tists who are going to work in those places especially from local populations funding of the science naturally collaboration of the scientists in the developed world obviously important when you go to these places you learn that political support for these endeavors is crucial partnerships you've just heard about and the NGOs from Bill Gates to advocacy groups for specific diseases play a major role here industry has a role to play it's too cumbersome to try to explore in the five minutes I have been assigned one needs ways to attract scientists from those countries back to the countries and that means having laboratories and domestic situations education for their kids that allow them to return it's helpful to make the science cheaper I'll come back to that point in a moment the client on the cost of sequencing would help attention to many social and legal issues of course is crucial and some of these especially the intellectual property and attitudes toward genetics and genetically modified organisms is absolutely fundamental to trying to pursue genomic sciences in these countries a very important feature that was emphasized by many around our discussion table is the importance of being connected by email and by access to the scientific literature some organizations including the NIH are to be commended for efforts like PubMed and PubMed Central that help Biomed Central a private organization that makes global free access some journals have made some of their publications available to the poorest countries in the world that's to be commended as well but clearly we're very deficient in getting the full repertoire of what we do paid for by NIH and many other organizations two parts of the world that could do science if some of these conditions were met and what kinds of specific things need to be done to have developing science have genomic science and for that matter other kinds of science as well done in developing countries we've all recognized here in many times the importance of genome sequencing centers and if one is going to do genomic science and things related to it maybe not simply sequencing but genotyping of insects and other kinds of things you need centers especially in countries where the scientific expertise is slim and widely distributed you need to bring it together into a coherent place where people can talk to each other an example in Bamako Mali a center from malaria research and training surrounded by the one proponent of the NIH not the one we're here paying our bills today but another institute AID in collaboration with US AID and this is the kind of thing that's done the genomics there at this point is simply looking at chromosomes and doing karyotyping on some genetic marker studies on insects isolated in different parts of Mali a second issue is getting more scientists from advanced countries into these places not just as helicopter scientists but people going in and staying for protected periods doing some training and learning the culture an example of what that might mean is provided by the history of genetics the predecessor to genomics many of you probably don't know that JBS Haldane one of the founders of our field spent the last nine years of his life doing corn genetics and other forms of genetics and archeology and anthropology as well in India with his wife who was also a geneticist so this is a way for superannuated scientists who no longer can get their R01s to practice their their wares in a very beneficial and stimulating situation some of us we're doing the same experiment over and over again we need to change the pace we need to focus on a different kind of disease we might do better work there are other things like developing low cost technology I've mentioned and specific aims to do that could be incorporated into the plan that you're developing here making more international workshops some held in developing countries to stimulate work of the kind we're talking about and free access publishing and archiving needs to be much more widespread and there are efforts like the public library of science that many of you are familiar with that's an effort to not only advocate for but develop the free access journals so what should the role of the genome institute be well, two of these are sort of Applehood one is trying to increase activity in these domains that all institutes by persuasiveness working through Dr. Z and others and working with the Fugitive International Center which has this as an explicit goal focusing attention on the LC problems which are going to be fundamental to doing research in many of the countries we're talking about two specific things came up in our discussion I thought were particularly interesting one is to advertise grants for developing for example genotyping methods that would be particularly cheap and facile in countries where they could be used for instance we're doing genetic epidemiology and other kinds of things on for example strains of infectious organisms these kinds of things would have a big impact first of all because the development of the methods would be useful everywhere that they would be an important foundation for building science in these countries the final point is to use existing projects that are in the genome institute that have an international character like the HAPMAP project or new programs to build collaborations with scientists in developing countries and try to enhance the infrastructure of research locally I'm happy to take some questions Okay, questions, comments? I have sort of responsibility of the Anopheles genome in terms of information at the moment and it's been amazing actually how productive scientists can be in developing countries out of from the information base one thing to remember about the genome is that the export is predominantly information and if you can export the information you really empower the scientists I've been incredibly impressed by the sort of science that goes on as well in the developing countries I think there's a tendency to think that it's somehow second rate it's not second rate and I'd like to add that I really feel that the internet access is one of the is a surprisingly stupid bottleneck to the developing countries it's a stupid bottleneck to have because otherwise there'd be so much information to these scientists now so I'd really like to emphasize that point I couldn't agree more thank you very much Barbara? First I'd like to say that I think it's wonderful that a field struggling with its adolescence considers what to do with its superannuated practitioners There's room for adolescence too Barbara It makes my future feel good Anyway, but what I was going to ask about I don't think any of the people who I've heard suggest this are here and I don't know if your group considered it but I've heard the idea floated several times in the way of this impact on the rest of the world that as we draw in the private sector as well as in the public sector but especially in the private sector things that are eventually lead to treatments, drugs and profit from among other things the genomes of chimps, gorillas, etc that it might be appropriate to take some very small fraction of that profit and send it back to the struggling areas where habitat preservation is a huge issue and a compelling one and I have further heard that when people have floated this issue in downtown Washington where something might be done it's been laughed at as being, you know, totally there's just good idea no way it's going to happen we don't care now I don't know whether any moral suasion coming from this sector to even consider it seriously as part of our roof is appropriate but seems to me like it's worth a thought It's a good thought I'm reminded of an effort I made in front of the leaders of all the pharmaceutical industries to suggest that all of them that have bonanza drugs that make more than $500 million in a single year put the money above a certain level maybe 10% above a certain level into a bank on a kind of tithing system and that money would be used to found a kind of inter an inter-industrial company that would work on diseases of disadvantaged countries if they made money some of that money would go back to the companies but it was a way of trying to think about the same thing to take excess profits and pop them back in but we did discuss some of these things the educational problems the ethical sensitivities to some of the things you're mentioning actually we consider the first barrier that getting the money back is I think possible but difficult One more Just a point that came up last night clearly the problems of nutrition infectious disease are important in the third world but the leading health problems in the third world are still heart disease and stroke