The Pioneer Of RNA Splicing And How He Changed Modern YouTube

We're here at the HP Garage, the Silicon Valley's birthplace, and really kind of the cradle of innovation in America with a great innovator, we have Adrian Cranor, the pioneer of RNA gene splicing, and we're really thrilled to have you here. Thank you for having me. One thing that I love about you, I mean, part of the American dream in this whole package is about the American dream. Immigrants are a big part of the American dream. You're an American immigrant. Maybe tell us a little bit about your back story and how you got here to the point of where you became one of the 250 greatest American innovators. Certainly, yeah, I came to this country 49 years ago to go to college, so I grew up in Uruguay in South America, and as I was finishing my secondary education, I decided to get into research for a career in biology. Genetics was something that interested me. I wasn't quite sure how to do that, but I felt that coming to the U.S. would be the best possible place to do that type of work, and I, of course, I needed to receive the training and education to do that. So I received a scholarship to go to Columbia, and I arrived in the Fall of— So many Americans, new Americans who came to New York from somewhere else, and there you were. Correct, yeah. So, yeah, it was 1977. I arrived at Columbia, and I majored in biochemistry, and then when I finished that, I went to graduate school at Harvard, also to study biochemistry. So that was five years in grad school, and from there, I was recruited to Cold Spring Harbor Lab in Long Island, and that's where I remain. I've been there now almost 40 years. And so it's been a 40-year journey. Walk us through what that's been like. I mean, to work on one thing for a lifetime, it must be both exhilarating but also terrifying. What if you're going down the wrong hole here? Tell us about that journey. That is true. You know, in doing science, you're taking risks, but what keeps you going is the possibility of doing something that no one has done before. It's innovating, it's discovery, you know, really curiosity-driven science. In graduate school, I began to study RNA splicing, and the whole process, the fact that genes have exons and introns was discovered in the year I was a freshman in college. I probably didn't find out about it for another two or three years, but when I started graduate school, I chose that area because it was so cutting-edge and so little was known about it. It's a fundamental aspect of how our genes work, and yet we had no idea, you know, how does this process actually happen? So I did that for my PhD, but then I continued it as a postdoctoral fellow. I took a risk there because I had an opportunity to work independently at that stage to continue what I had done in graduate school. And so that's a bit of a risk. I'm glad they took that risk on me, and I took the risk to try it myself. And although we have remained in that area, we've changed the way in which we study things. We have to evolve to become more multidisciplinary just to be able to answer the questions that our own research and the field creates along the way. And yeah, so the reason I stay with it is because there are still many questions remaining. If we achieve the full understanding of RNA splicing, then I would work on something else, but we're not close to that. We're a long way from there, right? Correct. What were the, on that journey, what were the, there must've been some doubt periods, you know, did I take the right path? Or maybe there weren't, but what, you know, any journey like that, you're gonna have periods. How did you fight through some of those low periods? I never stopped being excited about the science. I mean, some questions maybe were harder to address than others, and so then we changed our focus slightly. You try to do what is, what seems feasible, although I generally find that I don't want my lab, you know, to just try to answer the easiest questions, but rather to challenge ourselves. If you do what, we don't wanna do what many other people are doing, what's the point? You know, we try to do something different, and either you have to come up with very unique ideas and, or try something that other people are afraid of doing. And so in that sense, you have to take those risks. And then what were some, what was your highest moment when you were kind of on this journey, and you're like, wow, we might be able to change the world here. There must've been like kind of a reckoning at some point. There were many, because when you discover something that nobody knew and, you know, okay, this is how this part of it works. And so then, of course, you got to write a paper and present it at meetings, but there are some bigger incremental steps like developing a drug that works. And well, how do we know it works? Along the way, for instance, we do experiments in animal models of disease. And then you see that, you know, these animals instead of dying, now they live and they run around. So clearly this drug is working. Now we have to take it to the clinic. And then, you know, of course, with collaborators and industry and clinicians, then clinical trials are done. For Spenbraza, which we worked on for spinal muscular atrophy, these clinical trials