 Okay. All right. Dan, you want to come up? Dan Kastner is the scientific director for the Division of Intramural Research at NHGRI, and he's with us today to give you a presentation about the division. Council has no direct oversight or responsibility to the Intramural Research Program, but we think it's very appropriate that you get a full range and understanding of all of the kind of science that goes on under the NHGRI. And so Dan's going to fill you in about the Intramural Program. And we do this just, again, for New Council, we do this every couple to a few years. We have a presentation by the scientific director to just sort of let you know what's happening on the other part of the Institute, which as, and I'm sure Dan will describe, has its own external advisory group, the Board of Scientific Counselors. So again, this is as much as anything just for your orientation to other things going on with Institute funds. Dan. All right. Well, thank you very much, Eric and Rudy, and thank you all for the opportunity to talk to you this morning. I realize that I have just half an hour, so I won't perseverate here. But in any case, really the Intramural Program is something that is near and dear to my heart. And over the course of the next little bit, we will talk about seven different things. First of all, I'll give you a little bit of background with regard to intramural research at the NIH in general, just in terms of how it operates. Secondly, I'll give you a big picture view of the NHGRI Intramural Research Program. Thirdly, I'll give you a sampler of some recent scientific accomplishments beyond what Eric mentioned just a couple minutes ago. Fourthly, I'll talk a little bit about the NHGRI Intramural Research Program as a genomic catalyst, as basically an organization that was developed, actually, at least in part, with the idea of Francis Collins back in 1993, that really the Intramural Program of NHGRI should be the engine that would drive the infusion of genomic thinking and technology into the broader intramural program of the NIH. Fifthly, we'll talk a little bit about scientific review of the NHGRI Intramural Research Program. Sixth, I'll give you a little bit of an update with regard to our budget. And then finally, we'll talk a bit about opportunities and challenges for the future, all in 30 minutes. So in any case, first of all, the distinctive features of intramural NIH, and these are things that I usually talk to the site visitors about when we begin our orientation for site visits. And so those of you who have been to site visits, perhaps will recognize at least this slide. So the first thing is that in the intramural NIH, there is really an institutional commitment to researchers over projects. And so it's a little bit more like the Hughes Institute than a grant-driven kind of environment. There is a quadrennial, heavily retrospective review process, and it varies from institute to institute as to what percentage of the review actually is retrospective versus prospective. In NHGRI, it's about 50-50 in terms of retrospective and prospective. In some of the other institutes, it's as much as 80-20 retrospective to prospective. Thirdly, because of the fact that we have this commitment to researchers and a quadrennial retrospective type of review, the intramural program perhaps lends itself to long-term studies that require stable funding. And it's a place where, at least to some extent, one can conduct high-risk, high-reward projects that would be difficult to do with typical R01 funding mechanisms. There are also specialized resources in the intramural program, and certainly the one that probably stands out the most is the clinical center of the NIH, and we'll turn to that in just a moment. Next, there's a critical mass in certain areas, and particularly in genomic medicine, I would say. In immunology, in structural biology, and in vaccine research, there is very much a critical mass in terms of really excellence in the intramural program. One of the things that the intramural program was specifically designed to do was to be able to turn on a dime. But when there are public health emergencies like the Ebola emergency, or back in the 1980s, the HIV crisis, that substantial resources can be marshaled to study those areas and to make progress relatively rapidly. Next, it is the intellectual home for institute directors and extramural program staff, and we really want to have a vibrant environment where these people can have an interest in science. And then finally, it is, of course, close to the seat of government, and it's not unusual for senators or Congress people to come to the intramural program to see what's going on, and we certainly want to have the best possible environment to show off to them. This is just a picture of a clinical center of the NIH. It's a 234-bed hospital where patients can be admitted at no cost to themselves or to the investigator who is admitting them. And because of that, it really does open the possibility for people to do research studies that are driven by the science. Of course, all of the patients have to come in on a IRB approved protocol, but still it really does open the doors, then, for a lot of intellectual freedom with regard to the clinical research. Within the NHGRI intramural program, just a brief