 Good evening everybody. There are lots of seats up here in front for those of you who are still standing and probably don't want to Remain in that position for the rest of the evening. I Want to welcome you to this. I think very historic gathering To try to map out the future of genome research no less a task than that And it's wonderful to look out on this audience and see so many thoughtful and distinguished characters Some of you people who have been in the middle of the genome project for the last dozen years And some of you probably have not and that's good And we certainly hope to make the most of the synthesis that happens when you put those two Kinds of people together in the same room or the same several rooms over the course of a couple of days And ask you to think with us in the biggest possible way about where the future might take us Now that we have this wonderful foundation to build on This foundation of the genome sequence and a whole host of other attributes that have been the outcome Over the last dozen years of the human genome project. I Thought in my introductory remarks here I would try to fill in a few things about the history of how we got to this place and Also remind you of a few of the things that are in this document that you hopefully have read carefully that are Already underway because hopefully you won't think those are bad ideas Since some of them are already well begun And then just sort of lay out the charge To the assembled group here of what we're trying to accomplish in the next 48 hours a very ambitious charge I think it is but I think we have the right people to make this happen first I guess I would like to Say some thanks here to those who have worked very hard to make this particular meeting happen and in that regard Within the NHGRI there are three people who have worked tirelessly over the course of the last year To shepherd along a wide variety of activities some of which I'll tell you about a little bit including numerous workshops But also especially the construction of this draft document that we're going to be discussing for these two days And that are the so-called three G's Eric Green Alan Goodmarker and Mark Gaier All three of those people have also taken on new jobs in the last year So perhaps I ought to tell you what their current roles are now within the Institute Eric Green just one week ago became the new scientific director of NHGRI stepping into that role Jeff Trent had occupied that role for all of the history of our intramural program and Jeff moved on to Arizona and Eric graciously accepted the mandate of a national search To take on this role and has already done so with great energy as you can imagine because it's Eric Green We're talking about here Alan Goodmarker known to I think many but maybe not all of you previously had been the senior clinical advisor to the director at NHGRI And he stepped into the role of deputy director on July 1st at the retirement of Elka Jordan And Alan will be moderating this evening, which means he's keeping track of my time right now I suppose and Mark Gaier probably known to many of you for his long and very Capable service when the extramural program overseeing a host of activities, but particularly in sequencing But also many other places became at that same time back in July our director for the extramural research program While I'm here I should also say there are two other people who just started their jobs at NHGRI today We thought this was a good day to bring new people into the program to see what we do every day We come out here. We have a great time. We eat great food and drink beer over at the pub And then we all go home in two days and that's that's what you call working for the government So anyway one of them is Chris Austin who's sitting here who just joined us today from Merck who comes in To be the senior advisor to the director for translational research Gene Jenkins actually didn't start today. I think she started a whole week ago is a clinical advisor And she's here somewhere and Laura Rodriguez started today as a special Expert related to the areas of education and outreach and a host of other policy matters So we have a bunch of new people here I would like to say because looking out it's so wonderful to see them that we have a number of NIH Institute directors Who have taken the time out of their extremely busy schedules to come to this meeting? And that is really a wonderful testimony I think to the fact that NIH does do a lot of these things together and see my fellow directors here is Really quite gratifying indeed and thank you all for for coming And I hope you all will get to meet many of these folks in the course of the meeting and go up and chat with them Because as we will no doubt be talking about throughout these two days the future of genome research Is not limited to the NHGRI it probably has an impact on virtually all aspects of biomedical research And if this future is going to be as bright as we all hope it will only happen because of partnerships and broad participation Amongst virtually all the institutes at NIH as well as a number of other sources of funding like our colleagues at NSF and DOE and DARPA all of whom are also here Excuse me I should also thank all of you for agreeing to come We have pulled many of you into various workshops over the course of the last year You must be approaching workshop fatigue and just the same how you turned up for this one And I'm sure we'll plunge in with great energy to the mandate And so thank you for that and especially to those who agreed to get make presentations or chair breakout sessions And I especially like to thank Susan Vasquez and Chris Wetterstrand who have worked very hard to support all of the Activities of the 3g's and getting this meeting together and a wide variety of other things to make this possible So thank you to all of you Well, let me just quickly run through a bit of the background of how we got here in November of 2002 And that relates to the fact that the genome project has from the beginning Been characterized by a series of carefully laid out scientific plans And you're now part of that history by being here as we once again try to do that The original plan for the genome project one can I think quite accurately say was laid out in this document By a committee of the National Academy of Sciences Which put together the original blueprint of what the genome project might look like including The focus on learning how to map before you try to sequence billions of base pairs Including the contribution that model organisms could very usefully play and a host of other wise Bits of advice that turned into the enterprise that became the human genome project and in many ways I think we are sort of at a similar juncture to where they were 13 or 14 years ago because that blueprint basically laid out most of what we have been focusing on You know for the last dozen years We've done it in a series of improvements or more Specifications on that original blueprint by laying out a series of other five-year plans the first one in 1991 the second one in 1993 because the first one quickly became obsolete because of advances in the science The current version of the five-year plan that we are I guess operating by although It also is looking pretty tattered at this point is the one published in 1998 Which was to carry us through October of 2003 But actually that will be taken over and usurped by the new plan which you're all part of now Which will be coming out next April Again the first dozen years of the genome project were characterized by a series of specific and explicit Milestones happily all of which were achieved on or ahead of the scheduled timetables only a few of those are here represented on this graph I could have added many more but obviously all of these arrowheads represented the delivery of some kind of a data set That was considered pretty valuable by the community that was served by it and the sequencing of a human genome Of course only really got underway in earnest in a pilot way in 1996 and then scaled up in 1999. I Should say for those who worried that this would never really quite get pushed to the finished state That many of us are working extremely hard to make sure that happens And even as we gather here to talk about building upon the finished human genome The folks that you see in this picture are working Essentially the Sun never goes down on this enterprise because it involves six countries around the world And this is the most recent photograph of that group when they gathered at Cold Spring Harbor in May and in fact Through their good efforts. We are now very close to having that essentially complete genome sequence And that is on track to be completed in April of next year Already a number of chromosomes have reached that state and others are moving swiftly into that particular point By the way, if you're interested in the managerial aspects of the project Because in fact that we're going to cope with those same questions with a number of the large-scale enterprises That we'll be talking about in the next couple of days This is an interesting document put together by Price Waterhouse Coopers that talks about managing big science In the context of governmental support and if you're interested I can tell you how to get a free copy off of the web Of course the sequence of a human genome and the analysis of it published in February 2001 in this document revealed a number of surprises about the sequence This was of course at that point an advanced draft and as I said we are now moving that into the finished state This also is an excuse for me to point out that this particular cover had hidden within it a Forecasting of events that are going to happen next April that being the picture of Watson and Crick Hiding down there in the double helix and of course it is next April when we will be celebrating the 50th anniversary The discovery of the structure of DNA by these two gentlemen In this single one-page paper in nature April 25th 1953 So in fact and this is an important context I think for what we're talking about here. There are going to be three big events in April 2003 I will tell you I had a chance to discuss these with both the president and the first lady this afternoon In fact at a meeting at the White House where they were honoring the new Nobel laureates But there's clearly a big event coming up here in 2003 three of them the 50th anniversary of Watson and Crick The completion of the sequence of all the human chromosomes and an announcement of a bold new research plan for genomics That's you we're counting on this particular gathering to make that come true And that will be published in a visible place Which means we have a number of steps as you can tell to go through from the document that you've been looking at That's something that would actually look appropriate in a scientific journal that somebody could read in a reasonable amount of time So Basically, we're here to answer the question which many people are asking all of the original goals of the human genome project will be Accomplished by April 2003. So what's next? Do we need genomics anymore? Well, let me first lay out one ground rule for this meeting. This is a bit of a pet peeve of mine We will in this meeting not use that term Because Think about it now wait a minute. Are we ready for the post genome era? We've been in a pre genome era a dog on it for the last how many millennia and we're finally in the genome era So why should we rush it? And somehow imagine we've already passed through that and moved on to the next it's almost as Nonsensical as postmodernism and you know where that got us So we are not in the post genome era when we get there We'll all decide that it's appropriate Okay, I did want to say Three things about three areas that are touched upon in the planning document But that hopefully you've all looked at which are already underway and to give you a quick snapshot of that because I think this may Not be apparent to everybody one of them is on the subject of genetic variation Obviously, we're extremely interested in the places in the genome where people vary and we're particularly interested in being able to apply that to uncover the genetics of common disease and differences in drug responsiveness and of course if you look at any particular place on the genome This happens to be chromosome 7. I'm sure Eric Green knew that immediately when he looked at this slide There are three places here. We're in fact there are is a snip But of course these because they're relatively close together You might expect would not be independent of each other But might in fact be correlated in haplotypes and in fact if you look at these three snips and look at a hundred chromosomes In this instance, you don't see the eight possible haplotypes. This is a particularly simple circumstance You only see for practical purposes two of them So of course this would be quite valuable as a shortcut if you were trying to identify a variant associated with disease This means you wouldn't have to test all of them across the genome if you knew the structure where these haplotypes are closely Constrained then you could pick your snips very carefully Cut your amount of work back Substantially and be able to sample the genome And so in fact a haplotype map of human variation are carried out by an international consortium involving five countries and nine laboratories Got underway just about two weeks ago The goal is to define all common haplotypes in the human genome that sounds a little grandiose And we will have to have a more nuanced version of what I mean by all common haplotypes here pretty soon That will make it then possible to carry out genome-wide association studies with perhaps 30 to 50 times less work And if you had to sample every snip by itself And this was initiated last month with samples of African Asian and European origin Again carried out by a very capable group of investigators all now working very closely together to achieve this goal So that is underway Another thing that's very much underway is comparative genomic sequencing Which is referred to in the document in which I think one can say is turning out to be a goldmine of interesting Biological information and thanks to the hard work of the sequencing centers and the technology developers the steady drop in sequencing cost Has made it possible to go well beyond the dreams of the original genome project and begin to add new genomes And quite substantial numbers for either draft or finished sequencing So at the present time one can look at this list and this is only a sample