outside.
KATALIN KARIKO: And so what we planned is to use in-vitro transcribed RNA and isolated RNA. We isolated from mammalian cells different types of RNA. And we exposed to them dendritic cells and measured the TNF alpha. And here is the result. This is the most important one, finding that not all messen-- not all of the RNA is equal. The in-vitro transcribed mRNA was the most immunogenic. And TRNA was not immunogenic at all.
KATALIN KARIKO: And all of this TNF alpha induction is coming from the RNA because RNA's treatment eliminated the signal. So we knew that the TRNA has a lot of modified nucleoside. 25% of it is modified. So we thought that maybe the modification is the reason. But of course, there were other things because these RNA were much shorter. And so there're many things in our mind.
KATALIN KARIKO: But nevertheless, we could see some correlation. And we wish that this in-vitro transcribed RNA would be with a lot, a lot of modification maybe. And then we would have an mRNA, which is not immunogenic at all-- but how we could do that. So you have to know that all of the RNA is made from the four basic nucleotides in our body. And after RNA is produced, different kind of enzyme-- modifying enzymes will introduce changes, methylation and sometimes very, very complex changes.
KATALIN KARIKO: But these modifying enzyme not only were not available, they were also not known. So what should we do? There are so many different kinds of modification in the RNA. I'm showing here the 108 different one. And how would we incorporate this to the RNA? Or how could we make it? So we did in a way that-- how nature is not doing.
KATALIN KARIKO: We purchased the nucleotide triphosphate. And actually, we purchased from TriLink-- recommendation of my organic chemist friend who was-- we were together in Hungary in the lab. And then he also work with RNA. And even today, he's advising me on every single organic chemical related and RNA-related projects. So Janusz Ludwig told me that we order from TriLink.
KATALIN KARIKO: And then I ordered [INAUDIBLE] which is naturally occurring in our body. Because I already learned during the years that if it is not naturally occurring in our body, it could be very, very toxic. So we purchased 10 of those because that was available in high concentration, these triphosphate. And we made the RNA.
KATALIN KARIKO: And five of them were not incorporated. So we generated the five. Of course, we crossed our fingers that from the 108, we didn't know which one is important. That maybe one of those five is still very important. So what happened is that after generating the RNA, we tested out on dendritic cells. And we found that some of them is still immunogenic just like the unmodified.
KATALIN KARIKO: One the blue is here. And some of them did not induce any TNF offer but turned out that those who were not inducing TNF alpha, all of them had some kind of modification in the uridine. So in this paper, we also identified that actually toll-like receptor 7 and toll-like receptor 8 is responsible. And 10 years later, crystal structure demonstrated why uridine containing single-stranded RNA or in the case of toll eight, which is present only in human cells-- why uridine, the nucleoside itself can activate and as a result of it, induce interferon.
KATALIN KARIKO: And for us, of course, we wanted to make-- I wanted to make RNA, which will code for a protein. So it was important to see that, whether it translates. Because the uridine modification is critical, we had three of them, three modified. None of them were immunogenic. But one of them was not translated, [INAUDIBLE] translated, similarly like the protein. And we had pseudouridine, which containing RNA translated so much better.
KATALIN KARIKO: And we spent two, three years trying to understand why this is translating better and also try to understand that how we could purify the RNA because we noticed already that there were some double-stranded RNA there. And so we work a couple of years here from 2008 to 2012 where finally, we could have an RNA, which was nucleoside-modified, purified.
KATALIN KARIKO: And we could test it out in people, in mice. And here in red you can see that when we injected the messenger RNA, very small amount, 0.1 microgram to mice, we could see that erythropoetin level-- this mRNA coded for erythropoetin was quite a long time we could detect and-- whereas when we had the unmodified one, the translation was much shorter. And more importantly for us, there were no interferon induced.
KATALIN KARIKO: Of course, it was 2014 when first time it was shown that if interferon is induced, usually the antibody production is not that favorable. But right now that we just try to understand the system. And we were very glad, and especially me because this is the first time I could see that an mRNA coding for a therapeutic protein is functioning because of the injection. I could see that the hematocrit was increased in the animal.
KATALIN KARIKO: The EPO makes more red blood cells. And then in the case of mice, the half life of those red blood cells is 40 days. And then weekly injection of the EPO could maintain for a whole month, the high level. And subsequent years here of the 2012, a lot of work was done to optimizing the system and code on optimizing as well as other structural elements we optimized, purified, and many, many different things we did.
KATALIN KARIKO: One of the also important is this cap structure, which first, we introduced cap one structure enzymatically. And later on, we used the CleanCap from TriLink. And so in one part, we could make a very potent RNA. So after all of this optimization, of course, our vision was now at the BioNTech is that we have to express the drug in the patient. And one of the study, what we did in mice when we delivered nucleoside-modified mRNA coding for bispecific antibodies-- and we could eliminate large tumors in mice.
KATALIN KARIKO: And subsequently, we also performed experiment where intratumorally, we injected the messenger RNA coding for cytokines and showed that not only the tumor, which was injected but remotely located tumors were eliminated in mice. And those studies already advanced to clinical trial. So while we were working-- and because my main interest was also always therapeutic making mRNA, coding for some therapeutic protein-- but colleagues on other field, they advance the formulation, which is a very critical and important part of the mRNA delivery.
KATALIN KARIKO: And Peter Cullis, Tom Madden, and Ian McKellen in companies like Protiva, Tekmira, and [INAUDIBLE],, they generated the lipid nanoparticles that were used for siRNA delivery. And then in this later years, they also adjusted this system to deliver messenger RNA.
KATALIN KARIKO: The important is that different kind of lipids are present in these particles. And now that with these formulation, it could be reached that the RNA formulated with this LNP-- it had a shelf life. So it could be frozen. And in -70, -80 Celsius, it could be stored for years. So previously all of the assay, all of the delivery material was that we put the RNA.
KATALIN KARIKO: We put the lipoprotein or put the transit in. And then in two, three minutes, we had to inject. So it was not very feasible to use in a therapeutic setting. So my colleagues, Drew Weissman and in his laboratory, Norbert Pardi did a messenger RNA coding for the Zika pre-membrane, and envelope protein, and formulated with this lipid nanoparticle provided by Acuitas.
KATALIN KARIKO: And he demonstrated that when these mRNA was injected to monkeys, then they were protective. And single injection of 50 micrograms in a monkey protected the monkey from a Zika viral infection. So this was done in a Drew Weissman lab by Norbert. And similar experiments were done at Rush University and also in a Moderna.
KATALIN KARIKO: And Moderna already initiated a clinical trial with using the nucleoside modified RNA, LNP formulation for influenza. And Norbert and Drew Weissman lab also used a similar formulation and the RNA for a HIV vaccine in animal studies as well as influenza and herpes simplex.
KATALIN KARIKO: And so studies already showed that no matter what, this formulation with the nucleoside modified LNP was very protective and very effective. And so all of these studies demonstrated that maybe the nucleoside-modified RNA is also the optimal for vaccination.
KATALIN KARIKO: Previously, we thought that maybe the unmodified one but these studies-- and Norbert subsequently did studies showing why follicular T helper cells is important for this good vaccine production and why the modified-- nucleoside-modified RNA get better response. So here we went for all of these years. And this last slide, which I'm showing you demonstrate what you already-- or what you know that we learned in 2020 that there is a virus is coming.
KATALIN KARIKO: And then we learned the genetic sequence in January. And through the one year, we finally-- by the end of the year, we could have vaccine, which I was lucky to receive and many others. And now that here in the US, everybody who want to have the vaccine could have it. And we already-- and daily, we can hear about mRNA vaccines.
