 Yeah, I have a question. So yeah, you you talked about the finding the common variants and rare variants and Made a strong argument that there's a lot more to find Sort of coming from a Drosophila background. I'm always wondering, you know, what kind of Special role model organisms might play one thing you can do. I mean in in Drosophila city Perhaps like G by E or G by G or other kind of thing Where will you not succeed and and what what opportunities might there be then? To transfer that to organisms where you can maybe manipulate them better. Yeah, so I think the human is Struggling I think it will succeed to identify the genes The human is a terrible setting to enter identify the interactions The scale is just wrong so we actually have certain advantages over flies with regard to gene identification namely a pretty small Population size a bunch of bottlenecks things like that that may simplify allelic spectrum in the human but Interaction both G by G and G by E is very difficult to do in the human And if you do the calculations of how many people you would have to look at I don't think it's a feasible thing So I think there's tremendous interaction with model organisms And when we ask at the end of the day, can we account for all of the heritability? It's very clear from a number of papers that what we count as narrow sense heritability Includes within it components of interaction and we're never going to get to the end without understanding them So I think it's the model organisms have a very important role to play Can I just add that? We there's a very robust model organism and you know organism specific genome Activity still ongoing it at all the centers as well as the microbiome project. We just chose not to focus on those today Because of time concerns so we would argue in HCI should indeed continue to we focus on the human just because that was our assignment So Richard I'm curious about so you guys can clearly do a lot of sequencing go after lots of samples How do you see the implementation into the clinic? Well, we do have we do have a bottle neck right now In delivering full annotated information to all comers But I think we're growing that very rapidly and that what we see though is that the You know necessity is a mother of invention So once we create the real demand for the speedy and effective annotation That is clearly palatable and digestible both from the research front and the clinical front then it comes We see but then in the private sector, but we also see it academically So in a way that it's it's pushing the the edge here What has driven the development of the things that enable it's an ableist to get to the next level? one So both Eric and Richard you talked about this dimension of case control studies or basic research moving into the clinic And I guess for someone who's really impatient. I'd like to know when the economics really transfer convert that around to When we factor in the logistics of Re-contacting individuals and the logistics of sequencing and bring all this When do we skip the case controls and go straight to the population and and then nest the the case is in there And then what does sequencing look like when we do that? Who's doing it and and where I think you can go first Yeah, well, I think you can do just an arithmetic calculation if you want 25,000 cases assuming you have a perfect background control rate and it's a 1% disease then you would have sampled 2.5 million people if it was a 5% disease it'd be five-fold less so and then you're gonna need a a Replication study, so I think the answer is depending on the frequency of the disease at some point It makes sense to get it out of a large population The question of course is do you have really good clinical characterization of those patients? So it better be a large population with really good clinical care and good health records So I that's your answer and it'll cross over for different diseases at different times And it'll be driven by the cost of doing this in Clinical settings, so that's the single disease answer But what if we're looking at a hundred and fifty like in GWAS then at some point It's not just you know that to 2.5 million will apply to a lot of disease Absolutely, if you're up for say 2.5 million for the discovery set and another 2.5 million for the Confirmation set if we could contemplate today the 5 million sample set and we had Incredibly good clinical characterization of those patients skip the case controls. Just go go for it I don't think we're close to that yet either in cost or characterization of the patients So my guess is that in terms of the layered portfolio of this institute You're gonna be thinking about a next five-year period where we take these very good case control sets Drive them to ground understand the issues in them and begin to segue into very large population studies where we take on many more So we might not take on two hundred diseases by case control studies But I think we darn well better take on 30 or 50 to really understand them But you're absolutely right it will cross over at the point where we can do it on extremely large populations well characterized so so a Big part of the answer line is the mode with which we move these data into routine clinically accessible medical records and the Degree to which we solve the issues of the ontology and the the phenotyping standards and the communicability Communication between the different aggregators of the data So I think we're all headed for the same world whether it's 10 years to 15 years or whether it's just five Really depends we believe if we can mount some programs that press on all the right points That allow those problems to be solved properly So when the data are truly flowing and truly ubiquitous that they are lodged in a way that you can do those kind of experiments Like an epidemiologist not necessarily like somebody who's scrounging up samples to do one study so do you have examples of where At your institutions the the data that you're generating from these from these sequencing Approaches have actually been implemented and are being delivered to patients and you have some examples of upon which to build Yes, we just passed 2,500 cases in our Mendelian diseases diagnostic group which mainly receives samples from children and Families with they have a developmental disorder or usually it's new has lit neurological involvement But also metabolic and skeletal effects the full range of metabolic disorders For which we now gain that figure of 25 percent solution rate because there's 25 percent of the cases We can identify a gene which is known to be pathogenic But all of those families receive back a report which describes different tiers of mutation Different levels