lasted five years. So there's a lot, you have to be very patient along the way, but there were strong indications along the way that this is likely working. Until at the very end, when a control trial was unblinded and the data and the control data were compared, there was no doubt that it was working. So that certainly is, it's different from a Eureka moment that's based on science. Those came earlier, but there is the proof that it actually can save lives and help people. And listening to this kind of trial and error, do you consider yourself more a scientist or more of an inventor? Yeah, I think a scientist. You know, when I think inventor, to me it was kind of abstract, but I was always picturing something like what I'm seeing here now, this garage. And I never could work on RNA splicing in my garage. Let's put it that way. I don't think it's quite, we don't have the hermetic ceiling here. Yeah, so I view it more as a scientist, you know, researcher. So talking about being a researcher and a scientist, you talked about the relationship with academia and corporal in the private sector. What are your learned experiences there? Because listen, we're sitting here, again, talking about this garage. We could walk to Stanford. It's not a coincidence that this garage is here. Yeah, absolutely. I mean, I think there can be and there should be a very intimate relationship between academia and industry. In my case, that's biotech and pharma. And the development of Spinraza, a drug to treat spinal muscular atrophy, I don't think could have happened in my life alone or in industry alone. My collaborators were Ionis Pharmaceuticals in the early stages and then Biogen in later stages. We just had complementary expertise and way of looking at things. And I think, you know, industry knows that they depend on academic discoveries for fundamental signs that people can't really predict necessarily. And then industry has more experience in drug development. And so it's, you know, it's good complementarity. Of course, that also depends on relationships among the individuals involved. And then it's not just the scientists who are interacting. It's also the, you know, the business people, the legal people, academic leaders. And those relationships can be good or bad or somewhere in between. No one has to kind of work on them. I think now there is a realization of how important that is. And so there's more experience and most universities have tech transfer offices with people who are very experienced in managing those relationships. Breakthroughs, you know, certainly in health science, sciences often take decades as your proof of how do you stay motivated over that long journey? This is not as if you're a true marathoner and how do you keep that going? How do you keep that innovative drive going? It's because of the excitement along the way. At any given day, I feel that we're trying to, we're working towards a short-term goal as well as long-term goals. Yeah, mini milestones as well as long-term. Yeah, so there's many mini discoveries along the way where you realize, okay, we learned something that nobody knew before and then you write it up. And of course, you know, we spend a lot of time managing and trying to raise funding to do the science and, you know, that's the necessary part. It's increasingly taking too much of our time, I think, but it's, and we're thinking and communicating and trying to come up with new ideas. And so all of that is exciting. Any journey that's worth taking has its skeptics. How did you filter those out or how did you deal with that? You know, sometimes we had competition, people who think, you know, our answers may be wrong. And so we, I mean, if we're wrong, we're wrong, but if I feel that we're right, then we have to kind of go back and obtain additional proof. That sort of took us off on tangents sometimes, but then I think people respected what we were doing when it came to trying to develop a drug for spinal muscular atrophy, but they thought it was a long shot. And I wasn't offended by that. I knew it was a long shot. We had no certainty that it would work. We just felt like this gets at the root cause of the disease and it's a logical approach and we need to try it. There's many obstacles along the way. And I think one way I usually manage that is, okay, maybe we do part A, and then what follows is currently viewed as impossible. But at some level, I feel that maybe it's not impossible. It may seem that way today, but when we get to that point, maybe there will be an obvious solution or we will be able to figure one out. So you take the steps. And I think it's partly based on my belief that everything has a solution. Everything has an answer. It may be very difficult, but it's generally not feeling like, okay, we got to this point and it's impossible and no one will ever be able to do this. I'm not saying that there aren't cases like that, but I tend to not think in those terms. Yeah, you never felt that way, but did your funders ever feel that way? What were the moments where it wasn't so clear that you would get the money to achieve what you've achieved? There's a cyclical nature to that. I mean, generally I've been pretty lucky getting funding. Currently it's a little bit tougher. And if you don't succeed with