 So, I will simply introduce the next speaker, who probably needs no introduction, former director of the National Human Genome Research Institute, now head of the National Institutes of Health, and clearly a major force in genomics for many years, Dr. Francis Collins. Wow, Eric, what an amazing start to an amazing day. Symposium is supposed to be a Greek drinking party, but I guess we don't get to do the drinking part, but this certainly does feel like a party to celebrate 10 years of the genome. And I guess in that regard, Eric, you must have been the appetizer, and I think I am now the soup. And then we will get on to the main dishes, which are going to be really amazing in terms of the information and the quality of the presenters, what a lineup has been arranged for today. It's really exciting to be part of this. So, in my comments, I thought I would just say a few words about where we've come from in the last 10 years, but mostly talk about where we're going with a few snapshots of the ways in which the application of genomic sequencing is already making differences in the lives of real people. And so I'll tell you a few anecdotal stories if you'll forgive me, and then I'll move on to talks about how we might begin to take a lot of these developments and move them more in the translational direction, because that is something that I think at the present time we have a special opportunity to do. Well, it has been 10 years since those covers both appeared, and now here we are to talk about what's been accomplished. As one example of the way in which the genome information has made it possible to learn more about disease, if you look at disorders with a known molecular basis, and you watch to see what's happened in terms of the numbers of those over the course of years, you can see the beginning in the mid-1990s as genome tools became more and more accessible. That began to rise dramatically, and we're now up to the space of about 4,000 of disorders whose molecular basis has been determined based upon what you can read in OMIM, just a dramatic increase in information about disease. And of course many of these are single gene Mendelian disorders. We've also come a long way in our ability to understand the genetics of complex diseases, and this is process that had its first success in terms of the genome-wide association study in 2005 with the identification of a variant in the complement factor H gene associated with macular degeneration. And then over the course of the next few years, as you can see from this diagram building up each one of these circles representing a well-validated genetic variant associated with a common complex disease, the number now over a thousand of such variants that have been discovered. Most of these with relatively modest contributions to disease risk, but pointing us towards pathways that must be involved in disease, which are exciting to contemplate in terms of their potential for developing new approaches to therapeutics. But I wouldn't say we've quite yet gotten to the point where all of this is turning out to be actionable in the average encounter between healthcare providers and patients. And this cartoon doesn't exactly give you a view of the future. First of all, they have this hard copy of the genome, which would probably not be the way you'd want to implement this kind of research. And you also have this obvious puzzled look of the care providers basically going, what the hell do we do with all of this? So I want to talk a little bit about ways, though, in which we are already getting to the point of being able to do things like this, although hopefully more effectively. And again, you've already seen the famous diagram. I'll show it one more time, but I bet you'll see it again during the course of today. That is the way in which the speed in being able to determine DNA sequencing is really driving much about what we'll be talking about in terms of genomics. And that dramatic drop that even exceeded Moore's law beginning about four years ago with next-gen sequencing coming online, making it possible now to sequence a megabase of DNA for much less than a dollar 15,000-fold improvement in cost effectiveness in the course of these last 10 years. How has this then played out in terms of applications to medicine? Well, let me give you a few examples. These, some of them from the published literature, show the way in which one can now take systematic DNA sequencing, not depending upon a hunch about what gene is involved, but actually looking at the whole genome either by exon by exon or the entire sequence, and being able to identify variants that are associated with the disease in a consistent way. This is one example, kabuki syndrome, where the MLL2 gene turns out to be mutated as a cause of this disease, which was too rare with too few families to be able to map by the traditional positional cloning strategy, but now in this work done at the University of Washington is understood at the DNA level. Other speakers today, no doubt, will mention other examples of this same sort. Rick Lifton, no doubt, will tell us about ways in which this has revealed interesting examples as it comes to salt and hypertension, for instance. Just published last week, an interesting example of this done here by Bill Gaul and colleagues as part of the Undiagnosed Diseases Program. These two siblings and three other siblings that are part of the same family have had this progressive debilitating joint pain, and this really remarkable looking x-ray showing the way in which they have calcium building up in the arteries of their hands and feet, but interestingly not in their coronary arteries. These two sisters were seen here in the clinical center as part of this program, an analysis done of the affected siblings narrowed down the interval where they all seem to be homozygous, and ultimately sequencing showed a mutation in the gene Nt5e, which you can see in the diagram here, is resulting in a very low expression, almost a zero expression from that locus. Well, this is an interesting example because it not only explains what's going on in this family, it actually reveals a pathway that we didn't know about before. The Nt5e gene encodes this protein CD73, which converts AMP to adenosine, and apparently the absence of CD73 resulting in the inability to do this conversion results in calcium building up in arteries in the pattern that you saw there. So this is a new disease, not previously described, but also shedding light on a pathway that was not previously understood. My