 So I will turn it over to him. All right, well, thanks very much, Eric. And thank you guys very much for the opportunity to talk with you this morning. So in any case, in the spirit of Eric's chronicling, the number of council meetings and so forth, actually the intramural program of NHGRI is now in its 21st year, having marked its 20th anniversary last year. And actually, my own tenure at the NIH is a little bit longer than that. I actually started at the NIH in 1985, although it may seem incredible to you that someone looking like me could actually have been here for that long, but it's true. I started actually in the Arthritis Institute and had an interest in the positional cloning of various genes that are involved in the regulation of inflammation. And certainly one of the things that was very exciting to us in the rest of the intramural program of the NIH was the advent of the intramural program of NHGRI, because that really did bring genomic technology, and it created really a critical mass of people who are interested in genetics and genomics to the NIH campus in Bethesda. And so this really was, I thought, a wonderful thing and something that really catalyzed the transformation, really, of the intramural campus. And so when I had the opportunity to join NHGRI in 2010, and actually I joined NHGRI on the auspicious date of 10, 10, 10, October 10, 2010, it's really been just a fantastic time getting to work with people in NHGRI since then. So in any case, I'm going to talk to you a little bit about the NHGRI intramural program. And just to give you an overview of the things that we will be talking about, first of all, I'll give you at least a little bit of a raise-owned debt for intramural research at the NIH. Secondly, I'll talk to you a little bit about the NHGRI intramural vision and what we do in our particular intramural program. Thirdly, I'll talk with you a little bit about the intramural faculty of NHGRI and its organization and recent reorganization. Fourthly, we'll talk about at least a few of the scientific accomplishments of the intramural program, at least a little bit adding to some of the things that Eric talked about a couple minutes ago. Fifth, we'll talk a little bit about how NHGRI intramural science is evaluated, both in the context of the blue ribbon panel review that we underwent back in 2011 and 2012, which, by the way, was chaired by David Page sitting over across from me in the corner, trying to look inconspicuous with this. And then also a little bit about our Board of Scientific Counselors' Review of Scientific Programs. I'll also talk a little bit about the budget of the intramural program and the vicissitudes that we've had to go through with the various sequestrations and shutdowns and so forth. And then finally, I'll end with a little bit in terms of new initiatives in the intramural program. So to get started, let's just talk first a little bit about what are the distinctive features of research at the intramural program of the NIH. And there are nine things that I've identified here on this slide that I think are important. One is that the intramural program tends to have an institutional commitment to researchers over projects more like the Hughes Institute. Secondly, there's a quadrennial heavily retrospective review, which is different from the prospective review that is seen most prevalently in the intramural program. Thirdly, because of the fact that usually funding is relatively stable, it allows for long-term studies that require this kind of stability of funding. And this lends itself, then, we hope, and we certainly strive for, high-risk, high-reward projects that would be difficult to do with R01 funding. Certainly, in the intramural program of the NIH, there's critical mass in certain key areas. Certainly, genomics now is one of them. Immunology, I would say, is certainly another that is world-class in the intramural program of the NIH. The structural biology, I guess, would be another to single out. Certainly, one of the justifications for having an intramural program is the idea that researchers at the NIH, currently sometimes, turn on a dime, changing their research focus to respond to public health crises, such as what was seen in the 1980s with the HIV crisis, for example. And the intramural program really took a leadership role in getting things going in that area. It's also an intellectual home for institute directors and extramural program staff. And so we want to have a vibrant intellectual community for these people to be able to take part in. It's close to the seat of government. And as Eric pointed out, sometimes we, in fact, host various people from Congress and the administration. And so it's very important to have really cutting-edge science that's going on here. And then finally, there are specialized resources that are available in the intramural program. And probably the one that comes to mind most prominently is that of the NIH Clinical Center. And this is really a unique hospital in the sense that it is a hospital where every single patient who is admitted is on a research protocol and where, in fact, there's no cost to the patient or to the investigator for the patient to be admitted. And so this really does then lend itself to doing clinical investigation in a very intensive way. And so the Clinical Center really has been the hub around which a lot of the research at the NIH intramural program has been done. In terms of the NHGRI's intramural research program, I'd