 So, I have the pleasure of introducing our scientific director of NHGRI. I want to give you a very brief history just to sort of set a context. We asked this council's main responsibility is to worry about the extramural side of the institute. But for now 25 years, the institute has had an intramural research program. It is under the stewardship, if you will, in terms of external oversight of something called a Board of Scientific Counselors, which is like all of you, fully certified, whatever you call your advisory roles and same kind of approval process, et cetera, et cetera. And so they worry about the day-to-day and the year-to-year aspects of it. But we do like and actually we're asked to make sure that advisory council has some familiarity with the extramural program. And so about every couple of years, we ask the scientific director, who's the director of the Division of Intramural Research to come and just give an update. And so it was time and maybe a few months too late, but we decided this was a good council to do this at. And so the other thing I would like to say is in the 25 years of the intramural program, there's been three scientific directors, roughly a third, a third, a third, not precise within a couple of years. Jeff Tratt was the founding scientific director and served until 2002. I then served before the current position I have as a scientific director. And then when I became director, it was one of the first things I did as director was of course launch a search to find my replacement because we needed to have somebody step into that role. And it's always, Dan likes to always talk about how on 10, 10, 10, October 10th of 2010 is when he started as a scientific director. He's come and presented a council at least a couple or a few times. I can't remember exact number, but it was time. And so we brought him here to just give you a broad-based overview, update what's going on the intramural program. And I'm sure I'll be happy to answer any questions you have so you hear about that side of the institute. So, Dan, I'll turn it over to you. All right. Well, thank you so much, Eric, for that kind introduction. And thank you all for having the patience to be here listening to what I have to say even after a fairly lengthy discussion. So in any case, as Eric pointed out, the intramural program of NHGRI is now 25 years old. Just to give you a little bit of background in terms of the intent in establishing an intramural program, the intramural program was founded by Francis Collins back in 1993 when he became the director of what was then the National Center for Human Genome Research and CHGR. And I think that it was one of his, in fact, conditions for coming here was that there would be an intramural program in NHGRI. And the vision that he had for the intramural program was somewhat different from the vision he had for the Hall Institute, which was basically to conduct the human genome project. And so his goals were, first of all, to capitalize on the unique resources of the intramural environment to establish a world-class program in genetics, genomics, and genomic medicine. So this was, from the get-go, oriented more towards the clinical kinds of things than in establishing the sequence of the whole human genome. The second thing was to catalyze the genomic transformation, if you will, of the intramural programs of the other NIH institutes. And I can tell you, having been here as a part of the Arthritis Institute, that was something for which there was a great deal of enthusiasm in the intramural program. And then over time, what's happened is that the intramural program has also become somewhat of an incubator for programs that could be exported to the broader genomics community. And in order to sort of jump-start things and get the intramural program up and running relatively quickly, deliberately the size of the intramural program, at least in terms of its budget, was larger than it is for the intramural programs of other institutes, where the average for other institutes would be on the range of 10% to 15%, whereas for NHGRI it's around 20%. So in any case, just to talk a little bit about the distinctive features of intramural NIH so that you can get a sense for what it was that Francis was hoping to capitalize on. And it's sort of apropos of the discussion that we've just had. The institutional commitment to researchers over projects. And so essentially the idea what has been for the intramural program of the NIH writ at large is that there is this commitment to individuals over projects. Second thing is that the review process is different from the review process for extramural investigators, in the sense that the review process is quadrennial and heavily retrospective. In NHGRI we have about a 50-50 ratio of prospective and retrospective review. But in a lot of the other institutes, in fact, it's more like 70-30 or 80-20 in terms of retrospective to prospective review. It also has the feature of more stable funding perhaps because of the fact that people aren't on R01 grants so that people can do longer-term studies that would be difficult to do elsewhere. And so for that reason there has been the preference for, and certainly we ask our intramural investigators to at least to some extent to embark upon high-risk, high-reward projects that would be difficult to do with R01 funding. And then finally there are certain specialized resources that we have in the intramural program that people can capitalize on in their research. Probably the one that is paramount among