 Can you hear me? Okay, so we're gonna go ahead and get started. We thank all of you for coming in from the beautiful day and for braving the traffic and the congestion out there to make it here. I would like to welcome you to our program this afternoon on behalf of the National Museum of Natural History and the National Human Genome Research Institute at the National Institutes of Health. We are going to talk today about what is your genome and in particular about the ways that we think that it will influence our lives and in particular our health. This is part of a series of programs that NHGRI has been working with the Museum on as a complement to the exhibit that's upstairs genome unlocking life's code, which I hope that you've had a chance to visit and if not, I hope you will take a few minutes or more than a few minutes and go upstairs after today's speakers to take a look and also I hope sometime when you're next inside you will take a look at the website that goes with that which has a lot of additional information about the science and the programming that we're doing around the science and around the ethics and societal questions as well that go along with the science and that website is UnlockingLivesCode.org so it's easy to remember with the title of the exhibition. Today in particular while we're here in the new Curious Center, which is a very cool facility that the museum has recently opened, we're going to try and bring to you some of the exciting stories about the science that's happening just a few miles up the road at the National Institutes of Health. In particular, as I already mentioned, we're going to be talking about genomics and we couldn't have two better speakers for you today to hear about this as you will see and when they're talking to you, they are both incredibly passionate and committed to the science and to what the science is going to do for all of us in our daily lives. So with that, I will just quickly introduce them so you can hear from them and not from me. First, we will hear from Dr. Eric Green. He is the director of the National Human Genome Research Institute and has been for the past four years. Before that, he has was a significant contributor to the Human Genome Project, which I'm sure we will hear about today as well from its start to its conclusion almost exactly 11 years ago on April 15th, 2003. And also he has received many honors and awards over time and is a huge Cardinals fan. So that's just something you need to know. To know anything about Eric. In 2011, soon after he became the director, he completed a visioning process for the Institute. But also for the field as a whole. So that we could begin helping to shepherd the science and the portfolio of all of the activities that are funded by and conducted at NHGRI to bring genomics to its clinical applications and so that it can start reaping the benefits of how it's going to inform our health and our health care. After we hear from Dr. Green, we will hear from Dr. Francis Collins, who is the director of the National Institutes of Health and a former director of our own Institute at NHGRI. Where he served from 1993 to 2008, during which time he led the international effort to complete the Human Genome Project, which was the great and audacious program to complete the first finished sequence of the DNA code, which is our instruction book. And again, you're going to hear a lot more about that from them. In his scientific life outside of his leadership activities at the NHGRI, he is a physician scientist who has discovered many disease genes and has then explored in his laboratory how the function of those genes contributes to the diseases that they are associated with. He's an elected member of the Institute of Medicine and the National Academies of Sciences and was awarded the Presidential Medal of Freedom in 2007 and the National Medal of Science in 2009. And he likes to sing, which we'll also get to hear about. So with that, I'm going to turn it over to Dr. Green and we will hear about the story. Well, thank you, Laura, for that kind and helpful introduction. So I'm Eric Green, Director of the National Human Genome Research Institute, and what Francis and I are going to do is both to try to convey to you some of these exciting developments that have happened in genomics that are very relevant to this exhibition that's here at the Smithsonian Genome Unlocking Lives Code. And also, from what I hear, I'm going to entertain you a bit. Now, let me say from the onset that we knew we were going to have a very heterogeneous audience here, and indeed we do. We have everything from, I don't know if it's middle school or grade school kids here who are taking notes, who have to do a report on this. To the other end of the spectrum, we have a number of volunteers who are expert at this exhibition because they're spending countless hours as volunteers. And then we have family members of the second speaker, who I'm sure are very sophisticated in genomics, and lots of everything in between. So what Francis and I thought we would do is to sort of split our talks. I'm going to try to build a foundation, just really give some very basic information about genomics, and which I think will serve as a very helpful background for both visiting the exhibition, but also a background for setting up the things that Francis is going to tell you. And then I'm going to turn it over to Francis for both his talk and other things that I think he has on his mind. So what I would start by telling you to set a context is that genomics as a scientific field is actually relatively young. It's really little over maybe a quarter of a century. In fact, I like to tell the story that I graduated medical school and graduate school in 1987, and throughout all of medical school and all of graduate school, I never once heard the word genomics. The reason why is because the word genomics first was put into the scientific press as a word in 1987, literally the year I graduated from medical school and graduate school. And I got involved, and the reason genomics had come to the fore as a field was because this idea of doing this thing called the Human Genome Project, which we're going to tell you about. And I've been involved in genomics ever since then and got involved in the Human Genome Project. But the relevance of genomics has changed substantially over the last quarter century, which is in many ways why we are here today giving this talk and why this exhibition has been put on here at the Smithsonian Institution. Because when I got involved in genomics some 25 years ago, what I would tell you is it was a field of study that was just relevant to people working in laboratory, biomedical researchers, sitting at computers maybe, but mostly at the bench pipetting things and studying DNA. Maybe when the Genome Project ended about 11 years ago, as you heard about, I think increasingly we saw relevance and you're going to hear about this for healthcare professionals. They got increasingly interested over the last decade in particular about genomics. But what's so different about now and increasingly the next handful of years in particular is that, and the reason we did the exhibition here and the reason we're doing programming like this is that genomics is becoming relevant to patients and friends and relatives of patients, which means all of us. And it's this expansive relevance of genomics to society that motivates us at both the NIH at large, at the institute that I direct, the National Human Genome Research Institute, and I really think the whole field to try to make sure people increasingly understand genomics because it'll be relevant to them as patients or as family and friends of patients, which again means all of us. Okay, so what I'm going to do in laying this basic foundation is really to answer seven questions and they're very basic and some of you are going to be completely know the answers to all of it, so this is really just to bring us all up to the same level. I'm going to tell you about what is a genome, I'm going to tell you what is a chromosome, what is DNA, what is a protein, what is a gene, what was the human genome project, and what is a genomic variant. And with that as a background you will be completely ready to go see the exhibition or revisit it and you'll be completely ready for what Francis is going to talk about when he takes over. Okay, so let's start with a very basic, what is a genome because genomics is the field of study is involved in studying genomes. Well, a very basic level, think about a genome as a blueprint, it's just a blueprint for living creatures. Well, you know, if you're going to make anything, you need some sort of an instruction book, you need a manual, you need a blueprint. If you were going to make a car, for example, you would start with a blueprint that listed all the parts and would probably give instructions on how to put that car together. In fact, by the way, the typical automobile is made up of about 20,000 parts. Remember that number, it comes relevant later. Well, the same thing is true for living systems. It's just that the blueprint that we use for living systems for instructing how the thing gets put together is this black box thing called the genome. And all living systems have a genome and are basically dependent upon that genome for telling how to put that thing together and how to make it work. And that's true whether it's a dog or a cat or a worm or a fly or a cherry tree or a human or even our closest relatives. All of them, all living creatures, all life forms need a genome. So genome is basically life's code, and that's the title for our exhibition. So that's a genome. Well, then what's a chromosome? Well, something's going to be needed to carry around that blueprint from cell to cell, and that's where a chromosome comes in. Because a chromosome actually is the thing that contains an organism's blueprint. So let's give a little more basics here. A human body consists of something like 10 trillion human cells, roughly. And essentially, every one of those cells and the inside of it, in the middle part of it, a structure called a nucleus, has a whole bunch of things floating around inside of it, and things are called chromosomes. I like to think of chromosomes as suitcases that carry around the blueprint, the genome, from cell to cell, from generation to generation. And every one of these cells carries around and given human body carries around essentially the same blueprint. So here, let's do a quick video, sort of ride through. There are a bunch of human cells, and if you open up the cell inside that structure called a nucleus, and floating around inside that nucleus are these things called chromosomes. So again, these are like free floating looking things, and in them contains the genome, the blueprint, the information, the code, if you will. So that is a chromosome. All right, well, what's in a chromosome? How does a chromosome, what's that blueprint information that's carrying around in that suitcase? Well, of