 Again, I want to welcome everyone and thank you for being here this afternoon for this very special event at NCSSM. We're so honored to have Dr. Francis Collins here with us today and spending the better part of a day with us, including the lecture this afternoon. I also want to welcome Dr. Collins family who is here today and other special guests Dr. Lou Muglia and Dr. Sam Houston from the Burroughs Welcome Fund who are here with us today as well and in particular I want to thank one of our outstanding seniors, Sellers Hill, for inviting his grandfather to join us today here at NCSSM and also thank Dr. Sheck for all of her work in helping to organize today's event, this very special event. So Sellers is going to provide the introduction for his grandfather so I'm not going to say much in the way of introduction other than to say how honored we are to have one of our country and the world's foremost scientists with us today at NCSSM. Through his research career and visionary work in leadership at the National Human Genome Research Institute where he helped lead the Human Genome Project and his leadership of the National Institutes of Health which is the world's largest supporter of biomedical research. Dr. Collins' leadership and work over his career has been responsible for some of the most important scientific undertakings of our time. So this is a very special event to have Dr. Collins here to speak with us today. So again I want to thank Sellers for inviting his grandfather to spend the day with us and for Dr. Collins for being here today and at this time I'd like to invite Sellers to come to the podium to introduce his grandfather so thank you. On paper Dr. Francis Collins is extremely accomplished. Paper as I should say, his EV spans 67 pages featuring numerous superlative accolades, New York Times bestselling author, director of the Human Genome Project, director of the National Institutes of Health and Presidential Medal of Freedom recipient just to name a few highlights. But understanding Dr. Collins' career requires little more than basic punnett squares. When you cross his mother a playwright with his father a folksong collector and drama teacher it's uncommon to get a geneticist. And uncommon his upbringing was, Dr. Collins was born on a farm in the Shenandoah Valley the youngest of four boys with 18 years separating the oldest from youngest. He was homeschooled without a defined curriculum something he credits for igniting his love of discovery. Skipping two grades Dr. Collins arrived at the University of Virginia as an Echol Scholar at the age of 16 earning his bachelor of science degree in chemistry four years later. From there Dr. Collins traveled to Yale University earning his PhD in physical chemistry while working as the sole source of income for his wife and daughter. Now if you're listening closely you'll recognize that physical chemistry is not genetics. While Dr. Collins was studying at Yale a course in biochemistry sparked his interest in the chemistry of DNA and RNA and after some consultation Dr. Collins returned to the south turned his doctor and medicine degree at the University of North Carolina Chapel Hill as a Moorehead Cain Scholar. After residency in internal medicine he actually returned to Yale again as a fellow in genetics where he worked to develop the technique of chromosome jumping a method that would be used to help identify the causative genes in myriad diseases such as Huntington's disease, cystic fibrosis, neurofibromatosis, and Hutchinson-Gilford progeria syndrome. Fast forward a few years and Dr. Collins was directing the Human Genome Project, an ambitious international undertaking with the goal of mapping the entire human genome within 15 years. On April 14th, 2003, 13 years after it began, the project was declared complete ushering in a new era of genomic research and precision medicine. Today, Dr. Collins is serving as the longest standing NIH director, first appointed by President Obama in 2009, but remaining in office under the Trump administration. As the head of the largest biomedical research institution in the world, Dr. Collins also holds a unique position at the intersection of science and politics, but with his unanimous Senate confirmation as proof, Dr. Collins has remained a champion of bipartisanship year after year testifying to preserve the multi-billion-dollar NIH budget while nurturing cutting-edge research, ending NIH support of research on chimpanzees and working to address sexual harassment and gender disparities at NIH institutions and in STEM fields. And although he obviously excels in science, when you look closer, it becomes clear that Dr. Collins's musical DNA was indeed preserved. Dr. Collins is as comfortable on the piano and guitar as he is with the DNA sequencing machine. I would also hope that he's equally as comfortable on the red Harley-Davidson motorcycle on which he enjoys cruising through Bethesda, Maryland. Still in touch with his humble roots, Dr. Collins holds family and faith as closely as he holds science, a position that sets him apart in religious and scientific spheres alike. However, even with his basic success in academia, Dr. Collins demonstrates that nobody is perfect. He will be the first to tell you that in college he received a single B. In drama, students, please welcome me in… please join me in welcoming onstage Dr. Francis Collins. I've been introduced at a lot of presentations over the course of several decades. This is the one I'll remember the most. Thank you, Sellers. That was remarkably articulate and warm and captured, yes, quite a lot of the things that I might otherwise have put into my talk, but maybe I'll put them in there anyway. And it's particularly wonderful to be able to be here at this school, the North Carolina School for Science and Math, and to have with me some family members, my wife, Diane Baker, who came with me from Washington last night, and my daughter, Sellers' mom, Dr. Margaret Collins, sitting in the front row as well. Yeah, we figured we all make this into a special family occasion as well as an opportunity to get to know some of the amazing students and faculty in this place. I think I was here about 23 years ago in the middle of the Human Genome Project when things were going hot and heavy. I couldn't actually find the evidence for that, but I'm quite sure I remember some of the buildings and