 All right. Well, thank you very much Eric for that kind introduction and I had kind of thought, you know When I took the position as NHGRI scientific director that I was coming in in era two and it only became evident about three weeks later after October 10th 2010 when there was the Famous Tea Party election that things were much different for us than than what I had originally Anticipated but in any case it's it's been a lot of fun. It's been a challenge. It's really been Something that has made us think a lot about our priorities And I hope that over the course of the next few minutes We can talk at least a little bit about that just to give you an overview of what I'm going to talk about This afternoon we'll start out just with some general things with regard to the intramural research and the in the NHGRI a little bit of its history some of its current Accomplishments, and then I'll at least give you an overview of the vision statement that Eric alluded to We'll then get into the nuts and bolts of the intramural program at least a little bit Talking about space personnel and funding and then finally we'll settle on the challenges and opportunities The two major ones of which are maintaining the scientific excellence of the program and Having an equitable way of allocating resources particularly in constrained budgets So in any case just to get started with this the history of the NHGRI intramural program as Eric said it was established in 1993 by Francis Collins upon his recruitment as director of the then National Center for Human Genome Research and Francis I understand actually did Really want to have an intramural program and part of the reason for that was to have it do something that was a little bit different From the extramural activities of the Institute so the extramural Activities of the Institute were focused very much on developing the infrastructure For the human genome project whereas the intent for the intramural program was to capitalize on the unique resources of the NIH intramural environment to establish a world-class program in genetics genomics and genomic medicine and Secondly to catalyze a genomic transformation of the intramural programs of the other NIH Institutes and at that time I was actually in NIAMs the National Institute for Arthritis Musculoskeletal and Skin Diseases Doing positional cloning in a different Institute and we really did look to NHGRI or NCHGR as it was called at that time as really a catalytic force that would enable a lot of Research directions that otherwise were challenging in the intramural program certainly with regard to the unique resources of the NIH intramural environment the one that is most noteworthy, I suppose is the NIH clinical center at the time that in NCHGR Established its intramural program the building was just This part of it this new Hospital complex was opened in 2005. I think it is but in any case it is the world's largest hospital dedicated just to research It currently has 234 beds I guess it is all patients who are admitted to the hospital are admitted on a research protocol And it really does afford all kinds of opportunities for one to do various clinical and translational and observational Projects and so it is an enormous advantage to be an intramural investigator With the availability of the clinical center other distinctive features of intramural NIH Include an institutional commitment to researchers over projects a quadrennial heavily retrospective review Which then enables perhaps long-term studies that require stable funding and high-risk High-reward projects that would be difficult to do in an R01 funded environment In terms of catalyzing the genomic transformation of the intramural NIH in the 1990s I think it's fair to say that the Institute the intramural program had an enormous impact and I've just listed some of the projects on this slide and the Institutes that were involved these are for the most part projects that were initiated by people in the other institutes But that drew upon some of the resources and the expertise that was brought to campus by the the genome Institute and so for example The identification of Alps autoimmune lymphoproliferative disease in NIA ID The identification by Marsden-Linahan of various kidney cancer genes Endocrine neoplasa genes in NIDDK tumor suppressor genes by Constantine Stratoccus and child health and so forth So that it really did the Institute had an enormous impact more broadly in the 1990s and another example of this Was Jeff Trent's pioneering work with regard to microarray gene expression technology Currently there's a lot that's going on in the intramural program of the genome Institute and certainly I don't have time Eric Did not give me the three hours that I had asked for to talk to you We were going to send out for pizza even but so I'll just List a few of the high points of some of the things that have been going on in the intramural program in the recent past Such as that one's Dransky's work showing that Gauchay mutations are very important predisposing factors for Parkinson's disease Bill Gaul and the undiagnosed disease program and the recent New England journal paper on Genetic form of arterial calcification as well as a nature genetics paper on gray platelet syndrome max munka has been doing genetics of holoprosencephaly and really really is a world leader in that field last B. Sackler finding somatic AKT-1 mutations and Proteus syndrome Francis of course with his work on Progeria Laura Elnitsky one of our tenure track investigators who's played a prominent role in the end code Publications that came out in nature just a week or so ago Paul Lou our deputy scientific director Who's had a couple of papers in the cell family of journals over the last year Chuck Venditti another tenure tracker? Who studies methylmolyneic aciduria and had a paper in nature genetics, and it's only two slides So don't worry. I'm not going to go on to the 10th or whatever But anyway, I think that many of you know of Elaine Ostrander's work on canine genetics Which has really led to