Announcement of the 2024 Nobel Prize in Physiology or Medicine

This looks good. So, ladies and gentlemen, good morning and very welcome to Nobel Forum for the announcement of this year's Nobel Prize in Physiology or Medicine. My name is Thomas Perlman and I'm the Secretary General of the Nobel Assembly. I will first read the announcement in Swedish followed by English. And then we will go on to present background to the prize and open up for questions. So, då kör jag igång. Nobelförsamlingen vid Karolinsk institutet har idag beslutat att Nobelpriset i fysiologi eller medicin år 2024 skall delas lika mellan Victor Ambrose och Gary Rankin för upptäckten av mikroRNA och dess roll i posttranskriptionell genreglering. Och på engelska. The Nobel Assembly at Karolinsk institutet has today decided to award the 2024 Nobel Prize in Physiology or Medicine jointly to Victor Ambrose and Gary Rankin for the discovery of microRNA and its role in post-transcriptional gene regulation. Here are the two laureates a few years ago. Victor Ambrose was born in Hanover, New Hampshire in the US in 1953. The work leading to today's award was performed at Harvard University and he's currently a Silverman Professor of Natural Science at the University of Massachusetts Medical School. Gary Rankin was born in Berkeley, California in the US in 1952. The work leading to his Nobel Prize was performed at Massachusetts General Hospital and Harvard Medical School where he's now a Professor of Genetics. I will now turn to the Nobel Committee Vice Chair Olle Kjempe who will describe the discovery. So please Olle. Ladies and gentlemen, this year's Nobel laureates have discovered microRNA, a tiny molecule that has opened a new field in gene regulation. Genetic information is stored in DNA in the cell nucleus. This genetic information is copied into mRNA and mRNA is then translated to proteins. Proteins are the building blocks that are responsible for major functions in our body. For example, neural function, muscle contraction, absorption of nutrients in the gut and defending us from invading pathogens by immune cells. Different tissues express different proteins with different functions. Since the DNA in our cell nuclei contains exactly the same coding information in all cells, the question is what determines that only the right genes are transcribed into mRNA and then translated into the correct tissue specific proteins at the right time. A first important step in gene regulation is governed by DNA binding proteins, so-called transcription factors, ensuring that only the correct genes are transcribed into mRNA. As a result, the correct proteins are made in each specific cell type. In fact, for many years it was believed that the main principles of gene regulation had been elucidated. The mechanism would, however, turn out to be more complex. For this year's Nobel Prize, an elegant little organism was the key. The tiny C. elegans has been used as a model for more than half a century. The worm contains only 1000 cells but still forms many of the different tissues as humans do, including a nervous system, a gut and muscles. Researchers had previously found two interesting C. elegans mutants with timing defects during development. The lin-4 mutant with that red label as shown on the slide becomes larger because one developmental program from egg to an adult worm is erroneously repeated. In contrast, the lin-14 mutant as shown with the blue label skips some stages during development and becomes smaller. The lin-4 and lin-14 mutants have strikingly opposite appearances and although the genes had not been cloned at the time, Victor Ambrose was able to show that lin-4 negatively regulated lin-14. This year's Nobel laureates Victor Ambrose and Gary Ruffin were intrigued by these phenomena and decided to attack the problem, identify the genes and understand how these genes work. Victor Ambrose started an effort to clone lin-4. Over several years he made painstaking efforts to hone in on the exact position of the gene. To the amazement of Victor Ambrose when he finally cloned the lin-4 gene, it only produced a tiny RNA that could not be translated into a protein. Concurrently, Gary Ruffin subsided in cloning the lin-14 gene which does translate into a protein as shown in the box on the left. During early development of the worm's elegans, the lin-14 protein is made but the production of lin-14 is suppressed by lin-4 during the later stages of development. Gary Ruffin was intrigued when he found that the negative control of lin-14 by lin-4 seemed to involve the terminal segment of the lin-14 mRNA that was not translated. As depicted on the box on the right side, he observed that the lesions of this region abolished the effect of lin-4 and therefore he postulated that the regulation might occur at the mRNA level. The observations by Ambrose and Ruffin were equally puzzling. How could these two so very different molecules interact with each other? As Victor Ambrose and Gary Ruffin knew each other from their days as postdoctoral fellows, they decided to exchange information about the lin-4 and lin-14 genes. On comparing their findings, it turned out that part of the sequence of the small lin-4 RNA matched complementary sequences of lin-14 mRNA in the terminal region that does not code for a protein. They then understood that the binding of lin-4 to lin-14 mRNA prevented the production of the lin-14 protein at the level of mRNA. At this point, they had discovered a novel and unexpected mechanism of gene regulation, microRNA. For a long time, however, microRNA was believed to be an oddity peculiar to cellulose. This perception changed seven years later when Gary Ruffin in the year 2000 identified a second microRNA produced by the let7 gene in the world. Unlike lin-4, let7 was found to be highly conserved and is present in humans and most of the animal kingdom. This finding made the previously dormant microRNA explode. As it turned out, many microRNAs are highly conserved throughout evolution over several hundred million years. In more complex organisms, a larger number of microRNAs have evolved, with