and application of genomics to those problems and then taking the fruits of that research to the third world is something that would be worthwhile If you look at the World Health Organization's commission on macroeconomics and health which was just published last year on the leadership of Jeff Sachs you'll see an analysis of these issues and what the commission tended to focus on were those diseases that we thought had low cost remediation in the short run and I think that's an important issue I think the kinds of things that we're doing in this country of cancer and heart disease and stroke and mental illness are going to be important in translating whatever solutions we come to to these parts of the world will be a very important endeavor so I appreciate your comment Okay, I think we will move on Next speaker is Paul Miller discussing public policy priorities for the NHGRI Oh yeah, sure First, let me explain as maybe the only one of the few lawyers in the room I am hoping that by the time of Arleigh three meeting Congress will fund my little small agency so we can afford PowerPoint and present some very fancy slides It seems very as exciting to me as the genome project itself Otherwise, we have a handout I also want to acknowledge Barbara Fuller from the NHGRI who was our scribe and who typed faster than I've seen anybody type and who was critical to pulling this together The purpose and goal of our discussion last night was to look both backwards and forwards over the landscape of public policy leadership that NHGRI has been engaged in and in a sense to decide where we go from here in a sense maybe a little bit of what that roof might look like We spent a bit of time in the beginning talking about what is policy in the LC context and maybe it was because of the participants in the room or maybe just the nature of where the LC program has been We were most comfortable in talking about policy in the context of federal legislative and executive branch issues That was primarily our focus and yet we acknowledged that policy LC policy in this context needs to be much broader than simply worrying about Congress and the executive branch agencies and so we need to in a sense we made an effort to break out and I think that the program needs to make an effort as important as federal legislative policy is to break out of that box to include such issues as sort of thinking about state regulatory issues professional standards and policy education and international issues the lens in trying to think about LC policy the lens through which the public policy agenda needs to be developed is that public policy should facilitate the genetic science we thought that that was a pretty important theme and focusing the LC program policy has to be grounded in NHGRI's science research even though science can inform policy it's a loop and so that policy also informs science so it's a feedback loop but that's one way of grounding the program to talk through some of the historical ways in which NHGRI does policy primarily through funding specific research and specific issues consensus panel approaches and so on and so forth however we acknowledge and we talked about that there's been a limited ability to have LC research inform policy development particularly legislative policy that the research somehow has a difficult way of translating itself into sort of more generic policy and the challenge that NHGRI faces is how to make those research papers that it funds relevant to the policy process and so maybe just because a bunch of ethicists want to carry badges we came up with this notion of an LC SWAT team which in a sense is a quick response team of experts who have a mastery of the library of information of knowledge of issues who are available to inform the legislative process in real time when Congress decides to pick up an issue or when the state decides to pick up an issue there's no time in a sense for going back and funding a research program we need to have real time people who are available to policy makers to make this all make sense and to be involved and we have to think of a way of translating the LC program so it's really relevant and along those lines at the legislative level the opportunity to capture the attention of policy making bodies is very very limited thus the leadership and strategic thinking is critical in these issues and the notion that NHGRI is uniquely situated to take the broad view of the policy impact of the genomic revolution within the federal government and beyond and is an organizing body by which it can step up to the place not representing any particular position but really bring people together within the federal government and so on and the same is reaching out to stakeholders prime directive and we spent a lot of time talking about how NHGRI must be cognizant and respectful of its stakeholders the audience for policy and that sometimes that should not get lost both in terms of what stakeholders are looking for and how NHGRI reaches out and talks to stakeholders thinking about the end users of policy and in that sense really creating an outreach model rather than just an outreach strategic model rather than simply a reactive model to whoever walks into our door with a proposal for a grant or with an idea or a response to a grant but really reaching out to stakeholders in a proactive and strategic way along those lines not to let big P politics dictate NHGRI's policy agenda it is certainly irrelevant as you move along but not to short circuit the brainstorming because something might be politically difficult or nuclear or what have you prime directive for developing policy NHGRI's stature and influence decreases exponentially the further it gets away from genome science and that's a very important theme to consider and to ask this one thing whatever the policy initiative is does it get in the way of people taking advantage of this remarkable science again that's the in a sense an organizing principle for thinking about what might be appropriate policy and so on talked about education we talked about the need for empirical data particularly within the legislative process and lastly again this sort of goes towards the leadership role of NHGRI and that is many professional organizations have developed their own policies their own thoughts on lots of these issues that are LC issues either with NHGRI funding or without and there is no way of really nobody has yet really collected analyzed and disseminated these policy statements making them more accessible to stakeholders thinking through the different ways that different organizations have thought about these issues and that is a valuable a resource and leadership role that we thought that we thought that NHGRI could provide at the end of our little handout we went sort of a catch-all list of just some ideas issues, policy issues that might be relevant to put on a policy agenda and in the interest of time you can sort of read through that I thought that the process and structure and thematic perspective of our conversation was more important to relate to you Questions and comments? Great, thank you Okay, in the interest of time we will move on and our last Summary leader is Maynard Olson discussing the study and the genetic basis of the healthy phenotype For the background to this special topic really had to do with one of the main themes of this meeting which had to do with really what is the NHGRI going to do on the second floor Jack's house There are a number of questions there and they've been vigorously discussed for a couple of days but a lot of them really hinge around the relative role of the NHGRI and other entities particularly other NIH institutes and private industry So in a general way I think the motivation for the second floor and for indeed a major emphasis of the NHGRI in the future in this area is the clear one that there's a responsibility to deliver on the promises that have been associated with the Human Genome Project for better health But one of the motives here was to try to explore with a little greater specificity examples of how that might be done There has, of course, been a strongly articulated view that the role of the NHGRI as well as providing data sets and new technologies that can be used widely in exploring avenues to better health for example by other institutes But I think that it's important in just looking at the context of this special topic to appreciate a couple of difficulties with that generalization One of them is that I think it's clear that as data sets and technologies move somewhat away from their very generic roots the reference sequence of the human genome efficient sequencing, efficient genotyping it is simply going to be essential that these data sets and technologies be