Brian Kobilka

Transcription

One on John Hennessy. Stanford's tenth President. And welcome to a wonderful day for the university. This is a wonderful day not only for Stanford. For our medical school and for our faculty. But in particular, of course, congratulations to our colleague, Stanford's new, newest, Nobel Laureate, Brian. He is a professor and chair of molecular and cellular physiology, And you'll hear from him shortly. I'd also like to extend our congratulations to his co-winner, Professor Robert Lefkowitz of Duke University with whom Professor Kobilka shares this prestigious honor. It was a set of collaborations earlier in their careers that started them on this remarkable journey. Something I'm sure Brian will want to talk about. Now, it's, we're holding this in the Paul Berg conference room, which I think is really auspicious. As you know, Paul won the Nobel Prize for chemistry in 1980. And just a few years ago, Andy Fire and Arthur Kornberg won for medicine and chemistry respectively. So today marks our twenty-seventh Nobel, and it is both humbling and gratifying, a tradition of excellence in our research and what our faculty had able to do. Like many discoveries, this work that won the Nobel has evolved over many years. It was here at Stanford that Professor Kobilka was able to build upon the work that helped us understand how human cells read their environment and sense it through mechanisms called g-protein coupled receptors. And, I have to admit that since I take a medicine that uses the g-coupled protein receptor, [laugh], I'm a beneficiary of this discovery. Many in the scientific community thought that his work might be an unattainable goal. But, he managed to achieve it, through hard work, diligence, And over many years, with a eureka like moment that occurred during its discovery, And I'm sure he'll share that with you. The, Stanford's long term commitment to basic science dates back many years, when the medical school was moved from San Francisco to here, and in fact Professor Berg was one of the first members of that newly formed basic science departments in those early days. Today it is the incredible commitment of our faculty researchers that a lifetime dedication to science and discovery that really ensures that we remain in the forefront of scientific discovery and the excitement which we all share today. I speak for the entire Stanford community regarding the pride we have in our medical school, of course in Bryan's achievement and our faculty on this day. I'd now like to turn the program over to Professor Pizzo. Thank you, well, thank you President Hennessy. Of course, it's a great privilege to congratulate Brian Kobilka for this extraordinary honor today. This is a landmark moment. It is interesting to note that just a week ago, we sat in Paul Berg hall with three Nobel laureates on this dais, celebrating the importance of basic science research. And, as I scan the room and look through the faculty who were there, I noted Brian, and wishfully hoped that we'd be here at some point, Not knowing that this would be the day, exactly. This is a wonderful, wonderful accomplishment. As you know, Brian comes to this journey with just dogged dedication. He began at the University of Minnesota. He went to the Yale University School of Medicine. Then actually went to St. Louis Barnes Hospital, Did his residency in internal medicine. And then made the fundamental decision that to improve life, he would dedicate his career to research and to probing some of the basic mysteries of life. And, fortuitously he went to Duke, worked with Bob Lefkowitz, with whom he now shares this great honor, And unraveled, some of the most complex, mysteries that he'll share with you. It was a real tour de force, and it speaks to several things. Endurance, Brilliance, dedication, commitment to assailing the odds because you really passionately believe in something. And I think it also speaks to a person. Everyone in this room who knows Brian I think shares in just great admiration of what a wonderfully kind, generous, humble, thoughtful and courageous person he is. It's a great privilege for us to celebrate this moment with you, Brian, Because you epitomize what's really great about science. And in particular, the dedication of the individual in this era of big science. You speak to the era that really lets ideas mature and find their way into reality. Congratulations, Brian. . So, Thank you, President Hennessy, and Dean Pizzo for those kind words. And, as some of you know, I'm not very comfortable, in doing this. [laugh]. I just want to say that, I'm really fortunate to have, worked with, my co-awardee, Professor Lefkowitz, Bob Lefkowitz, and, to start me on this journey. I also want to say that I really have been fortunate to have my wife as a, as, as someone who's worked with me on this journey since, since those days in, in, at Duke and continues to the present. Stanford has been a really remarkable place. I'm not really sure how I managed to land here, but I, I did. And as I was telling somebody this morning, I think was the only place that offered me a job. [laugh] Foresight, foresight. [laugh] And so, I, you know, being here, you can have ideas which other people might think are crazy and probably, you're not qualified to do. But people at Stanford will try to