But an interesting sample of ongoing public large-scale vertebrate genome sequencing projects that have reached fairly substantial coverage Three at the bottom are just getting started the others though are coming along quite well And probably some of my numbers may even be a little out of date because these change almost weekly I would point particularly to the mouse because you're about to see I think a very interesting paper Coming out in a couple of weeks Describing the sequence of the mouse and a rather advanced draft with a very detailed analysis Carried out by a large group of computational experts In an effort that was spun off by the sequencing centers that did this lovely work And particularly want to credit Bob Waterston and Eric Lander for their hard work in organizing the analysis part of this Which you can read about in a couple of weeks including a fold-out that will have very beautiful pictures of what each of the chromosomes look like Where the genes are and a whole variety of other interesting features about the mouse genome laid out there for you to enjoy studying and using Number of people have asked how is it anyway that you're going to decide how to sequence additional genomes and many of you are Aware but let me quickly mention that we do have a very well laid out process now For trying to decide where to you turn the capacity of the sequencing engines that are available in the end publicly funded enterprises And that involves a series of white papers We basically ask Communities that are interested in seeing a particular genome sequenced To put down in a very explicit way the arguments in favor of that activity Those get submitted to a distinguished panel of reviewers who are not themselves attached To affectionately to any organism that hasn't already been sequenced and they review this and Bill Gelbart Is the chair of this and I think has done a lovely job of leading this enterprise and Assign the genomes that have been proposed either the high priority or the medium or the low priority been without further prioritizing within the bins Here are the organisms that are currently residing in the high priority bin and which are therefore Candidates to be moved into sequencing in fact some of them have already been claimed by sequencing centers And they will go into their pipelines very shortly and this review process goes on So if you have an organism you haven't seen up here that you think should be a candidate for large-scale sequencing That's the process to follow go to the website and you can see how it's done One other project. I just thought it quickly mentioned it is mentioned in the document It still seems to be one that a lot of people are not aware of is an effort to derive a complete set of full-length CDNAs for human and mouse this is a project supported by many of the institutes at NIH in a very generous way Managed by Bob Strasberg at least fine gold and myself and the goal here as I said is to try to derive a Clone that's not just available in silico, but is available as a clone You can order up and use that contains full sequence of the coding region of each of the human and mouse genes and As of a recent summary here We're doing pretty well here Whereas they're almost 10,000 now human full-length CDNAs that have come all the way through the pipeline and are ready to be used And another 8,000 or so that are in the pipeline on the way and mouse is slightly behind but catching up quickly And again those are available without constraints for anybody who wants to use them As another resource for moving into this next phase Well, those are just a few of the areas that are already underway. That's not an exhaustive list Another thing that I would bring to your attention because I think this is going to be critical for the future is efforts That we're trying to make in order to perhaps make it easier for the average graduate student or faculty member or Technician or scientist of any sort to figure out how to get access to all this data This is a special issue of nature genetics containing a series of some 15 case examples of how you might query the databases looking for information about where a gene is Where markers are what the structure of the gene is what its protein structure might be of the protein product Carefully constructed and tested on postdoctoral fellows to make sure that it's amenable to good educational outcome And in fact, I think we've gotten a very positive response from this Which was largely the work of Andy backs of anus interior Wolfsburg And if you have not seen this you can get a free copy printed out If you just go to the nature website or to the NHGRI website, it's available for free Together with very nice introductory essay by Harold Varmas Well, okay, so why are we here a vision for the future of genome research is what we're here to construct And now I want to get really to the meat of what I wanted to say to you about your role I Hope you did have a chance to look at this document in some detail because it has been labored over for low these many months And I'll explain how we got to it But in many ways this is a very much a draft a work in progress We did not bring you here to ask you to put a rubber stamp upon this and then we could all go home I will tell you that one does get sort of attached to certain parts of it after a while And so you may find that Eric and Alan and Mark and I are all sort of struggling and choking a little bit When you go after one paragraph or another, but that's okay. It's good for us. We should we should be prepared for this But again, I think one of the goals here is not to be Too bland about this too general and if there are places where we have not succeeded in the specificity Then you should tell us about that. I am recently read a story which was Requoted by Leon Eisenberg in a very interesting essay. He was writing on another topic But it's sort of I guess an appropriate anecdote to tell at this point Those of you familiar with the history of physics will know the names of Heisenberg and Pauley Well, Heisenberg after having been fairly successful in a number of the theories that he was generating Let it be known around 1930 that to his colleagues that he actually had worked out The basic plan for a theory that would connect all of the forces in in physics, including the gravitational force and the electromagnetic force All those things that would basically make for a unified field theory He'd worked it out and it was just a matter of figuring out the details and then he would publish it Pauley who was not exactly a fan of Heisenberg Wrote a postcard to a friend of his upon which he drew a very lovely Frame as one might use to frame a lovely piece of art Except in the drawing. There was nothing in the frame. He sent this to his friend with the caption I can paint like Titian all I'm missing are the details Well, okay, so If we have laid out a frame with nothing in it, then you should stop us and we should together Take up the paintbrush and make sure that we have put something Elegant and artistic and exciting and inspiring onto that canvas so that those who look at it Oh when they come to our art museum in the journal that publishes this next April will be inspired by it And we'll want to go out and do something with what they've seen Now how did we get to this point because a lot of time and effort of many people including some of you has gone into the various steps That led to today's gathering I think it could be said that this planning process got its major kickoff just about a year ago Right here in this room in fact at a meeting in early house in December of 2001 Although this diagram doesn't show it There were actually several meetings before that on specific topics like the haplotype map for instance But here is where we brought a large group of people together to lay out what I Eventually turned into the basic themes the areas where the opportunity seemed to be greatest For investment in the future of genomics research However in a two-day meeting of that sort there was no way to drill deeply down into the details of the areas that were felt to be most right for exploration and so each one of these red boxes represents a workshop which was then organized and To which large numbers of people came and gave forward with some very interesting ideas Which were then synthesized together into reports all of us and the NHGRI staff went to virtually all of those workshops Soaked up this information and tried to then put it down into some sort of draft form of the plan for the future Also, you will see on this beside these various workshops some of which have names It may be a little unclear in terms of exactly what they were if you're more interested We can tell you later There's a council meeting listed here and a special council missed it meeting listed there And that's a good moment for me to say that the ultimate approval of this research plan for the future rests with the advisory council of NHGRI Most of whom are here for the meeting and who have already seen a draft somewhat similar to what you're looking at but actually it's been revised quite a bit based upon their input and upon this particular meeting called genomics to health that happened after that September meeting Immediately after this genomics to health workshop There was a special council half-day meeting where additional input was obtained from all of those people and upon that We then built the current draft that you were sent 10 days or so ago We will in the next two days look carefully at that and I suspect improve upon it substantially It will ultimately then go back to council. It will be discussed in their February meeting Finalized and then the plan is to publish it in April of 2003. I Should say not only do we have the full council participating in this But a special subcommittee has been appointed to pay particularly close attention to the planning process These six individuals represented here have agreed to do that and have been on the telephone with us on several occasions In addition to face-to-face meetings and we'll also play an important role after this meeting and making sure we capture The wise ideas that you all put forward And of course the plan is broken down into these three pillars, which are not intended to be isolated But are actually interacting pillars if you can imagine that image And those will each be discussed this evening by speakers that we have asked to try to outline From what from their perspective or the major points for consideration We will not engage in discussion this evening because I'm afraid we will preempt The plan to do that tomorrow in all day in the breakout groups This evening is really to get us all kind of revved up and ready to charge into that part of it So here's my charge to all of you and it is to critique this draft plan in detail And your breakout group chairs will be working through this with you and that means what do you like? Yeah, that'd be nice to know to What do you not like and I'm sure there's stuff here you won't and particularly what's missing? What are we forgotten here? I would like you all to pay particular attention to these entities called grand challenges Which you will see boxed at the end of each of the pillar descriptions This is a formulation that seems to work pretty well in some areas and in others frankly I'm not sure we've quite got it right. We may be stretching a bit The idea here is the grand challenges are supposed to be sort of set aside from the overall description of the plan as The kind of thing that you would say boy if you could do that that would really change things Would if you could sequence a genome for a thousand dollars that would really change things in research and medical application and some of the areas in some of the pillars are particularly amenable to that and Frankly some of them are more difficult for us to try to formulate in that way And I think we would particularly like your thoughts about that because if they come across as squishy are not very interesting Then that's probably not a grand challenge So first of all does the concept work for each of those and are they the right ones? Clearly the way this is written down in this form of pillars There's a temptation I suppose for you to begin to think of these as Separate pillars or worse yet silos. That's not the intention and to the extent that you can identify areas of interactions That's worthy of knowing about now. Finally, please don't word Smith. This is a draft document It's a bulleted outline. It is not intended to be a publishable Set of paragraphs will get to that but that's not your job. So don't worry if you think the Infinitives should not have been split. We'll deal with that at a later date And here's particularly important because we've tried this out on a few groups and there is a temptation For people to look at this and go well, you know My area isn't really quite represented here at the level of importance that I think it deserves And so my goal and coming to this meeting is to stand up and say you need three more sentences about my topic Because otherwise it's not going to get enough attention That's not what we're here for folks And so I would really ask everybody to leave your own sort of favorite narrow research area if you have one at the door and Instead really think about this very big picture of where genome research ought to go and I empower the breakout chairs To have a little gong that you strike if somebody stands up and starts to get on their hobby horse about a particularly Favorite area of their own research that they think doesn't have quite enough coverage in this document I think that would be probably not a good use of everyone's time Okay additional queries finally And this is an important issue when we tried to write this document We found it absolutely impossible to try to put together a draft which laid out in a very Explicit and rather narrow way what the goals for the National Human Genome Research Institute would be Because many of the future areas of research in genomics that are most interesting could not possibly be done by NHGRI by Ourselves in some instances not by us at all and yet to leave them out of this kind of an exercise Where we're asking all these people to contribute their best ideas would be to lose to fail to capture Some of the most exciting Possibilities and so I am I'm frankly concerned that the way this is written may seem Over-reaching on our part or even presumptuous That we are putting together this draft document covering all this territory some of which we are clearly not in a position to lead And I hope