developed in a way that's driven by real applications That's how you get innovative technology You don't get it by abstracting it far away from the intended application And I think there's also a sense that there may be some structural barriers in just the way that biomedical research is done to the vigorous exploration of paths to new therapies that cut broadly across disease categories and actually don't have a natural vigorous home in any one categorical institute So that was the context and really I saw at least this discussion as an effort to take a first look at something I would present as an existence proof that there are areas of this type that the NHGRI might profitably explore on the second floor So Lisa Brooks did an outstanding job late last night after I went to the pub preparing these PowerPoint slides and they involve the potential benefits of increasing our investment in studies of the genetic basis of what we decided to call disease-resistant phenotypes I'll come back at the end very briefly to the broader issue of healthy phenotypes So the discussion was guided based on earlier input from the Genomes to Health workshop along the lines of a fairly specific proposal whose main motivation are some quite clear examples in the infectious disease area about how there has been a very profitable focus on the genetics of resistance as opposed to the genetics of disease susceptibility which has clearly been the dominant activity not just at NHGRI related research but broadly in the biomedical research community Two, just dramatic examples are actually a long list from the infectious disease area are the well-known finding of a relatively frequent allele in some populations of the CCR5 gene and all allele which when homozygous leads to essentially absolute resistance to HIV infection and indeed there are drugs in clinical trials which are really based directly on this observation and another example which to my knowledge has not been pursued pharmaceutically but certainly could is the long-standing observation that a homozygosity for a regulatory mutation which eliminates expression of the so-called dark gene the dupianogen receptor for chemokines on erythrocytes leads to essentially absolute resistance to debox malaria and indeed this allele is nearly fixed in sub-Saharan Africa So really the focus of our workshop is their room to try to extend this model more broadly beyond infectious diseases There are some interesting points about disease variants that have properties quite different from disease susceptibility alleles Our basic definition of them is that in some sense they're just the flip side of disease variants There was actually a lot of discussion about what that means, how you measure these disease-resistant phenotypes But the basic notion is that they provide resistance disease such that people with these genotypes do well under circumstances, environmental or genetic background where others do poorly and that there may be unique opportunities to exploit the study of this class of genetic variants for developing new therapies And really the core of this idea and I have only two more minutes so I have to oversimplify but the core of this idea is in the first proposition here that most disease variants clearly there are exceptions and most current drugs again there are exceptions to the production or function of a gene product and it's clear that this loss of function is indeed hard to correct and that in some sense as is the core of the dilemma which Alan Williamson referred to of taking molecular information about disease susceptibility and even building any rational path toward therapy at least any rational path other than gene therapy itself So the idea is that understanding protective mechanisms might lead more directly to the identification of doing drug targets because the idea now is to make small-balling drug which in a person with a normal genotype actually mimics the effect of the disease-resistant mutation and that indeed has been exactly the strategy in the CCR5 case and there's also the point that the genetics themselves actually provide one class of information that's extremely valuable to the pharmaceutical industry which is that it gives a human model if you like for the effects of eliminating that gene product and in the CCR5 case it was of particular interest to the pharmaceutical industry that CCR5 Delta-32 homozygotes as nearly has so far been ascertained after quite a bit of study completely normal phenotypes whatever defect is associated with missing this gene product is quite subtle under most environmental conditions So that's the core of the idea There are numerous challenges we're supposed to call these challenges rather than problems associated with implementing this type of idea and much of our discussion focused on them really at the very core of it is that people with resistant variants cannot show up at clinics The whole history of biomedical research is really a history of having provided health care services which attract people with diseases and we gradually build up this whole wonderful system of institutes and medical schools around these clinics and we draw blood and so forth as these people come through for medical treatment and even very rare diseases then present by this route for study people that aren't sick and doing well don't show up at these clinics and indeed we lack mechanisms by and large to ascertain them in society So there are numerous approaches to this challenge There was discussion of course that genesis have been doing this type of thing in the context of modifiers and lack of penetrance So that's an interesting strategy as essentially looking at relatives of affected individuals and people that as we have an increasing ability to genotype everyone and extended families to take more seriously the challenge of understanding lack of penetrance in severe diseases But I also really would just like to emphasize that we undoubtedly could come up with clever new ideas and there were actually some very interesting ones presented last night but this is not the time to discuss them I think really this is a problem that our best geneticist and this genomicist and indeed broadly the biomedical research community has actually not thought about very hard and one thing that NHGRI could do would be to stimulate some very bright and experienced people thinking hard about this problem There were a few ideas about how to approach this and I've listed them here The point being that I think that this list of examples could increase rapidly if there were more focus on the potential of this area We're in the process just for example to take studying both ends of the phenotypic distributions we're in the process of turning most diseases or trying hard to turn most diseases into quantitative traits pre-clinical symptoms if you like pre-clinical phenotypes are under a very intensive study and we're getting better and better ones for many disease processes and as you turn disease processes into quantitative traits then setting the disease resistant end of the spectrum going to be increasingly effective Clearly other institutes should be involved and we've already had quite a bit of discussion of the point that NHGRI should not be going it alone in studying phenotypes that are already under intensive investigation elsewhere at the NIH but I think there was a clear sentiment in this group that doesn't mean that the NHGRI should just keep its hands off the studies that involve phenotyping and recruiting human subjects and attempting to do genomic studies that are on this more direct path to therapy development there will for example as in many other relatively new areas of research be unique LC issues that need attention so that's it Questions? Wayne Frankel from the Jackson lab so not supposed to be hobby horse but one issue, one area that could help is use of animal models for looking at resistance Yes, no it's a good point and I really should have mentioned that there was considerable discussion of the potential of animal models especially mice where there is of course people have been quite struck by the genetic background dependence of many knockout phenotypes and that's a clear indication that model organisms could be used more intensively than they are now to focus on genetic background effects Richard The chemokine receptor mutations weren't found by genomic approach they were found by a functional traditional biological approach does that change your view at all? It really doesn't there were a lot of human mutations that had been identified and associated with phenotypes before there was any genomics or any ability to dehuman linkage it's just that it's a highly knowledge driven activity it was detailed knowledge of how HIV infects human