KATALIN KARIKO: So the public is well aware of what mRNA vaccine can do. And so with that, I would like to thank you for your attention.
JULIANNA LEMIEUX: Thank you so much for that terrific talk. Wow. It's just wonderful to learn about all of the work that has gone into this huge puzzle. and terrific. And if we can have you for a little bit longer, we'll ask you some questions both from myself and from the audience who've been sending in some great questions. So my first question is you've been working on mRNA for a long time.
JULIANNA LEMIEUX: So what is it about RNA that first caught your attention? What is it about it that's held your attention for so long? And have you ever considered working on anything else?
KATALIN KARIKO: So in the early '90s as the Human Genome Project advanced, everybody was focusing-- who were on that field, to introduce some kind of gene therapy is-- the monogenic diseases to fix and when the gene was known, they tried to deliver. But my thinking was more that many of the diseases are what we have is more like ache and pain. And then we just need a very temporary some kind of mRNA, which would be just transient so that it is good, that it is not forever.
KATALIN KARIKO: I was not thinking about ever to make a vaccine. And if I don't meet Drew, I am just keep trying to make a mRNA for therapy. And I don't know what point I would realize that it is immunogenic if he's not telling me that. But just during the first 10 years when I was working with the short RNA molecule, I learned all of this enzyme, which I can forcefully-- which I can-- many, many different enzymes.
KATALIN KARIKO: And I was just so used to work with RNA. And I thought that the messenger RNA could be a medicine.
JULIANNA LEMIEUX: Terrific. So getting into-- moving a little bit into COVID-19, when did you first realize that RNA vaccines were going to be so crucial in combating COVID-19?
KATALIN KARIKO: So even about the virus-- so when it was heard in February that what happened in China, I was not the visioner who realized that now, we need a vaccine. This was Ugur Sahin, our CEO realized that immediately. And I was not-- although I was involved in the Pfizer project. Because in 2018, we signed up with Pfizer to co-develop a vaccine for influenza.
KATALIN KARIKO: But I was not designing the COVID-19 vaccine. And then I was participating on a way that many of the elements, which eventually get to the vaccine. My team was working on that so that the cap, the formulation, and other things. But I mean, I hoped that the vaccine will work.
KATALIN KARIKO: And I am very glad that it turned out how it is. But why I thought that it definitely it would work maybe and will be as good, maybe I am just naive. I don't know enough about respiratory viruses that-- and so I just thought that it will work.
JULIANNA LEMIEUX: Well, I don't think it's naivety. I think it's working. So I think you were right about that. So you moved from academia to industry. And that's a move that more and more scientists are making nowadays, certainly, 20 or even 10 years ago. Was that an easy move to make? Is there anything that you miss about academia? And what would you say to people who are considering a similar move?
KATALIN KARIKO: Honestly, it was very refreshing. I myself together with Drew Wiseman, we established a small company. But we were, kind of, virtual company. But I learned about what important-- what is important for a product. But going to Germany and working at BioNTech, for me was refreshing that no longer another paper and other paper, which is the measure of your productivity.
KATALIN KARIKO: But you have to have something meaningful, a product which had to be functional, helping somebody-- a patient. And that for me, it was very refreshing and also how everybody worked together. So it was we need a product, and everybody was in. And so that for me, it was a great feeling.
KATALIN KARIKO: It seems sometimes in academia that people need to be first out, or last, or something. And they are already-- without starting the project, they're already fighting for those kind of position. And so that was-- and of course, it was nice that I had the excellent colleagues there at BioNTech. And Ugur Sahin, the CEO is also a scientist in the core, not just heading the whole company.
KATALIN KARIKO: And so that was also a great feeling. So I was very happy. And I am still there so just-- I am home office right now. I am missing them.
JULIANNA LEMIEUX: Got it. There's no doubt that your story, and your work has inspired many early career scientists out there, and probably some budding scientists as well. Who inspired you along the way?
KATALIN KARIKO: Definitely, my teachers even from the elementary school, and at the university, at the research center where I work. And I was so glad just in May, I met several of them. And I could thank them for their help because were behind the Iron Curtain. But they did their best to educate us.
KATALIN KARIKO: And so my colleagues, also those scientists who I never met but reading their paper, they were-- I was just so proud of what they have done, and also my colleagues that I'm working with-- work with in at the University of Pennsylvania and BioNTech. And of course, the vaccine needed all of the scientists not just BioNTech and Pfizer-- and their expertise.
KATALIN KARIKO: So those people who had to figure out technicality and many other things, I just admire all of them.
JULIANNA LEMIEUX: Terrific. So I want to get to some of the questions coming in from the audience. We have so many great questions. So Jean-- so this is getting back to the industry angle for a second. Jean asks, Don Kennedy said that science doesn't exist until it's published. What do you think of publication policies in biotech companies?
KATALIN KARIKO: So at BioNTech, we published our results. And so I just presented the Nature Medicine paper and Nature-- and all of my colleagues there. So when we are doing something, it's not just in a patent. But it is-- we put it out and public. And other companies as well we are doing that. So I haven't seen that at BioNTech that we have to hold back because of that.
KATALIN KARIKO: So great publications are out from BioNTech and so--
JULIANNA LEMIEUX: OK. Oh. Ann has a question. Do you anticipate that now more of our vaccines will be RNA-based vaccines? And why do you think we have just now deployed this approach?
KATALIN KARIKO: As I mentioned actually, even the SARS-CoV-2, it was not the first to target. Human trial by Moderna already run in two years before that in Germany. But of course, it was 200 people was involved in the trial. And of course, all of us wanted step-by-step to test out more participant and analyzing.
KATALIN KARIKO: But when we needed urgently, then things accelerated but emphasizing that nothing was caught that-- safety or something. It was about that already material was prepared for phase I or phase III before knowing the outcome. And of course, the government said to take over the responsibility, paying for it. If it has failed then that's how it encouraged the companies just to proceed.
KATALIN KARIKO: So that's why it could be done in a shorter time. But it will-- definitely, more mRNA vaccine will come. And it will be benefit for all of us.
JULIANNA LEMIEUX: Terrific. Beyond mRNA, is there a field or a scientific application on the horizon that you think is very exciting, something else going on?
KATALIN KARIKO: I mean, the messenger RNA application for different kind of diseases-- we have seen recently, Intellia reported that they delivered Cas9 mRNA. And they could edit and treat-- transfer doses in a patient by editing their genome in the liver. And of course, new formulations are coming that will reach the bone marrow cells.
KATALIN KARIKO: And then other diseases like toxemia or HIV can be treated. But the formulation, I see myself, is a number one, which will advance the field. I don't see much that the RNA-- what can be changed. But, of course, always you can improve. But formulation will open up new field. And that would be maybe the genome editing. So after all, maybe the transient-- because, of course, the Cas9 mRNA also and the enzyme is transiently there.
KATALIN KARIKO: And eventually, the messenger RNA will fulfill the promise of gene therapy because then it is permanent change-- will be resolved and editing disease genome.
JULIANNA LEMIEUX: Yes. Actually, that is a great segue to Charles's question, which was-- which you just touched on, which are, what are the advantages and disadvantages of using mRNA versus editing DNA?
KATALIN KARIKO: I mean, using the RNA is important because it will degrade quickly. Because if the editing enzyme is lingering around too long and because you deliver as a virus, for example, or a plasmid then it will be-- Cas9 or any editing protein will be generated for a longer time period and more likely that some unwanted adverse effect will happen.
KATALIN KARIKO: So the RNA can be modified in a way that it will be-- even the half life would be shorter because this would be critical for that. And this the same for the vaccine. You don't want to make a protein for the rest of your life. It will be very short period of time there and as well as the mRNA.