help you do them. And one of the collaborations that I formed really early on was with Bill Weiss in structural biology, who, who used to, I remember, early days when I would get crystals of salt or detergent, and he would come down and try to look at them and let me down gently [laugh]. So I appreciate that and, and you know being in Stanford you attract really fantastic colleagues, and, and students and post docs And I, I can't tell you how many times I've, I've thought you know, how am I going to hide the fact that I know this kid is smarter than I am. [laugh] And, and, and try to make him think that I know something. But so it's you know, I don't really know what else to say. It's been a, a, it's very big surprise. And I also want to point out that, you know, this, this work that I've been cited for is, Is a, in large part a, incredible collaborative effort. It started, a, a number of years ago, with a collaboration with Rogers and Hari at University of Michigan who's been a long time friend and collaborator as well, and it involved a, a number of people. Collaborations of, with people from Ireland, from Belgium, from you know, across the United States and, and a, and a number of really talented post docs. And I also want to point out a, a really brave post doc Soren Rasmussen, who took on the project together with Brian Devries and, and Rogerson Harslab. So I just want to this, this was a, this was a team effort, and, and I certainly want to acknowledge those people as well. So I'm not sure what else to say. That's nice. . We've got, we've got the opportunity for questions. If you're from a news organization please identify yourself. We'll do this Probably with a hard stop at 10.30. Duke is doing their announcement at 10.30. So. Lisa? Yes, can you explain what you're doing and why it matters? I study, a family of proteins that are important in, transmitting information from one part of the body to the other. So, we, our bodies are really complex clusters of specified cells that are clustered into tissues and organs. And they have to work in coordination with each other. And, you know, your brain is on the top and you have muscles and organs that are in the midway or all the way in the bottom, And there has to be information transfer. And that occurs by some cells releasing small molecules that either gets circulated or released in nerve terminals and then are detected by other cells. And the way they're detected is by receptors, and the large majority of those receptor are G-protein coupled receptors. So there, you're probably familiar with terms like adrenaline, dopamine, serotonin, histamine, all of these compounds are detected by G-protein coupled receptors. We see using G-protein coupled receptors, we perceive odors using G-protein coupled receptors. So there are important proteins that transmit information from outside of the cell, inside the cell. And, we've been very interested in understanding how they work, just because they are, they are, they are so interesting and important and also they are, they are really important targets for, for potential therapeutics, for existing drugs there, I've been, I've heard the, the number around 40-50% of, of current pharmaceuticals work on G-protein couple of receptors. But there are, you know, there are potential for other G-protein couple receptors to, to be used therapeutically and, and so they have been important targets for drug discovery. Then, just to follow up. Of the work that was done at duke, versus the work that was done here, and how does that compare? So the work that was done at Duke, when I joined the lab. We didn't really have any idea what these proteins look like. The, the Lefkowitz group had, had, Had made major strides in, in characterizing them using other tools. But we, we, we didn't, we didn't have the DNA sequence or the protein sequence. And, and while I was there, one of my colleagues, Jeff Benavick, succeeded in purifying a, a small amount of this protein from, I believe it was hamster lungs. And, and then, after purifying this protein, he chopped it up into bits with proteases and got some sequence. A couple peptides sequenced, and from that sequence, we were able to pull out the genomic sequence from a genomic library. And from that genomic sequence, we could deduce the, the amino acid sequence from the protein. So that was the first. First time we really had an idea that there were seven transmembranes and, and in fact, we were surprised that it looked so much like rhodopsin. In, in retrospect, we should've understood that that's what it would look like, but it was a surprise at the time. And. Excuse me, that was all done at Duke? That was all done at Duke. Yeah. And then what, what I've done here at Stanford is try to convert that, that linear sequence of amino acids into a 3-dimensional picture using x-ray crystallography. In the back. [inaudible] Reuters Television. Explain your emotional, physical reaction when you got the call. I guess I wasn't exactly sure if it was real to begin with. And I think everybody has that response. But I was extremely happy. [laugh]. I'm sorry I'm not more eloquent than this. That's okay in the science community this is called going to Stockholm. There was a reference made to your eureka moment. Can you elaborate? Yes, so the eureka moment for, I