overview of what it's all about. We have right now 22 tenured investigators and three tenure-track investigators, and actually we are in the process of converting one of our physician scientist development program members into a tenure-track position, and so this will soon become four tenure-track investigators. Three of our tenured investigators are members of the National Academy of Medicine and two are members of the National Academy of Sciences. We have 14 associate investigators. The associate investigators are like the research track at academic medical centers. We have nine adjunct investigators whose primary appointment is with other institutes but who collaborate with the NHGRI. As I mentioned, we have one member of the physician scientist development program, which is a program that Les B. Sacker developed a number of years ago to help individuals who have finished their clinical training get sufficient research background that they can compete for tenure-track positions. We currently have 513 personnel within the intramural program. This doesn't include contractors. With contractors, it's a little above 600. And after a reorganization that we did in late 2013, we now have nine branches and I will illustrate the organizational structure in the next slide. We have eight cores, the NIH intramural sequencing program, CIDR, which Eric alluded to in his talk, and then the Undiagnosed Diseases Program. The fiscal year 2016 budget for the intramural program is $105.4 million. So it represents about 20% of the overall funding of the NHGRI. And it's a far-flung operation with seven buildings on campus and two off campus. And that's just in part a product of the fact that the NHGRI intramural program is young relative to some of the other intramural programs. And so we've basically gotten space wherever we can as we've grown. This is just the organizational chart of the intramural program. A number of individuals are relatively new in their positions. So Paul Liu, our deputy scientific director, who Eric alluded to at the end of his talk, is the at least relatively new deputy scientific director. He replaced Andy Baxavanas, who took a NIH-wide intramural role with regard to computational biology. Paul replaced him. We have three new branch chiefs who were appointed at the time of the reorganization. And they are Charles Rotimi, Julie Segre, and Pam Schwartzberg. And then Laura Kaley is a relatively new acting chief of social and behavioral research. The intramural program of the NHGRI does tend to focus more on the dimensions of the density plot from the iconic 2011 figure in nature in basic understanding the biology of disease and advancing the science of medicine are the two areas that really are the major focus of the intramural program. And that's at least in part due to the accessibility of the clinical center. So there is more of a clinical bent to what's going on in the NHGRI intramural program than perhaps extramurally, although as Eric has said, certainly the intramural program has sort of blazed the way in terms of this and the extramural program I think is now very much orienting in this direction. Just highlighting a few of the things that have gone on in the intramural program over the last several years, one of them that really does highlight the ability to focus on a particular disease for a long time and to learn something about it and to make great headway is Les Bissecker's project on Proteus Syndrome. And Les actually began studying Proteus Syndrome 20 years ago back in 1996 with a natural history protocol. That protocol allowed for the delineation of a number of sub-phenotypes. Eventually, with the advent of next-gen sequencing, Les was able to demonstrate that in fact Proteus Syndrome is caused by activating mutations, Mosaic activating mutations in AKT-1. And at this point, Les actually has begun a targeted treatment protocol for Proteus Syndrome. So this is really an example of where over the course of a 20-year period of time with persistence and intensive study, we've gone from the delineation of clinical phenotypes on to a treatment protocol. Another example of this sort of thing is the work of Chuck Venditti, who was a member of, initially, a member of the Physician-Scientist Development Program. And during his tenure track, he became one of the world's experts in organic acidurias and in fact accrued over the course of time a very large cohort of patients with different organic acidurias. And this is just an excerpt from a paper that he published in Nature Genetics back in 2011 describing a new gene that's the cause of combined malonic and methylmalonic aciduria. Moving on to the social and behavioral research branch, Philip Shaw, who is one of our new tenure track or relatively new tenure track investigators, has actually at this point accrued the largest cohort of patients with ADHD who have undergone serial MRI scans. And so basically, what Philip is trying to do is to define a biologic phenotype rather than just going based on clinical phenotyping of patients. And so this actually illustrates some of the data that Philip has garnered, basically showing the connectome tracks within the brain that turn out to be highly heritable and in fact that correlate with ADHD. So just as we've learned recently that schizophrenia is a disorder