JULIANNA LEMIEUX: Got it. So as you mentioned during your talk, you've overcome some hurdles in your career, not receiving grant funding, for example. What kept you going through the tough times?
KATALIN KARIKO: Maybe I did not realize that it is a tough time because it was a lot of fun. And sitting at the bench and thinking about the experiment is always-- there is always a new solution. A new idea comes. And then we explain why the previous experiment did not result in the expected result, and why we didn't get that. And then you are high on that. You have the new idea maybe.
KATALIN KARIKO: And that will work. And then it is just have to enjoy doing these things. And maybe this job is not for everybody. But if you enjoy doing research then, yeah, that's what you need. Anyway, you don't have time to spend money because you are always in the lab. So little money is enough. But of course, it would have been better if some support comes way.
KATALIN KARIKO: I just counted 40-something grant I was not getting. But even writing the grant, I did not advertise to my colleagues. But I love to do that because I had to think through. And I had to read a lot. And it was fun writing grants. Now I can say that. But that's how I felt even when it was not appreciated. But I also not thinking about that those people who are evaluated and said, not good.
KATALIN KARIKO: I always thought that maybe I should do something better, improve. Maybe I did not-- of course, you never have enough background experiment, but maybe not articulated well enough, or something. And I always try to see what I can do to make it better.
JULIANNA LEMIEUX: That's tremendous advice. I mean having any rejection can either bring you down, or you can try to overcome that. So that's--
KATALIN KARIKO: Yeah. Actually, the Uniformed Service University was the only place where I willingly left because all of the other places I was sent away. But every time, it was when you are kicked out or terminated in your position, you just have to think that you have a new opportunity to find, a new job, or something new. And so that's how-- and not to think that much about that there is nothing fair.
KATALIN KARIKO: Of course, that other person is doing less research, and get promoted, or something. Because you have to always focus on what you can do. Because otherwise, you get disappointed immediately. And of course, life is not fair. But we are-- if you are at the bench, you are already a much better position that anywhere on the Earth, somebody. Because you are at-- you can do something.
KATALIN KARIKO:
JULIANNA LEMIEUX: So David Langer told Gina Kolata when she wrote her article about you, Kate's genius was a willingness to accept failure, and keep trying, and her ability to answer questions people were not smart enough to ask. So what do you think is the key to being a successful scientist? Is it what David Langer said or something else?
KATALIN KARIKO: You have to stay curious. You want to know. And if your goal is, I want to understand, how could it be-- and so many enigmatic things in science. So then you are not disappointing when you read something, you are thinking. And you are reading in paper somebody already published. Because you are happy. You wanted to understand. OK, somebody already helped you to understand.
KATALIN KARIKO: So you don't have to do those experiments. If you look at things this way, you are always happy even if people are reporting on what you were doing because you the goal has to be to better understand. And I don't take it that you are working for the company, or working for the boss, or somebody. If you are working on something to understand you put all of these things.
KATALIN KARIKO: And listen, your boss will be very anxious if you want to leave, if you are very good. Because you walk out and whatever is in your head is leaving. So you just have to read a lot. That's it. And then you can make connection between different things because, of course, you can look it up. Everything's on the internet.
KATALIN KARIKO: The knowledge is there. But if it is there, cannot make connection. It has to be in your head. And in whole, in the biology-- in our field is all working on analogies so some analog. There is a similar mechanism. And more you know then more you can think that, oh, there is a precedent for that. And then you can work from that on.
JULIANNA LEMIEUX: I want to share a comment, not really a question in the chat as well from Jean that says, as a scientist, I know it takes a long time to learn about each piece of the puzzle. Everything we learn, including from unsuccessful grant applications in multiple labs adds to the insights that only us older scientists can make. So I think she's sharing some of that sentiment there.
KATALIN KARIKO: So we have to learn from everything. The truth is that I learn more from seeing things, which I said that I will never do that. It couldn't be that way. So from the bad example, also I learn. So even if somebody treated me badly, I remember that I will never say do things like that. And for many other things, when organizing the laboratory, for example. When I left Penn, we had more than 6,000 RNA isolates.
KATALIN KARIKO: And to have everything-- I was a bookkeeper-- to make sure where it coming from, what is-- how it was characterized and setting up the whole system. Because previously, once I realized that people get lost samples because they cannot-- they don't have a system. So again, I set up the system because I have seen the bad example, how people lose things, samples, and other things.
KATALIN KARIKO: So that was you have to-- you learn from everything; good, bad. And if something happen that you lose your job or the experiment is not-- then you just learn from it. And it gives you an opportunity to go somewhere else, to do something else, or improve.
JULIANNA LEMIEUX: Terrific there are a couple of questions about using mRNA for cancer immunotherapy. What are your thoughts on that?
KATALIN KARIKO: So as I mentioned in the presentation, a messenger in-vitro transcribed messenger RNA was mostly used for cancer vaccines. And the first company was Mouritsen out from Duke University was the first one using. And then run clinical trial later, it was called Argus. And then also the Curevac in 2000 was established to develop a messenger RNA-based cancer vaccine.
KATALIN KARIKO: The challenge is that people say, oh, they work 20 years. And if they couldn't figure out how this SARS-CoV-2 vaccine could be good if they couldn't figure out. But for the cancer vaccine, the challenge is that what should be the antigen? So even if different antigens are identified, it's not necessarily that is a driver mutation. And so that's the major challenge. There are so many different mutations out there.
KATALIN KARIKO: And BioNTech, and Moderna, or Curevac, they have programs for messenger RNA-- encoding those neoepitopes so that those proteins that have mutations-- so the amino acid chain and then they could be identified similarly like the vaccine for infectious disease. But it is challenging. And so there are-- more science is needed.
JULIANNA LEMIEUX: Got it. And I mean, we're hearing so much in the news now about the variants, in particular the Delta variant. So one question in the chat asks, what do you think about the effectiveness of the current vaccine against the Delta variant? And what is the plan going forward for what is sure to be more variants?
KATALIN KARIKO: I mean, the data just came out. The BioNTech Pfizer vaccine was 88% effective against the Delta variant. And so as I mentioned, I am a biologist. I am focusing on the therapeutic use of mRNA. And I don't want to sound here like I'm a vaccine expert and an epidemiologist.
KATALIN KARIKO: But we just have to follow the science that-- what BioNTech, and Pfizer, and our scientific leaders are saying, and measuring. Because now that there's so much data is out they are collecting in Israel, in the US. And we understand that the vaccine is very protective still against these variants. And whether the third injection is needed or not it is up to the scientists to decide, who are measuring the different-- and following up the vaccinated people to see whether or how they get infected.
KATALIN KARIKO: But definitely, I got the vaccine. My daughter, my husband, everybody in the family, my sister-- everybody got the vaccine. And it is important for everybody to get the vaccine.
JULIANNA LEMIEUX: Absolutely. I also got the vaccine and all of us who got the vaccine. Thank you very much for all of your work. I want to-- just before I close, I want to end. There's so many comments in the chat about what an amazing talk this was, how it was just wonderful to learn about all the decades of work that have gone into this vaccine, that your background is inspiring.
JULIANNA LEMIEUX: And the curiosity is the mark of a true, great scientist. So thank you, again, for sharing this story with us. And I'll just end by saying that this brings us to the end of our discussion and concludes part one of our Women in Science series. I want to, again, thank Kate and Karla for this terrific discussion, and thank our team behind the scenes for making everything run so smoothly. And I want to thank all of you for joining us.
JULIANNA LEMIEUX: Thanks also to TriLink and the Vilcek Foundation for supporting this event. Please join us next month on Friday, August 13 when we'll be talking to Amy Abernathy, the newly appointed president of Verily's clinical research business and, again, on October 1st when we'll be speaking to Fiona Murray, the associate dean of innovation and inclusion at the MIT School of management. Also you'll be able to find today's event on demand, on GEN's website.