some of the people and remember thinking what an amazing place it was. But it's come a long way. This part wasn't here then. You've actually upgraded quite a bit, but the chance to be able to talk to you a little bit about what's happening in biomedical research is just really something I've been looking forward to. And I will tell you right now, I am unabashed and hoping that I can lure some of you into careers in this area because the time is now. We are in the century of biology, and we are at that point in the century now starting a new decade where some of the things that I would not have dreamed could be possible in my own lifetime are becoming realities. And I want to tell you about a few of them. First of all, I want to just say a little bit about my own background. I'll extrapolate from where sellers left off because I think oftentimes people are interested in knowing how did you get through this particular trajectory and end up where you did. And I know all of you who are currently looking forward to your own pathway, maybe feeling a little unsure about that and think you should have it all figured out, let me tell you a story about somebody who didn't have any of it figured out at all, and that would be me. So that's me. That's maybe eight or nine years old standing at the front gate of the farm in the Shenandoah Valley where I grew up, and then a little bit older trying to look sophisticated playing a guitar, hoping that somebody would want to listen to that, especially if they were somebody of the opposite sex. It didn't work out all that well for a while. Scientifically, I got turned on by chemistry in 10th grade by a remarkably talented, okay, maybe that wasn't the best juxtaposition. It is all about chemistry, you know. The chemistry majors loved that one, I can see. Anyway, yeah, chemistry seemed like the science that I wanted to do because it was so impressive in terms of what you could figure out. It was principle-based, it was elegant, it had mathematics along with the physics. Life science, on the other hand, seemed totally descriptive, boring, had nothing digital about it. At least that was my impression when I was studying this at your stage, and so I ignored biology totally. And I went off to get my undergraduate degree at the University of Virginia, and I majored in, you got it, chemistry, and love particularly the physical chemistry part more than the organic. I didn't take any biochemistry and went off to Yale to get a PhD in physical chemistry, and that's where, as sellers told you, to my surprise, I encountered that there was a chemistry of life. It was called DNA and RNA and protein, and I totally missed that, and it was incredibly exciting. And it seemed as if it was on a path towards a lot of discoveries happening that I might want to be part of. So how to preserve that pathway was a bit of a dilemma, but it was ultimately, it made sense to me to try to keep as much of my own options open as possible to go to medical school. Now, why that got me into medical school with that kind of answer to an admissions committee question about why do you want to be a physician is still a little bit of a mystery, but it did apparently succeed. And there I fell in love with medical genetics, the idea of bringing together the study of DNA, this wonderful information molecule with human illness, and I felt the sort of sense that something was going to happen here that would be a remarkable trajectory to be part of. So I did my medical school, I did residency, then I went back to Yale to learn more about the bench aspects of being a molecular biologist, and then ultimately ended up on the faculty at the University of Michigan. And my lab was engaged then in trying to use the tools, rudimentary though they were at the time, of identifying the causes of genetic diseases that were currently really not understood at all. And that was a tough job. There was no genome project, well heck, there was no internet, hardly, there was certainly all kinds of difficulties in finding out anything about DNA that somebody hadn't already worked on, which was most of it. And so trying to explain to people why it had taken several years, and we still hadn't found the cystic fibrosis gene, led me to go and have my picture taken in a haystack in Michigan holding up a needle saying get it, it's like finding a needle in a haystack, except it's even harder because the needle kind of looks like the haystack, it's all DNA. Ultimately though, that kind of worked. And in 1989, 30 years ago, working with another lab in Toronto, our two labs collaborating together did find the cause of cystic fibrosis, just three letters out of three billion that were missing as the common cause of this disorder. We went on and used the same approach to find cause of Huntington's disease, neurofibromatosis, and more recently, a disease of premature aging called Hutchinson-Gilford Progerius Syndrome, which has been a passion of mine now for the last 20 years, and for which we now have some effective treatments. But going back again to the 1980s when we were trying to do this, what you'd call positional cloning, finding a gene by its position in the genome without knowing what it was going to look like, it was brutal. It took years, it cost an awful lot of money, it burned out a lot of students. If we really wanted to do this for the hundreds of diseases that were waiting for that kind of information, we had to have a better baseline to work with. We needed a research tool called the sequence of the human genome. So the human genome project actually had this as one of its major arguments. We need to be able to do this kind of thing at scale. And reports got written, and sure enough, the human genome project got initiated in 1990. The initial leader, Jim Watson, none other, Watson and Crick, what an amazingly wonderful sort of poetic way for the discoverer of the double helix in 1953 and now become the leader of the human genome project in 1990. And so Jim managed to sort of get the process underway. And then Jim kind of had his ability to offend almost everybody. And after a while, when he called the NIH director, that would be Bernardine Healy, there on the left, a lunatic in front of an open microphone several times, he was gone. And I said, what? I'm having a great time in Ann Arbor. I love the chance to be doing this kind of research. Yeah, I'm a big fan of the