your forbearance will be forthcoming on that in the name of trying to actually capture good scientific Ideas and the way we've tried to indicate throughout the document where exactly those areas of emphasis lie as far as where the funds Would actually come from is with this set of asterisks and pound signs and squiggles Which are defined early in the document and which if you look at them will tell you what we basically from NHGRI Staff I think is the right kind of emphasis for a particular item in terms of who is going to be in the lead position And those are also very much Appropriate to question if you think we've got them wrong Although I would suspect that many of you probably won't care too much about that as long as an interesting idea has a chance of getting Supported perhaps from your perspective. That's less important. I will say from the funding agencies It's very important that we get that right and again I want to say how grateful I am to my NIH colleagues for coming to the meeting Many of you have already had inputs into various other steps of this We'll be having another meeting with the Institute directors or their representatives in December to be sure that we are moving this part of the process Forward so that whatever comes out of this does not represent a document that the rest of NIH doesn't feel comfortable with I have discussed this whole process on several occasions with doctors or Hoonie He could not be here this evening But he will be here on Wednesday and we'll give the final remarks about this and he is certainly Enthusiastic about this process and and he will explain on Wednesday how this interdigitates With a so-called roadmap process that he is engaged in for looking at the future of NIH Finally practical matters Plenary sessions like this one are being videotaped and webcast the one this evening is going to be webcast Tomorrow because not too many people are looking at it tonight The one on Wednesday will be webcast live through the NIH website Because a lot of people want to come to this meeting that we could not accommodate and this is our way to try to make it available It is a public meeting. There are some members of the press that are present It is hoped that the press understands that this is a meeting to talk about a draft document That's going to change and the real news about this plan will come in April when the plan is finalized and published But again, we think it's been a good thing throughout this planning process to have it be a very open Set of meetings and that applies at this time as well again because the plan is a draft I would ask all of you not to start making many copies and spreading them all around because it's going to change and people are likely to Get somewhat confused if there are multiple different versions floating around and again We'd like to save some of the punch of all this for when we have a final document ready for publication For tomorrow and Alan a good marker will tell you more about this at the end of the evening But on the back of your name tag your assignments for working groups are going to be there Now you will go to two of the three pillars for discussion And we've chosen carefully so that we have good representation in all of those and then tomorrow evening There will be a separate set of special working groups and your assignment there is also on your name tag The working group chairs for these pillar discussions will have time tomorrow afternoon to meet with each other and to Synthesize the outputs of their groups, and I think they've all been instructed ahead of time how that's going to go And perhaps most importantly the pub is open until 11 o'clock Those of you been to early house know that the whistling swan is down that away Just follow the crowd and actually I think they may stay open till 11 30 But last call is 11 so I thought you'd better know that and I think we'll have plenty of time this evening Socializing over there after we have our introductory talks, especially if I hurry up and finish which I'm about to do So this is sort of where we are looking over the horizon Adventurers and explorers. I think from my perspective. We have the opportunity now to take this remarkable Foundation that has been developed about the genome and build upon it in particularly in ways that are going to have Dramatic impacts on human health, but also that will affect our understanding of ourselves in other ways that will Profoundly affect our understanding of biology and will even reach out and touch society in all sorts of interesting Consequences that we need to both celebrate and be perhaps concerned about in terms of the possible things that could go wrong And I think because those are all part and parcel of it of this Discussion it is wonderful that we have all those three pillars on the table here for this Particular two-day meeting that we have people in this room with expertise across Those various disciplines and I'm looking forward to a remarkably exciting and interesting Conversation with all of you at the end of which I hope we will have something that really will chart a course For another five or ten years of wonderfully exciting science. So thank you very much Well, hello my Part of the evening I have a couple of chores to do one is to introduce the speakers But obviously the more important one is to make sure we all finish in time to get the whistling swan before it closes at 11 o'clock We'll get there well before then I promise you Or else I won't still be around tomorrow as a matter of fact. That's you know, it's interesting I've been deputy director now long enough to know what exactly is the deputy director do at the end here I one of the things the deputy director is in charge of apparently it turns out is to Occasionally and figure out the right ratio of how often you do this is that is the real trick to the job Occasionally trying to keep Francis's unbridled optimism and check and one way I would do that for instance is point out You know, he may have led you to believe that the three G's by being involved in this process Immediately be elevated within the ranks of the NHGRI to be historically correct and get this on historical record The way this process started out. In fact, it was two G's and H and a J Eric and Mark have been there throughout Originally Kathy Hudson and Alka Jordan were also shepherding this process through That began sometime last year It was this April that Kathy decided she really wanted to leave the genome and has done so quite well for herself And it was in June that Alka decided that she really wanted to leave the genome and has done quite well for herself having done So so it's a 50-50 proposition in fact being involved in the leadership of this effort so far So let me get that in the historical record Now what our speakers are going to do tonight for you we've not asked them to summarize in detail the pillars We know you have the document that wouldn't really be very exciting for you We think so we've asked them to do instead is to sort of explore out loud with you each one of them One of the pillars to give you their thoughts about them to sort of highlight the parts They thought were particularly important We're particularly intriguing perhaps perhaps give an example or two of where those pillars might lead us But also to help us focus on those parts that they thought really needed our attention before we leave in a couple of days Because as Francis said we really don't want this to be a rubber stamp kind of meeting We want genuine Heated debate input from people so we get out of here with a much better document that we came in from came in with So we've asked the speakers to help us kind of figure that out Our first speaker tonight our first pillar commentator. I guess is Rick Myers Who is the professor and chair of the department genetics and director of the Human Genome Center at Stanford University School of Medicine Rick received his PhD in biochemistry from Berkeley and did his postdoc at Harvard He then was a faculty member at UCSF before moving over to Stanford in 1993 Rick's research focuses on understanding the roles the genes play in a wide range of human traits diseases and behavior Including autism, atherosclerosis, hypertension, honeyton disease, progressive myoclonus, epilepsy, Parkinson's disease, depression, schizophrenia, a few others Now that list I have to say is based on his webpage But this part of his webpage is even more impressive so I'm going to quote this directly His webpage says quote He enjoys raising his son and daughter Woodworking and using his minimal talent in sports to coach his children's basketball and baseball teams Now luckily for us Rick's talents in approaching genomics are maximal not minimal So we've asked him to talk to you about that rather than about coaching basketball or baseball And he is going to take us on a tour through pillar one genomics biology biology elucidating the structure and function of genomes. Rick? Well, I'm following this Speaker is not an easy thing to do nor is trying to cover Elucidating the structure and functions of genomes in 25 minutes, but I'll do my best especially I'm not sure what I can tell you that you don't already know I do think the document was extremely well written with regard to this topic this pillar in that Almost everything that that I could think of was covered I think the difficulty is going to be figuring out where the asterisks and number sign should be because We would like to do much of this stuff and we are not going to be able to do everything I do think we need to talk at this meeting to try to figure out which ones of those should be the NHGRI's Function as well as thinking about what's practical regardless of who supports it This is the only pillar I could find on clip art that wasn't crumbling and in ruin So it's not a very good one. I didn't think that would be a good model. So so I hope this one's alright It looks like it's in New Orleans is somewhere Here's really what the pillar is is to find all the all the components of Really lots and lots of organisms of the biome has been used as to describe that Maybe all or as many as we can or examples from from all groups and then to figure out what they do now Now, you know, it's not that genomic scientists, you know invented this People have been figuring out parts and figuring out what the parts do but on a very very different scale And I think that's really what the genome project is brought is thinking about coming up with a way of thinking about this in a Highly parallel very high throughput way that really has made people think about problems in a totally different way The the document and don't worry. I'm not going to go through these one through five the document talks about these These critical elements. I think this is a good way to arrange it And technology being number one up there because really technology is what has got it That really is what got us to this point And we need more if we're going to do continue to make advances in the kinds of problems that we want to study So part of the all the rest of them is applying those technologies such as sequencing more genomes Finding the elements in them and I'll talk a little bit about functional elements trying to understand human genetics Essentially, how does the DNA sequence variation contribute to traits? It's a hard one at least a hard one Where we would like to go with it and then even harder. I think is figuring out how all of that fits together So I'm going to just touch on a few of these I'm really not covering all of them I'm going to mention at the end the one of the key ones that I left off of here that I think is really important in terms of technology But but let's talk a little bit about sequence to begin with Why sequence and I I think we really ought to Francis wants our advice and one of my advice make sure we keep sequencing. We really need to we need to get better at it And there are a lot of reasons. I think many of them are already outlined You know, sometimes you want to sequence an organism's genome so you can understand that organism, okay? Not just human but obviously the other organisms so even I mean the honeybee we will learn something about honeybees But there are other reasons for sequencing it as well. Okay, they have to do with lots of processes pathogenesis disease human health and agriculture Ecological issues bio remediation many that don't actually have to do with the NIH's mission Another reason is so that you can study evolution per se and in populations and how they move around and origins of populations and organisms And then a big reason and really maybe the one that we're thinking about the most is so that you can try to figure out Function and by function we mean of of all the components that specify in a genome that specify Proteins and et cetera other elements as well. So there's an important principle here I think probably everybody in this room Is well aware of is that the functional parts of genomes evolve slower than non-functional parts So we can certainly use this fact to help us identify functional elements and actually understand them to some extent So that means proteins non-coating RNA genes Regulatory sequences and elements maybe even so-called epigenetic Components may have sequence base. They might may not be entirely epigenetic Who knows if the chromatin code which is thought of as being just in epigenetic may have sequence elements that that help to specify it So here's one example of a very nice probably one of the most successful examples from Eddie Rubin Len Panaccio Just this last year where just at least initially by looking at sequence the human sequence and then comparing it only to the mouse at The time identifying in a region on chromosome 11 near the April depot protein genes these three genes that were well Studied by many many laboratories everybody thought they had this whole process figured out they had all the genes They already even had associations and knew certainly a lot about the functions of these and they just looked this way a Few tens of kb and found a region that was highly conserved. Okay, I think many of you know this story I don't show all of Eddie's and Len's Subsequent slides, but many many things came out of this. This was a hint that there was a new gene. They proved it was a new gene It was a transcript. They called it a po a 5 this highly conserved gene showed that they could Knock it out in mice and affect triglyceride levels and then went on to show in association studies that it was associated with With triglyceride levels in humans and that's now been replicated by at least seven