 Okay. Well, good afternoon, everyone. Thanks so much for coming. I know it's not the most lovely of why they're out there at the moment. All of a sudden, it seems that winter is upon us. But it's terrific to see all of you and to have you join us in this first of what will be six sessions that celebrates a quarter century after the Human Genome Project's launch. We hope to unveil to you some of the lessons that are beyond the base pairs of the Human Genome Sequence. We are very much here, and the reason we put this series together is to commemorate this 25th anniversary that happened October 1 of this year, so just a couple months ago, which really signified 25 years ago the official beginning of the Human Genome Project. And needless to say, with that project being completed in 13 years, now 12 years ago, it is hard to argue that it wasn't not only a remarkable success, but had an amazing impact on the entire landscape of biomedical research. And there's just so many things we've learned from this, even beyond the science. And those are among the stories that we hope to tell in these six parts of this series. There are many important lessons, really, about big biology, about how to do science in a different way, and take on new challenges in a contemporary light. I would point you, if you haven't seen, on the October 1 issue of Nature, Jim Watson, Francis Collins, and I wrote this comment piece that touched on some of the major lessons learned from the Human Genome Project, the three of us being the three people that have served as director at one time or other of what is now the National Human Genome Research Institute. And I will almost tell you for certain that some of the things that we talked about in this comment piece are things that will be touched on by various people that will be participating in this six-part series. So where the genesis of this in many ways also reflects a commitment the Institute now has to capture the remarkable history of genomics, the remarkable history of the National Human Genome Research Institute, and the history of the Human Genome Project. And in fact, we have, and I have established, a history of genomics program within the Institute. Chris Donahue and Chris Wetterstrand are really the key individuals that have stood this thing up. They have other staff now that are working with them, and we really are developing an infrastructure and an approach for not only capturing what's happened in the past in genomics and the Institute, but also going forward, make sure we have a way to do that. And among the things we do is to try to capture people's views and experiences in genomics, even in venues like this. And among the things we'll be doing in these sessions is videotaping this and making these sessions publicly available very much as part of the historic record. The other reason we decided to put on this six-part series was to, as I pointed out, commemorate and also celebrate what has gone on in the field, what's gone on at the Institute, and what's gone on in seeing things really change in biomedical research because of the early accomplishments of the Human Genome Project. We're also using it as a reunion. Some of you may have noticed there are a lot of hugs here that we're seeing folks from the Institute we haven't seen for a while, and we're drawing them back, and we hope that will continue for the next five sessions as well. And like I said, we will really very much look forward to having this available for the permanent archive in terms of a video of each of these sessions. So we thought it would seem actually quite appropriate in how to start. And so for this very first session, we thought we should start at the beginning and immediately remind people that, you know, this Institute didn't always exist. The notion that there would be an organization in the United States that would help lead the U.S.'s contribution of the Human Genome Project wasn't an automatic. There wasn't a blueprint for how to do this. In fact, it was so incredibly unusual for NIH to do something like this that it really required some creative energies of individuals to stand this up in the first place, both to help stand up the Human Genome Project, which was unprecedented, but also to stand up within the NIH, an organization that could tackle those responsibilities. And so we thought for the first session, we would bring back some of the people that were key at the very beginning of the Human Genome Project in the very beginning of what is now the National Human Genome Research Institute, but actually it wasn't even called it back then. Three individuals were immediately obvious. Elka Jordan is first, and we're going to get to Elka in a minute, sitting in the middle. And Mark Geyer was another obvious choice, and then there's this guy, Francis Collins, and he'll fit into this story as well. Now there is a small story about Francis. I should just have open disclosure now. The seat, the third seat was for him. We had every intention of having him here, and he had every intention of being here, but sometimes when you're the NIH director, you get pulled to other things. He is actually at the White House right now, meeting with somebody really important there, and unfortunately that couldn't be rescheduled and only came up about a day or two ago. So I don't think Francis will be here if for any reason he gets back to campus soon enough he will come join