course, that's the DNA. And DNA, you know, us scientists, we're pretty simple. We just abbreviate things because they're easier. So we just say DNA, but of course DNA, because it's a chemical, and the chemical is deoxyribonucleic acid. It's just easier to say DNA. And of course, DNA has been studied for a number of years because of the recognition that it was this blueprint information in chromosomes that carry with it the code for making living systems. And the big famous thing that happened in the 1950s now, something 61 years ago or so, was the discovery of Watson and Crick, of the double helical structure of DNA, this iconic view of DNA, how it has these two strands that come together in a ladder that are iconic, they're so iconic that you'll actually see both speakers not only have the icon on their tie, they're actually wearing the same tie by total accident, which shows you how nerdy both of your speakers are. But any case, but everybody, you know, nowadays knows this famous double helix. And it's really important to emphasize that the reason that this discovery by Watson and Crick was arguably the most important biomedical research discovery of the last century was because it gave the critical insight to explain how DNA was this blueprint molecule that carried the information from cell to cell from generation to generation necessary for making life form. It was just sort of the last piece of the puzzle. What then transpired after the 1950s, in particular in the 1960s to the 1970s, were better and better laboratory methods for studying DNA, for manipulating DNA, for being able to look at it very carefully and eventually to be able to figure out what it's made up and how its composition actually codes all this information for life. And to make it very simple, the bottom line is that DNA is made up of four chemicals. And those four chemicals are shown here, and as I always say, we like to make things simple. So we just think about the first letter, we think of them as A's, T's, G's and C's, but you can see the full chemical name there. And it is the order of those letters that encode the information for life. So the G-A-T-C-C-C-A-A, that's really what DNA is. It's just ordering of these chemicals along a stretch of DNA. And so scientists increasingly in the 1970s in particular, then the 1980s got better and better at being able to isolate DNA, be able to clone DNA, and be able to make a lot of it at laboratory and eventually develop the methods for being able to figure out the order of the letters, the order of the chemicals across a stretch of DNA. So they had abilities to do all these things. And for example, one of the simplest things, because you can't really see DNA with the naked eye unless you go to purify it. And shown here is actually some purified DNA, which looks like a big snot ball, right? Because when you purify DNA, it looks sort of like gunky and snotty. This actually DNA purified from a strawberry, that's why it has a little bit of a red tinge, and it's a really easy thing to do. But if you go up into the exhibition, one of the activities, hands-on activities, is that you can also purify DNA from humans very easily. We don't even need to draw blood or anything like that. We can just have swish a little bit of liquid in your mouth and you spit that out. And there's enough cheek cells that have DNA and then that come out with what you spit out that you could purify DNA. And that's exactly what it looks like. You can go do that when you're done here. Go up there and you can actually purify your own DNA and take it home with you. But of course, you could look at that snotty look in DNA and it still doesn't tell you the order of the G's, A's, T's, and C's. That required new methods for being able to read out the sequence. But if you had a magic microscope, you could just sort of zoom in on that and be able to, through a whole series of methods, be able to read out the sequence of DNA. And those methods were first developed in the late 1970s and then improved upon throughout the 1980s. And this is it. This is what DNA sequence looks like. In fact, this is a stretch of the human genome, if you could believe it. You can just see it's like this massive set of G's, A's, T's, and C's and almost impossible for the human eye to read it and interpret it. But somehow, in some code in there, has all the necessary information for making life forms. Okay, so that's DNA. But then what's a protein? Because you often hear about how DNA has information for making protein. But what is actually a protein? Protein is very different than DNA. Protein is like a part of a car in some way. Now, the analogy I like to use, because I think it's really simple, this is the first time you're learning about DNA and about proteins, is that proteins are basically the building blocks of cells and organisms, just like parts of a car are necessary for putting a car together. And the analogy I like are Legos. Because really, if you think of a given protein as being a different Lego of a certain color and a certain shape, you can use those Legos very creatively to build things, just like we take different proteins to build different human cells. And so in fact, of course, you could even build a human by through Legos, at least a caricature of one, if you will. And so proteins are the things that are made to put together cells and tissues and eventually bodies. And proteins, of course, are one of the things that are encoded in DNA, which leads to the next important concept for you to know, what's a gene? Well, basically, a gene is a segment of DNA, G-A-C-C-T-T-T-T-T-A-A-S, stretch of DNA sequence that has the instructions for making a protein. So to visualize it, here you have a chromosome, and if you unwind the DNA from a chromosome, you have this double helix, and within that are the G's, A's, T's, and C's, and this is a stretch that would have all the information necessary for making one Lego, maybe a red Lego that's rectangular shape, or in other words, for making one protein. Now you may ask the question, how many, for example, genes are there in the human genome? Remember I told you about cars, they have about 20,000 parts? Turns out that the human genome has about roughly 20,000 genes, roughly 20,000 genes. But what's really fascinating to think about, and it was one of the motivating things for understanding and studying our genome, is what did I tell you previously, out of the 10 trillion cells in the human body, they all carry around with them the entire human genome, the entire collection of human DNA, and yet, and they therefore carry around all the instructions for making 20,000 proteins, because they have 20,000 genes, they can make 20,000 proteins. But any given cell only makes a subset of those. So if you're a muscle cell, you make a several thousand proteins from several thousand genes, but you don't even use those other genes. And if you're a brain cell, you use a different set of genes to make a different set of proteins. And one could imagine, there must be a lot of extra information in the genome that says, hey, I'm a muscle cell, just use these genes and make these Legos. Oh, and over here, I'm a brain cell, just use these genes and make these proteins. And that's some of the intriguing, incredibly complicated things about the genome that we're still studying and will be studying for many decades. Okay, so I told you what a DNA was, what a protein was, what was a gene. Well, what was the human genome project? Well, the human genome project really was this idea that came up in the late 1980s and then became a reality in 1990, recognizing this incredible complexity in all of the DNA in the nucleus of every cell and all the genes and all this information somehow must be there in all those letters. And I didn't tell you this yet, but a human genome is about three billion letters. If you add up all of those G's, A's, T's and C's and all of those suitcases and those chromosomes, it comes out to be about three billion. And while three billion seems like a big number, it is finite. And the idea was, could we come up with strategies that allowed us to efficiently read out the DNA and be able to read out all three billion letters of the human genome? And it would take a big effort. It would involve many countries, thousands of investigators. In the end, it took 13 years, but it was doable. And that was the human genome project. And so it was basically an endeavor to, if you think of again, like an instruction book sitting in every single cell, just opening that book up and actually reading out all the letters of the human genome. So this audacious but successful project, which I participated on on the front line. Francis Collins, who will follow me, not only participated, actually really helped lead the international effort to see it be so successful was this incredible endeavor, both in its importance for science and really for humankind, but also its success. And in fact, what's often given as an analogy is this was sort of biology's equivalent of the moonshot, if you will. We are going to put a person on the moon, have no idea how we're going to do that, but we're going to do it. And they figured it out. Same thing with the genome project. We're going to sequence the human genome when it began. We have no idea how we're really going to do it, but somehow we figured it out. And so off we went. And from 1993, many thousands of people toiled away and slowly but surely uncovered this order of the three billion letters in the human genome. And importantly, not only figured it out, but got it out on the internet, freely available to everybody around the world for scientists and physicians and anyone who wants to study the human genome to be able to access it, almost essentially while it was being produced. And that sort of generous sharing of information is really part of genomics that even carries forward to today, where a lot of the data being generated is shared so that everybody benefits from this. So that's the basics of genomics and a basic understanding of what a the human genome looks like in a very generic way. But to serve as a transition to the stories that Francis is going to tell you, let me tell you a little bit more about how we are all a little bit different because each one of us has a unique blueprint, which is why each of us is a little bit different compared to the person sitting next to you. And it all relates to variants, differences, variations in our genome. So what is a genomic variant? Well, simply stated, a genomic variant is a difference in the genome between people and among people. So, for example, basically roughly, just rough numbers, if you take a stretch of the human genome, about every thousand or 1200 bases or so, there will be a difference compared to another person in this room. So we're not radically different. In fact, any two people in this room only differ about one out of a thousand letters across our genome. And what this looks like is that maybe at this particular position, which in some people might be a G, but