just like to talk about five things that our faculty identified as being very important in the process of developing a vision statement back in 2012 as part of the Blue Ribbon Panel review process. First of all, the NHGRI intramural research program really aims to lead the way on the NIH campus in the genetics, genomics, pathophysiology, and treatment of human disease, fostering a deeper understanding of human biology. And as I said, that certainly has been my experience as first an outsider to the Genome Institute. And then certainly this is something that we want to continue. Certainly the intramural program also wishes to conduct transformative science, to develop collaborations among basic clinical and social and behavioral scientists, to take full advantage of the intramural environment and the critical mass that we have in certain areas, and to catalyze change across the NIH campus. Certainly in terms of this heat map that Eric had in his paper in Nature back a couple of years ago, whereas the overall genetics and genomics community is perhaps more focused in the biology of genomes and the biology of disease right now. The intramural program, partly because of the accessibility of the resources of the clinical center, perhaps is focused a little bit more in terms of understanding the biology of disease and the science of medicine. So in any case, just a little overview in terms of the faculty in the NHGRI intramural program. Altogether, we have 45 investigators who are our research faculty. Of them, 25 are tenured senior investigators. Four are tenure track investigators. And this is actually a reduction in the numbers. When I started as the scientific director, we actually had eight tenure track investigators. And over time, some have left, some have graduated to tenured positions. And certainly given budgetary constraints, this is an issue that we'll come back to a little bit later in terms of the future of the intramural program is just being able to set aside the resources for younger investigators. And then finally, we have 16 associate investigators who are more like research adjunct faculty at a medical school. Eight of them have some independent resources of their own, eight work primarily for other tenured investigators. And then in addition to that, we have 10 adjunct investigators shown here who actually hold their primary appointments in other institutes but have a affiliation with the NHGRI intramural program. So in any case, this is just a pictorial showing all of the faculty that I just summarized on the previous slide. Two major events this past year in 2013 with regard to the faculty. First of all, we had the joining of the faculty of Gary Gibbons, who many of you know is the director of NHLBI. He, of course, recently came to the NIH campus. He's an expert on cardiovascular genetics and health disparities. And he chose to locate his lab and NHGRI's intramural program. And I think that just the fact that we have not only Gary Gibbons as one of our faculty members, but also Harold Varmas at his request and Francis Collins is just a vindication of the quality of the intellectual environment in NHGRI's intramural program and says something about the administrative support that NHGRI is able to provide as well. We did have one of our investigators, a tenure track investigator, Yardena Samuels, who took a tenured position at the Weizmann Institute in Rehoboth during this last year as well. So one new tenured member of the faculty and one person leaving. In any case, over the last year, just as Eric has reorganized the overall structure of the NHGRI writ large, our intramural program has also undergone a reorganization, which was at least in part recommended by some of the outside advisory bodies that we have. The goals, basically, of doing this reorganization were to increase scientific synergy amongst investigators to advance the careers of some of our mid-level faculty, certainly some element of succession planning as well. And as Eric mentioned a little while ago, Larry Brody has taken on the position of division director for the Division of Genomics and Society. And because of that, the Genome Technology Branch has been phased out, and the members of the Genome Technology Branch have been located in other branches. We have now two new, rather three new branch chiefs in the institute, Julie Segre, whom Eric mentioned with regard to the Service to America Award that she received this last year. Pam Schwartzberg, who is an expert on the genetics of various immune diseases, and Charles Rotimi, whose work concentrates on health disparities research and the genetics of cardiovascular and metabolic disease in the African and African-American populations. Certainly in this process, we tried to more clearly delineate the role of the branch chief in terms of scientific leadership and mentorship. And we have an expanded leadership group with now nine branches in terms of seven, as we had before. I'll just mention briefly that we have eight cores within the NHGRI intramural program. And certainly these cores have taken a leadership role on campus in terms of disseminated genomic thinking and genomic technology. For example, the Bioethics Core certainly has taken a leadership role in terms of helping investigators and other institutes to think about issues of informed consent in genomic studies, whether it be genome-wide association studies or whole exome sequencing. The Bioinformatics and Scientific Programming Core has a