cells in the PCR5 and candidate gene in those studies the point of genomics is that if you look at the fraction of interesting human phenotypes that yielded to just guesswork it was low and the genomics is brought to the table what Eric Lander once called an ignorant space approach to looking for what genes are responsible for what phenotypes and my own view of this subject is that there is a whole human genetics out there to be discovered that is essentially the mirror image of the human genetics that's described in OMIM for example I'd like to actually thank the six discussant leaders and actually for great presentations and I will now turn the rest of the events over to Francis well I would certainly echo your applause there for the special topics presenters I thought that was a remarkably interesting set of topics and well presented clearly those are some of the conclusions that we will need to figure out how to fold into the final version of this document that we've all been wrestling with and I promise you we will try to do our best to capture some of those very interesting ideas my task here and it won't take me half an hour it will be something less than that but we're not quite sure yet how much is to try to pull together where we have come from over the course of the last say 38 hours or so and particularly where we might then take it next in order to try to distill this into an exciting compelling document that conveys where genomic research could most usefully go next I couldn't help as we've been here at this meeting to think back on the last time we had an early house meeting to plan the future of genome research the month was May of 1998 it was a tumultuous time the goals of the genome project as outlined in the original Albert's document were within sight of being accomplished if we turned our attention in the most vigorous and energetic way towards scaling up of sequencing and a host of other related activities and yet at that very moment there was quite a visible threat to the possibility of the genome project ever actually being able to go forward in that fashion because of other events which I'm happy to say now seem to have sunk fairly far back in the fog of history at least for most people's attentions and here at this meeting we really haven't paid much attention at all to that particular unsettling that happened those four and a half years ago because I think it's fair to say whatever that was all about things have turned out pretty darn well and we now have in the public domain a very far advanced sequence of the human genome a variety of other genome sequences pouring out on lots of other interesting organisms technologies that continue to advance many goals that were not part of the original Albert's plan such as a detailed study of genetic variation already well on the way towards producing extremely useful data sets that are going to advance our ability to understand how the genome works ways in which we are studying genome function which we're not anticipated below those 12 years ago in which are already now yielding fascinating observations that allow us both to understand biology and to understand mechanisms of disease so thinking back on that time four and a half years ago it's amazing how far we have come in that interval but I think this is also important to reflect on because this has been a very different meeting than that one was and not just because of the historical events that were happening in May of 98 but because the goal here that we've been dealing with for these two days is a very different one in 98 and prior to that in 93 when we were meeting together to try to lay out the specific five year milestones we were very much guided by an overall blueprint of what we thought the genome project could and should accomplish and essentially we are now in a circumstance of being able to say it worked it worked remarkably well it's coming in sooner than expected and we have that foundation of the building that is now represented in the house that Jack built or whoever is building it that we are now using as our symbol of genomics of the future so it's been said before but I want to say it once again this meeting is really much more than what happened with that much smaller group back in 1988 that Bruce Albers chaired that tried to put together a much more ambitious and dramatic kind of plan about how to move a whole new discipline into the future we have the opportunity to do that again and I think you all have been doing it remarkably well and I want to say a few things about what I think we have taken away from this some of the major themes hopefully without repeating things that have already been said because I think we have had a fair number of summaries in various forms already that have been quite eloquent and articulate first of all let me say with regard to the document I think you did make it very clear that what we brought to you in advance of this meeting while it had content in it that I have largely heard mostly endorsed in terms of the specific areas that we called critical elements the ones that were the focus of NHGRI anyway most people have felt that is a pretty good representation of where the exciting science opportunities are on the other hand it was very clear that the formulation in the presentation did not do a service to the excitement that we all feel about this and which we would like to convey to the rest of the scientific community and in that regard not to be defensive but I think our document went through probably too many revisions before you saw it in fact I don't know what draft we were on but I know it was well into the 20s by the time it came to you and many hours had been spent on that and many people had had their fingers on it and it had benefited from the output of all the workshops that we told you about those dozen or so over the last year but that meant that all of those particular outputs felt some need to be included and many of them were perhaps in a way that did not achieve the prioritization that a document of this sort might have and in that regard this looked a bit like a document written by a committee and we all know the definition of a committee a committee is a group of individuals who represent a cul-de-sac down which good ideas are lured and quietly strangled so we may have suffered a bit by that particular kind of occasion but I think we've recovered from it quite nicely all of the day by the fact that you all are not shy and retiring and you have pointed out quite accurately opportunities to fix this I told you the story on Monday night about Wolfgang Pauley and the postcard he sent to his friend the postcard containing a diagram which was basically the only the frame of what might have been a wonderful work of art Pauley at the time being somewhat irritated by his colleague Werner Heisenberg who said he developed a unified field theory of whether all the forces of the universe except he had a few details to work out and Pauley's comment was well he could paint like Titian except he had still a few details to work out and that's why the canvas was blank at the time well I don't think we presented you with a blank canvas but I think we presented you with a canvas where the images were perhaps a little scrambled and not as appealing to the eye as they might have been and thanks to you we now have the chance to go back with our paint brushes and redo this image in a fashion that looks hopefully more like a classic of one of the old masters I don't know if it will be Impressionist or whatever but it will have I think much more substance to it and for those who look at it a chance to inspire will be greatly aided by all of this so a few comments this new version including all the elements I talked about at the beginning of the morning such as a preamble that really goes into some of the passion and the excitement will be concise to a level that the current version is not in fact we had been wondering because we do want to publish this next April in a prominent place and obviously the document you saw was much too long to appear in most journals that I know of we were already beginning to wrestle with the fact about well we'd have to have the web version that had all the details and then a shorter version that would get published I think that's wrong I think we should shrink this back based upon your good advice into a concise document and the document will be the document and it might have some sort of undergirding of historical information about how we got there but it needs to be self-contained it need not tell the reader who goes to the journal well in order to really understand this you'd better go to the web if we have to do that then I think we probably failed in our mission to excite the