think that there have probably been a couple of eureka moments in my career but the one that stands out above all others, is seeing for the first time a g-protein coupled receptor in the act of actually signalling. And this is a crystal structure that was reported last year, and when, when we actually saw that, it was amazing and so exciting. What did it look like? [laugh] That's hard to describe. [laugh]. Yeah it's a, well, it's a bit, with, what's really interesting and neat about it is you have a, a plasma membrane and then have our receptor which has seven trans-membranes. And this little molecule is stuck on the top, which is representing a hormone and it's activating this very large molecule on the inside of the cell. So it's, you know, how, how something small can be perceived by this really interesting receptor and transmit that information to, to a cellular protein that then goes on to turn on a regulator, a large number of other proteins in the cell. So, the it was very exciting. David Louie from ABC Southern. What's next on the horizon? I mean, your work is obviously not done. You've got a lot of people invested in, in continuing your research. What's, what's going to happen next? Well, we have several lines of research. One is, what we've discovered. We think is representative of, of probably the largest, the large number of de-protein coupled receptors. But I think you, you have to. We have to go back and make sure that it's, it is representative. So one of the, The projects we've, over the past couple years, we've isolated a number of other G protein-coupled receptor structures So one is a muscarinic receptor and, and, opiate receptors. And, and we'd like to get structures of those receptors with their G proteins. Which are, which are a different type of G protein than the one we've g-got. So, some of that is, you might say it's clean up work, but it's still very challenging clean up work. And, and, and, and we need to know, we hope to learn from that how certain receptors selectively activate one G protein over another. Another area of research that we've just submitted a grant in, and I hope that w-we will get funded is [laugh], is, is to try to take, what we're learning about receptor structure. And, and develop structure based approaches for drug discovery. So we try to take our, our discoveries and. And facilitate drug discovery, using these approaches. Now, this has been done for soluble proteins, but it's still a very big challenge for, for these, these receptors. And then the third area is to, it's a collaboration with Dr. Lefkowitz, and others, to try to understand how receptors activate a non G protein pathway, Which is the arresting pathway. So those are still fairly, There's, there's a fair amount of work to do. [inaudible]. Do you have any words to young researchers and young students? Thank you. I, I. I, I think that first I'd have to say this is a fantastic way to spend your life, In science, and it's hard, but if you're interested in and then you persevere I think you can be successful and it's always every day is, is, is a challenge and, and exciting. And, and, and certainly as you go from being a young scientist to an old scientist you, you, you're surrounded by young people with great idea's and, and enthusiasm and energy, So you still feel young even as you age. We call that the vampire effect, you see. Lisa? Seems that you pulled from several different fields in your research. If you could talk about the importance of interdisciplinary work. This, this was a very much an inter, interdisciplinary project and some of the, Some of the, the efforts, We originally didn't realize how important, they would be. My favorite one is, to, to give an example. We were, we had, succeeded in, in, making very nice preparation of our protein. And, by all criteria, it should have crystallized and it just wasn't. We then, sent some protein to, Georgios Skiniotis, Who is a, young, faculty member at Michigan, Who's a expert in, in electron microscopy. Now, our protein is, is much too small to actually get a structure by electron-microscopy. But we just wanted him to tell us what it looked like. You know, was it cl, you know, all aggregated? Or was it nicely behaved? He told us it behaved very nicely. And then he started looking very carefully. And even though everybody would have told him that it's not worth trying to go further, He did, he went further and, and he was able in fact to get some structural information from it. And he told us why he thought, you know, he provided some information to us that suggested other ways that we might approach this and problems that we needed to solve. So that was you know, that was very useful. Another approach that became very important is the a type of antibody that is produced by camelids. So they, they make a special kind of antibody. They're called nanobodies, And we took advantage of that through a collaboration with Jan Steyaert in Belgium. And the other. A really important part of this was, a, a collaboration with Sam Gelman early on, who helped us develop some special detergents. These, these membrane proteins have to be pulled out of the membrane with, soap-like molecules. And, working with, [inaudible] Soap and, and Sam Gelman, we developed a couple of detergents that, Particularly afforded great stability