in which there's excessive pruning of certain synapses, in the case of ADHD there's a deficiency in terms of pruning of certain synapses over the course of adolescent development. Another example of a focused examination of a particular group of patients that has led to great insight is Ellen Sudranski's work on gauchay disease and the observation that in fact mutations in glucocerebrosidase predispose to Parkinson's disease. And she has gone on, as illustrated in this slide, to make IPS cell lines from patients that have glucocerebrosidase mutations and have developed Parkinson's disease and has screened these cell lines with a compound from the NCATS, from the National Center for... But anyway the NCGC and chemical genomics and has identified a compound that actually has an effect in terms of the trafficking of glucocerebrosidase in the cells and thereby the accumulation of alpha-synuclein. And so this actually does represent then a possible therapeutic modality for Parkinson's disease going forward. This slide illustrates yet another interaction between one of our intramural investigators, this being Joan Bailey Wilson, with a very productive collaboration with Steve Wank, who is a gastroenterologist in NIDDK, identifying a gene that predisposes to small intestinal carcinoid tumors. And then on this slide, from Pam Schwartzberg's group, the identification of germline mutations in the PI3 kinase catalytic subunit as leading to an immunodeficiency and basically what happens in this condition is that because of activating mutations in PI3 kinase, there's actually an exhaustion of certain subsets of T cells leading to an immunodeficiency. From my own group, we described a condition a couple of years ago that we call DA-DA-2, which is deficiency of adenosine deaminase type 2. Now, some of you may know adenosine deaminase type 1 or just ADA is the enzyme that's deficient in many patients with severe combined immunodeficiency disease. In this particular case, the phenotype was one in which patients were referred to us with recurrent fevers and strokes. And these patients, in fact, had multiple lacunar strokes in the deep nuclei of the brain as illustrated here on these MRIs. These patients have mutations in adenosine deaminase 2. This figure here actually shows polyarteritis nodosa, which is another phenotype that can be associated with this condition. And in any case, having this cohort of patients and having some detailed phenotypic information about these patients and linking up with another group in Israel that had a cohort of patients with the PAN form of DA-DA-2 allowed us to at least start thinking about treatment for this condition. So in the cohort of patients that we have, they had cumulatively 44 strokes over 1,064 patient months, so roughly one stroke every two years. Because of the fact that we saw tumor necrosis factor in the perivascular areas in these patients, we started on our protocol TNF inhibition in these patients. And so in 383 follow-up patient months, same patients, 12 patients, zero strokes. So really, this is an example of how the intensive study of the clinical center does allow one to learn something that can do some good for patients. And then finally, another paper that we had just come out last week in the New England Journal deals with vibratory urticaria. So vibratory urticaria is a condition in which if you take someone's arm and put it on a laboratory vortex, they will actually develop a hive on their arm. And this is illustrated here in a control individual before challenge and after challenge, no difference in the appearance of the arm. Whereas in this patient, you can see the development of a hive induced by stimulation. And this is caused actually by mutations in a gene, ADGRE2, which encodes a novel protein, which is actually a mechanosensor on the surfaces of mass cells that actually can detect vibration. And these particular patients happen to have a mutation that leads to increased sensitivity to vibratory stimuli. So in any case, another interesting development. This slide simply illustrates some of the work that Francis Collins group is doing with regard to the epigenome in type 2 diabetes. And one of the things that they have found is that in islet cells, actually, there is a chromatin state that is specific for the islet cell and a stretch enhancer, as Francis calls it, which actually turns on the glucokinase gene in islet cells. Another interesting development, which is coming out, I believe, this week is a paper from Laura Elnitsky's group, which shows that there's hypermethylation of the ZNF-154 promoter in solid tumors, and that this actually could be the basis for a blood test for certain solid tumors. Here, turning to the canine side of things is actually something from Elaine Ostrander's group that deals with a venereal tumor that can be transmitted between dogs. And basically, this image just shows the chromosomal translocations that occur in these venereal tumors. And basically, in these tumors, there are a number of rearrangements, a number of mutations that actually are in immune-related genes that render these tumors undetectable, or at least very difficult to detect by the immune system. Work from Bill Paven's group, looking at SOX-10, actually shows a difference in terms of the activation mode