prediction would be we're going to see a lot of this because there are still more than a thousand, more like 2,000 diseases for which we know there are single genes involved, but which are rare enough that they have not yet been identified. In my own lab, I would say the availability of genetic tools to be able to investigate a very rare disease has been empowering in a way that's actually led now to clinical intervention. This is the disease Hutchinson-Gilford progeria syndrome, one of the rarest of human diseases affecting about one in eight million individuals and resulting in a dramatic form of premature aging as you can see in this affected boy. Individuals with this disease traditionally have lived only to about age 12 or 13 dying of heart attacks or strokes with a very rapidly progressive aging syndrome. It was possible using tools from the genome back now seven years ago to identify the cause of the disease, which turns out to be a single DNA-based change, and it's actually one that's rather unusual in that looking at it, you might conclude that this is a silent mutation because here's the normal sequence of laminae. Here's the mutation that you find in kids with progeria. It still codes for glycine. However, it does create a spliced donor in the middle of Exxon-11, which is not normally supposed to be there. That results then in an alternative splice that deletes the last 150 nucleotides of Exxon-11 resulting in a protein that's missing 50 amino acids. Interestingly, almost all children who have the classic form of progeria have this exact base change, and their parents are normal, so these are de novo mutations almost always in spermatogenesis in this particular nucleotide, giving rise to a very recognizable clinical phenotype. The way in which this causes disease is actually fairly clear based upon all the hard work that had previously been done on the biochemistry and cell biology of this protein called laminae, because laminae actually is synthesized and then post-translationally modified by the addition of a pharnosyl group near its carboxyterminus. But then there is a cleavage enzyme called ZIMP-C24 that actually takes off the last 18 amino acids, including that pharnosyl group, and the mature laminae is no longer tethered by that pharnosyl group to the nuclear membrane. It apparently needs that in order to zip code itself to its proper location just inside the nuclear membrane, but then it needs to be released. The mutation in progeria is such that it deletes the recognition site for ZIMP-C24. Those 50 amino acids that are missing include that recognition site, and so you end up with a protein called progerin, which is permanently pharnosylated, permanently anchored in the nuclear membrane, and which causes all manner of disruption and ultimately premature senescence of the cells. So knowing that this was the pattern worked out by others, and knowing what the problem was in progeria, we reasoned that one possible strategy, if this is a toxic protein, would be to try to cut back its amount, and that would be to use a pharnosyl transferase inhibitor to try to block this earlier step, recognizing that there are many other proteins that are also pharnosylated that will be affected. But pharnosyl transferase inhibitors had been generated by several drug companies because the famous RAS oncoprotein is also pharnosylated, and so those were available for use in a clinical trial, and these 28 kids are now more than two years into a trial with this, with preliminary data suggesting that this is actually working pretty well. This is a phenomenal kind of thing to be able to point to, seven years from gene discovery to clinical trial already two years along for such a rare disease, but perhaps that's a snapshot of where we might be able to go in the future as we get more and more information about the genetic basis of disease and about how we might connect that up with the armamentarium of targeted drugs, many of which may have been designed for other purposes, but which can be recruited for this particular application. Let me tell you another anecdotal but interesting example of how genomic analysis has led to an intervention. In this case, it's Nick, who you see here at six years old. Nick developed severe inflammatory bowel disease before his second birthday, something that looked like Crohn's disease, but obviously very early onset with multiple intestinal fistulas, unable to be fed PO, 100 plus surgeries, no diagnosis about what was going on. The folks at MCW undertook whole exome sequencing and found a mutation on the X chromosome in a gene called XIAP. Here's a gene that had previously been linked to a blood disorder, but not to intestinal problems. In the cases where it was affecting children who had a blood disorder, bone marrow transplantation had turned out to be successful. Without absolute certainty that this would work, the decision was made to proceed with a stem cell transplant that was done last summer. As of now, Nick has apparently pretty much resolved his intestinal disease completely, doing well with continued recovery. So here's an example where the sequencing led to an insight which led to an intervention which appears to have been highly successful. So genomic sequencing again connected to the clinic, albeit in a rare instance, but I think we will see more and more of this as we go along. The ClinSeq study, which you will perhaps hear a little bit more about during the courses today, a study being done here as a collaboration between the genome institute with several other institutes involved, particularly heart, lung, and blood, trying to identify ways to apply genome sequencing in a clinical setting, enrolling 1,000 volunteers, having their sequences determined to see how that correlates with their clinical phenotypes in a circumstance where they can be brought back for more extensive phenotyping depending on what is found. I can remember when this program was first proposed about three or four years ago, there was a lot of controversy about whether this was a good idea or not. The controversy now is, well, why didn't you start sooner and why didn't you enroll more people? The initial focus has been on coronary artery disease, lots of interesting discoveries. And in the panel this afternoon, you will hear from one of the participants, Rick DelSantro, about his experience, including the discovery of something pretty interesting that neither he nor we anticipated as a result of this kind of program. But I can't stop giving examples about applications