humans having more than 1,000 distinct microRNA genes. Today, we understand that the majority of all genes are regulated by microRNAs. Every microRNA regulates several genes, several mRNAs, and each mRNA is often regulated by many distinct microRNAs. Creating a robust system for gene regulation, the seminal discovery of microRNA has introduced a new and unexpected mechanism of gene regulation. MicroRNAs are important for our understanding of embryological development, normal cell physiology, and diseases such as cancer. As an example, tumors often perturb microRNA networks in order to grow. Victor Ambrose and Gary Ruffin have jointly been awarded this year's Nobel Prize in Physiology and Medicine for their discovery of microRNAs and its role in post-transcriptional regulation. I now hand back to Professor Thomas Perlman, the Secretary General of the Nobel Assembly. Thank you very much, Ola. So with this, we would be happy to answer questions. And you've already been introduced to Professor Kjempe, but on my side, I also have the chair of the Nobel Committee, Professor Gunilla Carlsson-Hedestam, and member of the Nobel Committee, Professor Richard Sandberg. We have a question up there first. Yes, yes, please. Second last slide, if you could get back to that one. I wonder how it's possible for the microRNA to get to the mRNA first, so to speak, so that it shuts down this mRNA and the protein is not made. I mean, if the mRNA is made first, then the protein would be made anyhow. And I also wonder what the different cell types, why is the microRNA, a special microRNA, active in one sort of a cell and not in another sort of a cell? Yes, these are quite advanced scientific questions, and I'll turn to Professor Richard Sandberg. So regarding the first question, so we skipped a lot of detail in this presentation, but the microRNA strand is part of a protein complex that finds the mRNA in the cytoplasm, and there it can recruit other proteins that help shorten the polyA tail, which leads to either translational inhibition or mRNA degradation. The second question about microRNA genes, I mean, they are also transcribed, so they're copied from the DNA into their RNA form, they are processed, and that can be done cell type-specifically. So a specific microRNA will end up in a muscle cell, whereas other microRNAs end up in, for example, nerve cells. And because of that, they can have cell type-specific effects on the mRNA. Hey, my name is Steffen Thumm from the German news agency DPA. Thomas, it's early morning in the U.S., so my question would be, have you already reached one of the laureates, and what did they say about being awarded? Yeah, nowadays, it tends to be a little more difficult. People have mobile phones on silent, but I was able to wake up Gary Ravkan. So I think he had a landline, I was able to reach him, his wife answered, and it took a long time before he came to the phone and sounded very tired. But he quite rapidly was quite excited and happy when he understood what it was all about. And he was so enthusiastic, and his wife too, so he handed over the phone to his wife, who also wanted to talk to me for quite a while, and they were thrilled about the prize and coming to Stockholm in December. I was not able to reach Victor Ambrose yet. I left a message on his mobile phone, and hope he gives me a call soon. Hello, my name is Bogum Ratajewski. I'm from the Polish television. A question I have is a little bit of comparison to the last year's Nobel Prize, because last year, with the Nobel Prize for the mRNA, the thing that we are most excited about, obviously, is what it can be used for, not only COVID vaccines, but also the prospect of cancer vaccines and solution to many diseases that we're facing today. So what about microRNA? How does it compare, and what could be the application of the discovery by this year's laureates? Thank you. I think this is a very good question, Professor Karlsson. Yes, thank you for that. So this year's prize is definitely a physiology prize. It helps us our basic understanding of all of the things you heard about, how cells differentiate and become specialized. Last year, of course, much more applied discovery that was translated into vaccine development. So two quite different prizes. But that said, having a basic understanding is, of course, the first step towards developing applications. So although there are no very clear applications available yet with microRNAs, understanding them, knowing that they exist, understanding their regulatory networks is always the first step. So this could still take a while. There are quite a lot of trials ongoing, and not only against cancer, but also in other diseases, cardiovascular, kidney diseases. There are other trials ongoing, but nothing that is very sort of close to an actual sort of application. But we want to emphasize that the importance of understanding the basic functions, and that is always the first step towards using this knowledge. I wonder if you are aware if the laureates have any patents on their discovery, and also if you could describe a little bit more about their collaboration. They were postdocs together, and how are their friends hanging out in the lab, or what's their collaboration like? Well, they were postdoctoral fellows together, but then ran separate labs, and focusing partly on different aspects of the microRNA. So the big findings were from 1993, when the first microRNA was discovered by Victor Ambrose, the lin-4 mutant. And then seven years later, in 2000, Ravkin came with the second. So if there had been any patents, they're no longer valid. Hi, this is Sanlian Live Weekly from China. A following up question about the clinical application, as Professor Hatterson mentioned, because microRNA has been widely used as a research tool to modulate gene regulation. What are the main challenges to develop a microRNA as a drug, or for its clinical applications? Well, I think there are many problems. I mean, one thing is to deliver it to the right tissue. The second problem is, of course, that microRNAs bind several targets. So you very easily get