scientific community about where we're going this is and this came up several times this is not a five-year plan this is a plan of unspecified duration just as the Albert's report really was although it had to lay out some possible timelines we're in a different circumstance this time and therefore we ought to couch this document in different terminologies and so we I think are going to be well served by having goals that are very ambitious but not necessarily all of them tied to exactly the same time interval now don't get me wrong we must not shy away from defining specific deliverables when they are well suited to the goals that we outline but we shouldn't force that kind of specific deliverable timeline when it isn't a good fit to the goals or the grand challenges that we think are most exciting for the future of the field there's a danger in being too specified in terms of a top-down kind of view of what the future of a field such as this is with all of the speed with which it's going to move and so there will be some of those specifics and some of those timelines when we are able to do so in a fashion that is I think likely to inspire good scientific work but we're not going to overdo it in this particular instance I think again the content of what you read in the original plan the core points will generally be preserved because they did get a positive review for the most part but again the formatting is going to be resolved in a fairly major way as you saw in this document which seems to have held up pretty well throughout the course of this morning which I take it as quite a miracle with a group of people with high and strong opinions so it must be really good then and we will undoubtedly want to stick with that with perhaps some tweaking around the edges and again that will involve in the document focusing with more of a bright light on the core issues that are the central activities that NHGRI needs to make as their highest priorities with some of the other opportunities for partnership of which there are many and many quite exciting included but probably moved to a particular that they're somewhat different and perhaps not outlined in as much specificity as the core elements I think some of the things that we didn't really quite resolve which are going to be very interesting for myself and my other colleagues at NIH and in fact in other agencies to wrestle with are some of the opportunities that do seem very much like they are core potential future actions of genomics but probably are beyond the ability of the NHGRI to do all by ourselves and we've had many of those in the past we are right now engaging in this haplotype map effort which is very much along those lines with the strong participation of 18 institutes at NIH besides ourselves as well as participation by the private sector and we're going to need to continue to pursue those kinds of models for some of the things here and I will just mention two and one in particular because I think it was a subject of some confusion this morning and didn't get discussed as much in this meeting as the document as perhaps the opportunity might present and that is this whole business of providing to academic researchers the opportunity to identify affinity reagents that will allow you to probe a pathway or to identify a particular protein in a fashion that most academic researchers do not have the chance currently to do and that would be by the availability of large small molecule libraries of various sorts and I might say I don't think that is a technology which is in any way considered to be static and while one of the ways we could do this as put forward I think quite accurately by Alan Williamson is to partner with the private sector to see whether access to such libraries could be obtained I think the ways in which we make those libraries and the compounds that exist within them are going to be changing and there's probably many possibilities in the next few years of libraries that are going to be more powerful than what anybody currently has and if we could collectively through NIH resources work on making that kind of capability accessible to an investigator who is trying to understand a pathway we would both I think open a whole new window of approaches to biology and at the same time provide an opportunity to at least take the first step towards development of therapeutics in circumstances where you do have a drugable target but perhaps the disease is not common enough to inspire much attention outside of academic circles and I frankly from a personal perspective I think that that is an area of which is a real paradigm shift possibility from the perspective of many people who are currently working in the laboratory including people who think of themselves as fairly sophisticated genomicists and it's one that we really ought to pursue with a lot more attention and intensity than has been possible up until now another area that I think we are really going to have to work on together across the NIH and in other agencies as well is this a very large cohorts and again this I will say perhaps is a little bit of my own hobby horse but I cannot imagine are getting to a point five to seven years from now and looking around and not having available the opportunity to discover whether a genotype phenotype correlation is really valid or not it's going to be wonderful to have disease specific cohorts collected it was pointed out today that many of the ones that have been collected so far are probably not done in the fashion that's going to be ideal for what we want to do next with genomics but all of those disease cohorts are by their very definition going to be biased and they should be biased if you're going to look for the genetic contribution to diabetes you don't want to just collect any old case of diabetes you want to load up your cases as much as you can with those that have the strongest hereditary contribution so they're going to be the ones that have affected family members they're going to be the ones that have an early onset and then if you're lucky enough to find a variant that seems to be associated with disease the immediate next question is going to be okay in an unbiased situation what is the relative risk contributed by that allele and if you don't have such a collection that's been done in that fashion and ideally one ought to just do this with a very large cohort that would be sufficiently large to look at most common diseases then we'll all be sorry and if we don't get started on that very soon we're going to find ourselves empty-handed obviously other entities are taking this on the Biobank and the United Kingdom being an example and one that's right now mired in some controversy but I think it's fair to say it's a very good idea and it's the kind of resource which if one can work through all the practical and ethical issues would provide something that would be a great benefit to those who had access to it I might just say that the Biobank in the UK if it happens may or may not be easily accessible to US investigators and frankly will not have the kind of diversity of participants that will help us very much at all with questions that relate to health disparities and if that is in fact one of our major goals in the next few years at NIH and I think it is and it must be then we can't count on our good colleagues in the United Kingdom to just sort of take care of this for us we're going to have to make an investment of our own finally just to wrap this up before I introduce Dr. Zerhouni I want to say the focus of this next plan on applications to health is not window dressing I know it's made some people anxious at this meeting because in fact the glory of genomics over the course of the last dozen years has largely been in what many people would describe as basic science after all the sequencing of the genome our most visible flagship certainly would meet in most people's minds that description but we now have an opportunity in the field in a direction that draws us much closer to direct applications to human health recognizing that we probably can't do a lot of that alone but that second story of the house is a really important one it's not just there as a political statement to try to protect us from being seen as perhaps somewhat less in the middle of things than we were 10 or 12 years ago it is a specific intentional effort to change the mindset to make it possible for people who do genomics not just to write in the first paragraph of their grant application why this might be relevant someday to a disease but actually to be thinking about it and to be thinking about it in a regular ongoing way and to be provided with the tools and the environment and the colleagues to make that a reality in a fashion that up