 Well, it's been a long day. I would bet for all of you And there's always the risk of being the last person in a symposium of this sort that everything will have been said by everybody Except the last speaker who then has to say it again, and I will try not to make that error It is at least an opportunity for me to say something from a personal perspective and not try to summarize the meeting I've been asked to do that occasionally at meetings that I haven't attended and that is truly a challenging task So I won't try to do that. I regret I missed all of the wonderful presentations because of a commitment made many months ago to be at a meeting in New York and I was in New York until one o'clock this afternoon. So thank you a cello. You actually were on time today Even at this symposium wasn't quite but that's all right So I do want to say a few things about looking back and looking forward It's going to be a pretty high-level view because I think at this point That's probably what you would want to hear from the NIH director who formally had a hand in this remarkable Experience called the human genome project So it will be a little bit of where did we come from and it will be a little bit of where we're going to go and Some of it will be serious and some of it frankly will be a little bit silly because at this point You're probably ready for some of that too So as soon as I figure out which of these buttons ah Well, this is what we're here to celebrate and I did wear my DNA tie And if nobody looks too closely you won't notice that one of the three strands here is actually a left-handed helix pay No attention two out of three isn't bad And you know the people who design these things apparently don't understand how critical that is For us to be able to hold our heads up or wear our appropriate garb But here we are and it is pretty remarkable to say it's been ten years since that Conclusion the first time we said we'd finished the human genome sequence and sort of meant it April 2003 But of course that didn't come about without a great deal of discussion and deliberation And David has already referred to the Albert's panel and this is the Albert's panel a publication there in green Which was very much an important step in giving this genome project some specificity some credibility Some scientific milestones a course over which one could actually see things go forward and know whether it was happening And that same time although not nearly as much referred to the Office of Technology Assessment came up with a similar report and that I think made a turning point But frankly for those of you who weren't around Even after the publication of this I would say the majority of the scientific community was either skeptical or actually frankly opposed To this project going forward because of the concern it was technically unfeasible It might take away the money for their R01s or it was just frankly so boring that nobody who was a good Scientist would want to work on it. There was that one too, which was all I thought rather patently offensive But there it was Unfortunately that did not come true because you could argue I think quite convincingly that one of the reasons the genome project succeeded was because it was So compelling it was so game-changing. It was so interdisciplinary It had such opportunities for creativity from multiple perspectives that it attracted Some of the best and brightest scientists of our generation Whether or not they had their arms twisted by Jim Watson. They all came and they came Enthusiastically and they stuck with it and they didn't worry too much about who was going to get the credit because that was obviously going to be a big team enterprise So it got underway roughly in October of 1990 as far as the NIH part of it and a couple of quick milestones from that 13-year enterprise, but I'll only hit upon maybe one or two I do think it's appropriate to point out that not only did the genome project break new ground Technologically, but it also broke new ground in terms of data release data access openness giving the data away And this particular slide a picture of the people who attended the Bermuda meeting in 1996 where this decision was made also includes a photograph of what was written on the whiteboard By John Solston and Bob Waterston leading a session that came to the conclusion that all the data from the genome project should be released Every 24 hours and there should be no filing of intellectual property claims upon this information It ought to be just out there for all the smart people in the world to begin to figure out how to use it and Again, that has really been I think a seminal moment in that it has changed the dynamic for genomics and increasingly for other aspects of Biomedical research as well into one where if you're involved in a large-scale community project of this sort It is your obligation to make that data available as soon as you're sure it's right Even in advance of publication, and I think that has enhanced progress in ways that cannot be overstated Well other milestones to mention. Well after a while we actually did get the sequence put together in a draft form We had a nice party on June 26th of 2000 even though John Solston famously said we were all a bunch of phonies because we hadn't actually published a paper at that point And there was a little bit of a problem there, but we got to that So February 2001 this paper describing a draft version of the human genome sequence with a cover intentionally designed to convey the idea that this was DNA but it was also about humanity and we had a little fun with that if You've stared at that cover closely. You may find there are a few surprises. There's one of them Just sort of hiding in there in the mosaic Watson and Crick whose discovery of course we celebrate today 60 years after the publication of that April 25th 1953 paper which essentially got this whole thing started And in 2003 ten years ago the finished version of the human genome sequence Possible to put out and some people said okay, that's good We're done with that now We're in the post genomic era and that's when I started to go nuts about that phrase And I will continue to for many years to come because until we've actually figured out the genome and how it functions Which I think David has made rather