JULIANNA LEMIEUX: For everyone at GEN and the Rosalind Franklin Society, I'm Juliana LeMieux. Stay safe. And we'll see you again soon.
KATALIN KARIKO: Thank you very much. And I just want to say hello to all of the scientists who work hard like me and just keep up with a good job.
JULIANNA LEMIEUX: Thank you. [AUDIO LOGO]
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[AUDIO LOGO]
JULIANNA LEMIEUX: Hello, everyone and welcome to this Women in Science event, the first in a three-part series co-produced by Genetic Engineering and Biotechnology News, or GEN, and the Rosalind Franklin Society. I'll be your host. I'm Julianna LeMieux, science writer at GEN. Thank you so much for joining us today. It's a pleasure and honor to have Dr. Kate Karikó here to talk about her work in the field of mRNA and how it has been harnessed to fight the COVID-19 pandemic.
JULIANNA LEMIEUX: Before we get started, I'll pass it over to the executive director of the Rosalind Franklin Society, Karla Shepard Rubinger who will tell us a little more about RFS and the Vilcek Foundation. Karla, over to you.
KARLA SHEPARD RUBINGER: Thank you, Julianna. The Rosalind Franklin Society is, again, so pleased to be hosting this Women in Science series with our colleagues at GEN. The mission of the society is to showcase and promote the careers of women scientists worldwide. Many, like, Rosalind Franklin work tirelessly without recognition but with an uncommon passion and commitment for their work. Dr. Franklin's now famous Photograph 51 was the cornerstone of the discovery of DNA but was given little recognition during her lifetime.
KARLA SHEPARD RUBINGER: Our speaker today so clearly fits this model. She is passionate about her work and has always been quite optimistic about her pioneering research on the mRNA technology. In a recent interview, she claimed, I never doubted it would work. This is confidence not bravado. Given the profound impact of her work, the Vilcek Foundation has just honored her with the 2022 Vilcek Prize for Excellence in Biotechnology ahead of schedule.
KARLA SHEPARD RUBINGER: We are excited to hear more about her work followed by a brief follow-up interview with Juliana and, hopefully, time for audience questions at the end. Thank you so much for all-- for being here, back to you, Julianna.
JULIANNA LEMIEUX: Thanks, Karla. Today's presentation is also being sponsored by TriLink. TriLink Biotechnologies, a part of Maravai Life Sciences is a CDMO helping life science leaders and innovators overcome challenges in the synthesis, and scale up of nucleic acids, NTPs, and mRNA capping analogs with scaleup expertise, and unique mRNA production capabilities, including its proprietary CleanCap, mRNA capping technology. TriLink continues to expand its CGMP, and general mRNA oligonucleotide, and plasmid manufacturing capacity at its new global headquarters in San Diego, California to support therapeutic vaccine and diagnostic breakthroughs so thank you to TriLink.
JULIANNA LEMIEUX: Lastly, I want to mention that we welcome your questions for Kate. So please just drop them into the Q&A of the Zoom. And we'll try to take as many as we can at the end of her talk. So it's likely that you hadn't heard of Kate Karikó before last year unless maybe you work in the field of RNA. It's probably, equally, as likely that you have heard of her before today. You may even have seen her on CNN.
JULIANNA LEMIEUX: Kate is the senior vice president at BioNTech. For her entire career, she has focused on mRNA, the molecule that has been thrust into the limelight because it sits at the center of two highly successful COVID-19 vaccines. Today, Kate will talk about her pioneering research in mRNA and how it provided the tools necessary to develop those vaccines. But her story goes far beyond her work in the lab.
JULIANNA LEMIEUX: It is also a story of perseverance, dedication, and a love of science. Kate, the floor is yours.
KATALIN KARIKO: Thank you very much for inviting me. And today, I will talk about development of mRNA for therapeutic. And it's not warp speed, actually, added by the organizer. But this is very true. It was not that fast that the vaccine itself was developed. So the RNA-- messenger RNA history has been 60 years. So it started in the 1961, discovering the mRNA.
KATALIN KARIKO: And through the years-- through the last 60 years, a lot of things happened. And although the first one, the date, '61-- I do not remember. But the rest of it, I was witnessing and participating in it. And because I don't have the whole afternoon to talk about all of these years, what happened, I'll just try to give you some-- how I witnessed all of these years.
KATALIN KARIKO: And since it was said also by Steve Jobs that only we can connect the dots looking back, so I try to connect those dots in my-- the past. And so how I started it is as a student, undergraduate student in Hungary. And I joined a lipid lab. And I spent the summer collecting specimen, fish fats just to try to understand how the fat composition is changing depending on what kind of chew they eat.
KATALIN KARIKO: And I collected these specimens. And in the fall, I went back and to the lab and analyzed that. And this was the time when two of the colleague also came, [? Erno ?] and Eva. And they decided that they want to use, and generate phospholipids, and use it for delivering plasmid to the cell. And of course, I was an undergraduate. Everything was new for me. This was also very exciting.
KATALIN KARIKO: So I joined them and participated in that study. Of course, phospholipid fraction, which actually they wanted to use was not available. We were behind iron curtain, and it was under embargo. And we went to the slaughter house and came back with a cold brain. And we spent the whole week isolating the required fraction phosphatidylserine ethanolamine fraction, and then wrapped it up the plasmid, and delivered to mammalian cells.
KATALIN KARIKO: So delivering nucleic acid with lipids was not novel, not new even in that time. Actually in the mid-'70s, Papahadjopoulos already described how to make liposome. And for me, the first paper really when mRNA was delivered into mammalian cells and primary mammalian cells was published in 1978, [? Dimitriadis. ?] And this RNA was not in-vitro transcribed because we don't know how to.
KATALIN KARIKO: At that time, we didn't know how to synthesize. But he isolated this from reticulocytes. And it was globin mRNA. So that was my work in the lipid lab as an undergraduate. And for my PhD, I went to the RNA Lab. I didn't know at that time that RNA and lipid were always so close to each other. But I stayed in the same institute.
KATALIN KARIKO: And my supervisor was [? Yanou ?] Thomas. And he made a cap analogs. And of course, today you can order cap analogs. But he made it for Aaron Shatkin and Furuichi who discovered in '75 that the messenger RNA has a cap. And to identify the molecules they needed reference material. And they needed a good organic chemists like Yanou who would synthesize and then send it to them. And it was interesting.
KATALIN KARIKO: I might mention that here all of my colleague, Janusz Ludwig and all of the others were organic chemists. And I was a biologist. And it was in all in my subsequent years-- I always worked with people who had a very different expertise than what I had or what I supposed to do. But here, actually, we didn't make mRNA. We were in the '70s. But we were interested to make a very interesting molecule, the two-prime five-prime link oligoadenylate.
KATALIN KARIKO: This was just discovered in 1977-- Ian Kerr in London. And it was assumed that when double-stranded RNA activates oligoadenylate synthetase enzyme, this molecule is formed. And this two-prime, 5-prime link small trinucleotide is activating an enzyme, which is responsible for antiviral effects. So we were in these '70s.
KATALIN KARIKO: And we needed so badly an antiviral molecule. We needed-- also today and it seemed that if we can synthesize that and deliver, maybe we have some very good antiviral compound. And the pharmaceutical company supported this activity. It is also-- I might mention here that whenever I subsequently work, I always kept my eye on all of those molecules I started with in my career.
KATALIN KARIKO: And then for example, the OAS just recently identified how important it is for those who have a COVID infection and SARS-CoV-2 infected people who had low level of for some genetic reason. They are very in serious trouble and serious disease form. So we were doing this. But the delivery was difficult although with this liposome, which we already did in the lipid unit-- could give a solution.