until now has only happened in some places at some times and I think if we collectively can come to that estimation that reality that would be a great service to the public who of course is expecting all of this and in fact to ourselves because I think that's where a great deal of wonderful science is going to occur a couple other things about the roof or the penthouse or whatever we're calling that third story I want to associate myself strongly with Barbara Wald's comments in her presentation although it wasn't particularly relevant to the topic she was talking about I like to the comments a lot I think we are in a circumstance here that bears some attention I am one of the strongest supporters you will encounter about the LC program and the wisdom that undergirded its founding when the whole project got underway and I think it has been a very successful experiment up until now in terms of connecting up research on ethical, legal and social issues with the science that moves the genome forward it is still an experiment it is still in progress it has happened over the course of the last few years where LC has taken on more of a role of the weeping profit the Jeremiah in the circumstance whose utterances largely are interpreted at least by most of the scientific community as predicting doom as basically pointing towards all of the reasons why there is something to be afraid of here and this notion of trying to couch the LC agenda in a more proactive way that emphasizes the positive opportunities is one that I think really deserves some close attention at this current time else we will end up in a circumstance where there is even a polarization between two communities that have so much to learn from each other and here I don't mean to be just saying that the LC agenda has turned in this direction I think frankly the scientific agenda perhaps for one reason or another has also begun to develop a bit of an attitude about the way in which the LC agenda is getting in the way and frankly I think that is also unfortunate and needs to be fought against in particular we've had this comment from several people about the way in which LC restrictions, or at least that's what they're interpreted to be they're really IRB restrictions they're really a common rule restrictions are getting in the way of people being able to do clinical research that they would like to do and I think it is well taken that it would be a very high priority topic for LC to take on an effort to try to map a pathway to get through this particular quagmire but I think actually the answer is not to eliminate protections against misuse of tissues unless somebody assumed that that's really what's being advocated for that will not work we must not lose the confidence in the public that we are carrying out this research in a fashion that is absolutely sensitive to their concerns about privacy and misuse of information frankly I think the principles here are fairly well worked out it's the implementation that's gotten really quite scrambled up and if it's possible it has to be possible for scientists and LC experts and public policy folks and yes even the government because HIPAA is involved in this who frankly need some help trying to sort through all the differing messages that they're getting if we can in fact get that all together and chart a course that maintains those principles but deals with an implementation that makes it possible for research to go forward in an ethical responsible way that would be a wonderful contribution and I think I agree with what's been said that that ought to be a very high priority right now for this community that we should all be proud of of having built and put together and speak to each other and can work together towards that kind of goal which is a benevolent one with much opportunity for public good well that's enough of that little bit of a speech let me finish my remarks here by just saying in a much more practical way what's next for this planning process you have given us wonderful ideas and I think speaking to Alan and Eric and Mark as I called them on Monday night and we will continue to call them for the next few months the three of them and myself will make an effort here in the next couple of weeks to try to capture the major elements of what we have heard in this meeting and reformulate the document accordingly and I'm not too worried about how to do that actually I think it's pretty clear how to do that in a way going gosh what did they say and what do we do now I think it's pretty clear what that pathway is we will call upon the leaders of the breakout groups because you all were wonderfully helpful in this process to vet what we come up with and see whether you think we captured it and we may call on various other people as well as we need specific expertise but soon after that we will then get our council subcommittee those six people whose names I mentioned to you right together to see how they think we're doing because again the ultimate approval of this planning document will be with the advisory council in that ultimate moment where they approve hopefully not disprove but approve this is going to have to come up in February at our council meeting in our open session at that point then it will be probably edited a little bit more and sent off for publication where the rest of the world will have a chance to see what we all did in April in a wonderful coincidence with the 50th anniversary of Watson and Crick in the completion quasi still a little bit but less quasi than before of the sequence of the human genome which at that point will have all of the chromosomes in the form now already enjoyed by 2021 and 22 and many others yet to come in the very near future so that's the pathway we're on and again some of you will get a chance to see these revisions we probably won't ask all 160 of you to do so because then we probably fall into that same situation of too many cooks in the stew but I think we've heard you and I hope you also will recognize that we have recorded your thoughts in all of the ways that our staff have been able to do during the breakout sessions and all of this and the plenary material which is on videotape so we can go back and recover your wise comments and by the way I would like to be sure all of the people who presented this morning make their power points available to the 3Gs so that we have those as well because there's some very good things in there and I don't want to lose them so that's the pathway we're on and again I would like to say this has been an incredible kind of gathering a gathering where we managed to bring together I think probably the largest intellectual collection of people thinking about the genome in a very long time some folks who were here were in fact I think quite impressed to see the diversity of expertise but also the depth of expertise represented by this particular set of attendees and it's been rough and tumble and that's exactly the way it always should be when we're talking about the genome and I think the outcome of this is going to be a dramatic improvement on where we thought we were three days ago and I hope you will all feel by the fact that you were here a sense of ownership because that is an intention that this is not just a plan of some government agency this is a plan of the genome community jointly generated by all of you together here at Early House and then put out for the rest of the world to hopefully have them take ownership of it as well so thank you for your very very important contributions to this and I would now like to go on and introduce the final speaker of the meeting my new boss Dr. Zerhouni Dr. Zerhouni has been here this morning and listening to all of the inputs it's probably a good thing that he didn't prepare his remarks ahead of time based on the documents I gave him last week in fact Dr. Zerhouni is the kind of NIH director who was preparing animated power points sitting next to me this morning while you all were talking so he's very much on top of the technology of immediate response in this kind of gathering I must say from a personal perspective his arrival on the scene not only about six months ago has been a wonderful wonderful thing for NIH Elias comes to us from a previous role as executive vice dean at Hopkins he has great and deep experience in how academic institutions of very high caliber operate and sometimes how they don't operate and have to be fixed and he has brought that expertise both in terms of science and in terms of management of a large and complicated organization to NIH with great energy it has been an absolute delight to have him present in our midst for these last six months one of his very first priorities has been to try to chart a course for all of NIH in the