the specialized resources is this that is pictured here and that's the clinical center of the NIH. It's basically a 230-bed research hospital in which all of the patients are admitted on a protocol and where there is no cost either to the patient or to the investigator for being admitted to the hospital. So this is something that should be, anyway, a great incentive for people to do clinical research and in the context of NHGRI to really embark upon genomic medicine-type projects. So in any case, just a little bit about the NHGRI intramural program. Currently we have 22 tenured senior investigators and it's a fairly distinguished group. Five of them are in the National Academy of Medicine. Two of them in the National Academy of Sciences. We have currently three tenure-track investigators. So we're a little bit right now short in terms of tenure-track investigators. Part of that has been because we have had some budgetary issues over the last several years. We also have three senior scientists who are non-tenure-track investigators who are still very senior in terms of their standing in their respective fields. And then we have 13 associate investigators. These are individuals that are sort of like research faculty, either research laboratory faculty or research clinical faculty. And then nine adjunct investigators who have their primary appointment in other institutes. We also have a number of cores, which are very strong cores in the intramural program that makes it so that people don't necessarily have to have huge labs in order to conduct the work that they do. We have a sequencing center, which is really outstanding, it's sort of a medium-sized sequencing center that has really some of the latest technology in terms of both production sequencing and in terms of research level sequencing. Our total staff is about 540 individuals, at least right now. And our appropriated budget is around $114 million. And currently, the intramural program is spread amongst seven buildings on campus, plus we have off-campus facilities both in Rockville and in Baltimore. The intramural program is also distinctive in the sense that it is the home to at least some of the leadership of the NIH. And the NHGRI intramural program has been really a haven for a number of institute directors and NIH directors over the course of the last several years. And in the past, Harold Varmas, who was first the director of the NIH and then the director of the Cancer Institute, who was also housed in the NHGRI, and then Betsy Nabel, a past director of NHLBI. So in any case, going back to my own history in the institute, actually before I became a member of the institute, I was a tenure track investigator in the Arthritis Institute. And really, it was something that had a catalytic effect on my own career. The advent of the NHGRI intramural program at the NIH, in the sense that really it brought the tools of genetics and genomics to several of us in the intramural program who were doing various positional cloning projects at the time. So back in 1993, we had mapped the gene for familial Mediterranean fever, but at that point had not yet identified the gene. And so having really a group of people who had expertise in various areas of mapping and transcript identification and other parts of the effort of finding a disease gene actually was extremely important both to us and to other investigators in different institutes as well. And so that led in 1997 to our finding the gene and then sort of to flip it the other way around in terms of then utilizing some of the tools of the special tools of the intramural program of the NIH. We then established a clinic in which we have so far seen over 2,000 patients with various disorders that in some cases it's FMF, but in other cases it's other inflammatory conditions other than FMF. So this has really been something that has been catalytic for us. This is just a table from a review that one of my fellows wrote last year just itemizing the list of diseases that we now recognize starting from FMF as the beginning point and about half of them the genes were discovered here at the NIH and the other half have been identified elsewhere. So it really has been something that has had an impact across the scientific community. We've also used some of these tools to be able to discover new treatments for patients, in one case, a disease that we discovered back in the early 2000s, a disease called NOMID, neonatal onset multi-system inflammatory disease. Patients have recurrent fevers and have chronic aseptic meningitis which usually leads to severe intellectual disability in these patients over time. Once we had found that mutations in NLRP3, which is a gene that regulates IL-1, were important in this disease, we started a trial of Anna Kinra, the IL-1 receptor antagonist, in patients with this condition and 18 patients with this condition. It really is sort of a vindication of genomic medicine in terms of the fact that it is like flipping a light switch in terms of the clinical manifestations of these patients. And in fact, just a couple of weeks ago I saw one of the patients who was a part of this protocol, whereas the natural history, as I said, is usually severe intellectual disability. He had just finished his freshman year in college in biochemistry. Another example, a disease that we discovered back in 2014, or published back in 2014, actually a disease where patients were referred to us because they were thought to have NOMID, but actually they had strokes rather than aseptic meningitis. It