 I wake up every morning and I look in the mirror and I say for five minutes no I'm sorry I can't do that no I'm sorry I can't do that and then the phone rings and I say sure I'd be happy to do that so I'm moderating the session having not participated in any discussions on this topic prior to now and there's a hand up. So I'll help you out. I guess I'd like us to be cautious about talking about standards of care in a setting where the community will not be able to exercise this standard of care for many years to come. We won't have the resources we don't have the knowledge and we don't have the tools that will be available to us. The process is laudatory we definitely want to be able to do this and I'm grateful that it's possible but please don't tell us that this is going to be standard of care in five years because there's not enough money for it. I'd say that also it's hard to identify or define what standard of care is for a disease that is one-off really one-off yes yes. I'd also like to bring up around your point towards therapy I mean I think one of the things that we're seeing is is that how we're defining therapy is also interesting and that often these people are misdiagnosed and they're being treated inappropriately and so I would categorize if you're taking them off the wrong medications or you're taking them away from surgeries and you're taking them into a realm where the parents then can make some reproductive choices those are also a lot of outcomes that we find that the families are interested in but the misdiagnosis in this game is huge and the number of times patients are taking the inappropriate drugs is also big so I think we have to be careful on treatment towards cure and then better management of the case even when we don't know something. We're going oh sorry yeah going on to that because I mean it was very provocative I would just unbalance to say that there is a difference between a treatment slash cure versus something being actionable because you use both words and I think a lot of things are actionable once a diagnosis is made so you know so I hope that the success of this enterprise will not only be judged by who we've cured it by some gene therapy because that for sure it won't happen only in a minuscule amount of cases but but working on actionable features I think is a possibility and for the second point that was interesting about epigenetics and environmental I agree that this is too small of a sample I would leave I I would leave it to see there is a small window if there are cohorts of similar patients with similar genetic variants of which the environmental studies could help understand variations in the phenotype it's the cohort big enough maybe maybe not I don't know so I want to say a comment about the bioinformatics aspect of this that a lot of people a couple of other presenters talked about and I think knowing that how stressed the bioinformatics support in most institutions is I don't think anybody is gonna take voluntarily take on this task of developing some sort of bioinformatics tool that will integrate all this data and the only way that is going to happen is if the common fund or NHGRI thinks about putting out an RFA and so that there's money behind I think it's a very worthwhile project and one of the metrics that we're going to look at downstream 10 years downstream what happened to that data is going to depend upon that bioinformatics support and I think we need to have some some of money there maybe based on RFA which the UDN or the common fund can help write to ask you know institutions or experts who are who do this day-in day-out basis that hey here's the data set tell us how we can better integrate it and so there's it can help people and that needs to be thought about now so that the RF can go out in a year or two years and that by the end of the eight nine years project or UDN cycle we have some tangible website or tools one thing that this question that's up here having just sat in on meetings in my institution about ideas of restructuring the graduate programs in in biological sciences you can get through our programs in molecular biology or cell biology without ever having seen a picture of an entire whole organ much less a vertebrate organism likewise many of our medical students who will then go on to be residents and fellows think the CRISPR is a breakfast cereal and so I think you can't I mean you can't have education that is going to make everybody an expert in everything but I'm interested in thoughts of the group about ways that this network and participants in this network could help bridge that gap some by having you know at least some level of education for the molecular geneticist or the genomicists on on diseases and how they affect physiology and likewise for those who come through the medical route and residency and fellowship how to better incorporate knowledge of some of these things other than just I'm going to send a genetic test so I want to add to that that that those people need to think about developmental genetics in other words as a pediatrician I can't help but think there are different pathophysiologies at different ages the reasons drugs don't work or kill a baby is because they've got a different physiology and then the thing is by the time you get to an adult adulthood you may have been warped by something that happened three or four steps earlier and I think there it's really important as we're searching through this genetic pile to think of something that actually happened and was functioning in an earlier stage so we've already adapted a rotation for residents and med students so we've got neurology medicine genetics I mean it won't happen overnight but I think it is an increment toward changing mindsets good I think it's still a problem that that transition that integration requires you finding the right person at the right time I think we have I mean the basic problem is that cell biology and clinicians use completely different terminology if if we shared terminology if there were quantitative phenotypes in the clinic you wouldn't need special informatics that is essentially designed to capture ontologies