genome project, but somebody else should lead it. I'll talk to you, but my mother told me one thing I should never do is to become a federal employee, and that's what's required here. So I thought about it, and then I said, no. She called again, and in the interim, I kind of thought about this. Yeah, it was inconvenient. This was not part of my life plan, but there was only going to be one human genome project. And it was very controversial at the time, and most people predicted it was going to fail. But to have a chance to actually steer that and to say no, because it wasn't convenient, it wasn't the right time, ultimately, that didn't make sense. So I said yes. And I moved my lab and all of my other enterprises from Ann Arbor, Michigan, to Bethesda, Maryland, and began the process of trying to figure out how to make this dream come true, because we had promised that in a 15-year period, by 2005, we would have a reference sequence, all three billion letters of the human DNA instruction book. At the time I arrived in 1993, we could maybe sequence a couple thousand base pairs of DNA on a good day, and you got to go to three billion. We kind of figured out if this was going to work, you had to build up the technology. You had to practice on simpler organisms with simpler genomes, but ultimately you would have to be sequencing a thousand base pairs every minute, 24 hours a day, seven days a week, if you were going to actually get this done. And this one slide represents 13 years of the lifetime of the genome project, and most of it things that were totally consuming for me. One of the things we did with the genome project, probably hard to see that, I'll tell you what it says, is to have an ethical, legal, and social implications program. This is one part of science where we decided we weren't going to wait until some future point to think about the ethical consequences. We were going to think about them now, and invest in them now. And that paid off nicely in the sense that we now have laws in this country that prevent genetic discrimination on the basis of health insurance or employment, and many other things as well. The real sequencing of the human genome didn't get started until 1996. We didn't have the technology that was ready. But one of the things we decided that year, and this in many ways when historians write about the genome project, might be the most significant thing they say, is we decided the data has to be given away. This is not the kind of database that you're going to hoard or patent or keep to yourself. We decided we were going to give away whatever DNA sequence on the human had been derived in a 24-hour period, put it up there, so that people can start working with it. That kind of idea that it's just not ethical to hang on to what should be our shared inheritance was accepted, embraced by all the people working on this project, and it was unprecedented at the time. We weren't going to publish anything about this for several years, because there wouldn't be enough to say about the whole genome. But as soon as we had useful data, people should be able to start working with it. Finally, we had a draft of the human genome and the year 2000. Published some papers about that in 2001. And in 2003, all of those goals of the genome project were, in fact, completed two years ahead of schedule. That was good. $400 million under budget. That was really good. Congress liked that part a lot. But where were we at this point? Sure, it had been an amazing ride. And we now had, in a public database, this 3 billion base pair sequence, a reference sequence derived from some anonymous donors. But we're all different. We need to understand what the differences were. And we had to understand how this worked. Only about 1.8% of the genome coded for protein. How about all the rest? What's it doing? It must be really important. So we had to manage to come up with a lot of other public projects that would inspire an understanding of what the human genome functionally was really doing. This whole enterprise, I've got to say, would never have happened without the contributions of scientists from six countries, 20 institutions. Essentially, I ended up as the project manager for a project of 2,500 scientists. And nobody worried too much about who got the credit. We just were going to make it happen. And it had to happen for all of the chromosomes at the same time. So now, here we were with that sequence trying to figure out how to make it useful. For me as a physician, I really didn't want this to be the outcome where people are going to have genome sequence going, I don't know what it means to you. So we had to do other things. All the projects that you see here, each one of which could be a long discussion, were other projects that we mounted in the aftermath of the success of the genome project to provide further information about how to interpret it. And that effort goes on today. So I had another five years of leading the efforts to identify these kinds of projects and make sure they got going and that the data was high quality and it was accessible to everybody. And then I got restless. It's like, OK, I've been doing this for a while. Maybe there's something else I'd want to do. So I took a break. I said, I quit. They gave me a nice party. They took up a collection that allowed me to design my own guitar. You will notice that guitar does have a double helix on the fretboard. Yes, and that is mother of pearl. And that was pretty nice. I got to ride my motorcycle more with my wife, which had been sort of not getting a whole lot of use for a few years. And I wrote a book about precision medicine or personalized medicine, trying to forecast where all of this study of the genome might get us to if we applied it to clinical purposes. I think that sold about 32 copies. But I'm sure those people enjoyed it thoroughly. And then, to my surprise, I got called back to NIH. By President Obama, who, after his election, figured he had to identify somebody to run the place. And I was asked to consider nomination. And after long conversations around the kitchen table with Diane, I decided, yes, how do you say no to this? And maybe we could do this together as a couple, try to manage the way in which NIH could be not just a government institution, but also a place that cared about people, cared about families, cared about all of the things that