groups Eddie can tell you more about this But a beautiful story, and I hope we have many many many more of these now This was a little hidden one in the human sequence that had been around for a while The people hadn't noticed part of that had to do with getting good sequence But primarily so that you could compare to something else too that's comparing it to the mouse also comparing it to the Parallel's within the same organism so Aaron Sadaw's helped me on on much of this part of the talk where he thinks about and many others think about this This problem the following way and it's a little it's going it's taking a similar idea to what was done in the previous slide and Going much deeper. Okay, so if you look at this evolutionary tree, okay I don't know if you can see that these are different organisms listed here humans up here each one of these little circles represents a Part in the lineage where new functions are developed. So these are mammals here for instance in this circle here means This is where you would look at functions that are specific to mammals in their anatomy physiology, etc You go down here the same thing would be true for For the tetrapods, etc You go down here for vertebrates, then you go down for coordinates So one of the things that's very important is to think when we're thinking about sequencing is what do we want to Sequence and something like this would help guide you depending on what kinds of questions you want to ask Let me try to go a little bit more detail So here's an example where instead of just a simple sequence comparison what Aaron did with Collaborating with Sarah from Bats a glue and Eric green on sequence that Eric's lab produced of over about a two megabase region In the cystic fibrosis locusts is went through and identified places within this two megabases where 20 base pair stretches Were highly constrained. They didn't show much variation. They were way over the neutral Substitution rate, okay Or way under I should say but and so here I don't know if you can see the different colors But the blue ones are the ones that are highly conserved that are exons and like at least for the known genes And they may and you might even get some hints about about unknown genes By doing this kind of analysis and the purple ones are in non-coding sequence And as you can see there are lots and lots of sequences and this is turning out to be typical There are lots and lots of places where there's highly conserved segments and in genomes And there's bound to be information there Now that's that's on a fairly low level of resolution Looking sort of at that level, but if you look in and home in on that when this is based on about eight species seven or eight species their sequence and look at this Flank five prime flanking region for the C met gene It's about a kb here and if you go through and you actually now he's plotting the rates of evolution And if anything this down low here means that it's very very constrained very highly conserved And what happens is it you identify these these circles here are known DNA binding sites Some of this has been studied in great detail even biochemically where the sites have been looked at by by What Eddie Rubin called slow-motion biology where many many laboratories study the same site And then maybe another laboratory will study the next one, but lots and lots of detail is known about these But look what happens you also identify some that are very highly constrained that have not been studied yet Okay, so I think this is going and this is drilling down not quite at the single base level You and Aaron points out that if you really want to get figure out which of these 20 bases here Are the important ones you'd have to go even deeper in your sequencing Okay point here in the previous slides These are regulatory sequences that we're looking at and if you want to look at regulatory sequences You probably part of the question is what do you look at? How do you what organisms how many? I The the real answer to that is all we want to sequence all of them We want to sequence as much as we possibly can and I'll talk about how we might achieve that or at least mention how we might achieve it Until we can sequence all we want to choose very very selectively very carefully this grasp committee that that Francis was referring to Is The group and aren't is on that group amongst a number of other people who think about the kinds of organisms that make the most Sense these genomes are big by the way if we're going to look at mammals and invertebrates We're generally talking about big genomes Okay, so for this kind of study where you're trying to think about drilling down and looking at the base pair resolution For regulatory sequences you need to do something like this where you're getting organisms that Where the where the group of organisms allow you to look at this level of neutral substitutions per site around five Okay, this this level a lot lower for these few organisms here It's actually including I think the cow and dog are fine for the mammalian parts list, but if we want to get Deeper we're going to have to get the single base resolution within the parts like I was referring to in the previous slide We're going to have to go further, but it's not 50 organisms here. Okay, it's a few it's again carefully selected okay, so Achievable with a few well-chosen genomes Now that's that's to think about regulatory sequences I'm an old transcription person and I do like to think about regulatory sequences In fact, I spent a lot of my time doing it but I think we need to probably think about proteins at least as much if not more and And Aaron has and many many many others have this is something that Another slide that he gave me using a similar concept where you build Evolutionary trees to do sequence comparisons and again it requires Sequences of multiple organisms and by the way, this isn't a little snippet of EST sequence This is genomic sequence. That's pretty high quality if you're gonna if it's going to be too rough You're not going to be able to make these calls Okay So not saying that it has to be pristine finish the way that we're trying to finish the human genome Or we are finishing the human genome, but but but it has to be close to that It can't be a Light draft of the sequence and we can talk I think part of our job here might be to figure out what what that needs to be But anyway, here's an example of a DNA binding proteins the Mib protein Where there here's the DNA helix and this is the in the structure is known actually of several of the proteins and the Parallogs what our end did was did the tree and the Basically the evolutionary comparison to say which parts were constrained and which parts weren't and the bluer It is the more constrained it is and so you can see the parts that bind to DNA are highly highly conserved and Highly constrained and the parts that don't bind to DNA even though by the way These are identical repeats of the mid of the mid protein all three of these are and yet this one has Diverged quite a bit. Okay. Now. That's one where you have this the structure and so it's easy to see how that fits This is a model. He's done this on a number of other proteins. I think we want to do this for every single protein We have that would but requiring sequence but not structure Okay, and we'll get at least hints of the places of the protein proteins that are important I have to say I naively thought about this problem for over the years has been let's just get a couple of sequences We'll compare them and we'll figure out what parts of the proteins are Conserved and that's where the important residues. It's a lot more complicated than that you have to do this kind of analysis Analysis and it does require multiple sequences for multiple organisms and for proteins you have to go much broader Okay, so this is where we now are going away from mammals down into other vertebrates. Okay And I'll let the the professionals tell you what what those should be, but I think I hope the concept came across Okay, so so we need to sequence. All right, so we we're pretty good at sequencing de novo We need to do de novo sequencing I think we'll need to do de novo sequencing for from from now on and we'll need to re-sequence meaning we'll want to Look at the sequences of the genomes of individuals from organ organisms whose genomes already sequenced The documents set a goal of about this many gigabases Sequenced by 2008 by the NHGRI there are other groups that will be sequencing that are and will be sequencing as well So if we take this draft, that's about 15 to 20 times what was done there actually that's a 6x shotgun We really want to probably do these at 10x 8 to 10x shotgun So it's 25 times or so what we did here now I will say what we did here was a lot of years of learning curve Okay, and we've already been there. We don't need to relearn that in fact I think that the the groups are indeed poised to be able to take this on although Even though we've seen a lot of efficiency increases, I mean it's huge increases since we started I've tried to put a number on this I did this experiment. I have to love showing this off. This is one of the last experiments I did a few years ago a lot of years ago But before we had we had kind of sequencing that we do now It really was probably ten dollars a base pair and probably maybe even worse than that and the quality was awful And I was pretty good at sequencing it was just awful compared to what because we didn't have any of the notions of what we have today So the capillary technology today I it's you can quibble about these numbers and I don't don't get hung up about the exact cost This is roughly what we're estimating at the workshop this The summer and maybe it's a little bit better than this a little bit worse than this But for the big groups who are really really efficient have a lot of automation And with the new machines that have been incrementally improved over the years about three cents a base for 10x shotgun Okay, that's that's that's You know three to six cents a base, okay? If you want to finish it at cost more I'm not going to spend time talking about finishing now This is where I really don't want you to pay too much attention to the numbers because I may be too optimistic here I may be too pessimistic But if we want to do that over five years, it's going to be you know more than a billion dollars If that's really the way that we're thinking about it. We don't have this kind of money. Okay, so that's not the way It's going to happen. All right But we can't what is needed is at least a few fold increase It doesn't mean that we have to do this for you know, attempt the cost I think a few fold increase will make a huge difference a tenfold would be great and one day I think we will want a hundred fold Decrease in cost. Okay, so that we really can sequence the biome, okay Again, don't quibble on the numbers. The point is it's a big number if you do it even with today's Really really really great improvements compared to To even two years ago Okay. All right, so let's let me keep talking about the parts list a little bit So what is that parts list? It's it's obviously the genes and proteins I'm doing precious little to talk about proteins and I do think we need to do that at this meeting It means coding genes that code for proteins. It means ones that don't code for proteins There are alternative versions of these lots And unusual versions things that are happening that we didn't expect and then of course sequence variants, okay? There's also regulatory elements that affect transcription like these elements and there are others as well And then other regulatory elements that affect things like nuclear matrix attachment, etc There are many many others maybe recombination, etc that we we almost don't even even touch, okay? One of the points here is that we want to study these we need lots of computation a lot of what I talked about earlier for sequence and looking for Sysacting sequences was computational. You don't do just computation you need experiments as well And we need high throughput experimental methods not just to to verify but also to find the things to begin with and understand How they work, okay, so we I do think this is a really noble goal getting this I think it was referred to in the white in the paper as as a catalog a full catalog And we ought to do that I will say as an aside There's a process in place to do this on a very detailed level for 1% of the genome I don't know if France has referred to this for 1% of the genome I think there's a great way to start but we hope to get that done quickly so we can move on to a lot more of the genome I I'll Tout the another part of the parts list again, and France has already referred to already told you about this is the Mgc in mammalian gene collection project I'm going to make and if you combine that with the and this this the Mgc combined with the NCbi sequences very strong In keeping with the free release of data free release of clones free release of the data rapidly of everything as soon as possible There's another effort when you combine those there's about fit about 17 to 20,000 non-redundant full-length I say clones full-length sequences the clones are available here. I'm not sure if you can get all the clones for these I think you probably can Action item in my view is that we ought we're this is a pretty good project this this project I think is going pretty well I think we ought to do it on a much much larger scale not human and mouse only we're already starting to do the Mgc Is now it's not mammalian anymore I guess we're gonna have to change the name because it's doing frog and fish, but we really ought to do other organisms Meta-zone. Oh good good Okay, very important Here's something that I think we you know it wasn't actually discussed in the document very much But these alternative versions of genes I mean genes are a lot more complicated than we want them to be they are alternative splices are probably the The rule rather than the exception they're certainly happening in lots and lots of genes and unfortunately many many different versions and Those cdna efforts are barely even addressing this problem now. It's too hard and so Big challenge I think is to try to do that and I think we have to there's an enormous amount of biology These aren't little vert different slightly different versions of proteins They have huge consequences and some of the in the few cases where people study them in some detail I really like this part. I we used to call these unusual things about the genome They're not unusual Sean Eddy can tell you that