number of courses that they offer for the broader community, including one that is currently starting, at least the most recent edition of which had over 1,000 people signed up on campus. And videos of that course are kept on YouTube. And there are literally hundreds of thousands of views of the lectures in this course. So it really is something that disseminates genomic thinking and technology, not just to the NIH campus, but in fact to the broader community. And several of these other cores, of course, have had a major role in terms of disseminating these technologies to others at the NIH campus. Another feature of the intramural program is NISC, the NIH Intramural Sequencing Center, which was founded several years ago as a medium-sized genome sequencing center that provides, at least at this point, next-gen DNA sequencing and sequence analysis. It has a budget of around $7 million a year. And Jim Mulliken is the director. As you can see, there's a number of different sequencers that are available. And last year, NISC produced about 45 terabases of high-seq output to 55 principal investigators and 11 different institutes. Again, underscoring the fact that NHGRI really does serve a broad role for a number of intramural programs at the NIH. Eric also mentioned the undiagnosed diseases network and, of course, the undiagnosed diseases program was the progenitor of that. This was established by NHGRI clinical director Bill Gall back in 2008. And Bill had the vision of attracting patients to the NIH with seemingly inexplicable conditions referred throughout the country, performing comprehensive both clinical and molecular genetic analyses of these patients and discovering a number of heretofore unknown molecular lesions defining new genetic diseases. And, of course, it is now the parent, if you will, of the undiagnosed diseases network of the common fund. So just a few highlights, some of which Eric has talked about, but others not, just to give you a flavor for some of the things that are going on scientifically in the intramural program. Here is a paper that was published in the New England Journal of Medicine last summer from Bill Gall's group on a gene VPS45, which encodes a transporter molecule that transports, among other things, adhesion molecules to the cell surfaces of white blood cells. Patients who have loss of function mutations in this gene have an immunodeficiency, have a problem with neutrophil function and, in particular, neutrophil adherence and migration. And so these patients have an immune deficiency. A second clinically related paper is one that Les Beeseker co-authored. It was a opinion piece in JAMA dealing with reporting incidental findings in the clinical setting. And of course, Les Beeseker has had a major leadership role in this area through the ClinSeq initiative that he started, and certainly has participated in a number of the approaches to this, including the American College of Medical Genetics list of actionable variants that should be reported. Another important paper from the intramural program is one from Julie Sigrae's group that was published in Nature last year dealing with the fungal microbiome on the human skin. And then, as Eric pointed out in his comments, Julie and Evan Snitkin in her lab, as well as Tara Palmer and David Henderson from the Clinical Center were involved in a very important study, identifying basically the transmission of a resistant organism through the Clinical Center and effectively dealt with that and really established a paradigm for how to do this in clinical practice. Other important papers from the intramural program here is one from Pam Schwartzberg's group defining a new immunodeficiency disease caused by mutations in PI3 kinase. These patients have EBV and CMV infections and have a problem with the formation of the immunologic synapse. A paper from Inza Yang's group dealing with heterotopic ossification. This is actually a very important problem in some of the returning veterans from the Middle East who have had amputations. And actually, at least some of these individuals develop calcifications at the stump of their amputation, which can be then very, very painful to them with their prostheses. And Inza has had a major interest in identifying the molecular pathways that lead to heterotopic ossification. A couple of papers from the husband-wife team of Joan Bailey Wilson and Alec Wilson dealing with various genome-wide association studies that they've done over the course of the last year on myopia and on craniosynostosis. Couple of papers from Charles Rotimi's group dealing with body mass index in individuals of African ancestry and Charles's continuing contribution to the 1000 Genomes Project. A couple of papers from tenure-track investigators, one of them Chuck Venditti, who's done really incredible work developing a cohort of patients with various metabolic acidemias and identifying the molecular basis of those diseases. And then Daphne Bell, another tenure-track investigator in the Institute who's been looking at whole exome and whole genome sequencing of endometrial tumors. And then here, a paper from Steve Parker, a postdoc in Francis Collins Group, identifying a group of enhancers, stretch enhancers similar to the super-enhancers that Rick Young's group has been looking at and identifying their role in gene regulation and human disease. And a paper that Eric alluded to from Andy Baxavanis' group on the comb jelly and its sequence. And then here, a set of three