aren't just the hard science. And that's what we have done. And to my surprise, thinking that I would be done with that after eight years, I was asked to stay on by President Trump. And so now, 10 and a half years along, continuing to have this amazing responsibility and opportunity to try to steer the largest supporter of biomedical research in the world, the National Institutes of Health. Now, NIH, most of you know a little bit about, but let me just remind you, has really two kinds of missions all built into one statement here. Part of it is fundamental knowledge, basic science. And the other part is the application of that knowledge. And our funding is about 50-50 in each of those areas. And oftentimes, the fundamental knowledge is what leads to the breakthroughs 20 years later. If you don't invest in the fundamental knowledge, you won't have those breakthroughs. So it's a wonderful way that this kind of fits together. And we work with lots of other partners, and we work with industry and advocates and foundations to try to make sure, both domestically and globally, that we're doing everything we can with every dime that we have, which comes, by the way, from you and your families, because NIH is supported by the taxpayers this year to the tune of $42.6 billion that we have the ability to spend. And we want every bit of that to be spent on the best science. We have the most rigorous peer review system in the world to make sure that happens. We do some research in our own laboratories there at NIH, primarily in Bethesda, although some of them are nearby here in Research Triangle, the National Institute of Environmental Health Sciences is part of NIH's intramural program. But most of our money goes in grants to institutions all over the country. And when you hear about a breakthrough in biomedical research in a university, whether it's Stanford or Duke or the University of Chicago or anywhere, it's extremely likely that that was supported by NIH. We also do a lot of training, including training graduate students and postdocs. At NIH, we have post-baccalaureate students who come after college and spend a year or two in full-time research. We take summer interns, by the way, the summer internship program for NIH is now open for applications. If you're interested, just go to the website and see what the application looks like. We do a lot of communication of medical information. Our websites for medical information are amongst the most heavily traveled in the world and we make sure that those are actually evidence-based because there's a lot of stuff about medical care on the internet that's not evidence-based. And we do pretty well in terms of supporting the best and brightest scientists. We always keep track of how many Nobel laureates have done their work supported by us. And every year we get to add new ones. This year, the Nobel Prize in Physiology or Medicine, which was for this remarkable work understanding how cells sense the presence of oxygen and what to do about it. Well, two of those, Bill Kalin and Greg Zamenza, are NIH-funded for long periods of time and are good friends. Even in economics, two of the economics award winners for the Nobel were also NIH grantees. So if you're looking for examples of people who have done well, you will often see how they got NIH to support them and we're proud of that. But more than that, we've contributed to the overall improvements in health in this nation and across the world in substantive ways. This is a longevity curve, which just goes back to 1970. If I went further back, you would see that the survival 100 years ago average was about age 50. And now we're up to close to age 80, although I will have to tell you the last few years we've been actually losing ground. And it's primarily on the basis of the epidemic of obesity combined with the epidemic of opioid abuse and opioid overdose deaths, which is heartbreaking. But look at what we've done in terms of things that we've made advances with cardiovascular disease, which used to be the cause of deaths of many people in their 40s and 50s now falling more than 70% in the last 60 years. Cancer death rates falling steadily over the course of the last 20 years, now about 30% down from where we were in 1991. And those of you in this audience who are students probably do not have that experience that many of us did of thinking of HIV as such a death sentence, but it was in the late 80s and early 90s, you were lucky if you survived a year after an HIV diagnosis. And now a positive HIV test means you better find a way to get on therapy, but if you do, your survival is gonna be pretty much the same as it would have been anyway. We need to, by the way, figure out how to cure the disease so you don't have to take those medicines all the time and we may get there, but at the moment, it's still a remarkable story. So that's going well. And I could tell you across many different areas of research right now of many exciting things that are happening in almost every field from basic to clinical. But I thought it would be fun in this audience, since again, I'm trying to recruit you to work in our workforce and that means something that maybe would inspire you could happen in the next decade or so. I asked sellers if you all would recognize what that car was, because I was a little afraid I was dating myself, but apparently you all have heard of Back to the Future, so yeah, that is the DeLorean that was so prominently featured in that film. So we're gonna go back to the future or actually just to the future and say what are some things that could happen in the next decade that you would find exciting? And I could pick about 25 ideas, but I'm just gonna pick three. And one is basic science and one is about prevention of disease and one is about treatment of disease. So let's start with a basic science one. And it's the brain. The human brain is the most complicated biological structure in the known universe. You have 86 billion neurons between your ears. Hopefully they're all functioning right now. And each one of those on the average has a thousand connections. So this is an incredibly complex system and yet we are just bold enough to think that in the course of the next 10 years we're going to figure out a lot of how it works, how those circuits in real time do amazing things like interpret incoming information, like allowing you to initiate