us, but I wouldn't count on it. Now the good news there is we can make much more fun of him because he's not here, and I plan to do absolutely that, and I hope Mark and Elka will even be more candid about some of the experiences with Francis at the helm, but we're not there yet. We're not even at Francis at the helm yet. We're going to go back to start with, to the very beginning. The very beginning of the Institute actually wasn't even an Institute, wasn't even a center, it actually started off being an office. And I'm going to show as we proceed through a series of questions, various pictures, they're absolutely designed to embarrass Mark and Elka, and so that's absolutely going to be the case because you show pictures of anybody when they're younger, it's usually a little embarrassing. So I thought it was only fair to start off by embarrassing myself and tell you my vantage point of this entire discussion is basically from that era in my life I can tell you that it was about 1988. This picture was either 88 or 89. I was about a second year postdoctoral fellow in Maynard Olson's lab, also relevant because Maynard Olson will be the second speaker next month. Maynard will be here as part of the series as one of the founding intellectual fathers, if you will, of the Genome Project. And I knew about this thing that was about to start called the Genome Project, and I knew about this thing called NIH, didn't know much about it, and I knew that they were starting to get organized to possibly help be involved in the Genome Project, but I didn't know much. But I heard lots of stories mostly through Maynard, but believe me, many of the things we're going to discuss here, my vantage point was far, far away in the middle of the country just as a postdoctoral fellow just trying to figure out what I was going to do with my life scientifically and otherwise. But I did know enough, and I certainly learned enough in the past quarter century or so, to appreciate there's some great history to unfold, and that's what we're going to try to do now for the next hour or so. So with that as my vantage point back then and what I know a little bit now, I would have done a little homework, I want to start really at the very beginning. And the very beginning was Elka Jordan was recruited, and here's a picture of Elka at about that time. Elka, you're going to, it's probably, it's not going to be easy for you guys to see it, but this, you're going to see pictures. That's okay, for Mark, he doesn't want to see any of these pictures of him. So Elka, you were working at NIGMS, if I have it, and there was this guy, Jim Watson, who we're going to get to in a minute, who was going to come on the scene and sort of run this office of genome research, but even before he got here, you were enlisted to sort of be the seed leader to help start to stand up this new office, is that right? Tell us sort of how you got, how you first contacted, and what was your first responsibility of waiting for the arrival of Watson? I have to tune this on, right? Yes, there you go. Okay, so I was in NIGMS, I was the Associate Director for Program Activities, and I was quite happy there. Meanwhile, in the scientific community, there was a lot of roiling going on about the genome project. There were the pros and the cons. There were the people who said NIH should never get involved because it will take money away from better research. And then there were those who said NIH must get involved because this is all about diseases and that's what the NIH is about. And there was a famous meeting at Reston, the Reston meeting, which really got NIH on the map. It was called by NIH and all the luminaries in the scientific community that were relevant to genome project were called in to give their opinions. And they came up with two recommendations basically. One was that NIH should get involved and the second was that NIH should create a special office or unit to handle this project outside of any of the institutes so that there would not be any competition for funds with other research in the institutes. And behind the scenes, there were also negotiations about who should run the office and somehow or other Watson was identified to be the leader. And then there must have been conversations about who should be on the staff because shortly after that, I got a call out of the blue from Jim Weingarten. And Jim Teller, Jim was the NIH director at the time. Jim Weingarten was the NIH director at the time. And he asked me if I wanted to head up this office. This was a big step because there was no telling whether this project would succeed, whether the project would even live because you had to have money. The money came from Congress and who knows what Congress was going to decide. So it was a risky thing, but it seemed like the most exciting thing I could do. And so I said yes. Elka, did you know Jim Watson at the time? I knew Jim Watson vaguely. I was a postdoc at Harvard in the same department, the Biolabs, and I was with Messelsen and we had joint lab meetings. So I'd seen him in action. And everybody warned me about Jim Watson, especially about Jim Watson and women. And you didn't hang up the phone. I decided I was a mature woman I would take a chance. So another name that arose somehow was Mark Gaia. And so I immediately set about trying to recruit him. All right, let me put you on pause there. I don't want to get to Mark yet, we're