there are many many non-coding RNAs probably a lot more than we Then than even he knows and we know what some of them do We don't know what the vast majority do but they clearly are functional elements really important functional elements we study promoters and Regulatory sequences in my group as well as many other groups do or trying to do this sort of on a global scale Alternative promoters look like they might be incredibly common I don't want to put a hard number, but the thousand that we've looked at we've I mean sorry the 16,000 We've looked at we've found about 20% of them by directional promoters. There was a paper just published in in cell We've found something similar as well where this is present in probably five to ten percent of the genes where they're really close To each other and transcribe out in this direction and we're finding that these things seem to be co-regulated I'm sure other groups are studying this in some great detail, too and then anti-sense George Church and many many many others are trying to look at this on a global scale and I think these are our functional elements and that we need to Kind of incorporate them into all of our thinking rather than just going after full-length cd nas for instance Figuring out how the parts work So even the simple cases are really complicated. This is Eddie Rubin gave me this one And this is actually a sort of simplified version of any typical gene in terms of the way. It's regulated. Okay, obviously you've got the alternatives Slices here doesn't show alternative starts that happens a lot as well anti-sense etc And then all the binding sites and regulatory components and it's really hard to fit This is why lots of labs study one gene Okay, I think we need to try to figure out how to how to get those use those as general models But get out of that mode only I mean we need to study it at this reductionist level But we need to study it at a more detailed and a more global level as well How all these fit into complex pathways and networks I think is a really hard problem I this has the the People use of the term systems biology or a lot of different ways of thinking about this and it is true People are doing clever things and coming up with clever ways of looking at this. I do think we still need New technologies and computational tools and by the way, this isn't just RNA. This is protein That's the problem. That's even makes it even harder to try to look at those Roger Brent gave me this on the airplane It's just a good example of Each one of these little components is one of those previous slides, okay So really really complicated and this is just for one one process in in mammalian biology an important mind You but it's still it's the point is is that there are many many complicated intertwined steps and you know if we want to try to understand them on a global scale We're going to need the parts and try to figure out how they fit together I just picked a couple of things in technology that I thought were interesting and useful This is just just one version of something similar that a number of groups are doing David Sabatini's web page I stole these off just reverse Transfection how many of you in the room have done where you take cells you put them in a dish and you put DNA on them And you study what happens. That's a standard. Yes, my mouse is better Maybe but we do a lot of tissue culture Transfection for for mammals and other other organisms This is doing it backwards where you put the DNA on a slide so you can trans basically you can do 10,000 20,000 Transfections in one of the slide and then study the results of it not quite there for really really making this automated and Totally high throughput, but it's almost there I think this is going to be even with the artificial Arrangement of the the fact that it's tissue culture cells and etc We can learn a huge amount out of it about not just regulatory sequences about how proteins are how genes are expressed and actually protein functions In fact, that's what some of these are whether or proteins that are being expressed and affecting cells Another area is how proteins that do regulate transcription or actually other Processes when they bind to DNA, how do they do it actually in living cells? And this is one of the things that I love about this approach chromatin immunoprecipitation or chip And I won't go through the details of this of the procedure most of you probably know it I think we need to do this on a very large scale to try to find where proteins are binding under different conditions One of the ways of doing that is to analyze them where they're binding by having the genome or at least the regulatory sequences if you know them laid out on Microarrays and doing double color just like the RNA microarrays and we've been doing some of this a number of other groups Are doing it as well, and it really looks like it works. This is with heat shock factor protein one binding to what just at least our initial Slides with 768 promoters soon to be 16,000 promoters. Okay, so To summarize that part and I've got one other topic right after this This really summarizes a much of what I said or includes the parts that were in the white paper that that I didn't talk About which is that we need to be thinking about these processes for proteins genes and the networks From a bunch of different overlapping points of view. Okay from sequence analysis all the stuff that I told you from interaction analysis I don't even probably need to mention those although I think these technologies can use some improvement for for really getting active the Answers on a global scale here and then expression analysis, which of course is very well Figured out I think for RNA levels, but not yet for proteins Although I will say that there are techniques coming along both for RNA and protein where we can try to think about and quantitate Almost on a microarray scale what's happening in within a single cell or within a portion of a single cell like in a synapse By a variety of bead approaches that are somewhat similar to arrays One thing I wanted to give a plea for here, which we didn't really talk much about in the paper There it was mentioned and I think is that all of this underlined by it should be should be covered by Experiments where you do genetic analysis where you where you actually have some idea that something is going on You can really prove it or at least get a much stronger evidence for by doing a genetic experiment And so let's do genetics on a high throughput level Ron Davis and others have done this on yeast and their C elegans as well with and mouse even has some higher throughput than it used to be but Zabre fishes may be heading in that direction as well But I think this is something that turns out to be very important And that's a good lead-in for the for the last part which is is human genetics And I'm not going to talk much about it because of the of the that's going to be covered more in the next talk But there is a lot of technology issues here And there are a lot of technology issues here and I want to make this is I guess maybe this is a hobby horse I'll I'll try to back off if it is the easy thing way to think about this is looking at for the causes of Mendelian traits By using positional cloning approaches the hard ones are the complex traits, which we'll be talking a lot about Okay, both of these need sequence genes lots of genotypes phenotypes and human samples sometimes lots of human samples And I think the phenotypes in human samples We don't think about those as being technologies are but it's probably it underlies We might as well not do it if we don't get those right because we'll waste our time Here's the the hobby horse. There are 11,000 genetic genetic disorders more than that actually now in OMIM okay for single gene traits in humans I call them diseases and I got yelled at one time because I forgot that we they're not all diseases, but traits, okay? And we know that what's interesting is that we know the about 2600 a little less than a quarter of these are actually mapped okay, and they've been mapped by genome You know genomic approaches and about 13 I say only because I actually think 1300 is a pretty large number actually That's a lot of knowledge now None of these have led to any treatment or not in any cure for a genetic disease Some of them have led to really important diagnostics. Okay, hemochromatosis being a good example There are others as well and some of them are wanting for diagnostics. We have them Maybe have the gene but are not they're so rare. They're not being used The Ryan and Dean receptor and malignant hyperthermia being a good example That was easy and had good technology to do that might be something that would be worth using even in most surgeries or most times when people are under anesthesia The point here is that we're going to find these anyway Okay, meaning and it's become easier and easier and easier because the people who are going out and looking for these Are using the stuff that we're putting into the databases I think we should continue to encourage and foster that because we've learned so much biology from this and we will continue to learn it So I'll end on this slide just to say that if we want to look at human Genetics and and really understand how variation contributes to traits we need to do a lot of different things And many of them are Francis touched on some of these this is going to be a hard problem I think to try to find the genes involved in multigenic traits a few of them are being found But it is difficult One of the things I want to point out is that even as something as simple as that the discovery of snips and the Genotyping of snips we need to be several orders of magnitude better And I want to point out we still don't have easy ways of finding the other kinds of mutations and ones that are bigger than snips deletions Etc. You can find them. It's a lot harder work I think that obviously they Rearrangements can can have a big impact and so we probably want to have systematic ways of going after them So I hope I touched on areas that that you probably knew much about but At least made you want to think about some of the topics we want to want to work on here The one of the ones that I didn't cover at all on that technology I thought that was a really interesting one was synthesizing any DNA molecule a cheap way of doing that It is very interesting to look at how hard that is now You think you make a bunch of oligos there all goes are getting cheaper and cheaper and cheaper It's a really expensive process to make a long DNA, but and but if we could make you know Many kilobase sizes pieces of DNA rapidly, so it's the ease of not just the cost but the ease of which to do it We would we would be able to do a lot more I think there are many many reasons why the clones are not desirable. All right, I'll stop there Thanks Rick for doing a very nice job not only of moving the plan ahead But doing what's I think difficult for all of our speakers Which is that many of us live in maybe one or at most two of these pillars There are a few of us in the room that live in all three and I think Rick did a very nice job not only of moving the plan along but also doing something that was of interest and made people I suspect to spend much of their lives in pillar one think again about it But also those of us spend most of our lives under the shadows of pillar two and three making it accessible And giving us some things to think about as well Our next pillar commentator for pillar two is going to be Bob Tepper Bob is the chief scientific officer and executive vice president for discovery at Millennium Pharmaceuticals I know many of us have always wanted to have a job title of being vice president for discovery Bob received his MD from Harvard Medical School as a member of the unusually distinguished class of 1981 There's at least one other member of that class in this room I don't have this have a microphone at the moment and complete his residency in medicine in Massachusetts General Hospital He also served as chief resident Bob later served as director of the laboratory of tumor biology at Mass General's Cancer Center before joining Millennium in 1994 He has filled a number of roles at Millennium becoming his chief scientific officer in 1999 Bob was also a founder and former member of the scientific advisory board of cell Genesis Incorporated He currently serves a member of our own National Advisory Council for Human Genome Research To the many of you who heard Bob's wonderful introduction summarizing talks that last month's genomes to health workshop will come as no great surprise We've asked him to introduce pillar two to us tonight and therefore to talk to us about genomics to health translating genome-based knowledge into health benefits Now that you know we're both the same age, I hope you can make your own Observations of phenotype. I didn't hear that but sounded good Well, as you can see this is a fairly broad topic I'm not sure that we could even scratch the surface tonight let alone solve all the problems of how to employ genomics successfully to understand better disease and health and Obviously, this is not a new process genomics from the beginning has been used to understand health problems But one principle that I'd like you to think about tonight and perhaps over the next couple of days is really one that has less to do with technology and What diseases and whether therapeutics or diagnostics or preventative strategies should predominate? But a little bit about organization and maybe I'll start with just a question Maybe we could all ask ourselves. Do we have the right type of biomedical institutions currently present to actually answer this question How do we bring genomics which is a very technology intensive? discipline to something as broad and elaborate as providing health care in this country let alone the rest of the world This is an enormous problem But one I think is is considerably a problem of organization and if nothing else I ask that people think hard about perhaps thinking out of the box on what type of organizations The NHGRI and and other institutes can help create to do the type of work We need to expeditiously move genomics findings into into the health care setting Starting very basically and I'm sure many of you Would agree with this premise that genomics really is not a field But again as a mindset and it's a way of approaching problems In biology, but also now and in the future in medicine that it does things a little bit differently And I think if it's one thing that we can all agree that genomics did For biomedical