in other people might be an A. And that is a variant. That is a difference between people. And some of these are very common, where maybe it's 50-50. In some cases maybe it's 90-10. In some cases maybe it's 99-1 and so forth. So you can sort of think about your genome as this whole series of G's, A's, T's and C's. And if you're going to differ about one out of a thousand compared to the person sitting next to you, that means scattered across your genome are a whole bunch of these letter differences. A G versus an A, a C versus a T are these variants, which I indicate here as V. Now, let me stress that the great majority of these variants we are convinced really don't mean much. They don't really influence your biology. But a subset of them do. And a subset of them might not be particularly good variants. They may be variants that confer risk for getting a disease or might overtly cause disease. And then there's other variants that might be good variants because they might protect you from getting a disease or maybe they would indicate that you'd respond well to a certain type of medication. And so the idea, of course, is wouldn't it be wonderful if we could study these variants on a very large scale and catalog them, make them available on the Internet, and then have scientists go through and begin to study which of the variants are not important to worry about, which ones might be relevant to disease, and which ones might be important because they're protective to disease and so forth. And those kinds of studies have gone on since the Human Genome Project ended and continue in the future. And Francis is going to tell you more about how interested we are in variants because of their role in health and disease. So that's sort of genomics. And genomics, again, I think of as this comprehensive study of DNA of an organism, and that would include helping to understand differences in genomes and variants in genomes. But, of course, each one of us consists of basically a blend of genomes because we got one copy of a genome from our mom, and we got one copy from our dad, and we sort of got blended together. Some of our variants came from our mom, some of our variants came from our dad, and this allows me to answer a question that's often asked, what's the difference between genomics and genetics? And everybody will give you a slightly different answer. I tend to think of genomics as studying of DNA, sort of comprehensively laying it out, the structure and the sequence and variants. And genetics begins to be when you're looking at inheritance, when you're looking at how the different variants came from different parents and how they interrelate. And so this is the cartoon I like to think about it. This is genetics, right? This is how it works. You get some things from mom, you get some things from dad, and you are a blend. This is what families are all about, if you will. But to really make this real, bringing it back to genomics, so thinking about genetics and the blend, we could pick another family because families are very helpful for just understanding a little bit about how genomic variants get differences. You know, let's take another family, so family may be familiar to some of you. So if we once again go back to RG, in reality, every person will have two copies of that stretch of DNA, because they would have gotten one copy from mom and one copy from dad. And so you have, basically, you're going to have two versions of that. And you can see if we sort of go through the family here, you can see the first lady has a G and a G, the one she got from her mom, the one she got from her, and both cases was a G. Here the president got a G on one case, but got an A from one of his parents. And then they start to blend as they start distributing those variants to the two children, and you can see one of the children gets a G and an A, obviously got A from dad, and the other one got one of the G's from mom, and the G, the other G came from dad. So that very much starts, you can start to get a sense of how you get your variants from mom and dad. Leading me to the idea of what we have learned increasingly, this is a nice setup to what you're going to hear the kinds of stories Francis is going to tell, is what does a typical person's genome look like? If we sequenced one of your genome, and we could readily do that in a matter of a couple days for a few thousand dollars, we'd be able to read out all of your letters in your genome. And we're beginning to learn, having done many, many such studies now of literally thousands of people who have had their genome sequenced, what a typical genome looks like in terms of variants. So let's give some just simple numbers for you to remember. Any one of your genomes has about six billion letters in it, or nucleotides. Now remember I said a human genome is three billion, but remember you have two genomes in you. You got one from mom, you got one from dad. So in aggregate, your whole genome is about six billion nucleotides. And if we sequenced your genome and you did the arithmetic and what we now know, there are about three to five million letters, single nucleotide variants, places, one of those Gs, A's, T's or C's, that'll be different, let's say, compared to the person sitting next to you. So out of six billion, about three to five million differences. By the way, most of those three to five million differences we've already seen already in the genomics community. We could go up on the internet and we could find it in some other person out there. And so most of these are actually quite common and we see them at a reasonable enough frequency in the human population that by doing the studies we've done, we now know about them. But a small subset of your three to five million variants, we won't have seen yet. In fact, about 150,000 of your three to five million variants have not previously been seen. They're probably sufficiently rare, maybe limited to your immediate family or maybe your slightly extended family, but we haven't seen them yet. And interestingly, we now know that on average, about 60 variants that you have are not an either parent. And you may say, well, how did that happen? I got a copy from mom, a copy from dad. How could it be? Well, it turns out that in the process of copying all that DNA, those three billion letters, one copy from mom, one copy from dad, every once in a while a little typographical mistake gets made and done, get corrected. And about 60 of those examples in you. Now, probably the majority of those 60 probably don't mean much, but maybe a subset do. And maybe that's why you might be slightly more at risk or less at risk for a disease compared to a parent because of these very small number of new letters in your genome that wasn't an either parent. So that's the primer I wanted to give you about genomics, a little bit about genetics. Before I turn it over, let me emphasize one other thing that I think is very relevant to the exhibition in particular. As I said, genomics has really been around as a field for only about 26, 27 years, and it started out really pretty much focused on the Human Genome Project. But when you go up in that exhibition or even if you just watch the news and see stories that come out about genomics, what has been truly spectacular about this field is all the different applications that have come out and continue to grow substantially. And almost every one of these in one way are touched on in the exhibition. And in fact, many of these other ones are also touched on in other exhibitions at this museum. And you're hearing about this all the time, whether it's related to ancestry or if any of you watch CSI, forensics, genomics is all over the place, and so forth. And it's really incredibly gratifying to see how genomics has spread far and wide even beyond human biology. But of course, Francis and I work at the National Institutes of Health, and that has a very heavy health emphasis, as you might imagine. So what we've most, what I've mostly talked about in Francis is going to extend upon our applications of genomics to health, disease, and medicine. And in particular, what he's now going to extend on what I've described and now take you into much greater detail into how the role that genomic variants play in our traits, and in particular our diseases that we are at risk for, and the role that genomics therefore plays in health and disease. So with that, I will stop. I'm going to turn this over to Francis. And then when he is done, we will both take questions from all of you, and we look forward to that. Thank you very much. Well, thank you, Eric. Yeah, I'm the other nerd with the DNA tie, and this was not planned, but I can tell you there's a special credit for anybody who can, at some point during the afternoon, tell me what's wrong with this tie because there's actually a problem with it. That's very, very sort of high sophistication level question. It took me a while to realize that there's a problem, but there is. But it is a double helix, and we're talking about the double helix, and Eric has given you a wonderful introduction to a wide variety of the details about genomes that we need now to begin to delve into the medical implications of all this. By the way, I want to say thank you to all of you for being here, and I know some of you struggled quite a bit to get here because of all the traffic issues on the streets and on the metro. We came down on the metro as well, and yeah, it was pretty hard jamming onto the cars, but we're glad you're here on this beautiful Saturday. And I'm going to talk for a little bit, but then we really want to have a chance to hear questions from you about how this all fits into your own understanding of biology or maybe questions you have about your own health and what genomics could reveal about it. So I'm the director of the NIH, and certainly from my perspective, one of the most exciting things that's happening in all of medical research is this revolution in genomics, because it's giving us insights into the details of a very central aspect of living things, the instruction book, which we've only just recently been able to look at. And that's got everybody pretty revved up with excitement about where this can take us. I thought I'd start with something a little personal since genomics tends to get that way, so you know who that is? That would be me. I think I'm maybe eight or nine years old. That's the farm I grew up on in the Shenandoah Valley about two and a half hours from here. And I'm happy to say I have here today one of my brothers who is sitting there in the front row and his wife and a whole bunch of our friends from Stanton, Virginia. So yeah, this is kind of a family event. Thank you all for joining our family reunion here. And it also is a reminder of how, in fact, when you talk about genomics, you quickly are getting into family connections. So well, here would be another one. That would be my Sib ship. Those are my three brothers and myself after one of our annual tennis games. And you might imagine that