to the complex. And, and then finally we crystallized this in, in a lipid environment. And that lipid was a special lipid produced by Martin Caffrey in Dublin. And, I am, I am probably leaving out some other really important. But it was, you can't imagine. And, and there were, there were, there were always people who are willing to, To try something, even though they knew that most likely it wouldn't work. Here at Stanford, did you tap into the, multi-, the other disciplines? Again, I'm, I'm really nervous that I am missing somebody. I mean Bill Weiss, who provides great advice about crystallography, and data collection, and processing. Pardon me, excuse me. There are two points in your career that are juncture points. And one of them is when you decided after doing your residency, to join the lab of Bob Lefkowitz, and not pursue clinical medicine. I think, tell us a little bit about that decision and the second which is really so central to everything you've done. How did you keep going when everyone kept saying, or the data kept saying, this is really hard. What was it that kept your resolve in place? Well so the first question is when did I decided that I wouldn't be a cardiologist. So I, I went to Duke with the, and joined the cardiology program, but they had the opportunity to start doing research first, and, and so I started in the lab, and pretty much, I just fell in love with the process and, and the people and, and clinical medicine is, it was, it was very interesting as well, but it's very different in, in, in this respect and I never, I, I, I had to do some clinical work. I decided after about two years that I, I really didn't want to be a cardiologist. But I was forced by my obligation to, to do, the intensive care unit. So, I made a lot of people there very nervous. Because I, I came to the intensive care unit after two years of, in the lab. And, but and, and I did enjoy it. But I, I really decided, at that point, that I wanted to primarily do research. And, and it was, it was not a decision that I made all at once. I think like everybody who has the option to do clinical work, you kind of hold onto it because you're afraid you might fail in research. Mm-hm. So I have to admit that and I think we hope, we try to keep, keep our skills long enough, but I, I, I, did, I, I can, confess this to Dr. Pizzo, right now, Cuz I, I, I continued to do the clinical work while I was here, by moonlighting on weekends. [laugh] To, to, to, to pay the mortgage. [laugh] But, Me too. [laugh] so, you, you, you know, I gradually decided that, once you do, do it, you're not doing it enough, often enough, you feel, you're, you're not as competent as you should be so then you just quit. The other question. Is about the pursuit despite the adversity. So the, the, the answer to that came from a colleague fellow the ethical lab person, Henry Doleman, who's now professor at U, UNC in North Carolina. And he described it as irrational optimism, [laugh]. In that you always think, even though something fails, you'll go home and at the end of the day you'll be a little down. And then you think of an idea. Hm. And it;s, oh this one's going to work. Hm. And, and so you keep. Just thinking that something's going to work. Yeah. That's great. Professor, Jason Bennett, KLIV radio. Can you compare Duke and Stanford? The facilities, the atmosphere. [laugh] Did you just come here for the weather, or is there something about Stanford? [laugh] Did you comment on the football team? [laugh] Well, at, at Duke it, it was. It. It was primarily in one very large lab, the Lefkowitz lab was a well-funded, relatively large lab and, and there aren't very many large labs of that type anyway here. And, and, everything, everything was self contained in that lab. We rarely had to go out for any, any other expertise. At Stamford, the, the, the groups are smaller, but what's particularly interesting about Stanford is that, that the medical school campus and the undergraduate sciences are all together. So in one very small geographic area, you can, you know, cross the street and talk to someone in physics or chemistry or engineering. And that, that was really, I think, very helpful. I remember early on I, I had some problems and I needed some chemistry expertise and I just walked to the chemistry department and started knocking on doors and asking who would know how to do this and I came away with an answer. Well, okay, that specific problem that I was having at the time was to try to make a,, A reagent that helped us to purify our protein. And I, I knew in principle how to do it, but I didn't actually know all the details and, and so. It, it, I really did, I had no idea who over there could help me, but it was easy just to walk over there and find out. I've, you know, I've spent time talking to Dr. Morner on a number of occasions about some, some crazy ideas that. And he, you know, he would entertain some experiments and, and, and give it a try and Dr. Zaire and so. Yeah. I would say, you know, many of these efforts failed but they're still, You know you learn from them and, and, and I think students and post-docs learn from them even, even sometimes things fail. They can be useful educational experiences. I've got time for one more. Or not. [LAUGH]. Thank you very much. Thank you. Congratulations. Good job.