of genomics to clinical medicine without touching on cancer, and Linda Chin will no doubt say much more about this this afternoon. But I do think since cancer is a disease of DNA, the fact that this effort jointly between the NCI and the NHGRI is a real flagship of the opportunity here to be able to apply this kind of approach to a comprehensive understanding of what makes a normal cell become malignant. We now have seen many developments coming out of that, obviously beginning with the first three types of cancer that were approached in the pilot phase and now an expanded effort aiming to try to characterize 20 cancer types in detail over the next four years, working as part of the International Cancer Genomics Consortium. As just one example, the work being done at Wash U on acute myeloid leukemia comes to mind, where that group has been first able to identify in the very first complete DNA sequence of a cancer. They all the changes in a genome of an individual with AML, but now expanding that to 50 patients to 150 patients, finding this recent discovery of a recurring mutation in a gene involved in making a protein which has to do with methylation. Lots of opportunities here to understand a disease for which we desperately need new ideas about ways to treat it. And I'm sure you will hear more about the applications relating to cancer during the course of today. So let me now just switch though to a broader question about are we in a best possible position to take these discoveries about rare diseases, about common diseases, about neglected diseases of the developing world, and move the fundamental knowledge that's coming forward into its application. Because that can be a very broad yawning gap sometimes, sometimes referred to as the valley of death here in my image, it's more like a river. And what do we need to do to cross a river? Well, we need to build a bridge. And so the idea here, which has been underway certainly at NIH for many years in many applications, is to invest part of our effort in taking those basic discoveries and moving them in the translational direction towards new therapeutics. Again, this is something that has been primarily thought of as an enterprise of the private sector. And the private sector has been putting huge amounts of dollars into this, as you can see by this yellow line over the course of the last 15 years. But the results have not necessarily been as gratifying as one might hope. If you look at those blue bars, these are the number of new molecular entities approved by the FDA each year. And if anything, it looks as if the success is declining despite those increased investments. On top of that, Pharma is pulling back investments in developing new therapeutics in certain areas, particularly those involving the brain. Biotechnology companies, which are a big part of the engine of discovery, are many times now struggling because of the difficulty in getting access to venture capital at a time where the economy has been not so vigorous. And venture capitalists are looking for quick wins instead of long-term investments. And this kind of work has to be considered as a long-term investment. And again, there's a big problem because the success in going from an initial idea to an FDA approved drug is truly challenging. As you can see from this diagram where you may start out with 10,000 ideas and end up with one approved drug after the course of many years. And so this means that the whole enterprise is enormously complicated and expensive. So could NIH do something more now with this deluge of discoveries about molecular basis of disease to contribute to this? Not that we're going to become a drug development company, but could we build upon the experiences already successfully carried out by NCI and NIAID and other institutes that have been in this space to try to provide a platform for this sort of drug development on a broader scale? Interesting paper that just came out this week documenting the fact that NIH does in fact have considerable experience and a track record here that something like 20 percent of truly new molecular entities with new applications over the course of the past few years have come out of public sector research initial investments followed up by commercial application. So it's not as if we don't know something about this. And in fact, we actually have a number of programs already in place that could expand this effort and perhaps provide a broader platform for drug development. And I just want to tell you briefly about a few of those. This is of course a schematic but a very oversimplified one of the way in which one goes from learning about a disease molecular cause, which is after all potentially the same as identifying a target for therapeutics and carrying that all the way through to FDA approval and even to comparative effectiveness research after that. That involves assay development, high throughput screening, a lot of medicinal chemistry, the preclinical efforts, which are sometimes called the Valley of Death, the FDA investigational new drug application, then the phase one, two, and three trials. The NIH Molecular Libraries Initiative funded now by the Common Fund, which has been in place for some five or six years provides these particular capabilities and has been used by investigators to develop more than a hundred effective probes for research. And about half of those look as if they would be promising to carry on to the next phase of preclinical application and ultimate clinical trials. A new arrival on the scene is something called TREND, the Therapeutics for Rare and Neglected Diseases Program. And this is again specifically aimed at that preclinical space and is attempting to try to deal with the fact that we have a very large need here for attention to rare diseases of which there are some 6,000 or so and only 200 have any pharmacotherapy available, but many of them have had their molecular bases uncovered in the last few years. Progeria is just one example. It also is intended to focus on those diseases that are high prevalence in low income countries but are neglected because they occur infrequently elsewhere and therefore have a relatively limited market size and therefore companies are less inspired because of economics to invest in them, although fortunately that is changing to some degree because of support from things like the Gates Foundation. But still the needs are great. So TREND was funded by the Congress currently at $24 million to enable the development of new drugs for these categories