there's some genetic tendencies here to be athletic, which might be sort of true for some of us, but you would definitely notice their genetic tendencies to have really skinny legs. It's pretty hard to miss that part. And there's also genetic tendencies for other things in our family. All you could argue about what is hereditary and what is environmental, but here's another example of the four of us in a particular place where we often find ourselves playing music together in the ancestral home in Stanton, where my brother now lives. And it's sort of one of those things that has been part of our experience. Now, I wouldn't say that that's necessarily attributable to a particular C or T in my genome and theirs, but it probably has something to do with musical aptitude because you will see certainly families where that is on wild display. I wouldn't necessarily say that's true of all of us, but it is one example of how inheritance can play a role in a lot of things, but not in a clean cut way, not in an easily understood way. Well, you heard about the human genome project from Eric, and it was my privilege to serve as the field general of this enterprise over an amazing period of years, which ultimately involved 2,400 scientists in six countries all working together to try to achieve this previously unimaginable goal of reading out those three billion letters of the DNA code. And at the time that we really got revved up, that meant we had to read a thousand letters a second, seven days a week, 24 hours a day in order to achieve that kind of number. My gosh, when I was a postdoctoral fellow in the 1980s, reading a thousand letters of the DNA code could get you a PhD, and that had to get done every second by this team, but they did it, and a lot of it was building the technology so it got better and better, and you could do this faster and faster, and at affordable cost. But now we want to talk about how do we take that information of all those C's, G's and T's and help these apparently confused physicians here trying to figure out what to do for somebody who needs some medical advice and they're having trouble with the interpretation. This is a big problem. Reading out that script, okay, we did it, but it's written in a language that we don't understand. So a lot of what we've been doing since 2003 is to try to figure out how to read this language, how to figure out where the genes are, what are the proteins they make, what about those variations and what role do they play in disease. And that meant we didn't stop after sequencing the genome. We had to add a lot of other projects on top of that, something called HapMap, which was focused on all those variations that Eric talked about. We actually then went on to sequence not just one genome, but a thousand genomes, so we could really get a sense of what the variability was between people across the world. We then wanted to understand what are those regulatory signals that tell genes to turn on in muscle cells or in brain cells, as Eric was talking about. Those must be in there somewhere too, and that was a project called ENCODE, but that is a very complex story that is still very much evolving, but we are getting there to figure out what those signals are. Only about one and a half percent of that DNA genome codes for protein, and some people were dismissive of the other 98 and a half percent as if it was just filler along for the right, not so. In that 98.5 percent are all these complicated signals that allow you to go from being a single cell, you all once were a single cell, think about that, and then develop all of these complicated tissues, including the most complicated structure in the known universe, the human brain. All of that, some has to be specified in a limited instruction book with just three billion letters and 20,000 genes. So there's a lot of clever stuff that has to be encoded within all of that, and we've been trying to figure that out. But let me now turn to the medical part of this. So Eric talked about the fact that we have these variants, that most of them don't have much significance, but some of them do. Some of them might place you at risk for cancer, or me for diabetes, or somebody else for Alzheimer's disease. How would you find those? Because most of them, let's be clear, are not predetermining, they're predisposing, they increase your risk a little bit, or maybe decrease your risk a little bit. To find those, you basically have to do what we call an association study. You find a thousand people with diabetes, and you find a thousand people who clearly don't have diabetes, and you scan through their genomes, looking at all those variable places, trying to say, is there one where the people with diabetes have a higher proportion of the G? And over here, they have a lower proportion of the G. That tells you that must be, in some way, a risk factor for diabetes. When we started this part of the project six or seven years ago, for diabetes as an example, we knew about two places that we thought were involved, and we weren't that sure. We now know about 80. In fact, if you look across all of the common diseases where this has been applied, this is what you get. Let me explain what you're looking at. These are those chromosomes here in a cartoon form that Eric talked about. They're numbered from one to 22 in the human, one being the biggest, 22 being the smallest. Ignore all those colored balls for the moment. One, two, three, and so on. This would be a chromosome spread from a male because there's an X and a Y. Males have Ys. Females have two Xs. What are all these colored circles? Those are the position where researchers have found a variant that is associated with risk of disease. There's a huge number of diseases here, Parkinson's, Alzheimer's, diabetes, Crohn's disease, everything you can think of. Somebody has done this study. And for something like diabetes, the answer is 80. For something like a high cholesterol, there's a couple hundred in here. For something like height, how tall you are, there's 400 of those. So there's a lot of complexity here. Now, this immediately raises the question, would you like to have this analysis done on yourself to find out which of those risks you're carrying around, and would that change in some way your own approach to keeping yourself healthy? That may be something we'll talk about in the discussion. I've had that done on myself. It was useful, but it's very squishy information that's constantly needing to be revised because we haven't uncovered all of the answers about heredity for disease yet. We're still just scratching the surface. So we have that kind of information. This is all about common variations in the genome, the ones that you can find in lots and lots of people, but increase or decrease your risk a little bit. But there are other situations where you have a very rare condition where DNA analysis can be even more dramatic. And I want to tell you about those. The reason this has become possible, by the way, here we go, is that what cost us a fortune back at the beginning of the human genome project has now become much, much more inexpensive. So the original human genome project over the course of 15 years, that's how long it took, cost in the neighborhood of three to four billion dollars. But sequencing that one human genome was in the neighborhood of a few hundred million. Now look and see what's happened to the cost since September 2001. So just 13 years ago, 100 million dollars. Now today it's about, oh, maybe a little less than 10,000, and a company just about two months ago announced that they thought they could promise it was going to get down to 1,000 by the end of this year. We used to sequence DNA using instruments like that that looked like phone booths. We now have instruments that look kind of like that. I'm holding one of those up. This is an ion torrent machine the size of a postage stamp. Just amazing technological advances that have happened. So this is now becoming practical if you're sort of trying to solve a detective story to use this tool of DNA sequencing to see if you can come up with an answer. And of course that cost will continue to drop. There's no end in sight. And many people believe that as it gets more and more below 1,000 dollars, many of us will want to have this information derived on ourselves, put in our medical record, and then it'll be there when a question comes up about what's there that might be something you'd want to know. A very important application of all this DNA analysis is cancer. Because cancer is a disease of DNA. It comes about because of mistakes in DNA, particularly in vulnerable places. Remember Eric was talking particularly about that 60 mistakes that you may have that arose in sperm or egg that gave rise to you. Those are then going to be in your system for your whole life. But mistakes happen while you're walking around every day too, especially if you happen to get zapped with a little bit of ultraviolet or maybe a cigarette smoke gets into your lung or some carcinogen causes that cell that got exposed to make a mistake. And if that mistake happens in a vulnerable place, it may result in that cell growing when it shouldn't have. So when you hear about cancer and you try to think, what is cancer? Cancer is a disease of DNA mistakes. Some of them happen probably at random because copying 6 billion is hard and occasionally a mistake just happens. Sometimes they happen because of some outside influence that causes the mistakes to happen more frequently. But that's what cancer is. And that means that if you're trying to understand a particular individual's cancer, a very important thing to do is to look at the tumor itself and say, what's wrong there? What mistakes have arisen that's causing those cells to grow? And if you know that, maybe you can do a better job of picking the right treatment for that person that's actually matched to their cancer and not to some sort of general idea. So we are transforming our approach to cancer from a one-size-fits-all chemotherapy approach, which nobody is very happy with, to something that is much more individualized, targeted, developing drugs that are based upon a knowledge of what pathways have gone awry in cancer and then trying to match the drug to the patient. And we have now, through this cancer genome at NIH, built a very extensive catalog of what goes wrong in certain types of cancers, including the ones that you see here, as a means of moving in the direction then of coming up with a totally new strategy about how to approach this disease. If you ask about inherited diseases, look what's happened here. These are now conditions that are largely inherited. Many of them are conditions where each parent carries one misspelled copy of a gene and they happen to both pass the misspelled copy to the same child. Then that child has only misspelled copies and they come up with a disease. We call that a recessive disease. The parents generally are completely unaware that they carry such a glitch because they have a normal