of significance different levels of action ability And so we've built the infrastructure to allow that to happen including the genetic counseling and the follow-up of the families And also the trickling back of the samples that are not solved into the research arena So we can do more discovery to boost that 25 percent My institution Cancer is where that's starting to happen More than anything else. So really within the next year We expect that all patients that come into the cancer center with acute myeloid leukemia will be sequenced At least at the level of exome and transcriptome as we move to also trying to get whole genome sequencing into the mix Tony did you ever? Yeah, one of the rationales for the the sequencing at scale was the missing heritability argument Can you make an estimate if you had 25,000 cases and control sequenced? What would you gain all of it? Part of it. What does that mean for other things we should be investing in so look it depends on what true genetic architecture of each disease Is at 25,000 you can certainly say you have 90 percent power to detect Low-sci with a given selection coefficient and a given effect size It gets you to reason reasonable effect sizes in the neighborhood of three or four fold increases If it turns out that the natural world has put an awful lot of the heritability at such low-sci You find them if it's the case that the natural world has lots of things of smaller effects Still intermediate between the common variants but kind of weak rare variants you don't find them as much I think what we're seeing already though is that in each of the diseases where we've increased the scale Even though we know the power is exceedingly low There are one or two interesting results coming out That suggests that the number of really interesting results that will emerge with an increased scale Will be in the neighborhood of of scores to 50 or 100 such results How much that will add up to the heritability? I don't know and I almost don't care because if I get handed drug targets that is knockouts that are protective That drive pharmaceutical development that may be okay Even if it for example like common variants look like they get about 30% Maybe these might get another 30% and maybe another 30% may go to interactions and other things that we can't nail down So I don't think you can estimate it But what you can tell is your power to find it given the structure of it and we can tell that Just like with that schizophrenia example with common variants There's a lot more that will be found with larger scale But I can't promise you how far it will get only that there's a lot of biology that's that will still be found Yeah, so Rick, I liked your slide. It was something like big questions emerging technology insufficient Insufficient technology at the time. I wonder you know in the last hour We've seen hesitancy to move from genotyping nexomes and the community has some hesitancy moving from exomes to genomes And I wonder What do you think the community needs to be doing to push this field so that mantra up there doesn't read the discovery of the Exomic faces of human disease, but the whole genomic faces of disease What do you think that we as a community need to be doing to push that envelope besides cost? I think the simple answer is we simply have to commit that more projects are going to be have whole genome sequencing as their Primary activity. So the cost is obviously an important factor But it's also much more difficult much more computationally intense and hence more expensive to do those Analyses much much deeper data set, but you know, we've really skimmed the surface So TCGA, I think maybe 10% of all samples had whole genome sequencing And in some of those cases that really drove some discovery for certain tumor types But if we if we thought about some large projects where we got much deeper into whole genome, I think that would Drive us forward. It's worth noting that The power to detect in a whole genome is dramatically lower than the power to detect in an exome in an exome you aggregate all the mutations in a gene and And they're all pretty relevant Please many of them are pretty relevant in the whole genome. You have to figure out where to aggregate If you aggregate over too little a region You don't have enough events and your power goes to hell and you need 20 times more samples If you aggregate over a big region most of which is not functional Your effect size is diluted and your power goes to hell and you need 20 times more samples So this is a case where things like NHGRI's ENCODE project is really crucial because you actually have to aggregate over Functionally meaningful units to find anything Otherwise, we're not talking about 25,000 samples. We're talking about a half a million samples So this is going to be an interaction with the biology and the analysis And I completely agree with Rick that we want to do some whole genome projects to begin to explore it But we probably still want to have an excess of exome projects because we're better powered Yeah, no, I actually want to follow up on that point because I actually feel that that's actually incredibly important there's a whole sort of layer of functional biology that In my mind at least the three centers are involved with that I didn't hear a lot about here There's a lot on the sequencing of large cohorts and what you could hope to identify there But there's a whole Spectrum of other activity that CRISPR-Cas9 stuff that you guys have been doing and so on that would be great to hear more about and sort of a vision for more of an integration That could help us go The sort of base pair to bedside that you guys keep talking about because one big concern that people have is we're gonna Go wholesale the sequencing you're gonna be sequencing and then there's not a lot of information You're gonna be able to return back because we will have missed the boat and that and then the functional biology Couldn't could three more our assignment was to talk about this if you care to have us back The functional end of it would be really important to talk about as well Yeah, along the lines of the technology development and we've seen how sequencing technology is really driven and enabled Many of these kinds of studies and you elaborated some on single cell technologies and others Could you elaborate more on if you had your wish list of technology? Development needs it would help enable this your primary goal here so of Sorry, are we on of I'm not sure completely got your question duty of sort of functional characteristic of annotation or What other technology developments to help this could be in the proteomic space or whatever but what other If you had your dream list of technology