some kind of motor movement and have it go the way you want it to. Or laying down a memory and retrieving it. We're gonna figure all that stuff out. Maybe even consciousness, maybe. People will debate whether that's likely or not. And a lot of this is building new technology. So we have recruited a whole bunch of engineers to come and join this effort. Here's an example of one of the technologies where you can take a brain, in this case it's a mouse brain, and you can render it optically transparent by basically moving all of the lipids out of there with a nice bit of chemical trick. But you retain all of the anatomy in a very detailed way. And you then stain it, in this case it's been stained with something that doesn't actually light up all the neurons because then it would be too busy, but some of them. And you can image it and then you can use your appropriate three dimensional way to travel through it. This is a mouse, a normal mouse brain where you're seeing only a little bit of the complexity. And imagine that what that would look like for a human and that we might actually be bold enough to think we can start to understand what all those cells are doing and what all their connections allow them to do. This is the kind of thing that we're on the path towards achieving. Let me show you another example that I think is a little bit breathtaking, but it's the kind of thing that we're now able to do. People who have really awful epilepsy, who have not responded to drug therapy. Sometimes the only thing left is neurosurgery where you try to identify the exact place in the brain that is triggering that seizure and then figure out how you could go in and ablate that with some sort of a surgical procedure. But you don't wanna get the wrong spot. So people in that situation are often put in the hospital, the skull is opened, electrodes are placed at high density across the whole surface of the brain and then they're there for a few days waiting for a seizure to happen so you could see exactly what happened. But these are people who can also be approached about would you like to take part in research so we can see what your brain is doing when you're carrying out a certain activity. And here's an example of that. So this is a person who has been involved in such a study, that matrix that you see there is electrodes that have been placed over the surface of the brain and they're gonna get this person not to actually speak, but to think about speaking. And after they've done some training of an artificial intelligence system to be able to interpret those brain signals, they're gonna see whether hooking that up to a voice synthesizer. This could be resulting in intelligible speech from somebody who's actually saying nothing but just thinking about it. So here's the video of that. And again, the person is gonna think what they're saying and that's gonna get decoded in this synthesizer. Now the first sentence. The proof that you are seeking is sign millable in rules. That person just thought that. The proof that you are seeking is not available in books. That's what the sentence was they said later. The proof that you are seeking is sign millable in rules. Just thinking it. Another one. Just thinking. She feel even then must not say any process. Not perfect, but pretty good. Shipbuilding is a most fascinating process. That's what they said when they could speak. She feel even then must not say any process. This is all recent work just in the last year from UCSF. Imagine how that could be incredibly valuable for people who have otherwise, for instance, paralysis of the vocal cords been unable to continue to speak but can still think about it. So giving voice. That's just one example of the kinds of things that are coming out of this study of the brain which is on a remarkable trajectory right now supported through the Brain Initiative. What about prevention of illness? For a long time, going back even in the middle of the genome project, dreamed of the day where we would all have our complete genome sequences which has within it predictors of your future risk of illness and how you might be able to use that information to individualize recommendations about how to stay healthy. Instead of doing the one size fits all which people generally tend to ignore anyway because it doesn't sound like it really fits them. But to do that, that means you have to have technology that's affordable and you have to do it on lots and lots of people so that you can actually get beyond one size fits all to the individual and understand how those things play out and you need not to just measure their genome, you need to look at their environmental exposures, their health behaviors, what they're doing every day, their diet, their exercise, all of those things and you need to do it on a very diverse group of people, not just a bunch of white men which all too often in the past had been the way in which research got done. Well, in addition to that, you might want them to walk around with wearable sensors to keep track of what's happening like my Apple Watch and many of you have wearable sensors on right now. Imagine doing that and turning it into a public database with anonymized data so that you can't figure out who these people are, but you can do the research so that anybody with a good idea can start to figure out what are the correlations and the connections between things that keep people healthy and how do they differ from one person to the next? That would be called precision health and that is an enormous data science challenge and that is what we are now engaged in and it led to this conversation in the Oval Office with President Obama about five and a half, six years ago about the idea that this might become a major new national program to understand all of these factors and how they play out in health and illness and that was subsequently announced at the State of the Union and then initiated and it is now in place as a program called All of Us. All of Us aims to enroll one million or more, I'd like more, people living in the US taking into account all these individual differences with a mission to accelerate health research and medical breakthroughs. Where are we now? As of two days ago, 372,000 people have started enrollment, 243,000 are all the way through including collecting blood samples and urine samples and getting various physical measurements and making their electronic health records available and filling out a whole bunch of questionnaires and agreeing to have their wearable sensor data captured as well, all of which will be anonymized so that researchers won't know who each person is but will have access to the data to understand it and this is in fact called All of Us and you, if you're 18 or older, can join this today simply by going to joinallofus.org and see what that takes. And this is a very diverse group. 