KATALIN KARIKO: But it was quite tedious to make with this film method and the wrapping of molecules. And so we ran out of funds. And I ended up in Philadelphia in Professor Suhadolnik's laboratory. He was the-- he wrote the textbook on modified nucleosides. And he was mainly interested in different kind of analogs. And all of this had some cytotoxic effect.
KATALIN KARIKO: And one of them actually, cordycepin, which I already used in Hungary because it was easy to make two-prime, five-prime because it was three-prime doxy molecule. And the professor also discovered that pseudouridine could be made some microorganism as a de novo nucleosides. But I learned here that all of these nucleosides is quite toxic.
KATALIN KARIKO: But here, again, my responsibility was to focus on this two-prime, five-prime nucleotides. And we did so many different modification introduced into nucleotide linkage, and nucleobase, and the five-prime. And we also changed the sugar in it. And of course, we would have needed very much a antiviral compound because here now we are in the '80s.
KATALIN KARIKO: HIV was a very serious problem. And there were no cure for those patients who'd get infected. Although we couldn't use this molecule, but because we set up all of the assay, which was related to this interferon induced mechanism, we participated in 1985-'86 in a clinical trial run by Hahnemann University where double-stranded RNA was used to treat HIV patients.
KATALIN KARIKO: These were mismatched double-stranded RNA. It is like the poly I:C. But there were some mismatches there and it was less toxic. Actually, double-stranded RNA was-- early '70s already was a clinical trial, and even today is not approved because when too little is not enough, and too much is too toxic. And interestingly is that time, we didn't know how double-stranded RNA-- in using their furan.
KATALIN KARIKO: And we had to wait up until 2001 when the first molecule, the first receptor was identified that it was toll-like receptors. But this time we didn't know. And I was always curious how a double-stranded RNA could induce interferon. I have to leave, again, the laboratory. And I ended up at the tour in Uniformed Services University of Health Sciences where I learned a lot of basic molecular mechanism.
KATALIN KARIKO: Although the plasmid isolation was we still did a very tedious caesium chloride ultracentrifugation. But many things I learned there, which was just introduced. And one of them was the triazole, which was John-Chomsky-introduced. And it made RNA isolation so easy. The TARC polymerase was the molecule of the year in '89. And T7 and SP6 phage polymerases were introduced to make RNA. And for me, it was important that-- one day a student from [INAUDIBLE] lab walked in with a lipofectamine.
KATALIN KARIKO: And he said that it is good for delivering nucleic acid. So it was-- a lot of progress was made. And then I learned all of this right there. And then I worked here one year and ended up in University of Pennsylvania. And my colleague, Elliot Barnett and cardiologist, he paid my salary. And then I tried to apply for grants, which is known that it was not very successful.
KATALIN KARIKO: But he had money. And then we started to use messenger RNA. And the idea was that it would be a therapeutic RNA. And we will apply for different research as well as therapeutic purposes. And so we made an mRNA. And this coded for urokinase. And that was the first success of what we had because when we delivered this receptor, actually needed post-translationally modified glycosylated and GPI anchored to the cell, all of this decoration is needed to be functional.
KATALIN KARIKO: And we were surprised that delivering the RNA cell knew all what to do. And then we get functional protein, which bind to the urokinase. Of course, prior to that, I did a lot of effort to deliver-- to treat cystic fibrosis and the receptor I delivered to cells. And it was never get the full protein. And it was-- so I was very anxious to make sure that when we deliver an RNA, certain cells has to have those things, which is needed to process properly the protein to make it functional.
KATALIN KARIKO: Anyway, that Eliot was doing bypass surgeries. And then we had blood vessels. And we tried to see how we can apply it to deliver some kind of therapeutic encoding mRNA so that the patency of that blood vessel is better. But the changes came when Eliot had to leave. And charismatic resident, David Langer convinced the chairman of neurosurgery that neurosurgery needs a molecular biologist.
KATALIN KARIKO: And they should give a lab. And then this is when I get a lab. And then I get some funding and we started to work with David. His idea was to make a eNOS-encoding mRNA because he identified a problem in subarachnoid hemorrhage, the blood vessel vasoconstriction. And he thought that if he could deliver the mRNA there. And locally, the nitric oxide is released by this and made this enzyme.
KATALIN KARIKO: Then it can have a vasodilatation. And so we did a lot of studies, looked at-- through [INAUDIBLE] in small pig. We traveled to Buffalo, looked at rabbit models. We were in Chicago and checked out in subarachnoid model system in the university. But we had to go back always and try to improve because we couldn't show that it works.
KATALIN KARIKO: So I stayed in neurosurgery and try to make mRNA for stroke treatment and with different model. But David had to leave. And then I met Drew Weissman who happened to arrive to Penn from Anthony Fauci's lab. And his main goal was to develop a prophylactic as well as therapeutic HIV vaccine.
KATALIN KARIKO: And he was experimenting with-- he used human dendritic cells. And he tried to use plasmid and other-- and peptide protein to make the dendritic cells to present this antigen. And really, we met at the Xerox machine, the copy machine. And luckily, because it was in '98-- and from 2002, I did not copy anything. I was reading all of the papers digitally.
KATALIN KARIKO: But at that time, I still had to copy and put in to the cabinet as all of us did a scientist. So we were talking. And I told Drew that, oh, I can make that mRNA that he was interested. And he used that. And he was very happy that it activated this in-vitro transcribed RNA, the dendritic cells. And he get a good immune response.
KATALIN KARIKO: And he get-- high level of antigen was produced. I was not very much worried of that result but more when his study showed that inflammatory cytokines were secreted by this RNA that was made. And that was very bad news for me as I wanted to use the mRNA to therapeutic purposes and, as I mentioned, for stroke treatment.
KATALIN KARIKO: And that is the last thing a stroke patient would need, more inflammatory cytokines to induce. So to tell you just what happened during this time in other people's laboratory, I might mention here that in the '90s-- the early '90s, other people what they did, there were one application for therapeutic use. It was vasopressin RNA for Floyd Bloom. They published at the script where they could show therapeutic benefit.
KATALIN KARIKO: And other people also use mostly for vaccination. And there were two papers here. The first one was by the French team, Pierre [INAUDIBLE] and his colleague. They delivered with liposome, actually, a nucleoprotein specific influenza encoding the RNA. And the same kind of RNA was-- same kind of encoding, the product was used by the Karolinska Scientist, [INAUDIBLE]..
KATALIN KARIKO: He used a self-amplifying RNA. And he injected it naked to vaccinate. But most of the '90s, and from '95, and later on actually focused on cancer vaccine. The messenger RNA-- in-vitro transcribed messenger RNA was used for cancer vaccine. David Curiel used the-- he also injected the animals in the RNA as naked. And Gilboa, actually, he used lipofectamine.
KATALIN KARIKO: And so the scientists already focusing on using not the mRNA coding for some kind of a lipoprotein but try to find some use for messenger RNA. And I withdrew to try to understand that why this messenger RNA in-vitro synthesizing is immunogenic. We thought that maybe because it's coming to the dendritic cells from outside.
KATALIN KARIKO: And so what we planned is to use in-vitro transcribed RNA and isolated RNA. We isolated from mammalian cells different types of RNA. And we exposed to them dendritic cells and measured the TNF alpha. And here is the result. This is the most important one, finding that not all messen-- not all of the RNA is equal. The in-vitro transcribed mRNA was the most immunogenic. And TRNA was not immunogenic at all.