of SOX-10 in pigmentation, where it is activated versus Alenoma, where it is inactivated. And then, work from my own group, looking at Pyron, the protein that is mutated in familial Mediterranean fever. This is something that we have under review at Nature, basically showing that, in fact, Pyron is controlled by roe-GTP aces. And in fact, there are certain bacterial toxins which poison Roe-A, one of the Roe-GTP aces, and that this is what actually is being sensed and what regulates the Pyron inflammatory. This mechanism, which is known as the guard mechanism for regulating innate immunity, is something that, at least up until now, has only been seen in plants. And so, it's at least the first example of where this guard mechanism is. So anyway, then turning to the impact of the NHGRI IRP on the NIH campus and beyond, just a few things that I will briefly mention. First of all, many of our investigators, our experts in particular diseases, that then can be referral centers for investigators other places. This is just an illustration of Max Munke's work with MUNCA syndrome, which is a form of craniosynostosis, and essentially just illustrating a recent review of his group on this topic. But there are many intramural investigators that essentially serve as experts in these diseases. Next gen sequencing at NISC is another area where the NHGRI intramural program has really had a major impact, and this graph simply shows that over the course of the last five years, that the number of samples that NISC has sequenced has gone up by an order of magnitude, and that if one looks at the samples, at least the investigators who have submitted the samples, because this is something that is available to investigators in other institutes, that in fact, the majority of samples are from other institutes. And so this really does serve a very important function at the NIH. Recently, Les Beesecker and Jim Mulliken spearheaded the Clinical Center Genomics Opportunity Project, which is a project that allows investigators from other institutes to do whole exome sequencing for medically important diseases. So this is another area where NHGRI is taking the lead in terms of genomic analysis in the intramural program. Of course, Les Beesecker's ClinSeq program is another example of this, in which essentially the basis of genomic medicine has really been defined. And just some examples here of some of the papers that have resulted from that. And then, of course, as Eric alluded to, the Undiagnosed Diseases Network, which is really an outgrowth of the Undiagnosed Diseases Program, which Bill Gaul established in the intramural program back in 2008, which is now really grown into something that has had major impact across the research community. And in connection with that, our Social and Behavioral Research Branch has really spearheaded the analysis of a lot of the secondary findings in the Undiagnosed Disease Program and in the ClinSeq program. And so that also has software has been made available through a number of our intramural investigators. And just for lack of time, I won't go through all of those. We have the current topics in genome analysis series, which now gone on for 12 years. And actually, Andy Baxivanis and Eric have had a leadership role in that course. And you can see here that testing to its impact, there have been 740,000 YouTube views of posted lectures to date. Then moving to other areas of impact, I'll just mention Charles Rotimi's role in terms of the H3Africa work, Julie Segre's work, defining the landscape of bacterial and fungal organization of humans, her pioneering work with regard to tracing hospital acquired in a recent paper from a set of papers from Sean Burgess, basically laying out a strain NIH one for zebrafish, CRISPR-Cas9 mutagenesis, targeted mutagenesis of 162 different loci. And then finally, the all of the CRISPR-Cas mutations that science in the intramural program is evaluated by board of scientific counselors, a set of outside experts. John Atkinson is currently the chair of our board of scientific counselors. The three members who are highlighted in yellow are our newest members, Lucille Adams Campbell, an epidemiologist from Georgetown, Jeff Murray, many of you know AIDS Foundation, and Tim Towns. The investigators in the program are rated on a scale of outstanding, excellent, and very good. And at least over the last four years, 27 have been rated as fully outstanding out of 39, which is approximately. Just to turn to the budget, and I see that we're nearly out of time. The budget this year, as I mentioned, is $105 million a year. It has been relatively flat over the last several years. And so when I took the position as a scientific director in 2010, it was $104 million. It did go down and it's now beginning to go up. On average, our investigators have had a 16% reduction in overall budgets over this period of time. We have recruited two new tenure track investigators that I will just mention. Adam Philopipe, a bioinformatician from the National Biodefense Analysis and Countermeasures Center, that's a part of the Department of Homeland Security. And Adam was actually in the part of the Department of Homeland Security that would screen the white powder that people would receive in the mail, or might receive in the mail, to determine whether it