51% of the current participants are from racial and ethnic minorities that are traditionally underrepresented in research. A significant number are rural in their background. A lot of them come from lower socioeconomic status groups so we're trying to really understand health disparities in a much more profound way than we've been able to before. This is going to be transformative. We'll be to a million in the course of the next two or three years. All of these people will have a complete DNA sequence determined and they will all get all their data back. So if you want a free genome sequence and you want to be able to interpret it yourself, sign up, this will get this to you in about two or three years. Costs a little bit. By the way though, that first genome sequence that we did back in 2003 cost about $400 million. Sequence of a genome now is about 800. Go figure. And it's coming down. The $100 genome sequence is within reach. So that's a big deal in the view of many of us. There's even a bus that goes around, gets people signed up. I don't know if it's coming to Durham but it should. And we are going to make this into one of those moments. If you heard about Framingham, the study that told us almost everything we know about predictions of heart disease, this is like Framingham except on steroids because Framingham was 25,000 people and just cardiovascular disease. This is 40 times bigger and it's all diseases and it's a lot of technology that Framingham didn't dream about. But now let me do the third example which is the treatment one. And here I have to tell you about what's happening in gene therapy because it is truly exhilarating to see some of the progress that's been possible in the course of the last few years. And we've been trying in this space now for 35 years and had many ups and downs, some spectacular failures as well as progress bit by bit but we really hit our stride now. And let me show you some examples of how that is the case. In order to do that, I got to talk about CRISPR-Cas9 and gene editing because this is such a powerful technology that has emerged just in the last four or five years. Arising from basic science studies of yogurt and bacterial viruses, CRISPR, which most people, if you ask them, can't remember what it stands for. Well, that's what it stands for. It's not particularly transparent in what it means but the real action here is not CRISPR, it's Cas9, it's this enzyme that's derived from bacteria and it has the ability to do targeted editing of any genome as long as you provide it with a guide RNA that has the appropriate sequence so that it will go hunting around until it finds a match and then Cas9 will take its task at hand and in the simplest form, we'll basically make a cut right there. In some of the more elaborate forms, you can actually do repair, you can fix one base pair that you wanted to have a BNA instead of a T. That would be by the way exactly what you'd wanna do for sickle cell anemia, correcting point mutations. Now at the basic science level, this is drastically accelerated things in every research lab that works on human or mouse biology and it's well, big deal in agriculture research because you can start to make all kinds of changes. Think of this as basically find and replace for DNA. And it's a specificity and sensitivity and efficiency is truly remarkable. Let me show you a quick animated version of this because it's kind of nice to see in some sort of reasonably scaled way of what this really looks like. So that's the guide RNA and the big blob is Cas9 and it's ready to find its match. And here it is, it comes in basically the orange strand there invades the double helix because it found a perfect match there. And then Cas9 recognizing that says, okay, this is my enzymatic activity and does a cut right in that way. Now you have a double stranded break in that DNA, a little bit of lost bases along the way but there will be this effort by the cell to try to repair it. It will put it together but usually not quite right. So you end up with a version of the DNA that now has a mutation. That's the simplest form where you basically have lost function of that gene. In more elaborate forms, you don't lose function, you change function. Now applications of this have to be thought about very carefully and let's be clear about the difference between a germline application where you're modifying the DNA that's going to be inherited and passed on to the next generation versus modifying a cell in the body like in the bone marrow for instance or the liver that is not gonna get passed on. The first version, the germline version has profound ethical consequences if we're talking about humans. The somatic version certainly has ethical consequences about safety and informed consent but it doesn't carry this same significance about redefining what it means to be human. So if you were thinking about applications of gene editing, I would argue you would wanna stick to the somatic and not go down the path to the germline for humans. For mice or plants, yes, we've been doing that but not for humans. We are special characters ourselves and if we don't know what we're doing we probably shouldn't be changing our own basic instruction book. Unfortunately, not everybody seem to have understood that and this is actually a iPhone photo taken from one of the people in the audience in Hong Kong in November 28th of 2018 when this particular scientist, JK Her, pronounced that he had actually decided this was okay and described data where he had modified in an embryo, two different embryos to give rise to two twins whose genome had been modified in the germline. Supposedly to make them resistant to HIV in an argument which medically really did not hold up and certainly ethically did not hold up at all. There were immediate objections to this from those present at that time, the Second International Summit on Human Genome