would be based on actually rigorous quantitative measurements in multiple dimensions that's the fundamental problem I think is that we speak different languages we haven't spent any time integrating you know hard mentioned it earlier everybody will have completely perfected every back end pipeline long before any clinician on the planet is able to actually in real time use that information to manage a patient yeah I run a developmental biology program at Baylor College of Medicine and what we're trying to do is entice MD PhDs as well as MDs to come and work in our labs Brandon runs a program that does that and I think that's very that's for my lap has been very efficient because they bring the language and they learn the science and the scientists in the lab the PhDs learn you know the nomenclature and the process and for the UDN that's been very useful and I think we can we're trying to institutionalize that by bringing that into some of the course work and I think this is an avenue that should be pursued in other programs as well what could be done maybe at a network level so I know that Eric had to leave but there for one thing I'm familiar with there's a summer course at Aspen of all places generally on experimental neuro therapeutics where it's basically four to five days of pretty intensive education and experience in clinical trials design and methodology for neurologic diseases and whether there might be some mechanism to support something like that that would be done by the network that would provide again four to five days through one would hope some funded mechanism to provide something that is is really at multiple levels much if it would be didactic but there would certainly be opportunity for something other than that but it seems like this network is in a position where they could really you know bring bring some outreach I guess to young people who are interested in this kind of field other thoughts on this the virtuous cycle the bench to bedside to bench to bedside to bedside well it seems to me that in matchmaker either gene match or matchmaker exchange there are a lot of variants or proposed deleterious variants in there but I don't often see the basic scientists who are interested and have expertise in those genes you do sometimes but not often enough I wonder if there's anything that NIH could do in terms of pushing their funded scientists or that we could do in terms of getting the word out in the community to do more of that it's because they're not aware of it I start getting emails now when I give talks and I mentioned gene matcher it sparks it creates a spark but it's they're not coming to your talks and you know it's just the two communities are two separate that's why mixing the communities is really important in this case I know there are a few a few graduate programs relatively new that are in translational biomedical sciences which basically many of these are through the CTS eyes but the goal there is not to have this neuroscience or molecular biology or this or that but the people do their dissertation research in one specific area but the idea is to try to bridge different specialties with some problem with those programs often as they completely do not focus on mechanism but on therapeutics and so they go for a drug design without knowing why they're going for it and how they just try and I think that's not the right approach these translational programs should go mechanistically and focus on mechanism and not on therapeutics well that was provocative anybody else yes I would second exactly what Hugo said I think a lot of the problems I mean for example to push back a little bit on Steven's comments in very few therapies have any mechanistic underpinnings whatsoever in the majority of therapies in clinical utility clinical use today have essentially zero mechanistic background and so I think that's one of the sort of corollaries to this entire program is the only way that you might potentially advance things is getting a diagnosis which at least gives you a chance of moving in the right direction I'll take a point we're about rebuttal I used to be a cardiologist but I ran a big cancer center so I agree in cardiology nothing mechanistic known but in cancer the great revolution in the last decade or more is mechanistically based and if you'll remember I did argue for mechanistic focus which I believe will lead to therapeutics in the genetic era but I think that's where the emphasis be not don't not be silly to try to jump to therapeutics like the animal models but but I still think that mechanism is going to be the main answer and the I take Howard's point exactly certainly good diagnosis can help manage my many many ways I don't dispute that but I'm talking about for the future of this program and impact is going to have the very best thing that could happen period would be to go all the way to a mechanism one of these diseases and innovate some treatment for that one patient whether it's gene modification or whatever it is you know vitamin supplement right maybe they are folate deficient whatever it's going to be but go all the way to that because one example will be statistics every time when it comes to getting this funded into one of the institutes or where it's going to be so I think that that needs to be the focus and avoid trying to go out and do all the other great things you could have an impact on I don't disagree with the impact in medical education and the psychological response of patients and their families I think there could be one but I think you'll be diffuse and won't get ultimately have the impact that this should have five and ten years from now this is not where the funding goes though right now we're supported in the model organism screening center not to do functional studies but to just show that the variants are causative that's the end and we should I agree fully invest into mechanism in fact there's several cases in my lab where that's happened and already predicts a strategy as to how to pursue a bunch of projects I think it's really important that more money is poured into that we've oh sorry Howard so I think that in terms of this point