a number of science papers published in the last several years yardena Samuels Who's actually taking a tenured position at the Weizmann Institute? In a few months has been a leader in whole exome sequencing in melanoma Julie Segre had a paper published in science translational medicine a week or two ago on Bacterial whole genome sequencing to track nosocomial infections Jim Mulliken the head of our sequencing center Has had a couple of science papers in the last year or so on the Neanderthal genome and deep sequencing of HIV one neutralizing antibodies Charles Rotimi had a New England journal paper within the last few months on genetics susceptibility to Potoconiosis Pam Schwartzberg a real expert in T cell signaling and the immunologic synapse Inza Yang who's had a couple of nature family journal articles on skeletal development and I'll just add my own lab which had a New England journal paper on PLC gamma to signaling and Immune dysregulation and we have another paper that will probably come out in nature later this fall on Signaling the inflammasome so there's a lot that's going on in the intramural program There's a lot more than what I said But this is just to give you some sense that it's really a vibrant and exciting place and a lot of really good science is going on this slide in addition to illustrating some of the Title pages of some of these articles is also a testimony to the slowness of a PC rather than a Mac and on which this talk was Composed but in any case you can see the the evidence for yourselves So in any event and when this is done we can move on to To the rest of the talk, I think there's only Here it is that's the end of that one so In any event and then you know talking about the effect of the intramural program on the broader intramural program of the NIH I don't think that there is any doubt That it continues to have really an enormous impact much greater than the percentage of the budget that That we are and we're I think around 3% overall of the intramural budget of the NIH but certainly we have a much bigger footprint whether it be with regard to being the the expert source of sequencing on campus or the development of the Center for chemical genomics or the trans NIH RNAi screening facility or CIDR the Center for Inherited Disease Research Which I think Bob actually was The founding father of a few years ago These are all things that have had a broad impact on the investigators on in a number of other institutes We do a lot of education the current topics and genome analysis had 1200 or rather 1500 enrollees in 2012 and we have it on YouTube. So there's a lot of views of it The medical genetics and genetic counselors training program also have a big impact the UDP I think you've already heard at least a little bit about that It's had an enormous impact that is now spreading through the common fund Extramirally, we have been a major supporter of a large zebrafish facility and developing libraries of retroviral and ENU mutagenized fish We have a gene therapy consortium that we lead and also Charles Rotimi's Center for research on genomics and global health. So there's a lot of things that we've been doing one of the things in terms of just where we're going with things the blue ribbon panel did very wisely ask us to come up with a vision statement which we did and Actually, the vision statement is in the materials as Eric told you I've just excerpted a few Items from the vision statement to give you a flavor for it Certainly the overarching goal as I've already said is to lead the way on the NIH campus with innovative research into the genetics genomics pathophysiology and treatment of human disease Leading to a deeper understanding of human biology. We certainly have a commitment to excellence as an abiding principle We recognize the synergies among basic research clinical investigation and social and behavioral Implications we want to capitalize on the things that are important in the intramural environment whether it be the specialized resources or the colleagues that we have As collaborators and we are committed to catalyze genetics and genomics across the NIH campus And we are committed to make use of the rigorous external review and advice of the board of scientific counselors and NHGRI council to help us with our decisions We had four areas of emphasis that we enumerated in the vision statement The first of them being Developing and implementing state-of-the-art genomics technologies and analytic tools and disseminating across the research community The second that deals with clinical and translational research taking advantage of the availability of the clinical center Thirdly advancing at least in specialized in chosen areas studies in basic science and then fourthly our commitment to training in the field In terms of where are we going? The last paragraph of the vision statement deals with that and we point out that we have built a very Integrated program of genomic technology clinical investigation and basic science and what we see is our Goal for the next ten years is really to exploit these opportunities and to set An example for others in terms of how to do it and how to bring together technology and clinical investigation and basic science and certainly in terms of this I'm sure now A very familiar heat map we see the role of the intramural program as being primarily in the middle three domains understanding the biology of genomes understanding the biology of disease and advancing the science of medicine certainly the Understanding of the structure of the genome has been more the domain of the extramural program and certainly in terms of the Practice of medicine perhaps just because of the differences in the way medicine is practiced at the clinical center We're not the ones Necessarily to be taking the lead in that area in terms of the nuts and bolts of the intramural program at least as of this year We are spread out across the campus. We're actually in seven different buildings on campus and a couple of buildings off campus The personnel are broken down the