clear. We are a long way away from We're still in the genomic era. Let's be sure up. We are happy about that. We're celebrating that. We're making the most of that We did of course not stop there to focus on human variation a natural place For attention to be turned and an opportunity also there for a large-scale Coordinated international effort and a lot of technological Developments in order to speed up the ability to do SNP genotyping Coming forth as the HapMap project and moving quite swiftly Creating an ever-deeper database of human genetic variation and making it possible as you heard I'm sure from Nancy Cox earlier today to make a wide variety of discoveries about common variants that are associated with risks of common Disease here depicted by this myriad of colored circles now numbering well in the thousands and Yes, while many of these do in fact convey rather modest odds ratios to say the least They are nonetheless clearly statistically significant I should mention that one of the hoped for outcomes here has been slow to happen namely to use this information to try to identify new possibilities for intervening for those common diseases and I'm having the experience right now Finally after a few years of wheel spinning Working closely with 10 pharmaceutical company heads of R&D to try to figure out how could one apply filter to this set to actually Identify those GWAS findings that are most likely to be pointing to a drugable target that we didn't know about There must be some in here because the the positive controls turn up on this list If you're looking for evidence that this might be a good way to find drug targets It will probably encourage you to notice that most of the known drug drug targets for things like cholesterol or diabetes Turned up in this particular survey without our having biased the situation to make it so so while this has thus far been I think somewhat disappointing as far as Predictions of individual future risk because the odds ratios are quite small And we're still missing a lot of the heritability and a lot of the environmental influences It still seems to me that perhaps the major advantage here is to understand disease pathogenesis and pathways and to utilize that Information to come up with new ideas about therapeutics and we really haven't taken advantage of that as we might have and it's time Of course, we needed to know as much as we possibly could About genomes and what we could learn in terms of full sequences and the folks that have been conducting that deserve a lot of Compliments and applause for what's been done and I guess just today I learned that the low coverage and exome sequencing of 2,500 samples which is one of the goals has now been placed up there on an FTP site So that there's even more data than before and this is teaching us a huge amount of interesting things about genetic variation across the world Already mentioned and I'm sure described in much more detail by Levi Garaway a direct Implication and application of the ability to do high throughput genome sequencing at increasingly low cost has been the application to cancer And I think we all see those data sets coming forward at increasing speed With great hopes that this will lead us not only to better ideas about how to identify Subsets of cancers which is happening almost immediately when one has these tools But also to target therapy more effectively and we are now somewhere in the neighborhood of having 11,000 tumors In the pipeline to be completed by the end of 2014 Through the NCI NHGRI effort the cancer genome atlas and more to come through the international effort But I think it would be remiss to simply talk about DNA sequencing as Study of the genome as our goal here for genomics in this genomic era Clearly I will align myself with a lot of what David said about the importance of understanding function and pathways and networks and Systems and I have found the end code project to be enormously Inspiring because of the ability to begin to do some of that and to develop methods that allow you to begin to see it Is how variation connects to gene expression and many other things as well And so end code now having produced remarkable data sets including the mod encode effort And I'm sure you heard more about this seems to me to stand also as a major Contribution to our understanding of what we should be doing to get the genome's function in front of us Of course in 2012 last year a big outpouring of results from that 30-plus papers So many papers and so much information in fact that nature had to put up this Explorer to allow people to dig through the data and find other connections if you were looking for a particular kind of information If you haven't had the chance to play with that Certainly people in my lab found that extremely interesting as we are trying to sort out how it is that the pancreatic islet Utilizes its genome in health and disease to make insulin or not enough But of course this is I guess just one example all of these things that I'm talking about about the proliferation of data sets that we increasingly depend on to understand biology and We at NIH became increasingly alarmed about whether we had our house in order as far as the computational aspects of that And so we invited some experts including some people who are here to advise us about what we should be doing About the so-called problem of big data, which I don't think of as a problem It's an opportunity, but it will be a problem if you don't prepare for it adequately and this big data of explosion Presents us with challenges both in terms of algorithms in terms of hardware and in terms of training and NIH received this report from the data informatics working group Now not quite a year ago, and we have acted rather swiftly to take action upon it We've put together a set of internal governing bodies that go across all of the NIH Institutes and started a new trans-NIH initiative which is called bd2k big data to knowledge which includes The potential of funding centers of excellence, but also a very major focus on training We don't want to see NIH supported trainees coming out of graduate training or postdoc training without being skilled in computational approaches to biology they will simply not be able to be competitive or Be able to make the kinds of insights happen