one source of funding, you try another. The reviewers may be looking at the same thing and one could be very positive, one very negative. You just have to keep trying. You're sitting here in a lab developing these things and then you get breakthroughs and they actually start helping humans. What was the first moment where you actually saw the human side of what you have discovered? Yeah, so I started working on SMA in 2000 and the drug we helped develop was approved at the end of 2016. But during that entire time, I was interacting with families and patients and their parents, going at least once a year to a meeting where you interact with clinicians, researchers, but also the patients and their families. So you know what the need is. And it's very motivational. And I do remember that early on, one parent said, we really thank you for what you're doing. It almost doesn't matter as much if your particular approach works, but you're giving us hope and that's worth a lot. So that really touched me and it sort of gives you extra motivation, no doubt. Right now we're in this incredible, you know, we're in this, again, this incredible place at this incredible time with AI emerging as a dominant technology. How do you see it affecting what you do? Yeah, well, we're at this sort of inflection point. I've realized that, you know, this is something that we should make use of and we're beginning to do that. And of course, it's not what I was trained in, but already in the last 20 years or so, I've been adopting multidisciplinary methods and the way you do that in part is by collaborating with people who have that complementary expertise. It can be very mutually beneficial and synergistic. Sometimes trainees come like postdoctoral fellows who for their previous studies, they bring in that expertise. And so again, there's a trade off of, they learned from our lab about RNA splicing, but they may bring in expertise, let's say in AI. Hopefully that's going to be happening. And yeah, I mean, I think it's something clearly that we have to adopt. Well, you mentioned trainees. What traits over your career have you seen that best serve innovators? I think curiosity is very important, but passion, you know, I never feel that I have to tell some, if I have to tell somebody and I never do, you're not working hard enough, that's just not the way to proceed. I mean, they have to have their own motivation. Hopefully I have chosen my trainees well enough that I never have to push them in that sense. You can guide them in what they do, but the passion, the inner passion to answer questions and to advance the research comes from them. Okay, so it's how they're wired. What habits have you seen over the years, both in terms of what you've done and in terms of who you've trained that you think make for great innovation? Well, there's creativity. I think there's persistence. You know, one could think of that as being stubborn, but I think it's important to persist, you know, just being receptive to other people's suggestions. So there's stubbornness in the sense that, yeah, you will persist on something that's very difficult, but it would be not a good trade if you just don't want to take people's advice or suggestions. You know, you have to consider that. We'll talk about, again, we're here at the Hewlett Packard Garage. You mentioned trainees, you mentioned teams. How do you, you know, I think the idea of an inventor in a laboratory by him or herself is a cliche, but most of the great breakthroughs, of course, are team-based. How do you get a team to work together towards a single goal? Yeah, I mean, I have known a few examples of people who worked by themselves or almost by themselves. And in my own institution, you know, Barbara McClintock was somebody like that. I think she was, you know, so far ahead of everybody else in her thinking. And I mean, she had occasional trainees that she could work with, but mostly it was herself in the fields. You know, she worked with corn genetics. I haven't worked in that way. I mean, I think what my team has is that people are interested in some of the same questions. You know, they joined the lab because they're interested in RNA and RNA splicing. Some of them are interested in genetic diseases or cancer. And so there's a commonality. You know, we have team meetings, you know, lab meetings every week. One person presents, everyone has their own project, but there is enough of a conceptual overlap that they're very interested and passionate about what their teammates are doing, their lab mates, and they can contribute to it with ideas and discussion and questions and so on. So it's, I mean, I think our group meetings are very exciting and it's something I always look forward to the next one. What do you hope that history says about what you've done in terms of RNA and just all the breakthroughs in general? That's not something I think about too much, but I think that recognition has come because of the impact on a particular disease and just the timing of when that happened. It was the first therapy for that disease, which was the leading genetic killer of infants. And it was also a way to change gene expression. And it was the first time that a drug was approved to do that in neurology. And so it was, I think, a milestone, but