next coming years which is now being referred to as a roadmap and he has vigorously brought into that set of discussions a number of senior figures in the scientific community some of whom have also been at this meeting and it's interesting to contemplate how that exercise which basically tries to look at all of biomedical research overlaps in many interesting ways with what we've been trying to do here in a much more focused way in the field of genomics and so I was particularly pleased that despite his many commitments he was willing and able to clear off this morning to come and be with us to invite him to come and tell you what he thinks about all of this and anything else that's on his mind. Elias. Thank you Francis you know it's interesting when you become director of NIH they invite you a lot to give either opening kind of remarks or closing remarks and I'm wondering always what's best actually opening remarks are not bad because nobody has talked about the subject yet you welcome everybody and closing remarks are really a lot harder especially with an assembly like this one you've done a lot of work I was trying to get a little briefing about what happened during the past two days and I heard that there were a lot of fights and I said that's good and especially following my predecessor Harold and also recognizing all the good work he's done to bring genomics to the point genomics are today and also looking at how great he looks I'm becoming optimistic again and especially that after that I could probably take nine years in India to do but the most challenging thing was really to follow Francis as you know Francis has an analytical analytical mind that is very comprehensive and it's very hard to follow Francis do I have these slides on? So what I wanted to do really was not not to summarize or try to say something that would be over repetitive but try to say something to share with you the lessons I'm receiving not just from this morning but over the six months that I've had at NIH and share with you my own approach to what we're talking about here and some of my concepts that relate fundamentally to the maturity of this field and what it is that you can extract from it that will teach us how to go forward it is a challenge because I think what we're experiencing here is a meeting of you know experts and you've gone through all of the issues and one of the things that I find quite interesting is the boldness of all the proposals and the depth of everybody's comments so let me just share some comments with you on an informal basis and again as as Francis was saying I put these slides together in the coffee break so forgive me if they're not complete or if they're misspellings my first reaction really coming down from Washington I say what am I going to say what's worth saying after your meeting and I said my first reaction would be to be speechless it's probably the best thing to do but for those of you who know me I can't remain speechless for too long so clearly what you've developed is a bold and comprehensive plan and I'm really genome-wide I understand David Botstein wants me to use that word so I'm using that word but really the interesting thing is that I have a little bit of difficulty with and that's the analogy of the house in fact I think in genomics what we're seeing is the result of a seed that was planted many years ago and if you think about that image that seed has grown and in my mind I see it more as an arborization what you're witnessing here at early two is an arborization of the field into completely different importance and directions to me it's more like a neuron actually think of a stem neuron that has evolved and has grown its axon and now it's developing synapses and dendrites to the rest of the system so in fact you're clearly dealing with a formidable problem a formidable reverse engineering problem which is at the core of biology and it is going to permeate through these arborizations we need to tackle it together and it's going to be much larger than NHGRI it's going to be all of NIH all of the world actually and we realize that now the reverse engineering problem you know and all the analogies about parts list and how parts function and so on you've heard those I'm not going to repeat them but it is a powerful analogy because frankly it is the most formidable problem mankind has ever known of reverse engineering at the single cell with a billion molecules and billions of cells and you try to compute that you realize that we've never faced a problem like this in the history of science in fact as we are disturbing our environment as we are changing the ecology of the earth and our own relationships to the environment mastering this problem may actually be the future or the lack thereof of our societies so it is a national priority in my mind and I say that very very clearly because if you do not master life sciences in the next 25-50 years what you're going to see is a humongous impact because of the cost of disease and the cost of disease worldwide on political stability societal stability our ability to fund education and as you know an educated public is a public that supports knowledge and all of those things are incredibly dependent on your work and you understand the big picture here so what you're doing really in my mind is an arborization that is permeating the entire process the thought process of all of bioscience and one of the things that I keep hearing and I kept hearing this morning is this issue of overwhelming scale and complexity and it's too complex too many data points what do we do with them well let me just give you a perspective that comes from my personal training and as I was coming this morning I was thinking about what example can I give you that will make the point I'm trying to make and the best example I could come up with is my combination padlock when I go to the YMCA to swim I have a four digit padlock and if you know your mathematics you know there are 10,000 combinations so it could be 9999 or 0000 and everything in between so you have about 10,000 possibilities very complex but my code is 6398 I'm telling you what the code is you need to have better sequencing capabilities but anyway here's my code 6398 so it's one of 10,000 now you're facing the problem of figuring out what was in my mind when I made that code and why is that code that code and could you really open my locker if I challenged you to do that well you could really there are 10,000 combinations you still will have to use the brute force approach that you hear and that is that accumulate all the data put databases and find correlations well but if you knew how I came up with that code I can show you how the scale and complexity of the problem can reduce itself by orders of magnitude so here's how I came up with this code the way I do it so I can't as I said 10,000 possibilities so I don't forget the code I have a little routine in my mind when I make these codes and I say alright I'm going to take the first number and I divide it by 2 so I fix 6 divide by 2 becomes 3 and I say the next operation is multiply that number by 3 so it becomes 9 and then I remove 1 remember it because otherwise I would have forgotten it but you you're going to say no but you see Eric is a good mathematician so Eric is going to say well but how does that really help your memory well I'll show you why it helps your memory now if I ask you the question how many combinations there are in 10,000 possibilities that would fit multiply by 3 minus 1 anybody has the answer Eric? half 10 okay who says less than 5 you vote now 5 or less than 5 come on Eric 3 why is it 3 because obviously you have if you start by divide by 2 you can only have an even number and so 4 divide by 2 is 4 divide by 2 is 2 and then my 3 is 6 and then 5 and then you can have another one too you can start with 2 2 and 1 and 3 and 2 because you divide by 2 multiply by 3 and remove 1 but what about 8 can't work because 8 divide by 3 is 4 multiply by 3 is 12 out of range is too much animation here but there are 3 possibilities as Aravinda said and a huge reduction in complexity I'm sorry? no because 0 divide by 2 is 0 0 multiply by 3 is 0 0 minus 1 is minus 1 and I don't have minus 1 on my padlock so what it is that I think the challenge in front of you is in my mind is that you have succeeded in essentially growing a new field and you have an identity crisis or problem or issue that you have to resolve is the field a discipline or is the field a tool for many other disciplines and that to me is the challenge the complexity you're facing is why are you scientists to define operating rules of the system because every operating rule of the system you can find reduces complexity by orders of magnitude the second is that