scientific personnel are broken down into seven different branches Illustrated on this slide all together. We have 45 investigators in the intramural program of them 23 our tenured senior investigators six of them our tenure track investigators, and then we have 16 associate investigators that are sort of like the research Faculty at a academic medical center. We also have nine adjunct investigators who are actually in other institutes But have a special collaborative relationship with our institute this slide just shows the photos of the Individuals who are our faculty members all together our personnel census is about 520 individuals In the intramural program currently in addition to having the various research laboratories We have eight different cores shown on this slide. We have the NIH intramural sequencing center Which is basically a mid-sized genome sequencing center that provides next-gen sequencing and sequence analysis It's total budget is about seven million dollars out of a one hundred and four million dollar total budget for the intramural program Jim Mulligan is the director. There's a staff of about 36. They have three High-seq 2000 machines as well as several other Sequencers and they really have been extremely Collaborative with intramural investigators being involved in a lot of disease gene investigations The undiagnosed disease program I think you've already heard about but just briefly to summarize. It's a trans NIH intramural Initiative established in 2008 by Bill Gaul who is our clinical director And sees patients with seemingly inexplicable conditions referred from throughout the country And they do comprehensive clinical and molecular analysis of these patients that are accepted into the program They've discovered a number of heretofore unknown molecular lesions defining new genetic diseases And have been a catalyst for follow-up projects in the categorical institutes in terms of funding Eric has already told you a little bit about that, you know about the time that Eric Took the position of scientific director of things flattened out and then I assumed the scientific director position here and actually and we'll talk about this in a little bit the The real dollars that we have to to deal with are perhaps at this point Becoming a bit more constrained just because of the fact that there have been a number of things that we've tried to do to keep Things going but there's just so much and with inflation. It's becoming harder and harder to keep everything going at the juggernaut pace that we would like it to continue Overall the NHGRI is 1.7 percent of the NIH budget We are 3.1 percent of the overall intramural budget. That's because of the fact that we do receive 20 percent of the Overall resources budgetary resources of the Institute, whereas many of the other Institutes have only 10 percent allocated to their intramural programs now one can have a discussion about that And I know that the blue ribbon panel thought deeply about that question as to whether that is still appropriate And I will let them weigh in on that But certainly one of the reasons that we have adduced for why perhaps NHGRI should have a higher percentage is that it really is catalytic for the other institutes as My experience when I was in NIAMS. We were not necessarily Catalyzing arthritis research or whatever in NHGRI whereas NHGRI certainly was catalyzing some of the things that we were doing in NIAMS And that's with no disrespect meant to my other my former institute of which I'm still very familiar In any case in terms of our overall intramural fund funding We spend about 30 percent of our budget on NIH infrastructure about 16 percent on our own Institute specific infrastructure 44 percent on personnel And 10 percent that goes for operating and discretionary funds And so that actually is a very telling figure because if we did have to make Major cuts in the upcoming fiscal year, which is at least a possibility We hope not a probability, but at least a possibility one has to consider the fact that to turn on the dime to actually be able to adjust the budget relatively quickly without having a little bit of time to adjust Infrastructure spending and reduce the personnel lines that becomes very difficult to do In terms of our challenges and opportunities First of all maintaining scientific excellence. This is an area that I think is extremely important and the standards that we Have discussed in the intramural program that we should that we feel are important and that our investigators should be held to are Does the work fundamentally change the way we think about or understand relevant areas of biomedical science Through the development of new methods does it change the way that we do science for clinical research Does it change the way we practice medicine whether clinical or basic? how would the field look if the intramural investigator had not been active for the last five years and Is the research worth studying with the special resources associated with the IRP these are high standards But I think that we have to Hold our investigators to high standards particularly in this time of constrained resources because we may have to make some difficult choices To help us with those choices Listed here is the NHGRI Board of Scientific Counselors a group of nine distinguished investigators from outside of the intramural program who help us to Do the quadrennial reviews of the various investigators in the program And over the course of the last I guess Six months or so we have developed some new standards some new approaches in terms of the review process We've implemented a more standardized format That is about 50 percent retrospective and 50 percent perspective We have additional ad hoc reviewers with the reviews to make sure that we have a lot of expertise And the subject matter that the investigator is working on we do an orientation with the reviewers in advance to articulate our Expectations to them We use now NIH wide standard criteria for reviews The reviews are supposed to be done before the site visit and