that we're counting on and we have a new leadership position the associate Director for data science, which you can see is very nicely abbreviated as ads because it is supposed to be mathematical and we have an acting ads namely Eric Green himself Who is both getting this enterprise going and also co-chairing the search committee to try to replace himself as soon as possible Because I imagine he's wearing enough hats already But anyway if you have great ideas about who would be the perfect person to step into this role I'm sure Eric would like to hear from you So all of this has in terms of the medical applications Resulted in pretty dramatic Consequences we heard from David that perhaps their 5000 Mendelian disorders for which we have the known molecular basis And in fact this comes out of OMIM. It's just about that maybe 4800 We are all pretty much in the same place here on these numbers and look at the way in which that has happened Beginning in the 1990s. That's not by accident That's because first genetic and physical maps and then increasingly sequence abilities came along and made this kind of effort possible And of course it's accelerating now with the ability with even rarer conditions to be able to use exome sequencing on very small numbers of families Sometimes even one or two to be able to find a mutation that is causative of the disease And that is going to cause this curve I suspect to jump up a bit more steeply in the next couple of years and that's a good thing And in a few instances at least that has resulted in dramatic outcomes In those instances where that discovery in the circumstance of an undiagnosed disease leads you to the idea of an intervention That you would not have come up with otherwise Here on this stage back in the fall We had something called the celebration of science and at the conclusion of that perhaps sort of the most Impressive example of how this sort of genomic sequencing has changed lives. We had on the stage the Beery family and the two Kids there not the one in the middle who's the older sibling, but the other two who are twins Came out after their mom and dad told the story of these two who developed an increasingly Awful form of neurologic degeneration and dystonia and were found on sequencing of their genomes to both be homozygous for the loss of function in a Previously undescribed a pathway which basically meant that he could not make either dopamine or serotonin and Simply by supplying them with both L-dopa and dietary supplementation of five hydroxy tryptamine These two went under a rather remarkable almost miraculous recovery in the space of weeks Now we wish that that would happen all the time and it doesn't but those examples do give one Some inspiration that we're on the right track here at least in some instances Obviously this worked because a lot of people had done a lot of very good biology Previously about the pathways that were involved so that you knew when you found the mutation what might be the right dietary and pharmaceutical intervention so That's the good news in terms of the discovery of disorders in the molecular basis the part that I think we should not feel So good about is this That as of right now of those 5,000 disorders or so They're only 250 of them that have a therapy that is considered to be appropriately beneficial a huge gap Now we all know that gap is a tough one to cross because there's so many steps involved and many of these are very rare diseases Where in fact the expectation of any real serious private sector interest has got to be muted by the lack of anything like a very Large market for financial purposes But I don't think it's appropriate though for us to just shake our heads and go well That's the way it is I do think there are things we can do to speed up the process of going from gene discovery to therapeutics that long 14-year typical Pipeline has some aspects of it that could be susceptible to new scientific ideas and are in fact being tackled now in systematic ways In partnerships between public and private that no company would undertake on their own And that was in fact the motivation to start for the first time in quite a while a new center at NIH the National Center for Advancing Translational Sciences, which is already I think made a significant impact in this space albeit with very modest funding The only new funding for this effort that was not already there from other things that were cobbled together Is something in the neighborhood of point two percent of the NIH budget? But it has allowed us to focus on things like how to do better job of drug Toxicology testing then they tried and true and often not so true a testing of animals It's also allowed us to set up a program to repurpose compounds that had failed for one application But might turn out to be just the thing for a rare disease where you just discovered the molecular basis And a few other things as well So I think it is an interesting development and one which while a very modest form of new financial contributions Potentially might get us closer to closing that yawning gap between what we know about diseases and what we can do about them and of course this was a Center that attracted some controversy anytime we do something at NIH that sounds like we're building a new enterprise People are worried about okay Where is that coming from and what kind of consequences where there'll be for funding of other things? it seems that we're in that space again here in the last month or so because We have a new kid on the block here in terms of NIH and Initiatives namely the brain initiative brain research to advancing innovative neuro technologies This is an enterprise announced by the president on April 2nd, which is very basic science This is an effort to try to build very fundamental ideas about how circuits in the brain work Starting with model organisms because the human brain is way too complicated with its 86 billion neurons But we don't really have at the present time a very good understanding of how to record Simultaneously from tens of thousands of neurons and be able to assess how it is in real time that some complex function is being carried out How do the emergent properties of the brain actually emerge? You'll never really learn that by studying one neuron at a time You've got to get into the