off-target effects if you directly bind to one microRNA. But there might be ways around that. Tumors quite often perturb the microRNA networks, and they can do it by deleting the genes, or by mutating genes that process the microRNA, or they can increase the production of RNA binding protein that binds the microRNA. And in that case, there are promising first tests to see if you can modulate the RNA binding protein. But to deliver microRNAs to cells and think that you get one effect, I think will be very difficult. Thank you. Hello, Paul Rees, Al Jazeera English. If you had to explain in just a few words, as some of us may have to do later, what the difference is between mRNA and microRNA, so that perhaps people don't get confused between this and the last ones. I'll ask Richard Sandberg to explain the difference. Yes. So, I mean, mRNA is the very fundamental intermediate between our DNA and the proteins, and it's sort of this step that carries the information from the nucleus to the protein-producing machinery. MicroRNAs, on the other hand, you know, they are very short, and their primary role is to act as a cell, as its RNA form, where it instead interacts with the mRNAs to tune or quite dramatically affect how, what amount of proteins can be made from it, to degrade the mRNA. So, nothing to do with COVID vaccine? Sorry? So, nothing to do with COVID vaccine at this time? No, not really. Let's see, is there any other question? I know it's as is usual that many are eager for the interview since that after the press conference, but still, if there's any pressing question, there's still time. Anyone would be interested in something? If not, then thank you so much for coming here today, and we'll see several of you at interviews. Thank you. Professor Ulrich Schempen, member of the Nobel Committee, can you summarize what this year's Nobel Prize was awarded for? What it was awarded for? It was awarded for microRNA and the way microRNA is a new layer in gene regulation, creating a network that makes gene regulation much more robust. MicroRNA is a kind of a complex concept for most of us. Could you please explain it a bit more in detail? So, this was discovered, the first microRNA, by Victor Ambrose in 1993, but it was thought to be an oddity, peculiar to a small worm, the C. elegans, for more than seven years, until Gary Rufkin detected the second microRNA, Let7, and then it sort of, the field exploded, and now more than tens of thousands of microRNAs have been identified in different organisms. So, it's been evolutionarily conserved over several hundred million years, and present in almost all animals. So, it must be important, right? And the importance is to create this very robust network, so each microRNA, which is a tiny molecule, binds to several mRNAs. mRNAs is the intermediate between our genes and our proteins, so it takes the information from the gene and makes the protein, but then it's modulated by this microRNA network, and this was a finding that was completely unexpected. No one thought, everyone thought the major problem in gene regulation had already been solved, but it's just the last 10, 20 years we understand there's a different layer that is equally important. How does the discovery affect our daily lives? Well, it affects our daily life in the way that, as researchers, we have a much better understanding how cells work, and we can see that in many tumors, if not most tumors, the microRNA networks are perturbed. So, the tumor takes advantage of this and tries to take away, delete microRNA genes or silence them. We don't have yet any way to treat these disorders where microRNA networks are perturbed, but we hope that someday that will come. It's the knowledge that is important. So, if I understand you correctly, there are no clear medical applications yet, in the future? That's correct. There might be in the future, and there might be special cases. So, some tumors delete the microRNAs, others mutate them, but there are also other mechanisms that, like increasing a protein that is RNA binding, that binds up, and then you can have a specific mechanism to silence that RNA binding protein. So, if we turn to this year's laureates, Victor Ambrose and Gary Rubkin, could you please tell us a little bit about them? Well, they are born 1952 and 1953. They did their post-doctoral experience in the same lab with a former Nobel Prize laureate, Robert Horvitz. But after that, they went to Harvard University and Harvard Medical School, respectively, and set up their own labs and worked on different aspects of microRNA regulation. So, Victor Ambrose was the first one to clone a microRNA, and Rubkin, he cloned the second one, and he was the one to propose that the regulation was at the mRNA level. So, they made a difference, but they haven't collaborated a lot on post-doctoral work as much as I know. But they did actually share some data between them. Yes, they did. And that was the key to this Nobel Prize, that they met and shared information, and could see that the lin-4 gene actually matched a complementary sequence of lin-4-2. And then this concept of a regulation at the mRNA level, and not only at the gene level, was born. And I understand that Thomas Perelman was able to get in touch with at least one of them. Yes, Gary Rutzkin, he answered very early in the morning, I think four o'clock there at time. His wife, in fact, too, according to Thomas, who answered. And, well, I guess his wife became happier than he, but... Looking forward to come to Stockholm. And finally, could you please tell me, 30 seconds, why are you excited by this year's prize? I think it's one of the big Nobel Prizes, because it's a completely new physiological mechanism that no one expected, completely out of the blue. And it shows that curiosity research is very important. They were looking at two worms that looked a bit funny, and decided to understand why. And then they discovered an entirely new mechanism for gene regulation. I think that's beautiful. Professor Ole Kjempe, thank you very much for guiding us through this year's medicine prize. Thank you for having me.