finalized shortly thereafter and we use a set of Standardized descriptors that are used across the intramural program now outstanding excellent very good good, etc and This will give us a way of comparing investigators from one branch to another with regard to the quality of their work and help me to make Decisions if I have to with regard to resource allocation and certainly for Investigators that have less than an excellent evaluation. We do have a process in place where at least initially they have to undergo a re-review One year and two years after their initial not-so-good review, and if things continue to be Less than optimal then there are processes in place actually to reduce their resources and even close their laboratories In terms of allocating resources the big picture is that the overall IRP allocation has been flat For several years and using the forbidden word that I didn't realize was forbidden Sequestration may impose an 8% and about 8% cut for FY 13 perhaps and we the problem Of course is we won't even know it the fiscal year begins in three weeks, and we won't know if this Actually will happen until at least three months from now Overhead costs salary increases and inflation have eroded buying power Options to raise monies from non-federal sources are extremely limited in the intramural program because of ethics rules that I'm sure some of you are now initiated into through your Service on the council political gridlock begets budgetary uncertainty in other words We don't know what the budget is going to be next year So it's a problem in terms of making commitments for large-scale allocations of monies Since I became the scientific director on 10 10 10 We've implemented about 15% across the board cuts for all tenured intramural investigators comparing the proposed FY 13 budgets that Investigators are getting versus the FY 10 budget that they had before I came and We have suspended three tenure-track Recruitments for budgetary reasons and have made no major capital equipment purchases in the last two years So those are the facts We have implemented a new budgetary model for our investigators And that is that in the past we had a formulaic system of allocating budgets where if an investigator a certain Sort of point in his or her career had a certain number of people in their lab Salaries of those people were taken care of centrally by the office of the scientific director And then they would get an allocation based on the number of people in their labs Because of the fact that we are making these cuts and that it really gives people perhaps a little bit more freedom to make Decisions as to how they spend their money. They're now getting a lump-sum allocation and at least within the law in terms of Civil service requirements and so forth. They can spend the money as they choose in terms of personnel versus supplies and equipment Allocations at least initially are being determined by historical factors in other words what people were getting last year But subsequently they'll be adjusted based on productivity and excellence with strong input from the BSC We're going to try to reestablish a centralized reserve fund for compelling opportunities and and or contingencies and this last year actually The investigators were very good about saving money, which we are now as much as we can Channeling into contracts that will perhaps buffer any budgetary cuts that we experience next fiscal year We have established a review panel to allocate subsidized sequencing resources at NISC This whole new approach has required new accounting measures and a change in the culture among both our investigators and our administrators So anyway to summarize this cheery talk first of all the NHGRI IRP is a vibrant research enterprise and I really do believe that and I am extremely proud of it and positive about it and and Do feel that it's it's a wonderful Opportunity to be its scientific director with a commitment to excellence and a focus on genomic medicine and fostering genetic and genomic Technologies throughout the NIH intramural community The IRP has recently strengthened its quadrennial scientific review process to reinforce this culture of excellence going forward And finally prompted by the current limitations and uncertainties of federal funding The IRP is implementing administrative changes aimed at maximizing productivity within budgetary constraints And that's 30 minutes exactly which for me is quite a feat So actually Dan let me Have you address a question that got raised earlier that I deflected or delayed until you were here is maybe just say a few words about the clinical center which you introduced us to but The question and Bob you can weigh in to get more specific just sort of what's the health and well-being of the clinical center with respect to You know how much it's being utilized to relative to its capacity But also there's been lots discussed debated and even written about sort of the financial woes of the clinical center With the rising costs of medical care in general and being embedded within the intramural program flat budgets everything else and so Sort of what's its fiscal situation? Yes, okay So first of all with regard to the utilization of the clinical center About maybe five or six years ago. There was concern that it seemed that intramural investigators weren't Utilizing the clinical center as much as they should be in the occupancy of the hospital was more in the 65 to 70 percent level than More in the 80 to 90 percent level that we would like to have seen but basically a number of the institutes responded to that by Encouraging clinical and translational research within their intramural portfolios with regard to recruiting more clinical and translational investigators and so actually at this point the utilization of the clinical center is is very good and and Is more in the 80 percent level? most of the time As far as the funding stability of the clinical center well, I can tell you it's not rolling in dough There's no question about that the clinical center is funded for the most