papers from NISC, and these are just some of a whole host of papers from Jim Mulliken and the group at the Sequencing Center collaboratively identifying sequence in various non-human primates, the neanderthal. And then in some cases, actually looking at other subjects, such as HIV antibodies and co-evolution of the virus itself. Unabashedly, I'm showing three highlights of work from my own research group, one of them a paper that we published in Nature a little over a year ago dealing with the biology of NLRP3, which is a gene that we found mutated in a particular kind of inflammatory disease a number of years ago in the role of calcium encyclical AMP in signaling through this pathway. This is a very important pathway, both in a number of rare hereditary disorders of inflammation and also seems to play an important role in more common diseases, such as gout and cardiovascular disease. Here, a paper that we published in Nature Genetics last spring on a genome-wide association study in Betchette's disease. The interesting thing about that paper is that we found variants of ERAP1, which is a molecule in the endoplasmic reticulum that trims peptides for loading onto HLA Class 1 molecules, and there's actually an epistatic interaction between variants in ERAP1 and a particular HLA Class 1 molecule. And then finally, the one that we're most excited about, and this is a paper that will be coming out online in the New England Journal of Medicine next week, and basically it is a paper that describes a new disease, Dada2, deficiency of ADA2, in children with recurrent fevers and strokes, and at least in some cases, polyarteritis nidosum. And ADA2 is actually a protein that's at least in function similar to ADA1, which many of you know of, is the gene that's mutated in at least some cases of severe combined immunodeficiency. But ADA2 actually is a growth factor that's involved both in endothelial integrity and also in the differentiation of certain subsets of monocytes and macrophages. So in any case, just to turn to a very important topic and that is evaluating intramural science, I'll talk about just a little bit about two things. One, the blue ribbon panel process that occurred in 2011 and 2012, chaired by David Page, and I will just give a couple of slides summarizing some of their findings. Certainly the panel did look fairly broadly at the science that's being conducted in the intramural program. This is a review that occurs every 10 years, roughly, and is intended both to take stock of what's going on in the intramural program and make sure that appropriate types and quality of research is being done and also to think about the future. And so in their report, the blue ribbon panel did say that the IRP remains an outstanding research enterprise and this is reflected by its scientific productivity, an excellent record of educating and mentoring, enhancement of the broader NIH IRP through the dissemination of genomic technologies, the development of an impressive research in clinical faculty, the establishment of a robust research infrastructure, and a spirit of collaboration and collegiality. The panel refrained from being prescriptive in terms of exactly what kinds of things the intramural program should be doing over 10 years, wisely believing that it's very hard to know what kind of science is going to be practiced 10 years from now, but at least in terms of general principles exhorted us to embrace, to continue to embrace a risk-taking culture, to insist on excellence, to continue to be a change agent on the NIH campus and beyond and did know one area of need, and that is the interpretation of the volume of genome information that's being captured and its integration with other clinical data, and I'll actually come back to that in a little bit when we start talking about initiatives that we're currently undertaking. On a more granular basis, the Board of Scientific Counselors, as Eric pointed out, is the body that actually evaluates the science that's going on in the intramural program on a year-to-year basis. Currently, our BSC is chaired by Tom Hudson, who is the president of the Ontario Institute for Cancer Research, and then there are eight other individuals who are on the Board as well. Each branch within the NHGRI intramural program is evaluated every four years, and certainly we have made this process a little bit more standardized and we hope have made it even more rigorous over the course of the last couple of years, at least in part because of the suggestions of our Board of Scientific Counselors and in part because of suggestions of the blue ribbon panel. And so when I meet with the BSC and the ad hoc reviewers, I do tell them that we're really looking for great science and in particular, I ask them to think of five questions in evaluating the scientists and their programs. First, does the work fundamentally change the way that we think about or understand relevant areas of biomedical science? Second, through the development of new methods, does it change the way that we do science? Third, for clinical research, does it change the way that we practice medicine? Fourth, whether clinical or basic, how would the field look if the intramural investigator had not been active for the last five years? And then finally, is the research worth studying with the special resources associated with the IRP? In any case, since I've been scientific director, we have implemented a summative rating system of outstanding, excellent, and very good for each of the investigators who is reviewed and over the course of the last three years that we've been using this system. 