gonna work, but was, although one last question and then I want to make a slight transition, did, was it Jim Weingartner that thought you were the right person for this job or was it Jim Watson who's told Jim Weingartner how to welcome? That came out of the advisors that were meeting at Western and I don't know who it was. Okay, now. I have suspicions, but in any case. You know, I was, I think I and Mark were probably the most well known in that community of the people at NIH and I think that's how our names came up. Although Mark wasn't at NIH, although we're gonna get at the time, or you were already at NIH at the time. I see, so, but then before, I thought before Mark arrived, I thought we had Jim arriving. Is that, I thought the order was you? Well, we were trying to remember. Yeah. Jim was hired by Weingarten to start October 1, 1988. I was hired by Weingarten to start October 1, 1988. And when did Jim start? He started October 1, but Jim was not at NIH all the time. Right. He was mostly up in Cold Spring Harbor. So I don't recall when he first came to NIH. So here's a picture taken shortly after Jim arrived and here's an article from Nature in September, I can't quite read, 88, September of 1988, talking about how Watson was the designated person to come to NIH. And you're all right and it isn't, I remember even hearing about this then that Jim was only, even when he was fully here, he was only here part of the time because he still spent a lot of time back at Cold Spring Harbor. He was a part-time employee. Right. And he was an expert. He was not a regular employee. And so he just came in when he thought he was needed or he felt he was... I think that was part of his deal with NIH. Was that he wanted to part-time? He wouldn't have to leave Cold Spring Harbor and move down here and it would be part-time. Also, he needed an appointment that would allow him to get travel reimbursement. Right. Right. Practical things like that. But so but Elka, you were the, here's a nice picture of you and Jim and I mean this was a team to start off with. And what was that like? I mean, because you said you didn't really know him that well but and he certainly didn't have much familiarity with the government and government work and in the meantime you had to do something in an unprecedented way with the genome project. What was it like those first few days working with him? Fortunately, Jim didn't show any interest at all in how the office was set up. He showed no interest in who was hired. He just said do it. So that made that easy. So. But he of course was very interested in the politics and in stimulating scientists to work on the project. So he was traveling a lot. I think he sort of earned his keep here but he wasn't physically here. And did he delegate, he let you make all the key? Absolutely. So you were in charge. I did not want to learn all about government structures. So among those early decisions was also to bring in this guy, Geyer. So Geyer arrives. That's right. And then now you have a threesome team. Here it is. There's an early picture of Mark. It looks just like Mark now. So I don't know why Watson has his eyes shut there but. No, I was number four. You're number four, I know. I'm down by the leadership though. There was other people hired so you were typing me number four. Well, when I went over there, I took my second day. Ruth Kirsten was eternally unhappy with me about taking so many of her staff but they were the ones who knew this subject matter. And my secretary, I had worked for me for many years so I felt confident that she could figure out how to set up an office de novo. And we moved into the attic level of building one. We had two rooms, which became three. Small. And she had to learn the ropes on how to operate in building one. Thank goodness. I don't know where she is now. She's not here by any chance, is she? Not that we can tell. And although the staff grew fairly quicker. So here's a picture, I think, from not that many years in. There are the three of you in the front and the nascent staff. But I bet you weren't in building one at that point. I bet you had already moved to a different building. I don't know where we were. Most likely we were in Lister Hill by then. Yeah, Lister Hill. It looks like Lister Hill. Yeah, I agree. But the two of you really, and here's a picture, really became key leadership, especially with Watson really delegating those responsibilities of running the organization and doing all the mechanics. Is that a fair summary? So tell us how some of the early scientific decisions got implemented. Implemented or decided upon, well, we had a advisory committee. One of the first things we did was to recruit and establish this program advisory committee. And they had meetings. And there was this famous Banbury meeting, which doesn't appear much in the record. I don't know why, but... I know there's a good picture from that, of the group photo. That was where the first five year plan was sort of cemented into concrete language. It took a lot of effort and milling about and people being unhappy, especially Norton Zinder would come, talk to me and say, this is not going, this is not working, we're never going to get here. But then all of a sudden towards the end, things coalesced. I guess we were running out of time, so people focused. So that's where the first year plan came from. And that got us on our way. We knew what to