development efforts that would help be enabling like we've seen Sequencing I mean in addition to the nucleic acid methods cheaper faster better sequencing functional assays that can migrate through vast data sets and petition Potentially interesting variants into those that you really want to study more into those that you don't need to study so closely That's the next big frontier D. We've got to be able to do functional studies not one at a time We're still in the mode where if you find a new gene It's practically a career investment for someone to do make a model organism do a bunch of cellular studies prove You know get their cell paper, etc. We need to accelerate that part of the process But we shouldn't be competing that with cheaper and more ubiquitous And indeed I think it's it's the marriage between the nucleic acids as a readout because when something's getting cheaper figure out how to Exploit it and these other technologies So the single cell RNA seek that Rick was describing that Aviv reggae has been doing and it's up to 15,000 cells now She's also thinking a lot about single cell proteomics. How do you do that? And then how do you do a hundred antibodies simultaneously? Well, you do it of barcoding with nucleic acids and being able to pull things down and cross label I think these crispers the the throwing in 70,000 crispers simultaneously and using nucleic acid readouts So I think there's a whole set of functional tools that that we need and they're at this intersection between Fancy technology like single flow cytometry for these single cell projects nucleic acid labeling new tools like crisper and I think the other half of what NHGRI needs to be thinking about is yes Find the basis of disease and then have a crank to be able to turn to function at them And I think there's a whole lot of important technologies that you can see being developed even a year and a half ago Single cell sequencing was not on the horizon and now it's totally clear. There are cell types in the immune system We've completely missed and they merge. There are cancers Glioblastomas which we've classified into four flavors a b c d. They're not really four flavors There are four sub there are four cell types a b c d and they occur at different proportions in different tumors and therefore we call the tumors a b c d But we should really be calling them according their proportion of the cell types There's a huge number of things about interpreting developmental responses by cells up to now when we study cells at different time points We're getting a gomish average of a synchronized cells I mean they're synchronized perhaps to you but to them they're working at different time periods when you look at single cells You can reconstruct the dynamics of that with much greater precision I think there's a world of engineering here in a world of computation that will come together around these sorts of things Eric I want to come back Statement about the exome so I'm a little bit surprised because I would think that the big genome sequencing centers One of the great assets you could provide is really getting the data on the whole genome because by whole genome sequencing We still get the exome data and the challenge we have is that we leave the rest of it on the table And here's a chance to actually look for the aggregate by sequencing more and finding where these regions are important So I'm a little bit surprised by okay easy to explain at the same price whole genomes any day Now the question is do I get 25,000 samples in their exomes and have 90% power Or 5,000 samples in their genomes and have about half a percent power your choice I would say that I would rather have the power to make discoveries first While the cost of the whole genome sequencing is coming down now if whole genome sequencing is down at 10 bucks or 100 bucks No question But at the point where you're not yet indifferent to an extra factor of five Then you're making a real trade-off you may say I get to see the whole genome And I might get to see and you get to discover nothing We need a portfolio of both. I'm in favor of a portfolio in both, but I want to be really clear There is a cost to deciding to look in an unbiased way to a genome that does have biases to it But this reminds me of the discussion early on there was a cost to sequence the whole genome Right and the point was was to figure out how to do it and you guys are the ones that figured out how to do This so if you mean is our goal total genome sequencing on everybody you bet All samples total genome sequencing if you mean is the next step over the next three four five years prove that you get meaningful biological results and Compromise by focusing in there because it's going to be more cost-effective to get more. Yeah, that's important There's no doubt. That's a temporary measure I'm still up for whole genome and that's why we have to have even in the whole genome project We had a long-term goal and there are a lot of very useful things along the way Genetic maps, which I recall you made some of and physical maps before when got to whole sequences I think we still have to use that logic here of prove Value at each stage while not forgetting about the full goal Please in that sort of discussion of the broad portfolio Projects we just heard the H3 Africa update the fact that they're doing genotyping in diverse African populations What world do you believe genome-wide associations in common variants and under study populations? What will play in the coming years in early in non European populations here in P in non Europe in on US population in non US populations well, I think it's it's absolutely clear that different populations have amazing Advantages that we must take advantage of so for example as you well know in Mexico There was this recent discovery but discovery about diabetes Particular allele present at 30% frequency in Mexico that causes a significant increase in risk diabetes But it's only half a percent in Europe So that's one where it's a rare ish variant in Europe and it's a common variant in Mexico And if we decided to focus on Europeans, it wouldn't just be politically incorrect It would be scientifically incorrect when you look at decode and the discovery of the particular variant associated with APP The you know there you can pick some things up in populations that have undergone bottlenecks So the world gives us a whole lot of really interesting population genetic variation having to do with its history The fact that it diverged and has different allele expectra that it has different bottlenecks that have scattered things different frequencies The right way to do this would be a partnership that involves certainly, you know our country But countries