one which we're kind of circling around I mean as we come back and we start thinking about the next round you know I think the R21s are a good program I think having the cores are a good program but the basic scientists often don't see a patient face they don't see that this is a case and in my experience if you bring cases to your basic scientists now this is a local thing but you bring them to your basic scientists you'll find a different kind of passion around it because it's not for a paper it's for a case and so one things I'd encourage is that we think about what this is going to look like in the future that we need to have our basic scientists tied in with our class that's exactly what we do at Baylor all my people from my lab who work on these genes participate in the discussion sit down see the patients hear the physicians you know present their cases and it completely changes their attitude and that's what should be done in the clinical sites invite basic scientists UCLA has people that have contacted me that they would die to work on these disease genes but if you don't invite them I was simply going to say that you know I mean we've we've actually used model organisms to discover drugs in from for variants taken from our clinical population so I hear where Steven's coming from but I think the reality is as Hugo says the the network is not funded to do this but the other reality I think is that you need animal models in order to get to causation before you get to therapy so I think one of the the sort of things I'm hearing at least is I think it's been a theme throughout the days there's just so much to get our arms around here that even just building the language whereby everybody can talk about the same problem is potentially one of the things that the network is really doing and I think everybody around the table has worked fairly hard to try and do that so all I'm saying is there are lots of problems that interface in this particular network and so understanding those interfaces maybe as far as we can go at a generic level although there will definitely be individual cases where we go all the way through to therapy yes so for the UDP before the UDN started there were a few cases where we were able to go from patient all the way to to therapy and I guess one of the lessons of that was a how long it takes and how many people and secondly that there's not a good way of sort of industrializing that process so it's fine to say that for a small group of patients or especially if you have a particular interest in a lab with certain expertise and we can find your lab that's great but how do you do this for tens and hundreds of patients I think is a particular challenge for us as a network to figure out the way we try to do then is if we don't have expertise for a specific gene that say it's a gene expressed in the gut or the heart or then there's plenty of people in the community we can contact and they're all eager to get collaborating and work with us so I think you can parse it out you just I think we found sort of mixed results in other words if obviously research funding is very precious and when you ask somebody to take something on they do a risk assessment and if you found something that is interesting to you in a patient but you can't convince the basic researcher that it overlaps enough with what they're doing or the risk profile isn't such that putting a graduate student or postdoc on it wouldn't be a waste of their time that it's just been a difficult discussion for us I remember early on we had a list of variants and we took it into the bills section lab and we said oh these are things we're very excited about nobody would touch any of it and we realized that we had to take some extra steps to somehow connect those cases whether it's preliminary lab work to show that there's a difference in protein levels or expression or something to make it a little bit more of a hook for that basic scientist to say it was worth their time anyway I just I think that we didn't find a perfect answer to that problem but that's something that we recognize is a problem I guess a challenge but did you stay within the NIH or did you reach out well we always try to reach out and I think that's something like what Rachel was talking about finding a broader group of people to reach out to because it's you know if we find the correct paper or if we know somebody or we try to throw as broad of that as we can but I'm sure there's ways to improve that as well okay maybe time for one or two more comments and then we'll wrap up I mean can NIH do anything in terms of an administrative supplement to those grants to give an extra $10,000 or something to make it worthwhile enough so we have done administrative supplements as well as our 21s to follow up on variants that were found in the undiagnosed disease program and as part of the UDN funding so far one thing from the cancer field that has emerged is the concept of co-clinical modeling and certainly Jim Anderson's life but at ORIP that that was a big discussion was thinking and Hugo you were there as well how do we think about paralleling some of the funding for modeling with some of the high-end disease at requirements so interesting discussion I think this is this is the 64 million dollar question is how to best do this and I think people have really pointed out some of the big challenges particularly when it comes to the way things are funded and challenges for funding things that don't necessarily fit into specific categories or don't build on what has been done previously I think just as an observation in the discussions I think the UDN model is one where in addition to having synergies and interactions at multiple levels of investigation within each center I think you know there's tremendous opportunity for interactions between centers that might bring different perspectives that will help move this forward but at the end of the day we still have many individuals who have are the first case of such and such that presents unique challenges going forward so I'm going to stop right there with my summary and move on and maybe we can get to our break a little early