KATALIN KARIKO: And all of this TNF alpha induction is coming from the RNA because RNA's treatment eliminated the signal. So we knew that the TRNA has a lot of modified nucleoside. 25% of it is modified. So we thought that maybe the modification is the reason. But of course, there were other things because these RNA were much shorter. And so there're many things in our mind.
KATALIN KARIKO: But nevertheless, we could see some correlation. And we wish that this in-vitro transcribed RNA would be with a lot, a lot of modification maybe. And then we would have an mRNA, which is not immunogenic at all-- but how we could do that. So you have to know that all of the RNA is made from the four basic nucleotides in our body. And after RNA is produced, different kind of enzyme-- modifying enzymes will introduce changes, methylation and sometimes very, very complex changes.
KATALIN KARIKO: But these modifying enzyme not only were not available, they were also not known. So what should we do? There are so many different kinds of modification in the RNA. I'm showing here the 108 different one. And how would we incorporate this to the RNA? Or how could we make it? So we did in a way that-- how nature is not doing.
KATALIN KARIKO: We purchased the nucleotide triphosphate. And actually, we purchased from TriLink-- recommendation of my organic chemist friend who was-- we were together in Hungary in the lab. And then he also work with RNA. And even today, he's advising me on every single organic chemical related and RNA-related projects. So Janusz Ludwig told me that we order from TriLink.
KATALIN KARIKO: And then I ordered [INAUDIBLE] which is naturally occurring in our body. Because I already learned during the years that if it is not naturally occurring in our body, it could be very, very toxic. So we purchased 10 of those because that was available in high concentration, these triphosphate. And we made the RNA.
KATALIN KARIKO: And five of them were not incorporated. So we generated the five. Of course, we crossed our fingers that from the 108, we didn't know which one is important. That maybe one of those five is still very important. So what happened is that after generating the RNA, we tested out on dendritic cells. And we found that some of them is still immunogenic just like the unmodified.
KATALIN KARIKO: One the blue is here. And some of them did not induce any TNF offer but turned out that those who were not inducing TNF alpha, all of them had some kind of modification in the uridine. So in this paper, we also identified that actually toll-like receptor 7 and toll-like receptor 8 is responsible. And 10 years later, crystal structure demonstrated why uridine containing single-stranded RNA or in the case of toll eight, which is present only in human cells-- why uridine, the nucleoside itself can activate and as a result of it, induce interferon.
KATALIN KARIKO: And for us, of course, we wanted to make-- I wanted to make RNA, which will code for a protein. So it was important to see that, whether it translates. Because the uridine modification is critical, we had three of them, three modified. None of them were immunogenic. But one of them was not translated, [INAUDIBLE] translated, similarly like the protein. And we had pseudouridine, which containing RNA translated so much better.
KATALIN KARIKO: And we spent two, three years trying to understand why this is translating better and also try to understand that how we could purify the RNA because we noticed already that there were some double-stranded RNA there. And so we work a couple of years here from 2008 to 2012 where finally, we could have an RNA, which was nucleoside-modified, purified.
KATALIN KARIKO: And we could test it out in people, in mice. And here in red you can see that when we injected the messenger RNA, very small amount, 0.1 microgram to mice, we could see that erythropoetin level-- this mRNA coded for erythropoetin was quite a long time we could detect and-- whereas when we had the unmodified one, the translation was much shorter. And more importantly for us, there were no interferon induced.
KATALIN KARIKO: Of course, it was 2014 when first time it was shown that if interferon is induced, usually the antibody production is not that favorable. But right now that we just try to understand the system. And we were very glad, and especially me because this is the first time I could see that an mRNA coding for a therapeutic protein is functioning because of the injection. I could see that the hematocrit was increased in the animal.
KATALIN KARIKO: The EPO makes more red blood cells. And then in the case of mice, the half life of those red blood cells is 40 days. And then weekly injection of the EPO could maintain for a whole month, the high level. And subsequent years here of the 2012, a lot of work was done to optimizing the system and code on optimizing as well as other structural elements we optimized, purified, and many, many different things we did.
KATALIN KARIKO: One of the also important is this cap structure, which first, we introduced cap one structure enzymatically. And later on, we used the CleanCap from TriLink. And so in one part, we could make a very potent RNA. So after all of this optimization, of course, our vision was now at the BioNTech is that we have to express the drug in the patient. And one of the study, what we did in mice when we delivered nucleoside-modified mRNA coding for bispecific antibodies-- and we could eliminate large tumors in mice.
KATALIN KARIKO: And subsequently, we also performed experiment where intratumorally, we injected the messenger RNA coding for cytokines and showed that not only the tumor, which was injected but remotely located tumors were eliminated in mice. And those studies already advanced to clinical trial. So while we were working-- and because my main interest was also always therapeutic making mRNA, coding for some therapeutic protein-- but colleagues on other field, they advance the formulation, which is a very critical and important part of the mRNA delivery.
KATALIN KARIKO: And Peter Cullis, Tom Madden, and Ian McKellen in companies like Protiva, Tekmira, and [INAUDIBLE],, they generated the lipid nanoparticles that were used for siRNA delivery. And then in this later years, they also adjusted this system to deliver messenger RNA.
KATALIN KARIKO: The important is that different kind of lipids are present in these particles. And now that with these formulation, it could be reached that the RNA formulated with this LNP-- it had a shelf life. So it could be frozen. And in -70, -80 Celsius, it could be stored for years. So previously all of the assay, all of the delivery material was that we put the RNA.
KATALIN KARIKO: We put the lipoprotein or put the transit in. And then in two, three minutes, we had to inject. So it was not very feasible to use in a therapeutic setting. So my colleagues, Drew Weissman and in his laboratory, Norbert Pardi did a messenger RNA coding for the Zika pre-membrane, and envelope protein, and formulated with this lipid nanoparticle provided by Acuitas.
KATALIN KARIKO: And he demonstrated that when these mRNA was injected to monkeys, then they were protective. And single injection of 50 micrograms in a monkey protected the monkey from a Zika viral infection. So this was done in a Drew Weissman lab by Norbert. And similar experiments were done at Rush University and also in a Moderna.
KATALIN KARIKO: And Moderna already initiated a clinical trial with using the nucleoside modified RNA, LNP formulation for influenza. And Norbert and Drew Weissman lab also used a similar formulation and the RNA for a HIV vaccine in animal studies as well as influenza and herpes simplex.
KATALIN KARIKO: And so studies already showed that no matter what, this formulation with the nucleoside modified LNP was very protective and very effective. And so all of these studies demonstrated that maybe the nucleoside-modified RNA is also the optimal for vaccination.
KATALIN KARIKO: Previously, we thought that maybe the unmodified one but these studies-- and Norbert subsequently did studies showing why follicular T helper cells is important for this good vaccine production and why the modified-- nucleoside-modified RNA get better response. So here we went for all of these years. And this last slide, which I'm showing you demonstrate what you already-- or what you know that we learned in 2020 that there is a virus is coming.
KATALIN KARIKO: And then we learned the genetic sequence in January. And through the one year, we finally-- by the end of the year, we could have vaccine, which I was lucky to receive and many others. And now that here in the US, everybody who want to have the vaccine could have it. And we already-- and daily, we can hear about mRNA vaccines.
KATALIN KARIKO: So the public is well aware of what mRNA vaccine can do. And so with that, I would like to thank you for your attention.
JULIANNA LEMIEUX: Thank you so much for that terrific talk. Wow. It's just wonderful to learn about all of the work that has gone into this huge puzzle. and terrific. And if we can have you for a little bit longer, we'll ask you some questions both from myself and from the audience who've been sending in some great questions. So my first question is you've been working on mRNA for a long time.
JULIANNA LEMIEUX: So what is it about RNA that first caught your attention? What is it about it that's held your attention for so long? And have you ever considered working on anything else?