17 out of 25 faculty got ratings of outstanding, one got a rating of outstanding to excellent, five excellent and two very good. And certainly one of the things that the Blue Ribbon Panel asked us to do is to have some sort of process in place if someone did get very good ratings and we certainly do have that in place now and investigators are up for re-review actually a year after their very good rating and then are totally re-reviewed two years later. And so we really have taken this very seriously. Turning for a moment to the subject of budget, I will just on one slide summarize at least the current budgetary circumstances of the intramural program. From fiscal year 2010 to 2012, FY 2010 was Eric's last year as scientific director and then the first two years from my scientific directorship. We had a flat budget of $104 million a year and from that $32 million are taken off the top for the maintenance of the clinical center and other central costs associated with the intramural program. In fiscal year 2013 because of sequestration, that figure was cut from 104 million to 100 million again with the same amount taken off the top in terms of overhead. In 2014, we budgeted for $98 million expecting that there would be a second wave of sequestration. Fortunately that has not happened, as Eric said. Over this period of time, we've converted the way that we do budgeting for individual investigators from a capitated centrally supported budget model to a bottom line approach where basically investigators are given a set amount of money per year and then they get to choose whether they spend it in personnel or services and supplies, figuring that that gives them more latitude to wisely spend their money in times of shortage. Overall we've done 15% across the board cuts in individual investigators since 2010 meaning everyone has been cut by that much and once we have these descriptors associated with each investigator then the budgeting will be based on their evaluations but of course we want to have it fair where everyone has been evaluated in the same way first. The actual fiscal year 2014 budget at least from what we understand will be about 102.5 million dollars. There are certain mandated expenditures like the 1% pay increase for GS employees and certain capital expenses that have been deferred but we do hope to be able to do at least one recruitment in bioinformatics during this year with some of the extra money that we have. Now turning to new initiatives just for a short time I'd like to highlight a couple of things. One of them is a sequencing project, the NHGRI clinical center sequencing project that actually a group of leadership the branch chiefs came up with that a meeting in August and Les Beeseker and Jim Mulliken have taken the lead on. So in any case what basically we're planning to do is to offer investigators in other institutes besides NHGRI whole exome sequencing at NISC on clinical center patients that reagent only cost and that's roughly half of the cost that investigators in other institutes would be charged otherwise if they were charged for the overhead cost of the sequencing. This is being further subsidized by competitive awards from Michael Goddusman's office so that essentially for those individuals that win one of these competitive awards they will have whole exome sequencing for their project at no cost. The sequencing we are implementing CLIA certified sequencing and Jim Mulliken is setting that up at NISC now. We do plan to return incidental findings to subjects and the genetic counseling service will be providing support for patients that receive those findings. The first year we're going to do this as a pilot with a thousand exomes offered although we hope to expand this as hopefully it is widely appreciated on campus and as funds permit so that it may expand eventually to all clinical center patients and would be integrated with some of the deep phenotyping capabilities that are available in other parts of the NIH such as the Center for Human Immunology and some of the neurology groups who have really top notch imaging capabilities. Second thing that I'll just mention briefly is the U01, Extramural Intramural Collaboration Mechanism. This is something that has been developed over the course of the last couple of years and it's basically a program that allows extramural investigators to partner with intramural investigators to write a grant application that involves patients that would be seen at the clinical center and the idea is that the extramural investigator might be conducting laboratory based research while the NIH investigator would be seeing patients phenotyping them and hopefully there would be then some integration between the two. The grants are for $500,000 a year for three years and basically our intramural program will be funding one new application a year so that eventually we'll be funding three at a time and simply because of the overall orientation of NHGRI's extramural funding, these applications should have a strong genomics orientation in order to be funded by NHGRI. There are a number of immediate challenges that we're facing here in the intramural program. Certainly one of them is just one that everyone has to face in these constrained budgetary times and that's maintaining a vibrant research enterprise in an area of flat budgets. Funding the NIH clinical