copy as well and they're fine. But if that one out of four chances happens where they both pass the glitched copy to the child, the child's affected, we have been able to uncover the causes at the DNA level of thousands of those, as you can see over the course of the last couple of decades, largely because the genome project has made that possible. So let me just tell you about an example. One thing that has helped us here is having a really organized effort to try to be able to uncover causes of illness in this situation. And the Undiagnosed Diseases Program at NIH, which has been underway now only for about three years, is a place where individuals who have disorders that have defied medical diagnosis for several years, sometimes for a decade or more, come for a very detailed analysis by about 30 physicians and they have to spend at least a week having all this looked into. And as part of this, they get their genome sequenced to see if there's a cause there. This effort led by Dr. Gaul, who you see down here, has now evaluated 3,000 possible patients and accepted 700 of them to come and has come up with a diagnosis about a quarter of the time, which is pretty good when you consider that these are absolute mysteries. And this is now a network that's being spread around the country because it seems like a useful program. But how do you crack a case of a rare disease? How do you sort this out? Let's approach this as a detective story the way that Sherlock Holmes might do. What are you going to do? So, location, NIH's clinical center, disease detectives, researchers from across NIH. The case, this is a real case, three young children keep having fevers and rashes and even strokes, children having strokes, that's not supposed to happen. What is going on here? These three kids have very similar presentation, but this is a disease nobody's ever described before. What is going on? Looking for clues. Well, because you're here at a genome talk, you can imagine, somebody wants to look at the DNA here. So, check the genome, let's see what you see. And these kids all had their DNA analyzed looking for somewhere in there an answer, a mistake that might account for this. Using these new sequencing technologies that allow you to do this at an affordable cost in a short period of time. And in these three kids, they found mutations in both copies of a gene called ADA2, which nobody had paid attention to before. But now that we know something about it, well, what do you know? It turns out it's a gene that's really important in making healthy blood vessels and immune cells. Well, okay, that starts to make sense because if that gene is not functioning and not making this enzyme called ADA2, you end up with problems with blood vessels and the immune system, fevers, rashes and strokes. So, this is now called deficiency of ADA2 or data2, a new disease described for the first time published in the New England Journal of Medicine, and very importantly, suggesting an intervention for these kids. Because here are two of them, Andrew and Haley, who came by to see me in my office a couple of weeks ago. They're back at NIH now undergoing experimental therapy to give them something called fresh frozen plasma, which is basically plasma from normal individuals that contains that enzyme, ADA2, that they can't make. The hope being that that will in fact supply what's deficient in their systems and keep them from having strokes, rashes and fevers. And this is clinical research, so we don't know the answer, but it's very exciting that it's been possible to get a diagnosis that leads to a therapy you never would have thought of without knowing this was the cause. So, we have all of those and in this instance, it's a possible suggestion of therapy and that's encouraging. What's not so good news right now is if you ask of those several thousand diseases for which we know the molecular basis, how many do we have proven treatments that the FDA has agreed is now appropriate to say this works, 250. So, a huge challenge right now at NIH and in any area that's doing medical research is to try to come up with new therapies for those others that are not there. Now, once in a while, we encounter one where the therapy, a light bulb goes on and we get an answer pretty quickly. And if you were upstairs already and walk through the genome exhibit, you might have seen this story about these twins who I know quite well, the Beery twins, Alexis and Noah. They were diagnosed with what was called cerebral palsy at age two, but frankly, it didn't really fit cerebral palsy because they kept getting worse. Cerebral palsy often caused in a premature infant by difficulties right at the time of birth with hemorrhage into the brain. Once it's there, it's generally not going to deteriorate and yet these kids were getting worse and worse. The mother, who's a pretty smart cookie, questioned whether this was consistent. So, she sought new diagnosis. She went to doc after doc after doc. A diagnosis of dystonia, which just means a muscle tone problem was made and just sort of as a guess, they were started on a drug that's usually used for Parkinson's disease, L-dopa. And they had some improvement, but by age 14, this was really not working anymore and they were deteriorating severely and Alexis was in the emergency room almost every week with respiratory arrest and it looked as if this is really coming to the end of what's possible. Well, what happened? Sequencing found a new genetic disease. This is the two of them after that jumping on the trampoline and what happened was they have a never-before-described glitch in the genome that prevents them from being able to make dopamine. That's why the L-dopa worked, but they also can't make another famous neurotransmitter, serotonin. So, they have to be supplemented with something that will allow them to do so and it turns out there's a fairly simple way to do that with a amino acid. So, between L-dopa and this amino acid, which you can get fairly readily, this is the result. We had them come out to NIH for a symposium we had about a year ago and they were, they brought down the house, I must say, at the end of that event. Alexis and Noah, this is Alexis here. This is Noah. Alexis, by the way, is running Varsity Track now for her high school and this was the kid who was having respiratory arrests and pretty much everybody assumed she was not going to make it. So, those stories are so exciting and I wish we had more of them. Let me just say a couple more things about how we try to go from understanding a disease to treating it that might also be useful, but we are going to get to your questions pretty soon. We don't always have the good fortune to look at the DNA mistake and say, well, you just need an amino acid. Usually it's more complicated than that, but if we understand what's wrong at the molecular level, then it's at least a start point to develop a therapy and the therapy is often going to be a drug therapy. So, how do we make drugs? How do you actually find out, how to identify in the sort of universe of chemical structures, which is what drugs are, they're chemicals, what is the one that's actually going to help somebody with some rare genetic disease? Well, I need to walk you through very quickly what that pipeline looks like. So, these are my cartoon version of drugs. They're all organic compounds. They're made up of things like carbon and hydrogen and oxygen and nitrogen and there's often a sulfur or a fluorine or a few other things in there, but they're shapes. Just think of drugs as shapes and it's a shape that you want to intersect or interlock with some target. If there's a protein that's running amok, you want a drug that has the right shape to bind to it and shut it down, or if there's something that's missing and needs a bit of a nudge, you want a drug that will bind to that and give it a kick, so it'll go better and faster. That's what the trick is of finding the right drug, but oftentimes you don't know, you can't just design it by looking at the situation. We're not that good. You have to do a very large screen, oftentimes of hundreds of thousands of these chemical shapes drugs to find one that looks like it attacks the target that you now know from studying the disease is the one you have to hit. So, you have to start with a very large library. We actually call it a library of drug compounds and then try to see what will work. So, you're now about to try to do that for a disease. Here are all these compounds and you've got to come up with your way of screening them and you often will start with a very large number of those. Let's say 10,000, that would be pretty modest in fact. And then you do a screen and you narrow it down in the preclinical space, maybe a few hundred, and then you have to go to a clinical trial with people and you aren't going to be able to do that for more than maybe five because it's very complicated and expensive. And if all goes well, you might at the end of, notice the timetable here, at the end of 14 years, you've got a drug. That's pretty frustrating. We can't wait 14 years for those thousands of diseases. So, a big part of what we are trying to do at NIH now, working with the private sector, is to identify what are the bottlenecks here that would allow you to get from the left to the right a lot faster than 14 years and get answers for those people who are waiting for them. For that, we started a new center, the National Center for Advancing Translational Sciences, which aims to do just that. One of the things that's kind of technologically cool that we're doing is to try to figure out is there a better way, if you're designing a drug for a disease, to quickly find out whether it's going to be safe or not because that's where we crash and burn a lot of the time. You get a drug, it looks like, yeah, it's going to work, but it turns out it's toxic. Well, you can't do that. But how do you do that without putting a patient at risk? Well, right now, we give those drugs to rats and mice and maybe sometimes to dogs or monkeys and we wait to see if they get sick. Very slow, very expensive, not the way to do things at scale. So maybe we could do this better if we didn't have to use other animals. We used people, but we didn't actually put the people at risk. We put their cells on a biochip and tested them out to see what would happen. Well, now we're getting pretty good at that. This is a very high-tech model of a lung. Does that look like a lung? Not really, but it actually has cells in it that represent a lung. Here's the cartoon of what it is. This chip actually has vacuum channels on either side, so it breathes and it has an air channel at the top and then it's got cells, human cells that are loaded up here, which are like the airway, and it also has blood channel underneath. So you could use that to test whether a particular inhaler is going to make the cell sick or not or even whether it's going to make them better. We're doing that kind of thing to try to speed up the process of doing this development. We're also