do. So tell us about those first funding announcements for the first centers and for the first set of things. It's almost gone out in 89, right? Because they were more early in the 80s. The first year, the office didn't have any money to give out. There was a little money in IGMS, which we sort of had some influence over. And then the second year, we became the Center for Human Genome Research and we had our own appropriations so we could actually do something. There was a program announcement issued by NIGMS, right? I think you were involved in that. It sort of started a few grants coming in, but those were really very generic kind of grants. What about the big genome centers? The genome centers, I can't remember exactly when we advertised for them. Do you remember that, Mark? No, but. Not the first. Not the first step, yeah. Because we had to figure out what they should be. But it was part of Watson's plan all along that there needed to be centers, that this kind of work could only work properly in an environment where there were teams of investigators from different backgrounds working together creatively. And what about the decision to not only focus on human maps early on, but also to have parallel efforts in model organisms and analyzing their genome. Okay, well that all came from the National Academy group that was established to figure out how the genome project should be conducted. And they really fought their way through to get all these recommendations, like include model organisms, start with a genetic map, slowly move into physical mapping and don't do sequencing until the technology is ready. And those recommendations were adopted by the rest of the meeting group and then later by our program advisory committee. So they stood through the whole history. I think the National Academy committee was really organized to address the question of should there be a genome project? The previous, the background to that is that the Department of Energy have made the proposal to sequence human DNA. The connection with the Department of Energy for, which was not obvious at the time, was that they were interested in the effects of low level radiation on human. And the primary one is effects on DNA, but the effects are relatively small and their advisor said the only way you're gonna be able to study that is if you have the sequence of the human genome. So the DOE project was started or at least talked about with Congress in terms of sequencing human DNA. And then the Academy got the committee organized, so the whole proposition of sequencing human DNA was very controversial. The Academy committee was organized to address that question. And the same disputes, same points of view ranged in the committee that there were some who thought this was too much and was not interesting research and would not be significant. And then there are the other side who thought that this had to be done. And the development of this stepwise approach for NIH, starting with model organisms and building up was the compromise. That's really what brought the two sides together and they could agree that even if you never got to human DNA and human sequence at this, there'd still be lots of good stuff coming out, the genetic maps, physical maps of the important model organisms, the genetic map of the human and so forth. Now another thing that developed around that time, shortly after Watson's arrival, which some thought was controversial at the time, I think ended up being one of the signature aspects of the Genome Project and also I think of the field of genomics was the development of the Ethical Legal Social Implications Program. Now the way I hear this story, told and I've seen this video, here's a frame capture from this video, it was a press conference shortly after Watson arrived in 1988, you can even see the timestamp at the top, where, and Elka, help me if you remember this, that he just sort of said out of the clear blue, unprompted, apparently hadn't talked about it with staff or anyone that we need to study the ethics of what we're doing along the way. Yeah, I think it was one of Watson's inspirations on the spur of the moment. But it was a fantastically effective one. It really changed the nature of the conversation because now the ethicists that were complaining had to put up or shut up. I mean, money was available, they could apply for grants and now they had to do the work. And also they went out, they gave lots of talks, they organized workshops, they wrote papers about it so that everybody, the community, scientific community as well as the public became much better informed about what Gino Project was supposed to do. Was the staff happy? I mean, sometimes staff doesn't get happy when the director says something like that clear blue that commits and moves something. Well, I think we saw right away that it was a brilliant stroke. How to implement it was another question. So I don't know for sure, but my speculation is that one of the reasons that Jim took the job in the first place was because he saw it as inevitable that there would be an expenditure of NIH funds. And he wanted to make sure that it was done well. And he was very concerned about the politics. He was big on the politics of science funding in general and was particularly sensitive to the politics surrounding the Gino Project. So that was a real driver for him about getting it done and getting it done properly. And