was a pathogen. He's an expert in algorithm development, single molecule sequencing. And then finally, Peter McGuire, who's being promoted from our physician scientist development program to a tenure track position. And this image just shows the metabolomics work that he's doing, basically showing that in a principal component analysis of metabolism, metabolites that in point of fact, one can separate subsets of T lymphocytes. So in terms of challenges for the future, continued faculty recruitment is one of them, expanded engagement with other institutes, a seamless integration of bioinformatics with bench science, or right now, renovating space in one of our buildings to bring together Adam Philippi, with two other individuals, Julie Segre and Laura Elnitsky, towards a molecular taxonomy of human disease, so that basically we're looking to do more of what I've described up until now, that is to say, identify monogenic disease genes, and then a 10,000 exome recall cohort is basically developing a cohort of patients at the clinical center, who will be fully genotype, and where we can call them back if they have interesting genotypes for deep phenotype. So I think with that, I'll call it to a close. I did actually make it in the allotted time. And if you have any questions, I'll try to answer. Thanks. You can certainly take some time for questions or comments. I guess I had a couple of budgetary questions. So the 105 million, I think you mentioned that investigators could have patients evaluated, yes, internally for no cost. So the cost of that actually, I didn't have time to go through that aspect of the budget. But we are actually charged each of the institutes that sees patients, we are charged a so called school tax, which is 14% of our intramural budget. So that since we have a approximately $100 million budget, that means that in essence, we spend about $14 million a year. So it's, it's quote unquote, no cost, but we're paying $14 million a year to have that privilege of being able to do that. Yeah, so the that 14 million is part of the 105 or in addition. That's right. And so that you pay that based on your budget, not based on the number of patients that you evaluate. That's right. And so we do have any idea of whether you're losing money or you're making money in the based on the number of patients that you're seeing. Yeah, well, right now, NHGRI is a little bit on the side of losing money. So that we actually could be good if we could see more patients. What about with the NISC? What's the finances of that? So the NISC, it's also part of the $105 million. And we spend approximately $7 million a year on NISC. And that basically allows us to maintain the sequencers, maintain at least some bioinformatic analysis of the sequence. We do have a program within the intramural NHGRI where people can apply for competitive grants, basically, or competitive funding of sequencing, where people can either have large flagship projects or smaller pilot projects that if they compete well in this process, they will be able to do. And then as part of this clinical center genomics opportunity, we do provide funding for 1000 exomes worth for other investigators. That's actually a joint project with Michael Goddusman's office, the deputy director for internal research, who basically is paying half. Yeah, so you might not be responsible for the answer to this, but so that $7 million is also part of the 105. That's correct. And you know how competitive you are with the commercial sequencing price wise? Well, yes, we, we are relatively competitive right now. To charge, if we charge internal investigators within NHGRI, the cost is about $500 an exome. Very good. Thanks. The other thing, Val, the other subtle thing worth pointing out about that is, since a lot of what they do is fee for service, I mean, and so people will vote for their feet. I mean, some people do go elsewhere, but the big advantage of having it done by them is there's at least some amount of analysis that comes for free and by colleagues like, you know, Jim Mulligan and others and Jerry Buffard, others in that group. And so the value added is, is the is the analysis by other members of the faculty. Thanks. Yeah. The first, thank you for the overview. Could you say something about the 10,000 individual recall cohort? I was not aware of that activity, how you were doing the recruitment, what the goal is. Well, you mentioned also the diversity within that group. Yeah. So right now, it's just in its early stages. Oh, sorry. Right now, it's, it's in its early stages, it's sort of clean seek on steroids, you could say. So clean seek is certainly at least the core of that. But patients from other institutes are being incorporated into this and probably will be something that will take a year or two to accrue all of the patients for this. And the idea is that if we have a cohort of individuals where we have deep genomic information, then we can, if there are investigators at the NIH or elsewhere who are interested in the phenotype that would be associated with a given genotype, that then we could call them back to the clinical center for deep phenotyping at the clinical center. Anything about the ethnic diversity in the group? And you answered part of my question. So these are patients ascertained through a