working with industry to try to make the best of their skill sets and the academic center skill sets. We just announced this new accelerating medicines partnership, AMP, that is now starting to work together on Alzheimer's disease, diabetes, lupus, and rheumatoid arthritis to try to see if we can speed up that 14-year timetable and end up with more successes in a short period of time. Well, let me finish with just a little glimpse of where this may take us all in terms of a future dream, and this will be quite futuristic and I can't tell you that any of it will come true. I know it won't come true if we don't invest in the research, but this is maybe something to think about as you consider what you learned here at the Smithsonian on a Saturday afternoon in April. So we're going to talk about Hope. Hope is a fictional character, but we're going to learn something about her. She was born on April 14th, 2003. Baby Hope is born on the very day that the International Consortium completed the Human Genome Project, Bethesda, Maryland, April 14th. So Hope and the Genome Project had something in common right on day one. The family heard that news, thought, well, that's pretty cool, put that in the baby book. Ten years later, just being a year ago, we had a big symposium, a big special event to celebrate that 10th anniversary. Here's the poster that was put up, but Hope was not so interested in that. She was having her 10th birthday. Okay, things are going well so far, but okay, now we're moaning the future. In 2023, nine years from now, Hope's aunt died at age 53 of heart failure. Family had not really had somebody die that young before. Everybody's kind of wondering what's going on here. There's a family, there's a Surgeon General tool up on the web. If you're interested, you can find it quite readily. Just type into Google, Surgeon General Family History, and it will allow you to collect from all of your family members their medical histories, put that into a standard format that you can then take to your doc and say, this is my family history. Is there something we should talk about here in terms of my wellness? This is actually quite useful. This is a genetic test, but it's free. You don't have to go to any laboratory or anything. Just use the phone, use the email, find out from your family what are the conditions that have afflicted them because it's not always something people talk about, and then get that recorded and then ask your physician, how could I use this because it's going to have some influence on your personal risks of disease, having an idea of what other people in the family have suffered from. Hope does that, uses the Surgeon General's tool and finds out that in fact, this is her output, average risk for Alzheimer's and breast cancer, low risk for colon cancer, but a high risk for heart disease. Based upon this, the doctor encourages complete genome analysis for the family. It's 2023, so it costs 100 bucks a person now, and it turns out that further confirms this risk for her of heart disease that her risk is about three times higher than normal. Well, that motivates hope. She hadn't been paying much attention to diet and exercise until then. Now she's deciding, I'm going to be healthy in my lifestyle, and she makes a real change that she's determined to stick with, and she does. So it was a good opportunity. Wasn't the news she wanted, but it was there, and now she can act accordingly. So further forward, 2053, she's 50 years old, has a happy 50th birthday, continuing to be in good health, maintaining a good lifestyle. She wears at that point a smart shirt, which is something that's probably going to come along a lot sooner than that, which is basically recording all kinds of parameters of heart rate, blood pressure, glucose, and everything else to make sure that she's staying in good health and is actually broadcasting that information to her doc in an entirely private way so that the doc knows also whether something's happening that's not right. Well, things don't always go well, because in 2071 she's out gardening, and she feels something's not right with my left arm. She's not somebody to sort of push the panic button, so she thinks maybe she's pulled a muscle, but her smart shirt knows better, calls the emergency responders, they show up at the door. She is immediately treated with a personalized drug therapy that's exactly right for her, and Hope is fine. And in 2103, Hope celebrates her 100th with a night of dancing, and Hope had something, by the way, to say about all this. She said, I remember celebrating my 11th birthday in D.C., April 14th, 2014. We came to D.C. two days early because we wanted to go to the Cherry Blossom Festival and go to the genomic exhibit, so maybe Hope is here. It could be, could be that Hope is here. So what is the goal then of NIH's investment in genomics and in medical practice and research? You can put it in three words. The essential goal, keep Hope a lot. Because Hope is all of us, and all of us deserve just exactly all of this that we can come up with, with research, with the dedicated people that are working on this, with patients who are willing to be part of our clinical research trials. We have a bright future indeed. Thank you all. Questions? So, yes, the floor is open. Sure, in the back. Thank you. Okay, so by the way, the ground rules are going to be if they're really straightforward questions, I'm going to answer them. If they're really hard, France is going to answer them. So, I don't remember that. Yeah, yeah, that was in your contract. The question, for those who didn't hear it, the question was, is genomic medicine, personalized medicine, do we think that's going to increase or decrease healthcare costs in the long run? Right. Go ahead. That's a hard one. That's a hard one. Because it's not a simple answer. I think it will decrease costs. First of all, the actual DNA analysis part of this, as you saw from those curves, is coming down dramatically. So that will certainly not be rate limiting in terms of people's ability to have the information. And a lot of this is going to be about prevention. And we all agree that one of the reasons our healthcare system is so expensive right now is because we wait for people to get sick and then we put them in the hospital and we spend oodles and boodles of money trying to get them better again. We would be much better off to prevent the illness in the first place. And this is a strategy to get there. Clearly any kind of new technology goes through a phase where that technology is a little uncertain and a little expensive. So there may be aspects of this that for a limited period of time seem to be driving costs up. But over the long course of time, I think this is one of our best hopes to bend that awful curve we've been on in terms of the cost of healthcare in this country and bring it back down to a reasonable place. You should start. I'll finish. So from the very beginning, the Human Genome Project identified ethical issues as crucial. And that was unusual. Usually scientific efforts have just sort of gone along until all of a sudden somebody went, oh my gosh, we've encountered an ethical dilemma. What do we do? Here the goal was to be prospective about it, to think about it. And we made real progress, I think, by having that proactive stance. For instance, genetic discrimination, which was such a huge concern for many people, led to recommendations from ethicists, public policy people, which after many years resulted in the signing of the Genetic Information Non-Discrimination Act in 2008 by George W. Bush. Not completely solving that issue, but putting the greatest concerns to bit. Many other issues, privacy. Do you want to know who else should be able to know? Is that something that we ought to be a cavalier about or should have better constraints about that? All of the questions that come to issues about newborn screening, a big question right now, should every newborn have their genome screened, sequenced into its entirety? Because it might tell you something really important to know. But on the other hand, you've taken away from that child the chance to say, I don't want to know because it's already done. And if you do that, how much of the information do you disclose? How much do you keep private? Lots of questions there. You have many more, I'm sure. No, I mean, it's a great question and I would extend it. So the study of the ethical, legal, social implications of genomics was novel going back to the very beginning of the Human Genome Project. But interestingly, we find it almost more important now than ever. In fact, the studies that we're doing at National Human Genome Research Institute, as we increasingly think about clinical applications, we find it incredibly important not only to study those things, but to study them embedded within the actual clinical research project. In other words, don't have the ethicists over here studying a problem, and the clinical researchers over here, but rather we have very integrated by design the studies so that hand in hand, these two things are being examined together. So there's practically not a program we are pursuing, a research program we're pursuing where we don't have a component of bioethics within it. Second thing I should say, and if any of you please look for this because you'll see it very prominently featured in the exhibition, is the fact that when we put the exhibition together upstairs, we recognize that so important with studying and understanding some of these concepts of genomics are some of these very vaccine societal questions, ethical questions, and other types of questions. And so we sprinkle that throughout the exhibition, where there are things where we ask the people, they can respond and they can give information and so forth. We even quantitate some of it so people can see how their answers are relative to other people who have visited the exhibition. Because again, we think to learn this, you should learn it in a very integrated way. It's not just clinical applications over here, it's societal implications over here. These are all highly interwoven. Yeah. Going through the training for genome guide on the exhibit upstairs, and you probably know we were offered the opportunity to do a group and read genome analysis, I was very surprised at the percentage of people going through training to be a genome guide who didn't want to know. They said, I'm not going to even take advantage of this because I don't want to know if there's something wrong. What kind of reaction do we have to that? Well, you have two people up here who have both had similar jobs or at least different parts of their career, similar jobs, and Francis already mentioned he chose to look into some of this for himself. I have yet to, so, but I might someday. And so maybe you want to give your view of what. Yeah, and then we can take a poll of what you all would say if this was offered as a little booth as you left the auditorium, and we said, we'll call you tomorrow with your DNA sequence. Would