the inspiration to have an ELSI program, Ethics program, was in part political, that it was his point of view that you weren't going to be able to sell the Congress and society on this ambitious, audacious effort, unless there were discussions about the implications about safeguards and so forth at the same time. And I think that was a good point of view about safeguards and so forth at the same time. All right, we're going to move beyond Watson. But before we do, I want to ask each of you last question, but just in bullet form, tell me the most enjoyable aspect of working with someone like Jim Watson and then what was the most frustrating thing about working with Jim Watson? And he's not here, so we can be very candid. One of each. Well, the most enjoyable thing, I think, was he was always unexpected. Kept you on your toes. And that was also the most frustrating thing. Mark? So, I don't know how many times I've told this, but my major impression of Jim was that he held and expressed opinions more strongly and more emphatically than anyone I'd ever met. When you talked with him, if you had a better argument than his, he would change his opinion on the spot and argue the new position just as forcefully. So, as a staff member working for somebody like that, you couldn't want much more than that to be able to interact in that way. One other story I'll tell. I don't know what it really answers the question you've asked, but one of my other major memories is Jim coming down from Cold Spring Harbor to testify at some congressional hearing or something other. And he was testifying in the afternoon. He came in the morning, spent a couple of hours talking with us about whatever, and then, you know, with perfectly serious, perfectly reasonable conversations. And he looked at the clock and said, up, time to go to play the clown. And off he went. Yep. When he would call, wait, wait, hang up. Of course, he called on the phone more often than he visited. There was no functional email in those days. And we'd always... No, there is a functional email now and Jim still doesn't respond to email. That's another story. As it may be, but I'm not sure there was one that communicated between Cold Spring Harbor and NIH. But when he called, he would sort of start conversation in midstream and then it would take a minute or two before you could figure out what he was talking about. Yep. So then there was a transition for what was then the center. Jim ended up leaving, announced he was leaving, departed. And Michael Gottesman, who is now the deputy director for intramural research and has been for a number of years, was asked to serve as acting director of the center. Here's a picture again of this in case of Mark and Michael. So my question is, and this then became a key partnership, Michael and the two of you. Here is a nice picture of the whole group, a slightly larger staff at this point, Michael and Elka and Mark. So what was the mood at that transition? So where all of a sudden you're losing Jim, the one leader and being put into an interim situation, Michael knowing there was gonna be a search. What was the mood of the staff? What was sort of the feeling around the center? Well, we were all worried about how this was going to turn out. Michael took the role of dealing with the outside world and especially the office of the director. He was able to assure us that we had the support of the director, Bernardine Healy, even if she didn't support Jim Watson. So that was reassuring. And there was a lot of firmament in the community. They were very concerned about whether the project would continue. So during this sort of dark time in the genome history, they somehow set up a regular communication with us so that we didn't know in detail what was going on in terms of their scheming, but we were reassured periodically that things were moving along, things moving along, meaning finding a new director. So there was not total panic, but we were worried. If Michael was here, and I don't think he could make it, he would say that he enjoyed very much serving in this capacity. He's actually very proud of that time in his service to the NIH. He did a fabulous job. And he didn't involve himself so much in the running of the center, or grants to be funded or anything. He really protected us. I can tell you from the view of the outside, again, by at this point, I was still a postdoctoral fellow, but at this point, I was heavily involved in one of the first genome centers that was established, funded at Washington University. And I vividly remember Michael actually being quite involved and engaged with the people, especially the leadership of that center, and there being a lot of confidence in him at Washington University. Recognizing this was an interim director, but that was somebody who was clearly doing the right thing and felt very comfortable having you guys also serving in a continued leadership role. So at least at one center on the outside, there was extreme confidence that things were going well, obviously waiting for the new director to be identified. I'd say in addition to worried, there was also a reaction on the part of staff of being extremely upset with Jim's dismissal and the way at which was done. I used nuanced language, but that's a fair point. And we were really very unhappy about that and that lasted for quite some time along with the worry of what comes next. And my most vivid