center is particularly an important one because as I mentioned it really does have a central role in a lot of the research that's being done in the intramural program and unfortunately the costs of healthcare go up regardless of whether the federal budget is flat or not and so of course the concern is that the clinical center budget then takes up a larger and larger proportion of intramural funds. Certainly we also need to stay at the cutting edge of genomic technology and bioinformatics and that's part of the reason why our first recruit that we'll be doing with some extra money is in these areas. We wanna continue to catalyze genomic medicine in the intramural program and of course we need to in some way identify a way of liberating resources for new recruitments since really the age of our faculty is something that's really of significant concern to me in terms of the future of our intramural program. Michael Goddusman's office and Francis Collins have also just within the last couple of weeks initiated a 10 year planning initiative for the intramural program of the NIH. So each institute with an intramural program is going to review its intramural program and develop a strategic plan. The main question is what should the IRP look like both at the institute level and across institutes in 10 years and how can we get there? Each institute will constitute a review committee of prominent extramural and intramural scientists for institutes with a recent blue ribbon panel review. The current review may be an addendum to the blue ribbon panel review or maybe we'll have a reunion of the blue ribbon panel or something like that. What did you write? The review should address both scientific priorities and operational issues and institute reports are due at the end of July. A combined report from the institutes is supposed to be transmitted to the advisory committee to the director in September and the ACD would be rendering recommendations for the future of the intramural program on December the 12th, 2014. So anyway, that's basically what I have to say. I did manage to do it in 40 minutes which is what Eric had asked. And so anyway, with that, Excelsior onward and upward. So questions for Dan? Well, I have a question about how you actually implement the high risk, high reward strategy. I mean, unlike venture capital where they spread the risk and they know many of their investments are gonna go extinct. I hear you have kind of a fixed body. You want scientists to produce results and yet you should almost strive for some reasonable rate of failure as an indication that the high risk strategy is paying off. So I'm wondering how you. Oh, it's a very, very thorny or tricky question in terms of how to do this because you're quite right. And certainly as we scrutinize investigators more with the Board of Scientific Counselors and look more carefully at what their level of productivity is, it certainly does encourage people to go for sort of incremental quantum kinds of approaches rather than higher risk, longer term kinds of projects. I guess that really the only answer that I can give is in talking with investigators and thinking about as we have reviews and discussions of people's work in the intramural program of encouraging them with the bully pulpit that I have of taking on sometimes longer term things. Certainly it's an important thing with the tenure track investigators to encourage them to do that kind of thing. Certainly one my own personal experience with this which I think Bob can probably remember because he was one of my reviewers back many, many years ago. Is that I took on a positional cloning project as what I was doing as a tenure track investigator. And so it was very much a high risk, high reward, long term project. And that certainly is my point of view as to what people should do is to try to identify things that are really important and bold and to go for them. But it is, you're quite right, hard to actually get them to do it. Bob. Actually Dan, that was a very, very wonderful presentation. Thank you. I wanted to ask you for a comment and then ask you a question. So the comment is I've heard from other people not in your institute, but in other institutes in intramural program of real problems with morale. And not just from the sequestration but also from an onslaught of regulations coming down that really restrict the ability of scientists to participate in meetings and requests for that they're PowerPoints, that they're gonna give it scientific meetings, be put up in the public domain and all sorts of things like that. So I wanted to ask you about how you're able to maintain morale because it looks like people are working hard and doing well. And my question for you is have you been approached by the FDA about the NISC Next Generation Sequencing Center, not only having to be CLEA approved but also requiring investigational device exemptions if any other information is gonna go back to patients? Well, with regard to your first question, I guess the, I don't know if that's the easy question or the second one is the easy question. So maintaining morale, I mean it is something that is really one of the most important things that one can do right now with the intramural program. And I think that part of the dealings with that have to do with the fact that we have a very, very flexible and understanding administrative staff in NHGRI who really do put the investigator first. That's not to say breaking rules but at least being flexible