complexity business and that was the motivation for this again a modest scale $40 million dedicated to this next year for NIH and FY 14 you're doing the math You'll know that slightly over point one percent of the budget, but just slightly But potentially also an opportunity to bring together scientists from multiple disciplines nano technologists engineers neuroscientists to see if we could kind of in a genome project Like way to learn to talk to each other and develop new ideas about what to do This project clearly needs just like the Albert's panel did a blueprint of what exactly are going to be the steps And that is something that is now under construction being led by a very capable team Which Corey Bargman and Bill Newsom are co-chairing in which by the summer will have some general ideas of what we should be doing First and by the summer of 2014 a more Albert's like panel So there are parallels here to the genome project, but we shouldn't overstate them because the genome project had a much clearer endpoint I don't think we're gonna be done with studying the brain anytime in my lifetime or yours Nonetheless, it was an exciting opportunity to think about sort of the next as the president called it the next great American Science project to try to see what we could learn about that most complicated structure in biology That we know of in the in the universe the human brain And but to work up to it gradually just like we did with the human genome It did attract some attention and some anxieties So yeah, there seem to be some similarities here between things that happen in the White House and what people say about it before or after So I thought it'd be fun To give you a little quiz here which appeared in Wired magazine This came just about a month ago where there were quotes put forward by Wired And they asked you to read the quote and to answer the question Was this a quote that was made in about 1988 about the genome project or is it a quote made in 2013 about the brain project. So here we go Okay, I mean you're gonna you're gonna get the answer here. I'm gonna tell you is it brain or is it genome and We'll give a little animation so that you'll get to enjoy that part too when you see the answer. So here we go So here's a quote The whatever it is project is bad science. It's unthought-out science. It's hyped science Is it brain or is it genome? Okay, genome. They say ah, you got it, right? All right, let's see. I believe the scientific paradigm underlying this project is at best out of date And at worst simply wrong. I hear brain. Okay, you're doing pretty well here They aren't all are alternating. It's not going to be that easy Concentrating hundreds of millions of dollars on this one mega project in the era of budget cuts is sure to starve hundreds of small more promising biomedical research projects Yeah Gotcha In contrast to some areas of physics which require extremely expensive facilities Biology does not have an obvious need for big science Our country's spectacular success in this area has depended in large part of the wide support of independent investigator initiated peer-reviewed research Genome. Oh, yeah, I even remember who said that one. I don't know if he does but we do Creative sciences bottom-up not top-down. Are we talking about central planning inside the Beltway? That was actually said by Corey Bargman who's now the co-chair of the group that's making the plan So they see you criticize. This is what happens. We put you to work It's gonna do absolutely no good to develop tools for a new generation of scientists If we in the process seriously damaged that same generation of scientists. Well, we didn't get the answer Oh, no, it didn't rotate. Well, I guess I don't know to be continued Yes, sorry leaving you hanging there arguments are made that the project will give birth to a new generation of technologies What good will that do in the absence of individuals trained and capable of applying these technologies? That was a real concern and maybe it still is We're still there the amount of money we asked to accomplish the task 200 million dollars a year Which has been floated for brain as well as genome is commensurate with the project's role in the fight against many serious health problems all right a positive yes and Everybody I talked to thinks this is an incredibly bad idea. I was genome That was genome. Okay, so maybe there's a pattern here and maybe those of us who start these kinds of enterprises or start talking about them Remember that but of course it doesn't mean just because genome turned out pretty well That the next big science project will turn out pretty well So you should all be watching carefully here and holding us accountable Okay, well briefly. Where is this whole thing going? I want to finish up with just a few brief remarks about the future and again I'm very much I think pointing you towards this issue of nature which included a really wonderful Summary by a lot of people but Eric and Mark led this enterprise And I like the graphic that they put forward here about the ways in which this enterprise is going to move forward as sort Of as a comet does but with a very broad reach across all kinds of Aspects from sequencing on up to medical applications and that all of those things ultimately We'll move a little bit to the right but not so fast because clearly we have a lot of work to do on the left side of this as well And the kinds of things that that paper points out in terms of genomic medicine Genomic space diagnostics need to become routine to find the Genetic components of disease Comprehensive characterization of cancer genomes We're in the middle of all these things defying practical systems for clinical genomic informatics uncovering the role of the human microbiome Fascinating and I'm sure Claire talked about that today and to get to 20 all of these goals by 2023 This these authors layout some fairly ambitious Milestones understanding the biology of genomes at the level that we don't currently bioinformatics and computational biology education and training and of course the important Aspect of keeping track of the implications of all this for society beyond the scientific and medical issues So let me finish with a little bit of a silly futuristic view here about where this will all go Assuming that it goes well, and