you take us up on it or not? Think about that. By the way, can we turn the lights on? It just seems like we're having an interaction here. We should have. I may want it this way for the video. Oh, is the video going to mess you up? No, it's okay. Okay. Okay. So, yeah, I was motivated because I thought it was good to start to think about how this information could be useful, and I was writing a book about called The Language of Life, DNA and Personalized Medicine, and I thought it would be sort of irresponsible to write about it without going through this myself. At that time, there were three companies that would give you this information direct to consumer. They cost between $400 and $2,000 each. The cost, by the way, has come down a lot since then. And I also wanted to see, would they give me the same answer? So, I sent my DNA off to all three companies, and I used an assumed name because I didn't think it would be good if they knew it was me. I used my name, by the way. Yeah, that's why you're getting all that marketing stuff in your email. And, you know, it was pretty easy. You scrape your cheek or you spit into a tube, and, yeah, a couple weeks later, you get an email that says the results are available. Here's your password, and you go and look. And the good news was they did all get the same answers at the DNA level. They all said, okay, in that spot, you've got a G, and they all said it's a G. That part, the technology is really good. But when they tried to interpret it, it was all over the place. Prostate cancer, one group said your risk is higher than the average, one said it's the average, one said it was lower. They can't all be right. They did all agree that my risk was higher than the average for diabetes, and that was a surprise to me. And my lab actually works on diabetes, so some of the things they were testing were things we had discovered, and now I was finding them out about myself, and I didn't like what I saw. And probably I was forced, therefore, to realize that my own lifestyle and diet and exercise was not well suited for avoiding that disease, and that actually motivated me. This is an N equals one anecdote, so don't take it too seriously, but it was a reason why five years ago I changed my diet, got into an exercise program, lost 30 pounds, which I have managed to keep off. So that was a useful wake-up call. A wake-up call you could have well said I should have had anyway, just sort of looking in the mirror, but that's another matter. So I found it useful, but I will tell you that the information is very much changing from day to day. I showed you that diagram of the chromosomes with all those colored circles. That is sort of new every week, and every one of those changes a little bit our view about how to make those predictions. And at the moment, I will tell you, the one company that was still offering that kind of medical evaluation was shut down by the FDA last December because of a concern that the information was so uncertain that it was not really justifiable to give this to consumers. There's a debate going on about whether that was an overreaction because consumers are pretty smart about sorting this out, and the company was pretty clear about what you know and what you don't know and telling people to be careful about that. Interesting, Jim Watson, the Watson of Watson and Crick, had his DNA sequenced, and he was asked, do you want to see the result yourself? And he said, I want to see everything except I don't want to see that place in the genome that predicts risk of Alzheimer's disease. Don't tell me that one. Of course, his genome then went up on the public databases, so it's kind of hard, I guess, to maintain that. But that is one to really think about because this Alzheimer's is a condition where we know there is a particular risk factor called APOE4. If you have one copy of that, your risk goes up three-fold. If you have both copies of that, it goes up 15-fold. And there's nothing you can do about it. So I think many people would be like, I'm not sure I want to look at that result. But most of the rest of it is kind of at the moment more recreational than it is medical. If you're curious, you might say, yeah, show me that. If you're a little worried about what it means and whether you want to go through the experience of having some news that isn't all encouraging because we've all got glitches. There are no perfect specimens. Sorry if you thought you were the one, but not going to happen. There's going to be news in there that you won't like and some other stuff that you go, well, yeah, good for me. It's all a mix. And maybe it's not quite time yet to start to really introduce this into mainstream. But people are curious. One thing you will find out is ancestry. And you can do that now in lots of places because your DNA carries an amazing history of where your ancestors came from. I looked at mine. I was hoping for something interesting, a little snippet of Asian background or something from the Middle East. I was just monotonously European. But other people have had some really interesting experiences when they go through this. And my answer, I think it's only a matter of when. I don't think it's an if. I think we're just at a phase right now where I will do it when it's medically relevant. Knock on wood. I'm extremely healthy. I'm not in any medications. But increasingly, we are learning more and more about tailoring which medication to give a patient based on which genomic variants they have. And in a heartbeat, if a physician came to me and said, all right, I want to put you on this medication, but I want to find out if you'll be a good responder. I want to do a genomic test. I would do it instantly. And if I would have a developed cancer of any type that we now knew that getting information about that tumor at a genomic level would be helpful in a heartbeat, I would get sequenced. So I'm just sort of waiting for that medical relevance for me. But it'll come. It may be two years, three years, or five years. It's absolutely going to be there. So who would want to have their DNA analyzed right now if it was free? So the majority. And some up there. Okay. Interesting. Next question. Yeah. Which one? In the back. Okay. Maybe just shout it. Oh, we didn't care. We just wanted to be over. So let me give the first part of it. I mean, one of the things to recognize, because I was there. I was young then, but I was there. Really, when the Genome Project began, we had a goal and we had really no clue how we were going to do it. You can't believe how early the tools were even for manipulating DNA and studying it, let alone sequencing it. So out of those 13 years, about the first six of them or so, we're just spent getting organized and figuring out how to do it. We first went through a phase of mapping out the DNA. That's actually what I did for a long time, of just getting all the DNA isolated and organized and figuring out how all the pages of the instruction book fit together. And that was before we could actually start reading out the letters. And so it really was an actively sequence for like the last six to seven years of the Genome Project. And when we first started actually sequencing human DNA, it was really low level. It was not at the thousand bases being read a second, 24 hours a day, seven days a week. That was only in the last couple of years. So it was really sort of very incremental at first and very being very organized. The question about whether we did it multiple times, in the process of reading out the human genome sequence by the Human Genome Project, you do it very redundantly. Every letter got read out on average at least 10 or more like between 10 and 20 times to make sure it's right. And then on top of that, there were programs that were put into place to sort of go back and spot check and basically proofread it by independently making sure we got it right. You want to say something about the quality? So the quality, because we did that kind of spot checking to be sure, is there was no more errors than about one every 500,000 letters. And I will say, however, there are parts of the human genome that are almost impossible to work with. You saw the picture of a chromosome. There's that constriction in the middle of a chromosome. It's called a centromere. And it's a very monotonous repeat of the same series of letters over and over again. We still haven't done those because we don't have a technology that can assemble something that's that repetitive. So we say we completed the human genome. There's a little footnote there that says, except for the roughly three or four percent of the genome that we are at the present time, our technology is unable to read. There might be some interesting surprises still in there. And when we figure out how to do that, we'll have another celebration and say we completed the human genome. Lots of hands up. I don't even know where to start. The world is somewhat concerned about pandemic diseases. And a number of years ago, we had an outbreak of respiratory disease called SON. And it turned out that VGI, which is a Chinese institution, was able to fairly rapidly lead out the genome of that positive organism and bring us the progress of that to a whole fairly quickly. Is that ability quite widespread worldwide? And should it be and can it be? Great question. Because we haven't talked about infectious disease. And of course, infectious organisms have DNA too. Whether they're viruses or bacteria or parasites, they all use this same instruction mechanism for what they do. And the first thing you want to know with an outbreak, whether it's SARS or whether it's the latest influenza, which is at the moment H7N9, is you want to know what is the DNA sequence, what's in there, because that will predict what proteins that virus is going to make. And that will give you some idea whether any of our existing medicines or vaccines are likely to work or whether we'd better get in a hurry and make new ones. And that technology is now widely accessible. You mentioned BGI, which is in China, which was a early player in the human genome project and now has become the largest sequencing center in the world. They are very quick to do that kind of thing. But we have lots of centers in this country that could do that in less than 24 hours and are prepared to do so. As a newer issue in this country of hospital acquired infections, and these are not viruses, these are bacteria, and they're bacteria that are resistant to all known antibiotics. And this is increasingly scary. I spent this morning working hard on a plan about how we might increase our surveillance and our genome sequencing ability, so that if somebody in an ICU, somewhere in this country develops one of these infections, you quickly get the complete sequence of that bacterium, compare it to every other bacterium you've ever seen, figure out how did it get there, what was the transmission, and what could you do about it in terms of an antibiotic that it might actually respond to? So yeah, big area of growth in