research was it thought very differently than most Biologists did in the past and how to organize and how to bring people together a very different disciplines not Communicating by telephone while also communicating by telephone and computer but also communicating face-to-face in a multidisciplinary Organization that allowed them to bring together new methodologies and new ways of Performing that really changed the paradigm. I think therefore genomics And I completely agree with Francis that we shouldn't be talking about a post genomic era at least for the next several hundred years if not more We we're just getting started and understanding genomics as a mindset in the Changing of biomedicine, which I think is is is going to be absolutely critical to Efficiently take advantage of what we're learning from the genome over the next several years and already it's happening genomics is making its mark I Apologize for those who saw this slide a few weeks ago, but you can virtually take any discipline of science There's a new one. I didn't put up here Which is actually very exciting called? Imaginomics and it has nothing to do with imagining things it has to do with imaging things and as for those of you who have been studying the field of Molecular imaging it's actually getting fascinating now how you can actually link fluorescent Tags to enzymes and receptors and actually follow Physiology with a camera outside the body and that's going to play an important role in how we link genomics and medicine in the future But these are just some of the examples of what we say and what we mean In terms of these different fields But we really don't mean what we mean because what genomics has done of course is it applied a new type of philosophy to how we think about Disciplines which were perhaps very isolated and not as interactive as they they should be for a long time But clearly people are thinking very broadly and our whole genome level on on multiple levels of complexity So for the first time and I'm sure you all Can relate to these four points for the first time we can really Understand health and disease or understand certain aspects of health and disease by molecular fingerprints now We don't have all the data now But again what we need now to think about is how we organize so that we can use efficiently the data We are gaining literally every minute of every day from Several years ago on about molecular information from the human and model organisms and symptomatic descriptors which are Again the the rule rather than the exception in medicine today think of words like diabetes and and and breast cancer Symptomatic descriptors can really be replaced by meaningful stratifiers and that's a that's a key goal We can't absolutely prove that that's going to change the way medicine is is Diagnosed and treated and certainly taught, but I think we all can feel that that Must be the case if we can arrive at the right way to approach these Mechanistic pathways and you saw a very nice example of one that was just shown By Rick Myers that Roger Layed out mechanistic pathways and of health and disease can be defined and certainly these pathways are going to cross from one disease to another So a very very important question. I think for pillar 2 for the for the genome Institute and its studies to answer over the next 10 years or What are the 10 20 or 50 most fundamentally important pathways of human disease or physiology? Which when perturbed Relate to human disease. There's got to be a prioritization in a hierarchy of fundamental pathways of disease just like there are for development and other biological studies So what are those and how can we put the most dollars and the most emphasis on those which are the most important for human disease? And obviously these have important implications not only for the development of drugs, but also for the understanding of disease pre-morbidly You've all seen red greener grams like this of transcriptional Information molecular markers already. We're learning about meaningful stratifiers This is just an example of a study done that we did in ovarian case cancer patients where you can clearly Identify markers That correlate with response and non-response to particular treatments and obviously this opens up completely new ways of thinking about Information it also raises the very important point that while model organisms Including the mouse and lower organisms will be absolutely critical for genomic and other Omic studies in the future There's a very very important experimental organism now that is is here and that's the human being and how we're going to use the human effectively as a As as an organism and I say that with the highest respect How are we going to use patients Carefully effectively to study information and how are we going to iterate on that information? And how are we going to house that information so that it's meaningful is very very important? How are we going to educate a New class of researchers to be able to use and iterate on this information So mechanistic pathways of health and disease one of the important things that this brings up is the importance that Informatic systems have had in really Performing genomic studies over the last decade and how this will be enormously important as we go forward The appropriate databases the appropriate ability to query information and to make that information Usable in a format so that researchers can continue to iterate again on information We go from a simple transcriptional profile to self-organizing maps to other types of kinetic profiles to pathway diagrams And then continue to iterate and build the type of computational systems We need to be able to bin information together. This is just another higher order Pathway analysis some informatic studies that that we've been involved with which again allow you to visualize Pathways upon treatment Condition a condition be and allow you to bin genes together in pathways and allow you again to see how pathways might relate to each other How are we going to continue to improve upon these systems so that we can generate hypotheses quickly not obviously coming up with a Definitive answer, but how to generate good hypotheses from complex information So how do we use visualization tools? And other types of informatic approaches to be able to use information effectively to generate important hypotheses again, a lot of what the genome taught us and I think what a lot of the next Application in this pillar genomes to health One of the questions we have to answer in addition to organization in which technologies is how do we do things? Efficiently and how do we do things quickly because we don't want to be studying the we don't want to be identifying the 20 or 30 or 40 most important disease pathways over the next 500 to a thousand years if we can do it a little quicker This For those of you who read the American Journal of Physiology, and I think this was about 98 years ago This just tells you that while we've come a long way in the development of drugs over the last hundred years We still have a long way to go I actually this is actually quite a well-known some of you may have seen this If you're interested in history of medicine if you and if you've looked at textbooks of history of medicine This was a pharmacy a couple of different pharmaceutical companies that were in a very Escher like way building their portfolio of drugs and You would agree. I'm sure that some of those drugs while at least I don't know what Lysitol is But the other two I do know what they are, but I don't really know how How either of them Do all their myriad of effects in terms of physiology and pathophysiology One turns out to be a little bit better drug than the other But they were both important drugs in 1905 and one of them you can see in the lower Right-hand corner of the slide a company I guess by the name of Smith That said the problem has been solved. They were talking about the problem of cough But the drug of course was a drug that we would not really associate today with having solved a lot of problems yet certainly has created a lot more problems in itself and I actually like this slide very much because it brings up really how Little we know about medicine even today when we talk about things that are specific treatments for diseases and again it just underscores the fact that we have Very very rudimentary knowledge, but a real opportunity to again to get very precise information on whatever phenotypes We're studying in the future the other point I wanted to make about this slide is something called disruptive forces Disruptive forces is a term used not so much in Scientific research, but it's used a lot when businesses describe technologies that fundamentally change the way they operate so the development of PCs was an example of a disruptive technology For many industries well the pharmaceutical industry has gone through a number of disruptive technology since It's beginning in the early 1800s. It really started obviously as a natural dye industry and its major Expertise has always been in chemistry And certainly over the first 140 years of its existence But then what happened from 1960 on is that more biological mechanisms started creeping into pharmaceutical Development as we started understanding different Different mechanisms and different target classes of proteins such as enzymes transmitters receptors and the light but what I would argue is that the pharmaceutical houses as well as Traditional academic institutions Neither are very well suited to really taking advantage of any of the four of the last Disruptive technologies that have occurred in the last 20 years and there are many but I just took out molecular biology the development of monoclonal antibodies novel drug delivery systems and the one in red which we're here to discuss tonight and that's genomics one could put new Methodologies of imaging etc. None of these Technologies while being disruptive had been effectively integrated into the organizations I think either in the pharmaceutical industry which is responsible of course for the development of the vast majority of therapeutics in the world Nor in in academic institutions So one of the challenges I think we have is how do we really incorporate these technologies and these Methodologies and how do we work in new types of organizations so that we can really take advantage of this information In this case for the development of therapeutics the opportunity is clear for those of you followed new drug development There's only in the last hundred thirty years or so about five hundred gene products that have been the targets of drugs and Certainly many of them such as morphine and its derivatives were targets were not known Obviously when the drugs were first identified or isolated, but if you take into account obviously alternative splicing And other forms of variation there. There are certainly well over 50,000 gene products that are going to be in the genome. How do we take advantage of these systematically and efficiently? to really Find new opportunities for disease pathways and for treatment Integrating genomics should have a major impact on productivity in the pharmaceutical industry and again for those of you Who have followed the pharmaceutical industry, you know It's an industry that is definitely thinking about its productivity and needs to over the next several years But genomics won't do that magically without the right organizations to really understand genomics in the context of the human organism so the approach obviously or a very Generic proposed framework for the genomics to health initiative would really be to use the Technologic approaches that we have to develop a detailed understanding of the genetic contributions of disease and And the gene environment Interactions and not only disease itself But what came out of our last meeting was to really define human health In its positive sense as a way that we can We can study as a phenotype to link genome information What are the components of good health that we should be able to identify and therefore not only identify disease pathways? But how do we just how do we study the healthy human organism and how do we maintain and deliver? healthiness to the public so Just to go briefly into some of the critical elements of this particular pillar As as in a pillar one methods development is going to be very very important to be able to reach this goal and obviously This is a goal that will be ongoing for many many decades The pillar one methods that were just described really focused on many of the technologies and tech Technologic innovations on the DNA RNA and protein level and I won't go into detail On these because they really are the subject of the first pillar But in addition think about the methodologies that we need to phenotype patients and Information we need to collect about patients. That's going to be critical methods development For this pillar as will the right computational systems and as I mentioned before the right the right organization These are all going to be very critical I will also point out that in addition to obviously collecting the right populations Understanding variation databases. I will want to I do want to point out two Important bullet points here and that of clinical phenotyping these methods are advancing very very quickly particularly the ability to image Physiology non-invasively it's been done very effectively with some systems now in animals to the point of being able to actually disrupt a cellular molecular pathway in animals and read out that pathway non-invasively through Imaging modalities that's moving very quickly to patient populations and I think opens up a whole new opportunity to study patients in a way Which is less invasive which and therefore should allow patients to be more amenable to testing Physiology versus pathophysiologic states, so I think that's a very very important area to consider And again the last bullet point If I haven't underscored it yet I do feel strongly that novel centers of excellence really partnerships of clinical research centers with industry developing therapeutics and diagnostics with the government as a as a vehicle to Support the development of new organizations of new centers and the training of new investigators will be absolutely critical if we're going to achieve Efficiently goals in this arena Again the understanding of disease mechanisms molecular taxonomy of pathologic states Being able to understand key pathways as I mentioned and really had a link these to better diagnosis and therapy Single gene disorders are I Think of great