turns out to be caused by mutations in adenosine, deaminase type 2, and these patients have strokes on the order of one every four years or something like that. And based on some of the findings that we had made with regard to the biology of this condition, we thought that perhaps treating them with inhibitors of tumor necrosis factor would be a reasonable thing to try. Before TNF inhibitors, in a group of 15 patients, there were 55 strokes over the course of 2,000 or so patient months. Since being on TNF inhibitors, these 15 patients, we've observed for about 600 patient months, and the number of strokes is zero. So in any case, again, is something where using the clinical center, one can have a big impact in terms of human disease. And then finally, a case that we're involved in more recently is a kid, 14-year-old boy from Bangalore, India, who was referred to us with recurrent fevers, with keratitis, with polyarthritis, and colitis. And it turns out that by exome analysis, he has a mutation in a gene that's involved in regulating ubiquitination. And it also turns out that there's a naturally occurring mouse knockout of that gene. Where if you cross it with a TNF knockout, essentially all of the clinical findings go away. So we brought this patient to the NIH, these are just some images. He was in a wheelchair at the time that he came to us a few months ago. So we put him on a TNF inhibitor, and here is a picture of him now, standing, as you can see. And I don't think that the audio on this particular clip works, but if it did you'd hear some music, and you would see that he is now dancing a few months after going on TNF inhibitors. So really this is something where using the clinical center has a huge impact in terms of both understanding the biology of human diseases and having an impact in terms of treatment. There are many, many other examples of this sort of thing going on in our intramural program. Here's Ellen Sudranski, one of our tenured senior investigators, who has been a student of Gaucher disease for a number of years. And she noticed that occasionally, in some of her patients with Gaucher disease, that Parkinsonism developed. And what's more, that Parkinson's disease was seen at least in a few of the relatives of people with Gaucher disease. And so actually she did a large study, which is summarized in this New England Journal article shown here, basically demonstrating that mutations in gluocerebrosidase, the cause of Gaucher disease, can also lead to Parkinson's disease. And in fact, this is now known as the most common genetic risk factor for Parkinson's disease and related disorders. What's more, Ellen has used NCATS, the Chemical Genomics Center, which is housed here on campus. And certainly it's another of the resources that people in the intramural program have at their disposal to develop a small molecule that actually can inhibit the biology of the genealogic process in Gaucher disease. And they're also now testing this in IPSCs, in dopaminergic neurons in Parkinson's disease. And so this is another example of using the Clinical Center to good end. Philip Shaw is one of our tenure track investigators in the Social and Behavioral Research Branch, who's a child psychiatrist and an expert on ADHD. And so he's used the Clinical Center to basically scan a cohort of kids with ADHD in the same scanner, the same MRI scanner, for the last 14 years, a real feat just to get a couple hundred kids with ADHD to stay still in a scanner every year for 14 years in a row. But basically Philip has identified now rather than just using clinical phenotype as the hallmark of ADHD has actually found that there are differences in the way the brain is wired that are heritable that one can look at in ADHD. And this slide just demonstrates that in kids who actually remit, because there are some kids with ADHD who eventually remit, they have a connectome, a wiring of the brain that is similar to individuals who have never been affected, whereas those who have ADHD persisting into adulthood have a wiring of the brain that remains abnormal. Another of the people who have really capitalized on the Clinical Center is Lass, Beesekker, who has been a student of Proteus Syndrome and other overgrowth syndromes for many years and through those studies, through the careful study of patients with those diseases, eventually made the paradigm shifting discovery that in fact patients with Proteus Syndrome have somatic mutations in the tissue, a non-malignant disease with somatic mutations. Lass has of course done a number of other things of great note, such as his leadership in the return of secondary findings in research protocols. And of late, he has developed a project with Richard Siegel in my old institute, the Arthritis Institute, the Genome Assertainment cohort in which there are a bunch of patients, about 1,000 patients who have undergone genomic sequencing, where essentially investigators in the intramural program can query those individuals, the sequences of those individuals, for mutations in their gene of interest and the patients are consented for callback, so that then deep phenotyping of those patients can be done. Bill Gaul, I think you're very familiar with Bill's work and the impact that it has had broadly. The Undiagnosed Diseases Program just turned 10 actually about a week ago and has had a number of milestones and of course it has been a case where the intramural program has been approving ground, if you will, for something that then has been exported to the extramural community