genomics beyond what we've talked about here is infectious disease. And keep in mind that viruses, certainly, but even bacteria, their genomes are very, very, very, very, very small compared to human genomes. So reading out the genome sequence of a bacteria is incredibly inexpensive. So doing this in a surveillance mode of multiple samples and sort of detective work becomes very, very approachable. You can do a bacterium for a dollar. Right. I've been told we could do two more questions and then I don't even know where to go. So there's just so many hands up, I'm overwhelmed. We're speaking from the... That's a problem. ...and whatever you're thinking. Yeah, well, this is certainly, we feel very responsible in terms of providing leadership for this area at the Institute I direct, National Human Genome Research Institute. And the story I tell, when I started at the beginning, I said, I graduated medical school 26 years ago, something like that. I never heard the word genomics once throughout medical school, neither did my classmates. And I have classmates scattered across this country practicing all different types of medicine. And I, whether it's infectious disease, whether it's genetics, whether it's cancer, it's completely finding... It's gonna find a way into their practice in a very profound way in the next few years. And they're young like me. They're gonna be practicing medicine another 20 years, maybe longer. And they are overwhelmed. I mean, they're gonna be overwhelmed. And so we are working, I will tell you, in a very... And Laura Rodriguez, who introduced us, is also involved in this, as well. We are working very aggressively with medical professional societies to think about what we could be doing to help physician education, including physicians who are out in practice. Meanwhile, lots of discussions going on at the medical school level, how to train the next generation of physicians. But by the way, I should also pause and say it's not just physicians. Think about it. It's pharmacists, it's nurses, genetic counselors, physician workers. I mean, every healthcare professional needs to deal with this. And when you... So we're working on this, but it's such a fast-moving train that we can't just deal with the primary level of education in their professional school. We need to be thinking, even the people who are out there already in practice. And physicians may be reluctant to raise the topic because they're uncomfortable with it, as well. So yeah, we don't have our house in order. Let me take this one. I haven't been ignoring people off to the site. Oh, now there's a couple of winners. Those are both tough ones. I think you like to talk about U.S. competitiveness and science. Take it over. Well, I am in this remarkable position of knowing something about that as the director of NIH, which is the largest supporter of medical research in the world. $30 billion of your taxpayer's money goes into this research every year. And we are on a roll in terms of discoveries that are being made every day. It's exhilarating to see the way this is moving. That's the good news. The bad news is that we've lost quite a lot of momentum in the last 10 years because even though that's a huge amount of money, it's about 25% down from where we were in 2003 in terms of our ability to support research. And so our biomedical research community is really struggling to keep going. If you're a young investigator out there at a university who looks to NIH to support your research, your chance of actually getting those funds is the lowest it's been in history. It's about 16%. If you send in a grant, that's your chance it will actually get funded, even if it's a really great idea. Traditionally, that's been more like 30%. So we are not doing right by a very talented community of scientists who have never had more opportunities than right now to really rocket this whole effort forward. Other countries, on the other hand, kind of looked at our playbook from 20 years ago and they're trying to be what we were. And China in particular is increasing its support of biomedical research about 20% a year, just rocketing that upward. So they're already way outstripping us in terms of a percent of their GDP. But in another four or five years, they will spend in absolute dollars more than the United States on biomedical research. And you can already see the consequences of that. Now I'm fine with China investing in this as long as the data is accessible and as long as the quality is good. I'm not at all upset about that. That's great. It's a worldwide enterprise. But why would we want to sort of exit the stage right at the point where things have gotten so exciting? Because it's clear that medical research is also a major driver of our economy. And we are losing out on the opportunity to build our economy back by not being as vigorous in this space as we could be. The return on investment is amazing. Take the human genome project. Somebody did the math, figured out we spent $3.8 billion dollars in those 13 years to get the genome project done. And then what was that worth to America? The most recent estimate, $965 billion dollars of return from that $4 billion invested. So what is that, $160 to one? That's not bad. What's the next big thing? We want to do a big project on the brain. Will we have the resources to do it? I'm sure it will have the same economic reach, but other countries may actually this time be ready to go faster than we are. That would be really regrettable. So thank you for that question. Now as far as weaponizing, sure. We worry about whether people could take the tools of genomics and say take an influenza virus and make it even worse. They'd have to be pretty diabolically deranged to do this because they'd not only be threatening the people they don't like, they'd be threatening the people they do like. Because I know of no way at the moment that you could weaponize an infectious agent so that it would only hit people that are in the other group because we are all so much alike. Coming up with a strategy like that is biologically not feasible. You'd have to sort of contain it somehow geographically. You certainly couldn't contain it biologically. It is something we worry about. And there are people who are doing that very experiment trying to figure out with the next influenza epidemic what would it take for nature, who is the scariest terrorist in this situation, to create a virus like 1918 where 50 million people died in the U.S. It's not that hard. It doesn't look like. And some people are wondering, should we be doing that research? Because suppose the thing escapes from the laboratory? I think we're better to know as long as we're careful about it. But there are instances, and this comes back to the ethics question again. Are there experiments we shouldn't do? Are the things we really don't want to learn? Or if we do learn them, are the ways that we can make sure they don't get misused? Knowledge is not itself something with moral quantity attached to it. It's what we do with it. But that can then rather quickly be an ethical or a moral debate. So we should let you go, but there's one sort of final abuse that you're going to have to suffer. It's traditional. And you heard some warning about this before. Might I please have the surprise instrument which is maybe while we're setting that up, let me tell you Francis and I are both going up to the genome zone, which is the back part of the exhibit immediately following this. So if you have more questions, and I know there were lots of hands up, we couldn't get to, we'll be up there for a while, happy to answer your questions individually. Just come up and find us. So I have to explain this guitar, by the way. You will notice it's not just any old six-string acoustic. When I finished my role with the Genome Institute and turned it over to Eric, the kind people who had worked on the Genome Project made it possible by their donations of funds for me to design this guitar, which was built by Huston Dalton, a wonderful luthier in my hometown of St. Virginia, where the front row comes from. And as you can see, it does have a double helix in mother of pearl on the fretboard, as well as a number of other less obvious features. It's a fine instrument. And of course, it has to have a name. You know, BB King has Lucille. So Francis Collins has to have a guitar with a name. So we had a contest to say, what should the guitar be named? And there was a hands-down winner. You remember Watson and Crick? Remember what they did with the double helix? You remember whose data they sort of looked at without permission? Who was that? Rosalind Franklin. Well, this is Rosalind. This is Rosalind. So you're about to hear from Rosalind. And so this is a song about DNA, naturally. And it's borrowing a bit from a more familiar tune, at least for any of you who weren't born yesterday. And because this has a little group participation component to it, and I thought it would be helpful to have a member of this audience come up and assist with the group participation, I'm going to invite my sister-in-law, Judy, to come up and assist with this little ditty, which is all about genetics. I'm on a mic. You can, depends on your level of confidence. Okay. So, yes. Here we go. A wrinkled peas and Darwin had all his finches beaks, but oh, oh, oh, we really got you now. You can't stop us now. We really got the code on you. This is your echo comes there. So I do. We really got the code on you. I really got the code on you. You got it, y'all. Yeah. Thank you, Judy. A Watson and Crick, they were the first to see that A matches T and G pairs with C, but oh, oh, oh, we really got you now. You can't stop us now. We really got the code on you. We really got the code on you. We really got the code on you. Baby is just read you, read you, read you, or read you. Just want to know we got you now. You can't stop us now. We really got the code on you. We really got the code on you. We know the full extent of it, but only together can we assure the benefit. Oh, oh, oh, we really got you now. You can't stop us now. We really got the code on you. We really got the code. You're so very cool. Thank you, Judy. Nice having a doo-wop girl whenever you need one. And again, Francis and I will be upstairs in the exhibition for a while afterwards, so we're happy to see you up there. This is Tai, I know. Oh, what's wrong with the Tai? Did anybody figure out what was wrong with the Tai? It has a stain on it. I know. I'm really upset about this. He's going to hear about this later. Well, actually, the bottom helix and the top helix are correct because they're right-handed. The middle one is a left-handed helix. It would still be left-handed. Yeah, unless you're looking at it from the mirror. If you had a mirror, you might say it. Is mine okay? No, that's left. That's left. That's right. That's right. You got three out of five that are correct. I have two out of three that are correct. We really know what we're doing here, people. Well, thank you all. All right, thank you.