like Finland that have a really interesting bottleneck parts of Africa that have bottlenecks parts of India have all sorts of bottlenecks Due to endogamy we ought to be thinking that way because if we really want to complete the discovery of human disease We're going to use the whole human population not just what's convenient any other questions from council Okay, Rudy you're going to take over There are a few last things to do in the open session we're going to move out to the council initiated discussion For the new members this is basically your opportunity to bring things to our attention We've been in charge of the agenda up to this point, but if there are Important issues you want to bring to our attention or perhaps Suggest topics for future reports that we could give to the council in coming meetings You have the floor Rudy yes, so you relevant to a lot of the things that both Richard was saying and also in in some of the things in Terry's report there the global alliance is having their big meeting in I think it's March, isn't it? Yeah, and I presume someone is coming from NHGRI I can answer that very quickly because I was going to mention it later No, I was just going to say that it would be nice to get some kind of report on your reactions to that at our next meeting Our already was thinking about it. There'll be there's like five of us going from NIH Mark Geier I figured I'm going Jim Astell Phil Bourne Harold Barmas. So there's five of us going and Absolutely, I will update you on what I think that's very important and very relevant to what we're discussing today completely agree the other issues Okay, so I'm going to draw your attention to a couple of items of interest They're linked in the open session agenda. There's an article from the Atlantic title when will you cure cancer? It's an interview between James Fowles and Eric Lander. I'm pretty sure Eric didn't send us that article someone else did yeah, okay And there's an update from recent activities provided by the National Society of Genetic Counselors Every year we bring to you the Statement of understanding between the council and NHGRI Internally we call this the memorandum of understanding This is basically it's a relatively short document and it Describes how we will conduct business between NHGRI and the council So we are required to bring it to your attention every year We're monitoring policy changes that go on at the NIH and we will introduce those into the MOU Those that are relevant to council activity So special council review was something that got implemented two years ago two years ago There are no substantive changes to the MOU. We went through it as staff. We changed a few witches to that I'm not going to bother to point that stuff out to you I'll just quickly Race through and give you some highlights and again, this is largely for the new members There are specific type of applications that we're required to bring to you things like program projects Institutional training grants cooperative agreements that there's a list in the MOU Council can take Four different actions when they're asked to review or evaluate those applications you can concur with the IRG You can defer for re-review if you believe or the PI is pointed out perhaps that there's a flaw on the review You can recommend for high or low program priority or you can defer because there's additional information that council needs There's a description of a process called Expedited council concurrence. There's a subcommittee of council and I think Jim is on it DD and Howard so these three individuals get a list of the SBIR and STTR applications About five weeks before the council meeting and they're asked to review and approve those applications This simply allows NHGRI to move forward faster on the award process for those There is if you look in the ECB the electronic council book There is a report of the early council concurrence so the larger council member the larger body of council members can see The report of those applications Staff administrative authorities NHGRI can take action on applications without council approval We can negotiate award amounts after they've come through the council We can make supplement awards and there are limits to that $150,000 or 25% of the total costs that were approved by council when the application came to council whichever is greater In the case of very large awards We're capped at a million dollars whatever actions we take We are obligated to report back to the council at the earliest opportunity So those are the features or highlights. It's a forge paid for page document. I would encourage the new members to read it It's pretty easy going Any questions or comments about the MOU? Okay, then I need a motion to accept it And a second all in favor Anybody opposed? Thank you very much Okay One last piece of business and that's to read the conflict of interest statement to you You must leave the meeting when application this this refers to applications that are going to be reviewed in the closed session You must leave the meeting room when applications submitted by your organization are being individually discussed In the case of state higher education or other systems with multiple campuses geographically separated Own organization is intended to mean the entire system except where a Determination has been made that the components are separate organizations for the purpose of conflict of interest determination You should avoid situations that would give rise to charges of conflict of interest whether real or apparent For example, you should not participate in the deliberations and actions on any application from or involving your spouse or child a recent student recent teacher a professional collaborator with whom you have had with whom you have worked closely a Close personal friend or a scientist with whom you have had a long-standing scientific or personal difference The NHGRI staff will determine the appropriate actions based on recency frequency and strength of such associations or interests Either positive or negative and will instruct you accordingly in Council actions in which you vote on a block of applications without discussing any individual one the so-called on-block action Your vote will not apply to any application from any institution fulfilling the criteria noted above that constitutes conflict of interest There should be a conflict of interest form at the table. Please sign them in comfort. We'll pick them up. I Think if you wield your gavel we're then done with the open session. Okay. Very good Sorry, we'll take about a ten minute break to clear the room and Disconnect the cameras and then we'll reconvene for about an hour to continue the closed session discussion. Okay