part by a so-called school tax Which is the tax on each of the? Institutes that has a program on the Bethesda campus that currently amounts to I think it's about 14 percent of Our overall intramural budget so that means that for us in NHG or I who have an intramural budget of around a hundred million dollars We pay about 14 million dollars to the clinical center off the top doesn't matter how many patients we use It's just 14 million dollars that goes straight to the clinical center and the whole idea behind that was that it would encourage The institutes to utilize the clinical center if they were paying this amount of money Whether they used it or not and so you know the idea was that well if you're going to be paying that amount of money You may as well at least have a program that uses it so The current budget for the clinical center is around I think $380 million a year somewhere in that ballpark that is basically raised through these school tax monies It has been difficult for the clinical center because of the fact that medical inflation is going up higher than the rate that they are Getting money through the school tax because after all if the budgets of the intramural programs of the institutes are flat That and your tax rate is flat Then you're going to be getting the same amount every year and if there's medical inflation Then you know you're not you're going to fall behind and so that has been a problem the Clinical center has dealt with that in several different ways One of them has been to shift the cost of some of the clinical research back to the institute So that for example certain things that had been paid for by the clinical center in the past are now the Responsibility of the participating Institute that certainly has been one of the ways that that's been done era funding did help out With some major capital Equipment purchases back a couple of years ago scanners and that sort of thing so that has helped and then there's also the possibility that the Clinical center will get at least some additional resources based on the fact that The clinical center is being opened to investigators in the extramural world through a new grant mechanism that would allow extramural investigators to collaborate with intramural investigators With regard to certain kinds of projects and might for example Collaborate with regard to cohorts of patients with rare diseases that we follow in the intramural program and so that may through Mechanisms that haven't been totally worked out allow for a little bit of Supplementation of the clinical center budget as well if it is regarded as being sort of a resource for everyone Not just the intramural program How does that answer question? It does but I thought then it might be worthwhile for you to also to talk a little bit about staffing Physician staffing in the clinical center in terms of who are who are these folks do they all are they all? investigators in institutes And the reason I'm asking this is that I've had some experience with the undiagnosed diseases program where there is some Skewing as to which kinds of patients are chosen to be investigated to some extent depending on What are the perceived strengths and weaknesses in various? subspecialties within the clinical center. Yeah, that's an extremely good point Bob So the staffing of the clinical center it is not Like a big general hospital or whatever where you would have necessarily Expertise going you know totally across the The medical spectrum certainly there is sufficient competence that I don't feel Uncomfortable one I admit a patient to the clinical center that if they have a certain thing go wrong with them that you know We're in trouble or whatever, but on the other hand it is certainly the case the clinical center is staffed by a combination of physicians that are faculty members in the various participating institutes, and so they vary in terms, you know some institutes Invest more money in their clinical programs than others And so you do have this kind of uneven strength across the clinical center where some specialties are very well Represented and others not so well at all And then there are some physicians that are that work for the clinical center that are people that say staff the radiology department and so forth, so it's it's a mixture of things and It isn't the case that it's it's uniformly Excellent across the board there are some areas of great strength and That can be on very rare diseases and then other areas that might be More common diseases where you know, we don't have anyone necessarily that's a world's expert And I might add some of those issues kits come up in discussions around Nationalizing the UDP that perhaps when they set up a network of extramural centers some of those Centers might have domain expertise that would both complement the clinical center But also complement each other and that may be certain types of cases would naturally get referred to those Play those sites that have the greatest expertise for a patient like that They asked me one more question, which is what is the current situation at the inch mirror on H for? Clinical trials that involve next generation sequencing or whole exome or whole genome sequencing in terms of clear approved Laboratory results and that kind of thing. What are you doing about that? Well, that's another important issue and each of the institutes actually is Having to pay for it on their own, you know, so it's it's basically a Patchwork quilt of different approaches to that There is not right now, although there's been discussion of it But there is not right now a clinical center clear approved lab that does that for everyone It would be great if we could get together and do it but right now given budgets I don't see that happening in the next year or two anyway Any other general questions for Dan? Okay, if not Dan's not going anywhere, but what Rick is going to come up and Give a report from the blue ribbon panel Review and as we know David Page is also on the phone. I'm expect he's going to also have some things to say as well