this is going to be a made-up story about personalized medicine Over the next shall we say 100 years? So this is about a baby named hope who was born on April 14th 2003 10 years ago Family heard news that the human genome project was completed because that was the day We had a big party at the Library of Congress and said we had achieved all of the goals of the HGP Well, okay fast forward 10 years to now We're having a 10th anniversary celebration and hope is turning 10 years old and having a nice party with a lot of balloons Okay, another 10 years forward Hope attends a funeral of her aunt who died much too young at age 53 Causing the whole family to be quite in grief and wondering what happened And that led to an interest on the part of the family and actually trying to look at their own family history and say Are there other people who might be at risk and what should we do about that? At the point where we are right now the Surgeon General's family medical history tool would be Likely placed to go and no doubt it'll be much better in 2023 and in addition There would be some genome analysis potential which may be by 2023 will have somewhat better Abilities to make predictions, especially if you combine it with the family history that free genetic test Maybe we'll be able to say something actually Fairly useful for somebody in this situation and hope turns out like a rant to have a higher risk of heart attack And so she decides okay I'm not gonna smoke and I'm actually gonna watch my weight and exercise and try to do something to reduce that risk All sounds fine 30 years go by Hope is celebrating her 50th birthday party in 2053 and She's also taking advantage of new developments in terms of personal health maintenance wearing a smart shirt Which keeps track of all kinds of bodily functions to make sure that she's doing well And it's also time for another party because the human genome is 50 years old and hoping her family are very attached to this too I can I can assure you but of course hopes getting older and In 2071 now in her late 60s hope feels some tightness in her arm while she's guarding She thinks maybe it's a pulled muscle But her smart shirt comes to the rescue says this is not good picked up some arrhythmia there calls the emergency responders who arrive She is actually treated quickly and because her information is readily accessible She gets the right treatment for her and ends up surviving what otherwise might have been a very bad episode And all goes well. She celebrates her hundredth birthday with the night of dancing in 2103 I Hope by then the clothes will have changed but oh well hoping her husband are still living in the past as far as their wardrobe So that's a happy outcome right and that's not too implausible to imagine it might happen I don't think we stretch too many scientific or social developments, but it didn't have to happen that way So now the darker side of this could we count on that kind of outcome for hope? Well, maybe not Hope's story gone wrong In 2023 her aunt dies of the heart attack. This is sort of the teachable moment But there's no online tool left for family medical history available Physicians have not learned how to use family history or genetic information genome analysis is dismissed And so nothing really is provided back to hope she makes some unhealthy life choices gains weight Maybe smokes occasionally and what do you know by 2038? She's developed high blood pressure She basically could have been tested to see what would be the right drug for her hypertension But that wasn't actually available or hadn't been developed or wasn't Paid for so instead she got a random drug that causes a hypersensitivity reaction, which was quite unpleasant She said these doctors don't know what the hell they're doing and stop the treatment So as she continued then eating an unhealthy diet gaining more weight Uncontrolled hypertension and now in 2053 she feels tightness in her arm while gardening There's no smart shirt in this scene. Dr. Dismiss is it as a pulled muscle She's taken to the ER three hours later in cardiogenic shock given standard therapy with a pro drug But you know what her particular metabolism was very slow So she didn't actually metabolize it into the active form Hope dies in the ER at just 50 years old having missed out on fully one half of her potential life span so that's not good and One of the goals I guess as we think about the future is to try to identify the kinds of actions that we have to take as scientists But also as people who care about the health care system To make sure that we give a better opportunity for this not to have this bad outcome So basically the essential goal of genomic medicine if you want to ask it What should it be and to get it down to three words? It is to keep hope alive As you knew that was coming didn't you and Hope in many ways is all of us hope is you hope is me hope is our families our loved ones We have the promise here with all the knowledge that we are gaining about the genome and how it functions And how it plays out in health and disease to turn these coming years into really dramatic advances for medicine as well as for science But it isn't automatic that that will happen and things such as this really awful event that we are living through right now called the sequesters Which slow down our momentum are to be regretted and to be pushed back against and we should do everything in our power To continue to make the case that we are engaged in an enterprise Which has the potential of enormous advances in human health and actually stimulate the economy? Which is something that people pay attention to and furthermore that genomics and all of what we do in medical research Is not just a random activity. It is a noble enterprise It is one of those things that I think we are all fortunate to be called to be part of To take the time that we have here on this planet to spend it in the laboratory or in the clinic Making discoveries about things that have mystified people for all of human history and then trying to apply them to the betterment of the human condition What a privilege that is so I want to thank you all for being here and for putting up with this final silly Presentation and I hope this day will linger in your memory. I know it will in mind. Thank you all very much