KATALIN KARIKO: So in the early '90s as the Human Genome Project advanced, everybody was focusing-- who were on that field, to introduce some kind of gene therapy is-- the monogenic diseases to fix and when the gene was known, they tried to deliver. But my thinking was more that many of the diseases are what we have is more like ache and pain. And then we just need a very temporary some kind of mRNA, which would be just transient so that it is good, that it is not forever.
KATALIN KARIKO: I was not thinking about ever to make a vaccine. And if I don't meet Drew, I am just keep trying to make a mRNA for therapy. And I don't know what point I would realize that it is immunogenic if he's not telling me that. But just during the first 10 years when I was working with the short RNA molecule, I learned all of this enzyme, which I can forcefully-- which I can-- many, many different enzymes.
KATALIN KARIKO: And I was just so used to work with RNA. And I thought that the messenger RNA could be a medicine.
JULIANNA LEMIEUX: Terrific. So getting into-- moving a little bit into COVID-19, when did you first realize that RNA vaccines were going to be so crucial in combating COVID-19?
KATALIN KARIKO: So even about the virus-- so when it was heard in February that what happened in China, I was not the visioner who realized that now, we need a vaccine. This was Ugur Sahin, our CEO realized that immediately. And I was not-- although I was involved in the Pfizer project. Because in 2018, we signed up with Pfizer to co-develop a vaccine for influenza.
KATALIN KARIKO: But I was not designing the COVID-19 vaccine. And then I was participating on a way that many of the elements, which eventually get to the vaccine. My team was working on that so that the cap, the formulation, and other things. But I mean, I hoped that the vaccine will work.
KATALIN KARIKO: And I am very glad that it turned out how it is. But why I thought that it definitely it would work maybe and will be as good, maybe I am just naive. I don't know enough about respiratory viruses that-- and so I just thought that it will work.
JULIANNA LEMIEUX: Well, I don't think it's naivety. I think it's working. So I think you were right about that. So you moved from academia to industry. And that's a move that more and more scientists are making nowadays, certainly, 20 or even 10 years ago. Was that an easy move to make? Is there anything that you miss about academia? And what would you say to people who are considering a similar move?
KATALIN KARIKO: Honestly, it was very refreshing. I myself together with Drew Wiseman, we established a small company. But we were, kind of, virtual company. But I learned about what important-- what is important for a product. But going to Germany and working at BioNTech, for me was refreshing that no longer another paper and other paper, which is the measure of your productivity.
KATALIN KARIKO: But you have to have something meaningful, a product which had to be functional, helping somebody-- a patient. And that for me, it was very refreshing and also how everybody worked together. So it was we need a product, and everybody was in. And so that for me, it was a great feeling.
KATALIN KARIKO: It seems sometimes in academia that people need to be first out, or last, or something. And they are already-- without starting the project, they're already fighting for those kind of position. And so that was-- and of course, it was nice that I had the excellent colleagues there at BioNTech. And Ugur Sahin, the CEO is also a scientist in the core, not just heading the whole company.
KATALIN KARIKO: And so that was also a great feeling. So I was very happy. And I am still there so just-- I am home office right now. I am missing them.
JULIANNA LEMIEUX: Got it. There's no doubt that your story, and your work has inspired many early career scientists out there, and probably some budding scientists as well. Who inspired you along the way?
KATALIN KARIKO: Definitely, my teachers even from the elementary school, and at the university, at the research center where I work. And I was so glad just in May, I met several of them. And I could thank them for their help because were behind the Iron Curtain. But they did their best to educate us.
KATALIN KARIKO: And so my colleagues, also those scientists who I never met but reading their paper, they were-- I was just so proud of what they have done, and also my colleagues that I'm working with-- work with in at the University of Pennsylvania and BioNTech. And of course, the vaccine needed all of the scientists not just BioNTech and Pfizer-- and their expertise.
KATALIN KARIKO: So those people who had to figure out technicality and many other things, I just admire all of them.
JULIANNA LEMIEUX: Terrific. So I want to get to some of the questions coming in from the audience. We have so many great questions. So Jean-- so this is getting back to the industry angle for a second. Jean asks, Don Kennedy said that science doesn't exist until it's published. What do you think of publication policies in biotech companies?
KATALIN KARIKO: So at BioNTech, we published our results. And so I just presented the Nature Medicine paper and Nature-- and all of my colleagues there. So when we are doing something, it's not just in a patent. But it is-- we put it out and public. And other companies as well we are doing that. So I haven't seen that at BioNTech that we have to hold back because of that.
KATALIN KARIKO: So great publications are out from BioNTech and so--
JULIANNA LEMIEUX: OK. Oh. Ann has a question. Do you anticipate that now more of our vaccines will be RNA-based vaccines? And why do you think we have just now deployed this approach?
KATALIN KARIKO: As I mentioned actually, even the SARS-CoV-2, it was not the first to target. Human trial by Moderna already run in two years before that in Germany. But of course, it was 200 people was involved in the trial. And of course, all of us wanted step-by-step to test out more participant and analyzing.
KATALIN KARIKO: But when we needed urgently, then things accelerated but emphasizing that nothing was caught that-- safety or something. It was about that already material was prepared for phase I or phase III before knowing the outcome. And of course, the government said to take over the responsibility, paying for it. If it has failed then that's how it encouraged the companies just to proceed.
KATALIN KARIKO: So that's why it could be done in a shorter time. But it will-- definitely, more mRNA vaccine will come. And it will be benefit for all of us.
JULIANNA LEMIEUX: Terrific. Beyond mRNA, is there a field or a scientific application on the horizon that you think is very exciting, something else going on?
KATALIN KARIKO: I mean, the messenger RNA application for different kind of diseases-- we have seen recently, Intellia reported that they delivered Cas9 mRNA. And they could edit and treat-- transfer doses in a patient by editing their genome in the liver. And of course, new formulations are coming that will reach the bone marrow cells.
KATALIN KARIKO: And then other diseases like toxemia or HIV can be treated. But the formulation, I see myself, is a number one, which will advance the field. I don't see much that the RNA-- what can be changed. But, of course, always you can improve. But formulation will open up new field. And that would be maybe the genome editing. So after all, maybe the transient-- because, of course, the Cas9 mRNA also and the enzyme is transiently there.
KATALIN KARIKO: And eventually, the messenger RNA will fulfill the promise of gene therapy because then it is permanent change-- will be resolved and editing disease genome.
JULIANNA LEMIEUX: Yes. Actually, that is a great segue to Charles's question, which was-- which you just touched on, which are, what are the advantages and disadvantages of using mRNA versus editing DNA?
KATALIN KARIKO: I mean, using the RNA is important because it will degrade quickly. Because if the editing enzyme is lingering around too long and because you deliver as a virus, for example, or a plasmid then it will be-- Cas9 or any editing protein will be generated for a longer time period and more likely that some unwanted adverse effect will happen.
KATALIN KARIKO: So the RNA can be modified in a way that it will be-- even the half life would be shorter because this would be critical for that. And this the same for the vaccine. You don't want to make a protein for the rest of your life. It will be very short period of time there and as well as the mRNA.
JULIANNA LEMIEUX: Got it. So as you mentioned during your talk, you've overcome some hurdles in your career, not receiving grant funding, for example. What kept you going through the tough times?
KATALIN KARIKO: Maybe I did not realize that it is a tough time because it was a lot of fun. And sitting at the bench and thinking about the experiment is always-- there is always a new solution. A new idea comes. And then we explain why the previous experiment did not result in the expected result, and why we didn't get that. And then you are high on that. You have the new idea maybe.