and of course starting at the NIH, the UDP, whoops, but now of course we have a number of centers as part of the Undiagnosed Diseases Network. Similarly, the National Chemical Genomics Center was a part of the NHGRI intramural program up until the first year that I was the scientific director. It's now a part of NCATS and is something that is broadly available for investigators in the extramural world. Larry Brody, another of our intramural investigators, has been the leader of CIDR, the Center for Inherited Disease Research, which has certainly had a huge impact in terms of both sequencing and genotyping more broadly. Charles Rotimi, the head of our Center for Research in Genomics and Global Health, has certainly had a big impact in terms of health disparities research and the study of African ancestry populations in genomics. And Max Munka, another of our investigators, has now in the same vein started a training program in which individuals from all over the world come for a month-long training program in genomics and genetics. The social and behavioral research branch has been sort of a pioneer in the sense that it is the first branch in the intramural program for social and behavioral research in any of the institutes of the NIH. Julie Segre, I think you heard in Eric's summary this morning that Julie has a paper that's just come out with regard to detecting various flora in the plumbing of the clinical center hospital, and really that's something that is very difficult to do in a hospital, particularly in a hospital that may be concerned about lawsuits and that sort of thing. And so certainly the clinical center has taken the lead in terms of those kinds of studies. Jim Mulliken, the head of our sequencing center, has been a pioneer not only in running the sequencing center but in various collaborative studies with the Vaccine Research Center and the Anti-HIV antibodies. Adam Philippi, another of our tenure track investigators, has taken the lead with regard to developing new algorithms for assembling sequence from long-read single molecule sequencers and has had a big impact in that regard. Sean Burgess, one of our zebrafish aficionados, has developed a line, an HDRI-1, of zebrafish for CRISPR-Cas9 modification so that there's a standardized zebrafish line for doing this and has developed a tool that one can search on the web basically for designing guide RNAs for developing CRISPR-Cas modification of the zebrafish genome. And then I'm almost done with the litany here, but Elaine Ostrander certainly has taken the lead in terms of canine genomics and Dave Bodine has generated a resource for people who are interested in the epigenetics of erythroid development in the mouse. So in any case, there's a lot of examples. These are just a few and certainly the faculty of the NHGRI has been very, very engaged in terms of developing tools for the broader community and in the process doing things that advance their own careers as well. Just in the last couple of years summarizing at least some of the papers that have come out from the intramural program, you can see that really there's a long list of papers published in very prominent journals and certainly there's a number of others besides the ones that are listed here. In terms of the review of the intramural program, Eric talked about the Board of Scientific Counselors and I'll mention that in a little bit too, but we also have a decennial in every 10-year review of the intramural program by a blue ribbon panel. And we had our last blue ribbon panel review back in 2011 and 2012. It was chaired by David Page and other members were Wiley Burke, Nancy Cox, Bruce Korf, Rick Myers, Bob Waterston, and Huda Zogby. And they both site-visited the intramural program but also reviewed a lot of written materials as well and had very positive things to say about the intramural program with regard to its scientific productivity, mentoring and training programs, dissemination of genomic technologies across the intramural research program, internationally recognized research faculty, robust research infrastructure, and collaboration and collegiality. What they did recommend was, number one, to continue to adhere to the model of investigator-initiated research, again coming back to that theme from the previous discussion, allocate resources based on rigorous reviews by the Board of Scientific Counselors, embrace a risk-taking culture, insist on excellence, and continue to be a change agent on the NIH campus and beyond. And in terms of the day-to-day evaluation of things, the Board of Scientific Counselors currently is made up of nine extramural experts, Brandon Lee is the chair, and you can see the other people who are currently serving on the Board. It's a rotating service. And each investigator is reviewed every four years. It's a quadrennial review process. What I ask the Board, the site visitors to do, is to address these questions with regard to investigators. Does the work fundamentally change the way that 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 that we practice medicine? Certainly the deletion test, 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 of the intramural program? To date, we've been using a relative rating system for the last several years. And to date, we have 60 evaluations that have been done. Some people have been evaluated more than once with this system. And 63% of the investigators have received the highest rating of outstanding. In terms of planning for the next century, the next quarter century anyway, but