it also immediately made it obvious that there's lots of other diseases where we could use this platform, this general approach, and that has been happening. Tell, what do you, speaking of history also, you know, we're at a period, for whatever reason, where there's more skepticism of science than there has been last few decades. What's your take on how we turn that around? Yeah, I mean, these are difficult times. I mean, I do think the public at large, and I speak to many different people from many different walks of life. Certainly in biomedical science, everybody's interested in that. Everybody has to deal with issues of, you know, health and disease and aging and cancer. And, you know, it affects people, it affects their loved ones, their friends, family members. So I don't think it's that difficult. If, I mean, I think education is very important information, you know, to have access to accurate information. And so, you know, as scientists, we can't just spend all the time in the lab. We also have to communicate about what we do and explain it. It is challenging when you work on various esoteric topics, but people want to know, and so we owe it to them, especially since we do research that's funded by the taxpayers. You know, it's our obligation to communicate that. And hopefully some people do it effectively enough that the public remains interested in science. Well, so you've been working on this for 49 years. Where do you see us in 49 years from now? Well, clearly there's going to be amazing advances. Sometimes, there's some things that proceed not linearly, but exponentially. And other things, it's a little unpredictable. You know, I was thinking about that, that, you know, so going outside of biology, but aviation, you know, we, you know, its first flight was, I think, 123 years ago. And so it's amazing. Okay, we've gone to the moon and back, but on the other hand- We went to the moon 60-ish years after we first took off. Yeah, and then it's been, yeah, I don't understand. You know, by now, we should have done a lot more if the will is there. And, you know, I came to this country in a Boeing 747. You know, the airline doesn't exist anymore, Pan Am. But, you know, that plane was, I don't know, seven or eight years old, but there are still some of them flying. And okay, it's no doubt a great plane, but it seems like we should have gone a lot farther in terms of air travel. Yeah, and so in different disciplines, that's also true. I mean, in biology, we've made amazing strides, but- What would be our best case scenario? What would be your dream for us in 49 years based on where you see where we are today in your field? Yeah, very effective treatments for cancers of all types, certainly treatments for many different genetic diseases, precision, personalized medicine. That's not only science. The science, there's already things that are possible to do with science, but then in practice, things are expensive. You know, who pays for it? You know, there's also social aspects, you know, economics. You know, there's many things that have to come together. The scientists have the obligation to kind of push this forward and it's happening. And, you know, of course it could happen faster and that requires investment. You have a better seat than almost anybody. You know, it's a question probably to ask the most in science, which is, you know, when can we get a cure for cancer? Is that a realistic goal in the lifetime of some of the folks? Yeah, I believe so. I mean, I think some major advances have been made in ways that aren't necessarily innovative. You know, with existing tools, you know, you can find more effective combinations, et cetera. And, you know, in certain cancers, there's been a lot of progress. There's a few where people were dying not that long ago and now it's much more manageable, but there are amazing approaches and therapeutics being developed. And then there could always be an unexpected discovery. It suddenly gives a solution that, you know, nobody could think of and it could come from where you least expect it. And we always have to be ready to capitalize on that. So I do feel that those solutions are possible. We just have to get there. Well, that might be a nice ending question for us in that, you know, if you look at this list of 250, if I had to look at one trade that kind of unified its optimism, it's the idea that we can solve. What is the one thing that makes you the most optimistic about the near-term future of American science? I think that they're amazingly bright and innovative people. And I, in particular, maybe I'm biased because I was an immigrant. I like that it's also people coming from all over the world with different perspectives. They have the opportunity to, you know, settle here and contribute to science. Some are coming for just training and then they go back, you know, some stay. It's the interaction among all these people working towards common goals. I feel that the sky's the limit. Well, from the days of Alexander Hamilton, America has drawn the best and brightest to do some of the best things. And you're a member of that club. We appreciate your time here in this place of innovation and this time of innovation. And thank you for all you've done for our country. Thank you for having me.