importance not only because they represent important diseases as As Rick Myers just mentioned But also because the so-called extremes of phenotype may be very very important in informing important disease pathways that are relevant For common disorders, we've certainly seen this time and again with certain rare cancers retinoblastoma For example opening up whole new areas of research for fundamental pathways That have to do with cellular physiology and what can go wrong in the cancerous state And I think underlying many of the single gene disorders will be very very important Information for understanding broader disease relatedness Obviously we want to understand the common complex disorders and obviously this is a very challenging Comprehensive goal. This is not one which will be done in isolation by the NHGRI But again, which will require the broad cooperation of all sectors of biomedical research And again Emphasizing training not only the right organization, but the so-called forgotten disciplines if you will Physiology is a discipline pharmacology broader epidemiology Epidemiologic training health outcomes research now using not only clinical markers, but molecular Markers and also health behaviors research how to study What what physicians and patients will do with information that we might provide based on this Barrage if you will of molecular information so the education of health professionals and the public obviously and supporting research to To allow this education to occur Will allow us to use this information more effectively and make more informed decisions Coming from basic information from the genome Obviously the quality and cost of health care is something which is not only Something which we'll talk about over the next couple of days, but I'm sure you understand is a very important topic For the next decade and whether or not genomics information will allow Effective health care to be delivered in a better way Or in a cheaper way versus a more costly way and how we employ these Capabilities is going to be a very very important And obviously elucidating the role the genomic approaches to health and health care can play in reducing Reducing health disparities. How do we understand a genetic versus non-genetic information? And how do we make sure that in using this information? We are actually striving to reduce health disparities rather than to increase it And then finally obviously had a continue to improve health not only in our own country, but developing regions of the world now when I first Present I was thinking about presenting this I thought actually this topic was focused enough that we could actually in 25 minutes Actually do all the research for these questions not only discuss the topics But I thought that might actually just take a little bit more time So clearly one of the challenges of this pillar is that it's highly ambitious I think what areas of this particular pillar we're going to focus on and how we're going to iterate on early successes As Francis called the Grand Challenges what Grand Challenges and I won't go through them all and then they're all not listed here But which of these Grand Challenges do we want to focus on and what specific things do we want to do? So that we can show in the next two and five and ten years that we're actually making progress in Bringing genomic information to health is very very important And I think the role that the NHGRI can play in this regard of course is Remembering the overall framework That from which genomics started and that's thinking differently about Organizations about disciplines about bringing people together in ways that is different from the way we do research today And I think it's absolutely fundamental to bridge this particular Effort genomics to health. Let me just Finish by saying I think the most important word in the pillar genomics to health is actually the word to because I think we all Know a lot of the issues of health and disease We're just scratching the surface, but we do treat disease today We also know a lot about genomics I think we know relatively little how to bridge these two today, and I think that'll be the subject of some healthy debate over the next Couple of days. Thanks very much Thanks Bob for a very interesting and useful talk. I think you're right to focus us on that too and Let's see if we can solve that a little bit more tomorrow Our next speaker obviously not a classmate of mine. She has a lovely head of hair Wiley Burke is a professor and chair of the Department of Medical History and Ethics at the University of Washington She received her PhD in genetics and an MD from the University of Washington and completed a residency in internal medicine and a fellowship in medical Genetics also at the University of Washington Dr. Burke was a member of the Department of Medicine at the University of Washington from 1983 to 2000 We're glad they let you ask long enough to come over and visit us where she served as associate director of the internal medicine Residency program for a number of years and was founding director of the University of Washington's Women's Health Center Wiley has a distinguished record of research explaining a number of the social ethical and policy implications of genetic information Her recent work includes studies of genetic counseling related to inherited risk for breast cancer Ethical and policy implications of genetic testing and genetics education for primary care providers Like Bob Tepper Wiley currently serves on the NHGRI's National Advisory Council for Human Genome Research And as those of you who know Wiley and her work or those of you even who just heard the listing of it for the first time will realize This is a very Broad pillar for any one person to have to grapple with and Wiley is certainly One of the few people in the field who really has been involved in such a wide variety and done it Well of research and thought in the area of so-called ethical legal and social implications and the other kinds of things are in pillar 3 So she's a wonderful person to speak to us about genomics to society promoting the use of Genomics to benefit society Wiley Thanks very much Well as Alan has said the third pillar genomes to society is the challenging pillar It's particularly challenging to to talk about this in the context of the fact that all genomic research occurs Occurs within society and has societal implications and so when we talk about this pillar I think we we need to acknowledge that I Also think I need to do something here with my slide So When we when we start talking about the third pillar genomics to society We have to acknowledge that all of genomic research occurs in society And it would be wrong to say that this pillar Incorporates all of Elsie as well That is ethical legal and social implications of genomics which have been a core part of the NHGRI mission from the beginning cannot be viewed as Sitting only within this pillar If we think about genomes to biology for example, we know that there are some very critical social questions That really fall within the first pillar For example, what research is publicly funded and as a result what data will remain in the public domain This has clearly been a profound issue for NHGRI in the past several years We've had a lot of talk about intellectual property And we need to keep talking about what are the appropriate approaches to defining and protecting intellectual property and to Allowing commercial development. These are Elsie issues in pillar one We have in genomes to health many Elsie issues I've picked out a few that I think are particularly crucial How do we define health and disease in the genomic era as we increasingly identify genetic contributors to all sorts of Traits as we've just seen How do we ensure safe and effective use of genomic tests and therapies as they're developed? How do we ensure fair access? But I think when we step back and look at the genomes to society pillar The other basic point that it's making is that genomics and all of our efforts Both within NHGRI other NIH NIH institutes within commercial development, etc All of them occur within our society Our society is a diverse and complex society and when we think about genomics entering into society in a variety of different ways And with a variety of different applications We can identify Both challenges and strengths that are particularly important to this transition from genomics into society I want to start by talking about some of the problems that we are already confronting The first is what I would call a very weak tradition in science education In fact, most people who major in science and math don't go on to become teachers And the result of that is that we have a very limited supply of teachers in many technical subjects The pathway to an education degree often involves very limited exposure And so it's probably not surprising that when us High school students are compared to other students at comparable levels They tend to do rather poorly In a in a comparison with other developed countries There seems in other words to be something of a disconnect between the science community and the public An irony in which we have the premier scientific establishment of the world And yet we have a public that is relatively Poorly educated to appreciate what science is accomplishing I recently saw a magazine article many of you may have seen it too that I think illustrates one of the potential Fallouts of that kind of disconnect. This was an article called DNA as destiny In wired magazine This month actually A reporter describes his own experience the first time as he said at a health human has ever been screened for the full gamut Of genetic disease markers And as you read the article, this is kind of a first pass at something that is being proposed as the health care of the future He was screened for dozens of SNPs As far as I can tell these included both markers and known gene mutations And I've just pulled out a couple of what were to me quite striking descriptions of the results First of all among the negatives He's very happy to know that he's as he puts it clean for the SNP associated with lung cancer On the other hand, he lacks the SNP that shields smokers from the risk of lung cancer So not altogether clear to me what that means Among the positives he's identified as having two mutations associated with an increased risk of heart attacks But it's also noted that he has an entirely negative family history many of his predecessors in his family, people he's descended from lived into their 80s and even into their 90s And so given that family history information, he's counseled that quote these mutations are probably irrelevant Unquote One might ask why did you test for them then? How was this information useful to you? And and my point here is that I think we may have a credulous public That will assume that a test like this is useful Where clearly there are lots and lots of questions about the clinical meaning of this kind of information But I also wonder if this speaks to another disconnect, which is a disconnect between What's happening in basic science and what I might call some of the really important social and clinical realities That govern how healthcare happens in this country in the world So I want to talk first of all about a very important sort of Bottom line reality of our society And that is that there are very marked inequities in income and in opportunity opportunities for education Opportunities for access to health care opportunities across a wide spectrum of social issues what that leads to is on the one hand in the Very affluent components of our society We see a tendency toward medicalization of a variety of things that we might consider normal aspects of life For example a tremendous growth in cosmetics in this country and a variety of other enhancements that occur within the process of medical care some of which are covered by insurance Payers some of which are paid out of pocket But all of which occur within the healthcare setting and we see increasingly some tendency toward a Sense that consumers particularly consumers that are willing to pay and have of course the money to pay Can can demand things or ask for things or insist upon things That might be in our view quite similar to the test. I just described to you things like Total body cat scans for example So we have that on the one hand, which we could say is an outgrowth of Of affluence and yet within this same society We have large sectors of our society that lack access to what we might consider very fundamental Components of health care lacked of access to a primary care provider on the basis of income But also on the basis of geography people who live in inner city locations For example people in my region of the country who live in Rural areas and have great difficulty having access to a regular doctor and as a result Many people in our society who have Lack of access to what we would all agree is the optimal the correct treatment for their health care problems I want to just review and expand this to a global stage The story of hemophilia Because I think it may serve as a an interesting object lesson as we think about our ability To to develop innovative genomic based Therapies so so i'm sure this is a history that's familiar to you and i'm just going to go over it quickly One of the great breakthroughs in understanding Blood disorders was the differentiation of factor eight and factor nine deficiencies the separation and understanding that these were two Molecularly distinct entities and this occurred in 1952 And as people understood and identified those blood factors They went to the next logical step and tried to figure out how you could provide those blood factors those proteins to people That were missing them on a genetic basis So there was a whole lot of experimentation with plasma products and supplementation with plasma And slowly over a period of about a decade and a half People who had otherwise faced a life that was likely to involve premature mortality and certainly involved Joint deformations and arthritis as a result of bleeds into joints began to have their lives dramatically changed Ultimately by the development of cryo precipitate concentrated cloning factor for many donors And this was miraculous when you when you Read the descriptions of people who went through this time. This was a tremendous Advance in people's lives. They could begin to lead normal lives and of course the next wave of that The unanticipated consequence was the wave of hemophilia that occurred in this population First case being reported in 82 most exposures as