to the extent that they can with regard to these kinds of things. And I think that with regard to the particular issues that you're raising has been very, very important. With regard to the budgetary constraints, the way that I've tried to handle that is by being totally transparent and by engaging the faculty in whatever decisions we make with regard to cutting programs or budgets or whatever so that it's not something that's coming down from on high but rather something that everybody's engaged in as a common response to an outside threat in a way. With regard to the FDA approaching NISC, well, no, so far we haven't heard that but that may just, maybe because we're not into it far enough for that to have happened. It might be worth while having a conversation with Anastasia-wise because the extramural newborn sequencing group has been approached by them. Really? Yeah. And we've been required to put in pre-IDE applications and they are looking very seriously at any next generation sequencing platforms including software that are used to generate information that's going back to patients. Wow. Okay, well, that's so boring. Actually, before we take another question, I mean, I should weigh in on the issue about morale a little, I guess, I mean, Bob, and coming from you is of relevance because of your longstanding presence in our intramural program and have seen various waves of phenomena. You know, and I also have my own vantage point. I mean, Dan's much closer to one on a day-by-day basis. I mean, I think there's no question that recent years, handful of years have just brought a constellation of stresses and strains to intramural investigators. I mean, budgetarily as part of it but some rather invasive attempts at requirements as well as other constraints around travel and et cetera, et cetera. No question. That said, I'd make two comments. One, I know it's also pretty stressful on the outside. So I think morale in general across biomedical research is not at all time high by any means. When I talk to people, I know lots of funding stress in particular. So I think it's there as well. I mean, the second comment to make is I also think that it's exactly what Dan said. I think the negative impact's gonna probably be last at NHGRI and I'm probably very biased in saying that. I do think we have an administrative approach to how we handle some of these things to try to make it as good as possible. I think fundamentally, morale has always been higher in our intramural program compared to a lot of other ones for a variety of reasons. So I think it's absolutely a case that it's an issue. I think it's probably more severe in other institutes than it is at ours for probably many reasons. But it's not just the intramural program. I think there's been morale issues across the whole Institute and across all of NIH for budgetary reasons, for restrictions on things like travel and so forth and then shut down, pay freezes, everything else. But I do think that we work very hard at the leadership and that's not just Dan and I, it's a whole suite of people to really try our best to buffer that as best we can. Tony, I know you had a question. Looking at the blue ribbon criteria for excellence in the intramural program, it talks about productivity, risk-taking excellence, but no one has mentioned innovation, which is one of the main criteria for the review of external grants. You may say that's inherent in risk-taking, but the example you give of positional cloning, you may just use standard technology and the risk is that someone else identifies the gene before you. So I just wanted to know how important innovation was in the way internal investigators are approaching their problems to add new value to the general field if they find a new way to do it or a new technology. No, it's a very good point and certainly, although it wasn't listed on those slides, it is something that we very much value and that is emphasized in the evaluations as we currently do them for people. I would say just with regard to going back to the positional cloning, I was doing that in the early 1990s, which was at a time when the approach was, well, you were involved in it too. It was not totally a standard approach at least at that time. But anyway, I certainly hear your point and I think that it is something that, although not mentioned, is very much a part of what we want to encourage. So great report and I want to congratulate you on actually following through on some of the things that we all suggested, it makes it feel worthwhile. And coming back to Marty's question about the risk-taking, I mean, I think that the having real, something we talked a lot about, having real rigor in that, in those every four-year reviews and actually having that be constantly reiterated and sort of conveyed by the advisors along the way, obviously risk-taking is in the eye of the beholder. It's actually bad. But then coming back to the question of morale and such and thinking about, I guess my sense is that the morale of a faculty is there's the underlying issues involved both reality and perception. And I think it's worth your conveying back to your colleagues that it's funny, the term flat funding would have an extremely positive ring in the extramural world. I can think of many institutions, it would be delighted to project flat federal funding. And it may be, and also thinking about the fact that many of your colleagues are spending rather less of their time obtaining that flat federal