you have to understand the inter elemental functions and I've heard that about functional genomics and understanding connected gene elements that are not forgive me I'm a radiologist so it's not my field but you see what I'm trying to say there's a lot of genes that interact through functions that you could quantify and then you have to be really in terms of understanding scale and complexity you have to be able to perturb the system in a way that is measurable and that you have observations that connect with the perturbation and that is why you're hearing these ideas about molecules for research molecular libraries that will allow you to probably change the parameters of the system so you can extract from there the inter elemental functions and most importantly I think you need sufficient data density I think in my mind what I think the field is facing is truly an information theory problem and let me just show you this now again these are rough graphics let's see if I give you a data point like this circle here I'm out of uncertainty around this you weren't sure exactly where the point was but it's certainly a point in the universe of data and I asked you what do you think this represents there's no answer to that but I'll give you a second one and then is this part of a line or is this part of a circle or two eyes and Mickey Mouse and I'll give you a third one what is that tough to say and the problem in information theory is that you need both data density and data quality in fact if I showed you what it is that I intended to form here I could ask you to give me the shape I had in mind and you probably come up with ten answers but if I gave you more data points all of a sudden you realize I was thinking about a rectangle and the rectangle to get to the rectangle you really need to have data points that have a lot less uncertainty around the point and many more points how you accumulate that data in genomics is going to be your challenge and fundamentally to me I need to understand how you want to go about it because I know one thing if you use brute force it will cost us ten thousand more dollars than if you use intelligent force and that's one area of the science that I think you need to promote and that is that modeling and capability for reduction in complexity and defining the key parameters observable parameters that you need to come up with the solution and you need three things you need density and quality but you also need temporal resolution which really comes to the issue of quantum jump in technologies that we need to accomplish and we will do this now Francis mentioned I have to say something about what I've been doing for six months so Francis mentioned the roadmap priorities and it's interesting there are four of them and they seem to permeate the entire NIH and permeate all the fields that we're talking about but they're also stemming very very strongly from genomics and those are emerging research technologies and you've talked about them RNAI libraries or very advanced imaging capabilities at the molecular level single cell three-dimensional structure needs to be understood the relationship of structure to function needs to be understood we don't have the tools right now to do this we need to evaluate them and then new pathways to discovery and what I just described in terms of mathematical treatment in the field is in fact a way to have a new pathway to discover new things the idea of comparing the healthy to unhealthy is a means to discovery it's not a field in itself it's a step in the discovery process now the third one which I think is very important to you is misspelled re-engineering of the clinical enterprise I really don't believe at this point that we have a clinical research enterprise in the country that will support your dreams you've heard cohorts you've heard the ability to share data you have the ability to in fact inter-operate clinical trials no, actually other countries have more advanced capabilities than we do so I think one of the issues we have to look at and I'm looking at is how can we re-engineer the clinical research enterprise to serve the new opportunities in science which we never had before ten years ago you wouldn't have had to have that discussion as you've had it today in addition human subject protections are coming to the fore and in addition the privacy protections are coming to the fore and I have trouble seeing how the research enterprise will serve science if it is not redesigned in a way that provides firewalls around these issues of privacy now you thought that gene was a difficult issue and you have Bermuda 1 and you may have to have Bermuda 2 again to talk about it some more but let me tell you the difficulties you're going to have in terms of human data and biological samples are going to be even more daunting and I think you need to be proactive about this and go forward and last but not least is the scientific team of the future and we're obviously on the same wavelength which is clearly an issue that we need to talk one of the sentence I came up with is as we were talking about let's sequence more genomes let's talk about variation really what we're looking at in the next phase is to go from the human genome to understanding the genome of all humans and that is a challenge I think that early tube needs to place on the table because I agree the specificity of the whole of the human genome process was a terrific move and you need to stay there because it is more challenging now to obtain funding and convince Congress, convince the public that we need to have continued funding that the genome is not the end of the road the beginning of the road and that requires public trust and one of the things that I would like to emphasize and I know you have emphasized public trust is paramount and when you look at public trust what is that? in fact the most important definition I've heard of public trust is the ability to predict someone's behavior and the public wants to have the ability to predict our system's behavior the system of research and our thought process the system of science because if they can't, if it's unpredictable then they will lose trust and trust is based also on education because an educated public is a trusting public they understand at the end of the day what are the pros and cons look at what happened in Zambia where genetically modified foods were turned down by a starving population ignorance is the enemy so we have to be hypersensitive to our diversity and I just want to emphasize that and I think you have emphasized the issue of consideration of moral and ethical implications so I know we're on time as you can see I don't remain speechless for a long time but I think I wanted to share where I was in this process as a new director is challenging sometimes I have to say that I have a very well varmed seat where I am thanks to Dr. Varmas and he has done an outstanding job in preparing the field I think it's our challenge to go forward and to develop it further with vision across NIH and really across the entire disciplines of biomedical sciences I'm in for the game I see that Dr. Insol our new director of the National Institute of Mental Health is here and I'm going to borrow one of his sentences when I introduced him to the advisory council he said he came to NIH fired with enthusiasm and was hoping not to be fired with enthusiasm and and I share his view thank you very much thank you Elias for a very provocative thoughtful sophisticated analysis of some of the major issues I think you put your finger squarely on a number of the things that we are facing in the next few years and it's wonderful to have your very thoughtful analysis resonating so deeply what I think all of us are hoping for the future and partnership with you and the rest of NIH is going to be crucial if these dreams are going to come true that's a fitting finale I think a really remarkable couple of days I want to thank all of you one more time for the time and energy you put into this particularly to thank those who performed in leadership roles and for me to thank Alan and Eric and Mark for all of their hard work and for all of the NHGRI staff who performed in various ways as scribes as well as running around doing a host of other things particularly Susan Vasquez for many of the logistical issues that were so smoothly handled one of which is that I have a note in front of me to say that the dullest van that's supposed to leave at 1230 is waiting outside and ready to go and so with that those of you who are wanting to stay for lunch it is now served downstairs please go downstairs and continue your conversations those of you who have to go Godspeed to all of you and we'll try to make the best of all of your wisdom thank you very much