best we can tell retroactively occurring between 83 and 86 And then beginning in the mid 80s, there were efforts to take serum based products and apply Double treatments to reduce the viral load But as a result of that there was a cohort of hemophiliacs In whom 40 percent Were infected with AIDS and amongst those who were most severely affected and therefore required more blood products The the rate was actually as high as 80 percent well We now obviously have moved beyond that We not only have serum products that are highly purified But we also have recombinant factor 8 which was originally made with a fair amount of albumin in it Although it was treated albumin now is we're moving toward a product. That's completely free of human protein That's serum based protein And so we actually have now as a current standard of care Recombinant factor 8 for hemophiliacs in the united states and we give treatment both prophylactically and on demand And this is miraculous. I think this represents a symbolic example Of what understanding the molecular basis of the disease can do in terms of Creating innovative and highly effective therapies And it's very expensive I don't think we can talk cost effectiveness. This treatment is so much more effective than any treatment that came before Both in terms of its ability to treat the disease and in terms of its safety That it makes sense that it costs a lot more But the reality is that in most developing countries of this just isn't possible In in the words of one expert purity is an unaffordable luxury Even serum products purified to reduce the viral load are not really possible If you look for example at the third the one third least developed countries In the world hemophiliacs are not known to the health care system There is no health care system that's sufficiently developed to find them let alone treat them My point here is that finding a genomically based therapy is very much the first step In a very big and complex task unless we imagine that these issues of access are only In developing countries there certainly are very substantial access problems in the united states as well So adult hemophiliacs in particular in this country Find their access to treatment limited by insurance caps lifetime caps In fact one of the sort of advocacy Activities that hemophiliac centers need to get involved in is helping to figure out helping people to figure out How they can change from one health insurance plan to another when they're getting close to their cap So they can start again with another health care system with another cap There are pre-existing condition clauses so that when you change You have to think very carefully about some sort of cover coverage to carry you over till the new insurance plan covers and Our local hemophiliac center just the our thompson my colleague who runs that told me they're now Hiring a whole new fte who will spend all of his or her time Working with individual patients on these kinds of issues There are a variety of coverage issues that result for some people with some insurance plans in there not having access Through the recombinant but having to use the serum based product and again geography plays a role These are realities when we find genomically based therapies And then want to deliver them to the people who need them. We have to think about these realities There are other realities and i'll just emphasize this one We have a diverse society and great richness because of that But we also have bias in our society. That is a reality I picked off just very easily a few striking examples from the eoc website Bias exists and we have to think about that as part of the social reality in which genomics research occurs and certainly part of the The context in which we might think about how genomic information either plays out amongst different sectors of our society with different opportunities or how Genomic interpretations of social groupings may Interact with a variety of biases in our society Now obviously our society has a lot of strengths as well We have expertise in a broad array of disciplines We have a unique and extraordinary scientific community And within our scientific community, we have a tradition of vigorous and open debate That I think is is an important cornerstone. We also have I think fundamentally a sense of fair play We have an eoc for example Many states have passed anti-discrimination legislation because of concerns about the possibility of genetic discrimination We have a lot of goodwill in our society and I think an effort to solve deeply troubling problems So i'm going to just uh come to make sort of three basic overarching points about how I think we should think about these kinds of issues Not only from the context of the third pillar, but really from the context of genomics research as a whole I want to underscore the value of multidisciplinary and interactive genomic research I think we learn a lot from knowing our history Uh, I think we need to uh incorporate the work of social scientists, medical anthropologists, philosophers In understanding the meaning that's applied to genomics Uh, in different social and cultural contexts We need to look at policy options and develop policy options for addressing problems such as the access problems that I've been outlining for you As we do this it's clear that we need to bring a very broad array of disciplines Into the world of genomic research a broad array of social scientists And the humanities But they need to interact with the basic scientists and the clinicians There needs to be an interaction across the board because good elsie needs to be informed by good science And good science needs to be informed by good elsie I think we need to explore the rhetoric of genomics We throw around a lot of phrases and I think we need to start thinking rigorously and carefully about what we mean by them What do we mean by genetic discrimination? My sense of it when I look at the kind of legislation that's been passed is that we think it's fundamentally unfair For people to lose their health insurance coverage because they've got a dna based test that says they have a somewhat increased risk of disease in the future And that makes sense to me But in fact we do make different rules for insurance coverage based on people's cholesterol level sugar level Whether or not they're smokers and things of this kind I think we need to think very carefully about what we mean and what we're trying to prevent and what we're trying to accomplish Maybe what we're trying to accomplish is one step toward the Broad access to good health care that I suspect we would all like all people to have in this country If not in the world I think we need to think about what we mean by health And how that influences our efforts to improve the public's health Taking into account our increasing ability in the near and long term For identifying all sorts of risk factors for all sorts of human traits We are going to need to be prepared to draw the line What comes under the health care umbrella and how do we define that? We need to ask ourselves how will genomics change society One simple way to think about it is the genomics is the next great Technicologic move forward And genomics is going to change society by giving us Penicillin a hundredfold, you know those kinds of products and many many more If that's so If that's really the way in which genomics is going to change health care society I'm not sure it's going to change fundamental meanings of who we are and what we are And when we talk about genomics changing society, I think we are talking about The possibility that genomic research will change how we think of who we are How we think about what our rights and obligations are How we function together as a society and to the extent that that may be so It's clear that scientists, humanists, philosophers, social scientists have to work together to understand that process I think there's room for normative research As well as Empiric research And I'm I'm going to also comment and I think this speaks to the DNA as to destiny example that I gave you to the The sort of medicalization of our society We need to be prepared for rigorous evaluation of new tests and therapies When does identification of genetic risk lead to net benefit versus net harm? I would propose that both will occur We cannot assume that knowing genetic risk is always a good thing There may be times where it leads to an adverse label To loss of employment perhaps or loss of other social benefits without any kind of Compensatory health outcome benefit and at the same time We wouldn't be having this conversation if we weren't quite confident that genetic risk is sometimes going to be an essential key To improving a person's opportunities in life. We need to be prepared prepared to look at that Question rigorously for every genetic test that comes down the pike What's the value added of genetic information? We need similarly to look at what genomic therapies offer us to what extent do they Either decrease or increase potentially health disparities and to the extent that they might increase health disparities What kind of challenges does that give us to go back to the hemophilia example? I think the challenge now with hemophilia is to figure out how to get the 80 percent of hemophiliacs That don't live in the developed world To have the same kind of access to therapy that the hemophiliacs lucky enough to live in the united states and europe And as we move forward to gene therapy the next stage in hemophilia treatment will need to keep thinking about that And always we need to think about all the stakeholders at the table and their diverse points of view As we think about what is a health benefit in deciding whether or not a genetic test provides a health benefit We need to be thinking about who's deciding that Who's deciding that and on what basis? Fundamentally, and i'm going to finish here We need to ask the question Will genomics foster power and privilege or enhance opportunities for all of us as i think we would agree it should Thanks Thank you wiley and thanks to all three of the speakers Francis has reminded us frequently in this whole planning process that we should be audacious And i think our three speakers have done a nice job of reminding us how audacious it is to merely think that we could begin to think rigorously about the breadth of ideas and concepts and issues you've heard presented over the last Hour and a half. Uh, I think we have our work cut out for us I will only add to that a number of logistic announcements just to sketch out the next 24 hours or so for you because this is the last time Except for meals, which are hard to talk over that we're going to gather together So let me just go over In chronologic order a few things for you The first is of course to remind you that as francis already warned you the whistling swan up the hill Is only open until last called 11 closes around 11 30 We had actually planned some fireworks for directly after that We found out that the federal budget requirements are such that we cannot pay for liquor We can't pay for fireworks. Essentially. We can't pay for anything to be a lot of fun for you So since we couldn't do that many of you wonder why we gather today fairly too It's because we came up with the sort of the human genome project of fireworks Many of you will know the leonid meteor shower will be featured tonight or tomorrow morning Perhaps if you step late enough at the whistling swan, there's no point in going to sleep at that point They will be the peak between 4 30 and 6 30 a.m. 5 30 to 5 40 is true peak Go outside. It's nice and dark here Face towards the east if you're not sure which side way the east is first face west and then turn 180 degrees And you'll be able to see them quite well Dress warmly. However Breakfast will be served from 7 to 8 45 in the morning in the dining hall the same place where we had dinner Then from 9 to 11 30 everyone will participate in one of six working groups each of which addresses one of the three pillars The six groups of course meet concurrently two on each of the three pillars On the back of your name tag you will find the pillar and room to which you have been assigned There's also a map in your packet a yellow sheet of the early campus Which will help you get around to wherever you're supposed to be We asked you to not change groups or move to other rooms or whatever for this session We've actually carefully assigned people to try to balance expertise and backgrounds And also to try to keep each group at a workable size After those sessions lunch will be available in the dining room from 11 30 to 1 After which starting promptly at 1 o'clock and going to 3 30 will be the afternoon working working sessions working group sessions Again, everyone has been assigned to a working group Discussing one of the two pillars that they had not previously discussed in the morning session Your name tag again tells you where you will be going to which pillar you'll be assigned Then at 3 30 everyone except for the this evening speakers or working group leaders and a few of the hri staff I think you all know who you are Everyone else has the next couple of hours off to rest and recreate Until 5 30. I'm sorry to tell you the whistling swan does not reopen until 5 30 at which time dinner is served over here So it's a difficult choice. I'll allow you to make that for yourselves Dinner will be available from 5 30 until 6 45 After which from 7 to 9 tomorrow evening everyone is assigned to one of six special topic groups again the back of your name tag I want to instruct you about that The final thing is to let you know that the north room If you're not sure where the north room is of course, you just face east and then turn to the left It's our administrative room down off of the where the check-in was It has computer setup. You can use that to check your email, etc Our contractor melinda gray will also be there to take care of arrangements or transportation back to the airport And then the other travel changes you might have If you have any questions about anything, please find melinda or Particularly susan vasquez of our staff is susan. Are you in the back of the room any place? There's susan right there waving at you. She's the person has the answer to everything else If you can't find susan you want to sell for second best though You might look for mark guy or eric reiner myself and we'll tell you where to find susan And I think on that it's my pleasure to thank you all for your very good attention And tell you to walk carefully in your way to the whistling swan See you tomorrow