funding than their extramural brethren. But, and that leads me back to a question that we, at the end of the Blue Ribbon Report that we raised somewhat delicately and it's not one that you can really, well, I don't know how you'd like to address it, but of course a particular vulnerability for the intramural program at NHGRI, and now seeing the new numbers, I would, you know, back at the envelope suggests that you're now approaching 21% of NHGRI's budget. And that compares with what I understand to be generally speaking about a 13% perhaps on average across the other intramural programs. And we also highlighted the strong contrast as much as we loved it and supported it, the extraordinarily investigator driven nature of the intramural program stands in such stark contrast to the relatively top down nature, strongly top down nature of the extramural program at NHGRI. And so if you juxtapose those two things, is this actually a question that's floating across the campus, one that you have to answer to? I'd just be curious to your take on that 21% question. Well, certainly it's a question that I've had to think about ever since I started as scientific director and certainly we are, if not at the top, close to the top in terms of percentages of the total institute budget that's dedicated to the intramural program. So in terms of my own take on this, certainly I think that it's absolutely critical for us to justify ourselves through the excellence of what we do. And that probably beyond anything else is probably the most important justification for whatever level of funding the intramural program has. I think that one can talk about the long-term, high-risk, high-reward kinds of things, and those certainly are good, but as was noted, it is hard to in practice implement that across the whole intramural program. So I think that excellence, at least to me, is the most important aspect of all this. Certainly with regard to the overall percentage that the NHGRI intramural program is of the total, we are very aware of that, and I think that at least in conversations that Eric and I have had about this, we recognize that it certainly can go no higher than that and that with time, perhaps if the overall NIH budget starts to go up a little bit, that it would adjust downwards as a percentage if the intramural program were kept relatively fixed while the rest of the institute was allowed to expand. As far as the, across the NIH campus component to your question for sure, that is something that is part of the discussion, it's part of the discussion in Michael and Francis's 10-year plan is thinking about what is the right size for the intramural program and if it is to change how to get there in a reasonable way. Eric, you may want to- I have a couple of comments. I mean, first thing I would say is the direct answer to your question, David, is no. It really hasn't been asked of us very much. I mean, we've not, or else not to me, directly not that I've heard. So we've not gotten that criticism or there not have been cries for us to decrease it. If anything, I would point out that if anything, our intramural program is increasingly asked to do more and more in the intramural program because of the desire to grow genomics and especially medical application of genomics in the clinical center. So I think there's, if anything, I've only heard a cry that only we could do more, that would be better for the enterprise. So that said, it's something we keep an eye on. I mean, we talked about this at multiple levels when the blue ribbon panel report came through, both to this council, to our Board of Scientific Counselors. It is no question it's something very visible. It's why we keep a very close eye on these reviews. I mean, a fourth of our investigators are rigorously reviewed once a year because they get it every four years and you can see they're doing really quite well and if that trend would change, we might look at things a little bit differently. So, and there's a lot of reasons why I still feel comfortable. I don't think the program legitimately should grow or could grow. There's really no resources to allow it to grow at least as a percentage, but I don't have strong reasons to think it shouldn't be the current size that it is. Howard? Just curious whether you use the five categories from the 2001 strategic plan as ways of looking at your portfolio and if so, how are you doing in each of those five bins? Well, we do look at it at least to some extent and certainly given the resources that we have for doing clinical investigations, as I was mentioning, we really are skewing more towards the biology of human disease and the science of medicine categories there, which is a little bit to the right of at least where the overall heat map is supposed to be at the present time. Of course, if you go back, if you go back before that strategic plan, the difference between intramural and extramural was striking. I mean, it was very little, very little, especially in the more clinically oriented domains going on extramurally and a lot of that was going on. Again, because the clinical center, the nature of it. So, but I think if you actually look at it now, I think they're overlapping much more than previously. Any other questions for Dan? Okay, thank you, Dan. Pleasure. All right, you've earned lunch. So I think most of you know the drill, it's one floor up. Please be back. We're a little behind schedule. Please be back no later than 1.30. Let's start promptly then.