KATALIN KARIKO: And that will work. And then it is just have to enjoy doing these things. And maybe this job is not for everybody. But if you enjoy doing research then, yeah, that's what you need. Anyway, you don't have time to spend money because you are always in the lab. So little money is enough. But of course, it would have been better if some support comes way.
KATALIN KARIKO: I just counted 40-something grant I was not getting. But even writing the grant, I did not advertise to my colleagues. But I love to do that because I had to think through. And I had to read a lot. And it was fun writing grants. Now I can say that. But that's how I felt even when it was not appreciated. But I also not thinking about that those people who are evaluated and said, not good.
KATALIN KARIKO: I always thought that maybe I should do something better, improve. Maybe I did not-- of course, you never have enough background experiment, but maybe not articulated well enough, or something. And I always try to see what I can do to make it better.
JULIANNA LEMIEUX: That's tremendous advice. I mean having any rejection can either bring you down, or you can try to overcome that. So that's--
KATALIN KARIKO: Yeah. Actually, the Uniformed Service University was the only place where I willingly left because all of the other places I was sent away. But every time, it was when you are kicked out or terminated in your position, you just have to think that you have a new opportunity to find, a new job, or something new. And so that's how-- and not to think that much about that there is nothing fair.
KATALIN KARIKO: Of course, that other person is doing less research, and get promoted, or something. Because you have to always focus on what you can do. Because otherwise, you get disappointed immediately. And of course, life is not fair. But we are-- if you are at the bench, you are already a much better position that anywhere on the Earth, somebody. Because you are at-- you can do something.
KATALIN KARIKO:
JULIANNA LEMIEUX: So David Langer told Gina Kolata when she wrote her article about you, Kate's genius was a willingness to accept failure, and keep trying, and her ability to answer questions people were not smart enough to ask. So what do you think is the key to being a successful scientist? Is it what David Langer said or something else?
KATALIN KARIKO: You have to stay curious. You want to know. And if your goal is, I want to understand, how could it be-- and so many enigmatic things in science. So then you are not disappointing when you read something, you are thinking. And you are reading in paper somebody already published. Because you are happy. You wanted to understand. OK, somebody already helped you to understand.
KATALIN KARIKO: So you don't have to do those experiments. If you look at things this way, you are always happy even if people are reporting on what you were doing because you the goal has to be to better understand. And I don't take it that you are working for the company, or working for the boss, or somebody. If you are working on something to understand you put all of these things.
KATALIN KARIKO: And listen, your boss will be very anxious if you want to leave, if you are very good. Because you walk out and whatever is in your head is leaving. So you just have to read a lot. That's it. And then you can make connection between different things because, of course, you can look it up. Everything's on the internet.
KATALIN KARIKO: The knowledge is there. But if it is there, cannot make connection. It has to be in your head. And in whole, in the biology-- in our field is all working on analogies so some analog. There is a similar mechanism. And more you know then more you can think that, oh, there is a precedent for that. And then you can work from that on.
JULIANNA LEMIEUX: I want to share a comment, not really a question in the chat as well from Jean that says, as a scientist, I know it takes a long time to learn about each piece of the puzzle. Everything we learn, including from unsuccessful grant applications in multiple labs adds to the insights that only us older scientists can make. So I think she's sharing some of that sentiment there.
KATALIN KARIKO: So we have to learn from everything. The truth is that I learn more from seeing things, which I said that I will never do that. It couldn't be that way. So from the bad example, also I learn. So even if somebody treated me badly, I remember that I will never say do things like that. And for many other things, when organizing the laboratory, for example. When I left Penn, we had more than 6,000 RNA isolates.
KATALIN KARIKO: And to have everything-- I was a bookkeeper-- to make sure where it coming from, what is-- how it was characterized and setting up the whole system. Because previously, once I realized that people get lost samples because they cannot-- they don't have a system. So again, I set up the system because I have seen the bad example, how people lose things, samples, and other things.
KATALIN KARIKO: So that was you have to-- you learn from everything; good, bad. And if something happen that you lose your job or the experiment is not-- then you just learn from it. And it gives you an opportunity to go somewhere else, to do something else, or improve.
JULIANNA LEMIEUX: Terrific there are a couple of questions about using mRNA for cancer immunotherapy. What are your thoughts on that?
KATALIN KARIKO: So as I mentioned in the presentation, a messenger in-vitro transcribed messenger RNA was mostly used for cancer vaccines. And the first company was Mouritsen out from Duke University was the first one using. And then run clinical trial later, it was called Argus. And then also the Curevac in 2000 was established to develop a messenger RNA-based cancer vaccine.
KATALIN KARIKO: The challenge is that people say, oh, they work 20 years. And if they couldn't figure out how this SARS-CoV-2 vaccine could be good if they couldn't figure out. But for the cancer vaccine, the challenge is that what should be the antigen? So even if different antigens are identified, it's not necessarily that is a driver mutation. And so that's the major challenge. There are so many different mutations out there.
KATALIN KARIKO: And BioNTech, and Moderna, or Curevac, they have programs for messenger RNA-- encoding those neoepitopes so that those proteins that have mutations-- so the amino acid chain and then they could be identified similarly like the vaccine for infectious disease. But it is challenging. And so there are-- more science is needed.
JULIANNA LEMIEUX: Got it. And I mean, we're hearing so much in the news now about the variants, in particular the Delta variant. So one question in the chat asks, what do you think about the effectiveness of the current vaccine against the Delta variant? And what is the plan going forward for what is sure to be more variants?
KATALIN KARIKO: I mean, the data just came out. The BioNTech Pfizer vaccine was 88% effective against the Delta variant. And so as I mentioned, I am a biologist. I am focusing on the therapeutic use of mRNA. And I don't want to sound here like I'm a vaccine expert and an epidemiologist.
KATALIN KARIKO: But we just have to follow the science that-- what BioNTech, and Pfizer, and our scientific leaders are saying, and measuring. Because now that there's so much data is out they are collecting in Israel, in the US. And we understand that the vaccine is very protective still against these variants. And whether the third injection is needed or not it is up to the scientists to decide, who are measuring the different-- and following up the vaccinated people to see whether or how they get infected.
KATALIN KARIKO: But definitely, I got the vaccine. My daughter, my husband, everybody in the family, my sister-- everybody got the vaccine. And it is important for everybody to get the vaccine.
JULIANNA LEMIEUX: Absolutely. I also got the vaccine and all of us who got the vaccine. Thank you very much for all of your work. I want to-- just before I close, I want to end. There's so many comments in the chat about what an amazing talk this was, how it was just wonderful to learn about all the decades of work that have gone into this vaccine, that your background is inspiring.
JULIANNA LEMIEUX: And the curiosity is the mark of a true, great scientist. So thank you, again, for sharing this story with us. And I'll just end by saying that this brings us to the end of our discussion and concludes part one of our Women in Science series. I want to, again, thank Kate and Karla for this terrific discussion, and thank our team behind the scenes for making everything run so smoothly. And I want to thank all of you for joining us.
JULIANNA LEMIEUX: Thanks also to TriLink and the Vilcek Foundation for supporting this event. Please join us next month on Friday, August 13 when we'll be talking to Amy Abernathy, the newly appointed president of Verily's clinical research business and, again, on October 1st when we'll be speaking to Fiona Murray, the associate dean of innovation and inclusion at the MIT School of management. Also you'll be able to find today's event on demand, on GEN's website.
JULIANNA LEMIEUX: For everyone at GEN and the Rosalind Franklin Society, I'm Juliana LeMieux. Stay safe. And we'll see you again soon.
KATALIN KARIKO: Thank you very much. And I just want to say hello to all of the scientists who work hard like me and just keep up with a good job.
JULIANNA LEMIEUX: Thank you. [AUDIO LOGO]
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