of diseases. And TREND at the moment has started off with a series of five pilot projects. TREND is being managed by the Genome Institute on behalf of NIH. One of those is a neglected disease, schistosomiasis. The other four are rare diseases, nemenpixi, hereditary inclusion body myopathy, sickle cell disease and CLL. The sickle cell example I'll just quickly tell you about because it's a nice example of how we can work collaboratively with the private sector for a disease where clearly a new approach would be most welcome. In this instance, the drug that's being studied, 5-hydroxymethyl-2-fuehrerol or AES-103, was originally discovered at Virginia Commonwealth University, picked up by a biotech company, AES-RX, but they basically have run into support problems so that they can't carry this all the way through to clinical trials without some help. TREND has partnered up with them to work on the preclinical aspects of this. You can see here the consequence of that drug, which increases the binding of sickle hemoglobin to oxygen when you add the drug, those sickle cells return to normal. This has now gone through much of the preclinical effort and is poised for IMD and potential clinical trials, which may very well be conducted at our own clinical center in the coming year or two. Just one example of the ways in which we believe the time is right for NIH to be able to make some investments, not in areas that the private sector would normally be pursuing anyway, but to de-risk projects that seem otherwise unattractive and carry them just far enough along for commercial investment to start to make sense and then hand them over, very much along the lines of what has been going on at NIH in some parts for some years, but trying to expand the platform and also use this as an opportunity to look at the process engineering of the pipeline itself. Are there more efficient ways to do this to try to increase the likelihood of success at the end? Besides the trend program, just another couple of things to mention. We have an increasingly strong relationship with the FDA to try to assist in the development of a regulatory science portfolio that would make it possible for FDA to more speedily review drugs that are put in front of them and approve those that are safe and effective. Peggy Hamburg and I have been working closely on this by the establishment of a joint leadership council between NIH and FDA to assist that process. All of this putting together is an opportunity which is now underway to try to create at NIH a new entity to be called the National Center for Advancing Translational Sciences, which will bring together the Molecular Libraries Initiative trend and RAID, which I didn't have time to tell you about the CTSAs, which are the clinical centers across the country, all 55 of them at academic centers, our FDA partnerships, the Cures Acceleration Network, if we get an appropriation for that, which we hope we will, and put that into this new center. And there's been a good deal written about this in the press. I think there's also some confusion about exactly what's intended, and it is our goal to try to clarify that as soon as with lots of input from lots of stakeholders, we have the details together. The idea, though, is that this National Center for Advancing Translational Sciences would interact closely with the clinical center, with other NIH institutes and centers that already have big investments in this area, with the FDA, with pharmaceutical companies, with biotech companies, with academic researchers, with patient advocates, with nonprofit organizations, and would provide sort of a hub of this kind of activity, which we expect will be going on also vigorously in many of the institutes, but perhaps this could be a central focus, particularly for process engineering, the enterprise. And maybe this would be a significant opportunity, then, with this deluge of discoveries of new drug targets for us to play a larger role in de-risking those efforts and making it possible for translation to happen a little bit more quickly than it currently has been. That would certainly be something I think the public would be extremely interested in. For me as the NIH Director, I think the time is right to do this. Maybe we couldn't have done this quite this vigorously a few years ago. Maybe if we wait five years from now, we would have waited a little too long. So, if you have thoughts about that or any of the other things that I've talked about, we have on our website, this is our homepage, a feedback site that you see there. Please do your blogging on our blog site as well as on the genome blog site. You're welcome to do so. I'm looking at this quite regularly to see what thoughts people have. It is, of course, a challenging moment, because we're here talking about great science all day, but we are also at a circumstance where our country is facing deficits and economic concerns. It is, for me, a source of considerable comfort and delight that we have a president who really gets it here in terms of the value of what we do here at NIH can contribute, both to human health and to a recovery of our economy. This is a quote from the State of the Union, cutting the deficit by gutting our investments in innovation and education is like lightning an overloaded airplane by removing its engine. It will make you feel like you're flying high at first, but it won't take long before you feel the impact. Well, I think it is certainly the case that what we do here is part of the engine, and I'm delighted to see this room so full of so many people who are working hard to make that engine even more efficient so the plane can fly higher and faster. It is my great privilege to have a chance at this moment in history to serve as the NIH director and to be here, to be able to celebrate with all of you 10 years of the genome, may the next 10 years be even more exciting and more productive than any of us can currently imagine. Thank you very much. We will take one question if someone's bold enough to want to ask the NIH director a question, and it's going to have to be a really good question. If I don't see anybody walk towards the microphone, go ahead. The microphone right next to you. In the spirit of festivities and back to the champagne, I do understand that the one person who can give you permission to have alcohol on campus is in fact the director. Is that true? I'm sure someone on your staff can find that out. And with that note, thank you very much. Thank you for having us. Learning things today. All right.