Editing. I put out a statement within hours after learning of this also to say that this was a flouting of international ethical norms and that certainly NIH would not support research of this sort. Subsequently there has been a call for a international moratorium that no further experiments of this sort in humans should be done that would result in heritable changes and I have strongly supported that as well including an article in this past week's Discover Magazine. And subsequently China after initially seeming a bit proud of what their scientists had done after recognizing the international outcry have actually taken him to task and just a couple weeks ago it was announced that he's been sentenced to three years in jail. So let's be clear, we are not at the point of knowing nearly enough to contemplate modifying our own heritable genome. We could do a lot of harm that way and it has all kinds of ethical and even theological consequences. At the same time, this technology has profound potential to do good if we go back to the somatic versions which don't carry those same ethical consequences and that's where I think a lot of us are enormously excited. There are 7,000 genetic diseases for which we now know the precise DNA mutation that causes the disease. Only for about 500 of those do we have a treatment and this would be the closest thing we've got to a scalable approach for all of those thousands of diseases and therefore we ought to be pushing really hard. And I'm glad to tell you that we are in fact making real progress in this area of gene therapy and I'll give you two quick examples. One is this disease. This is spinal muscular atrophy. For me as a physician who takes care of families with genetic diseases this is just about the most heartbreaking of all of them. These children are born looking apparently normal or maybe a little floppy at birth and then clearly something is wrong over the next few months as they don't learn how to sit up. Their motor tone gets progressively worse and clearly they're suffering from some kind of motor paralysis which has many times been compared to ALS except it's ALS for a baby and it's the same cells. It's the motor neurons in the spinal cord that are degenerating and these kids will die usually at about age 12 to 15 months basically dying of suffocation. They can't breathe anymore. Absolutely heartbreaking. Now we know the cause. It's due to a mutation in a gene on chromosome four that's been well worked out. So in this instance it was possible using a gene therapy approach to provide a copy of the gene that works infusing this with a viral vector intravenously and amazingly enough having it find its way to those motor neurons in the spinal cord in a very small number of patients. One of the earlier patients treated was Matteo. He was treated at just two weeks of age because his family had had a previous affected child so they knew he was at high risk and the diagnosis was made very early. He got the infusion, his parents watched and waited. Let me show you a little video of Matteo at about age almost three. That always jokes me up when I see it because this is a kid who really should not have made it to this point and not only is he made it. He's not standing on his tiptoes there, watching a minute he and his dad on the monkey bars. If that's not an amazing example of a scientific miracle, a miracle based on great science, I don't know what is. So that's becoming possible for that disease and this is now FDA approved as a treatment for kids with this disease and most states have now started doing newborn screening to find those cases immediately at birth because you need to treat early in order to save those cells that otherwise once they're gone, they're gone. And the final example I wanna give you is the first molecular disease, sickle cell disease. Described more than 100 years ago, we knew in 1949, because Linus Paulin figured it out, that this was a molecular disease caused by some kind of a gene mutation and gosh, in 1957 we knew it was the hemoglobin protein that had a misspelled amino acid and yet until very recently we've not had much to offer to the 100,000 people with sickle cell disease in this country and the millions affected in Africa. And it's come to be so common because the carriers for this are in fact protected against malaria. But the people who are affected live this incredibly challenging existence of daily pain attacks that are about as severe as anything you can imagine. Well, it's a genetic disease, so an approach to this undertaken at our own clinical hospital in NIH by John Tisdale and his colleagues has now been applied to a few patients and one of them is Janelle Stevenson and you see her here about a year after her treatment in this 60 minutes piece which was just put out in the last few years. Put your arms and move. Remember, Janelle used to struggle just to walk up a flight of stairs. And you fall. And a fall like this would have landed her in the hospital. Boom. Yeah. Good job, you did it. Bam. What was going through your head as you were watching Janelle being thrown down to the mat? I was just saying thank you, Lord. Thank you for medical signs and thank you for giving her a new life. New life indeed. Amazing story, if you get the chance to see that 60 minutes, it's now up on the web and you can see the whole picture of what she went through and how this particular treatment, which is not for the faint hearted, required a full month of hospitalization and a fair amount of risks, but she is now from every measure that we could actually look at, she looks like she's cured. So finally, I've told you a bunch of stories both about my own pathway as a scientist and about some of the things that are happening now at NIH and that I think will be happening in the next decade. Are there any lessons that I would share with you very quickly? Well, certainly from my own perspective, keep your horizons wide open. You never know what's going to come along that's going to be really your passion and you don't want to miss it. Nurture your curiosity. Always be willing to explore something you don't know much about and see what's there. Think quantitatively. I don't think I have to tell most of you this. Probably a message for different audiences than yours, but yes, and learning to code, you cannot be a scientist in life science if you're not really comfortable with