condition from another investigator. That's correct. Somehow you roll them in this. So right now, at least in clean seek, there are a number of patients who are African American, less has been specifically trying to expand the diversity of the clinical cohort on because of that. But it's a work in progress in terms of that. Just want to follow up on that comment, because when you said clean seek on steroids, because clean seek is volunteers, right? I mean, whereas the clinic, whereas the clinical center, and I just conferred with my colleague. So it's probably totally, yeah, but but but it seemed to be very, very different set of parameters that you're first, you know, characterizing the population. And in fact, maybe I mean, the people who come there are more selective for rare conditions, but they won't have the same selection bias that you'd have from a volunteer cohort. That's true. And so one of the things that it's is at least in the works, although it has not been formalized yet, is that Lass and Richard Siegel in an I am s are establishing a relationship with a Nova Fairfax. And they actually have been doing. Okay, that's a. Okay, that is a hospital in Northern Virginia. And they actually have been doing whole genome sequencing on just individuals who come through that hospital. And a lot of cases, it's through the obstetrics department. And so it's just normal deliveries. And they have actually 8000 individuals who have had all genome sequencing, where in fact that might shift the distribution more towards the type of individual that you're talking about of people that are just from the population. Yeah, so thank you. Thank you for that. Summary that I just have a have a two questions and it just shows my naivete about the about the intramural program. What is tenure? I know what tenure means that my place, but I'm not sure what tenure means here. That was one question. And then the other was the sort of the introduction is sort of high risk high reward, a long term investment in programs that couldn't be done elsewhere. And you showed some beautiful examples of science. I'm not sure. I agree that a lot of it couldn't be done elsewhere. And so can you talk a little bit about the things that intramural program does that, you know, that are examples of things that that really are, you know, such long term high risk high reward investments, or the turning on a dime. Is there anything going on in not Ebola last year? Yes, Zika, for example, that that, you know, if you tried to do it through ordinary grant mechanisms would take a year and a half before anybody got a dollar, start to work on it. So can you talk a little bit? Yeah. So with regard to tenure, first of all, so tenure is something that as opposed to in most academic institutions in which one can be tenured. And if you don't have grant funding, then it's going to be very difficult to maintain your, your research program. In fact, in the intramural program, tenure does involve a long term commitment to an individual, as long as they maintain their productivity as judged by reviews by the board of scientific counselors. And that's that's really the crux of the matter. The key is that people have to maintain their productivity in order to maintain their funding. But if one does maintain that, then it is a commitment in a way that one doesn't usually see in a university or academic health center. So that's with regard to tenure. Now, with regard to programs that people do in the intramural program that are high risk, high reward or things that can't be done other places. Well, I suppose that, you know, one can say that nearly anything, if one focuses enough on it, that one could do it in another place. I do think that the examples of some of the cohorts of patients with rare diseases, where in point of fact, it would be very difficult to maintain those cohorts over a long period of time. As I mentioned with lesbysackers work, for example, on proteas syndrome is something that sure, one could do it somewhere else. It's not as if it couldn't be done anywhere else. But certainly those kinds of projects are projects that would be hard to maintain anyway, in another in another setting. As far as turning on a dime is concerned, certainly, right now, there is an initiative in NIAID to start tackling Zika virus. And so there are such things as that certainly. Last year, Ebola, as you may know, there were Ebola patients that were at the clinical center of the NIH. And certainly in the 1980s, with the beginning of the HIV epidemic, there was a lot of work that was being done in the intramural program. But, you know, by and large, I would have to say that the most important thing with regard to intramural science is excellence. And that certainly is the thing that in our review process is really, really critical. Anything else? Okay. So thank you, Dan. Great. And Rudy, you're going to instruct us. So why don't we try to be back by 1.15 to resume the open session. There's a cafeteria one floor up that I recommend for lunch. You can bring your food back down here if you like, if there aren't tables available. You can also go upstairs on the fourth floor and visit the staff. You can leave your computers. Someone will be in the room all the time. I would advise you to take purses and wallets. Okay, see you at 1.15.