maybe the next century too, we certainly want to maintain a strong commitment to the things that I've already mentioned, risk-taking, scientific excellence, and leading genomics in the NIH, a merit-based resource allocation, strategic tenure track faculty recruitment. Because of the fact that we don't have a top-down system in which I or anyone else tells investigators what they should be doing for their research, if we want to shape the intramural program, then we do it basically through our recruitment. And so if we want to have a more bioinformatic-oriented or basic science-oriented that-have-you faculty, then we do that through the process of recruitment. Certainly, succession planning is something that we do have to think about. About a third of our investigators are now at the point where they could retire sometime in the next five years, and so we do have to think about those issues. And then engagement in an institute-wide strategic planning process, which Eric has already, I know, talked about a lot, and a new round of Blue Ribbon Panel Review, which will be upcoming probably in 2020 or so, that we would start that process as well. So anyway, that's the overview. I guess I did go exactly half an hour. So in any case, I'd be happy to answer any questions that you have if you do. Yeah, Trey. Thanks for the really informative update. With regard to the extra budget bolus that was sent the NHGRI's way this year, I think Terry might have said a few words about intramural extramural this morning, but could you comment, did you guys benefit from a few extra dollars this year and how did you-or how do you plan to use them? Yeah, that's a good question. So as-I mean, we can break it down into, you know, sort of the overall gains for the NIH for NHGRI and for the intramural program. So NIH, as you may know, got an 8.8% increase in its budget. Some of that money was earmarked for particular projects like the Cancer Moonshot, et cetera, et cetera, so that NHGRI, I think, got about a 5% overall increase. Eric and I have talked about the idea that probably the intramural program being at 20% but that's higher than what it would be nice for us to be. But if you do the thought experiment in terms of how you would fix that, so if the institute were to get a 5% increase this year, which it did, and the intramural program didn't get any increase at all, then we would go from 20% to 19%. And if we wanted to get down to 10%, you know, which is, you know, sort of the goal in a lot of institutes, so it would take us 10 years of the intramural program not growing at all, and the extra-and the rest of the institute growing at 5% a year in order to redress that. So basically, that would be very hard to do. Eric and I talked about the idea of building a 3% increase into the base of the intramural program so that the intramural program would grow by $3 million and actually this year, but it's not something that's a long-standing commitment, we did get an extra $2 million as well so that we actually have grown by 5% this year the same as the average for the institute. But the commitment would only be 3% for out years. In terms of what have we done with it, well, you know, there has been a lot of scrimping on things because of the fact that we went through a period of time where there was sequestration and then a flat budget. And so actually there's a number of pieces of equipment, capital equipment that have sort of gotten old and needed to be replaced and so we've spent a fair amount of money on that. We are recruiting a new investigator and actually we're sort of close to having a deal with him and we're excited about the possibility of recruiting other tenure-track investigators in the next two or three years. Certainly, you know, we have to have some balance, you know, with regard to, on the one hand, because genomics is a technologically-driven field, we have to stay up-to-date in terms of technology, but on the other hand, we certainly do need to have smart young people with energy and ideas as well, especially as the faculty grades. Okay, sorry. Other questions for Dan? Steve, go ahead. I was just curious, how did you, when you were talking about the ending deaminase? Adenosine deaminase? Yeah. Yeah, and then you jumped to that, to anti-TNA. Yeah, how did we make that connection? Well, you know, it's a very good question and certainly it's not something that's sort of an obvious this-than-that kind of conclusion. So it was really sort of a fortuitous thing. The patients came to us, a lot of them having already been treated with a lot of different things, high doses of steroids, cytoxin, IL-1 inhibitors, et cetera, and had not responded to them. It just happened on skin biopsies that several of the patients had perivascular TNF, and so we thought, well, maybe TNF inhibition would be a worthwhile thing to do. And as I mentioned, these kids have strokes every four years or something like that. And there are patients. They do come, they see us, we continue to follow them. And so it's sort of like sitting under the sort of Damocles or whatever to be taken care of these kids. And so it was just a try, and it turned out that it was fairly successful. But there's no real connection to the mutations of ADA? Not that we know of, at least as of yet. Well, Dan, thank you for coming and giving the presentation to the council. We're grateful for your time. So we have more of the open session, but I think we need a break. Run upstairs and get your caffeine boost and probably be back at 340, please. We'll resume then.