computational approaches. Find mentors who can advise you. We all love to be mentors to students. Don't be shy to ask. And then we like to continue to stay in touch with you. I have this whole family of students postdocs that I've mentored over 30 years. And most of them I still hear from and I still occasionally get asked for advice and I love that. So don't be shy to ask for that kind of help. If a new door opens, check it out. Maybe you didn't expect it. Maybe it's all wrong or maybe it's running the human genome project and you really ought to do it. If another one closes, especially one you were really counting on, okay, that feels tough, but maybe it's just as well. Maybe there's something else out there that's gonna turn out to be really more what you needed to find your passion and run with it. If you get the chance, you're doing science, try to pick projects that are really important. There's a lot of derivative science out there where you're kind of like taking the next obvious step. Somebody needs to do that, but if you're really creative, pick something that matters. It may be higher risk, but it may really change things. Pick the important ones. Don't be afraid to take those risks. And these days, science, certainly life science, is a team sport. So enjoy that part. Don't be a loner. Seek the power that diverse teams can bring to the problem. Don't expect, because I certainly haven't, to travel a linear career pathway. There are very few of those left anymore and certainly not in science. And be grateful every day that you're here at this remarkable school and live at such an amazing time in science, because that's what this is. Thank you all very much. We have a little time for some questions from the audience. Please. We have runners who are going to run to you. So please raise your hand and somebody will come and shove something in front of you. Was it hard for you to have the courage to change from a PhD to an MD and move pretty far? It was crazy hard, because I was already married. I already had a two-year-old daughter who's now sitting in the front row a little older than that. Cellar's mom was at risk here for my changing fields without having a better plan. It was really hard, because I had all these ideas about what I was going to do and there were a lot of potential sacrifices that everybody was going to have to make. But it was irresistible. And it seemed like, okay, it's going to cost me a lot of years, but it's scientifically what I'm excited about. I just got to do it. Yeah, it was hard. There was a moment. It was probably two o'clock in the morning. I was a graduate student toiling away on quantum mechanics. And I took a break and went upstairs and I ran into a graduate student in Don Crothers lab who was also a chemistry student, but the chemistry he was doing was DNA. And I said, tell me about what you're doing. And he told me and I was like, you mean really? You mean really life works like that? How did I miss this? Then I was hooked. Two o'clock in the morning, things do happen. Other questions? Question over there. Oh gosh, okay. So what kept you motivated whenever you're directing this really large institution? What keeps you going through your daily life? Well, several things. One is family and particularly my wife Diane because I said we do this together. So every day, if it's a bumpy road, I'll come home and we'll talk about it. I have a lab that keeps me going. My research lab works on diabetes and this rare form of premature aging. That keeps me going because I'm anchored to what's really going on in science. And I have students in postdocs to talk to about experiments they just did. But what really keeps me going is the patients that I know are still waiting for an answer. I wear this little button on my jacket which is actually shaped like a guitar pick for other reasons, but it is a reminder about what NIH really is for. We're the National Institutes of Health but a lot of people who come to us call us the National Institutes of Hope because they're hoping that through our research we will come up with answers for something that currently doesn't have answers. And when you think about that, it's pretty hard to feel sorry for yourself if you had a bad day. So all of that helps get the anchoring going. Well, I have a little surprise for you. If we have another two minutes, and I think we do, there might be something hiding behind this curtain. Let me go see what it is. The person who actually did the scientific work that allowed Watson and Crick to win the Nobel Prize. So this is Rosalind. And I just thought I'd wind this up with a silly song about the student experience. So the first couple of verses, these are your verses and the last verse, well, that's my verse, or you can imagine me impersonating one of your professors, particularly in biology in that last verse. Because I know you guys, this has got to be a tough time of year. You have a lot of stress on you with projects and research and courses. And okay, hopefully this is a little couple minutes of a break, thinking about that experience slightly tongue in cheek, hopefully without offending the faculty. And the tune will be familiar and you'll never want to hear it again after today. I came to SSM. I had some dreams, but I followed directions. I worked, I studied hard, made lots of friends that had connections. I crammed, they gave me grades, well, sometimes. And may I say, not in a fair way, much more than this, I did it their way. I learned so many things, though I know I'll mostly never use them. Some of the courses that I took were required. I didn't get to choose them. You'll find that to survive, it's best to play the doctrine airway. And so I knuckled down and did it their way. Well, yes, there were times I wondered why I had to cringe when I could fly. I had my doubts, but after all, I clipped my wings and learned to crawl and come home before sunset. I had to bend and did it their way. All for my verse, but now, my fine young friends, now that I am a full professor, where once I was oppressed, I have now become the cruel oppressor. With me, I hope you'll see the double. He licks his a highway. And yes, you'll learn its best to do it my way. Well, I'm just a man. What can I do? Open your books, read chapter two. If it seems a bit routine, don't talk to me. Go see the dean. Just start today. Love DNA. And do it my way.