memory from that is being at a site visit to one of the centers and sitting in the bar in the hotel in the evening. And one of the site visitors came down and sat down with me, we were talking and eventually it got around to the staff's concern about who the new director was gonna be. And he said to me, don't worry about it. It's being taken care of, you'll like the outcome. So I still to this day don't really know who was involved in that planning, those negotiations. That person when I recalled the story to him a couple of years ago swears he didn't remember it. But I do. And in about 10 slides, we're gonna ask you whether you did like that outcome, but that's when we get to the Francis era. Was, how did Michael deal with some of this angst about the way the transition happened with Jim? Did he deal with it head on or was that more left to the two of you? With respect to the staff? Yeah, just with respect to the staff being unhappy with Watson's departure and how it was handled. Was that, did Michael get involved in trying to deal with that or was that left mostly to the two of you? Well, no, he did reassure us that things would turn out all right, but as I say, the director of NIH did support having a genome project and that was the key. All right. So I'm the director at that time was Bernadine Healy, right? And so Bernadine was the one that did successfully recruit eventually Francis Collins to become the second director. Again, then was the center, National Center for Human Genome Research. And in a photo that I had not seen until we were preparing materials for today, there's this slide of Michael and Elka and a skeleton. And so Elka, do you remember the story behind this? That must have been one of our Christmas parties. Did it, by key was, did this involve alcohol? Because it so it wasn't on campus. No, we didn't have our Christmas parties on campus. Oh, okay, I got to talk to you. Oh no. I think they were at Elka's house. This was at your house, Elka? No, not that picture. I think by that time we were in some bigger space but I don't recall what it was. So what, do you remember what the nature of this picture was and why there was a skeleton with Francis's name on it? I have no, I'm not sure I even... How long ago was this party? Maybe he couldn't come. So maybe it was before he had been... Vetted. Vetted and confirmed. Francis' question mark. Well, eventually he was vetted and eventually he did arrive and he was very young looking back then. This was one of the earliest photos we have that I know of. But once again, and I think these pictures really tell the story. It really wasn't just about the director. These directors were always flanked by the two people here on this table. So here's a picture I predict either from an important workshop or maybe from a council meeting it looks like. Something like that. Mark on one side getting cut off in Elka sitting between Francis and Mark. And meanwhile, you know, I don't know exactly what year this is from but again, you can see the staff continuing to grow. Here was the time by that point you guys were located in an L.M. building. And so you can start to clearly see how much the organization had grown. So when you learned it was Francis. He was one of the grantees. He was one of the center directors. What was your immediate reaction? He was, yeah, he was a center director and he was also a member of... He was a member of the council, I believe, either the council or the program advisory committee. So we had already started to interact with him. We knew him and I think we were surprised. Were you immediately happy? Yes. You were promised you were gonna be happy. You were immediately happy. It was very reassuring. Very reassuring. That it was someone who knew the program obviously. Someone we knew at least a little and was respected by the community. So yeah, I mean, I think going back to Jim for a minute, one of the other things, one of his other major self-imposed tasks during the time he was director and I think again one of his big success was recruiting people to be center directors. Or at least recruiting people to put in serious applications. He very much wanted the people involved to be the best and the brightest. And so he went, I'm sure did a lot of arm twisting to convince people that this was something important for them to be involved in and that they should help contribute to it. And Francis was one of the people. And Francis was one of those. Right, and so clearly we knew not only of him and had it worked with him, but he clearly also had Jim's imprimatur on him as did all the other center directors. Right, on the other hand, he hadn't run much of an organization. He had been a division director in the Department of Medicine and he knew nothing about the government. So he arrives on the scene, I bet you noticed an immediate stylistic difference between Jim and Francis. Oh my gosh. And besides the fact that one of them sang and the other one didn't. But what's the first thing you noticed, okay, you knew life was not gonna be the same when Francis first showed up? He showed up. Oh, he showed up. The fact that he actually moved here. He actually was there, but initially he did travel a lot because he was creating the intramural program. So he was in the recruitment mode trying to persuade people to come. And that really took. He traveled to build the intramural program? He made me travel here when he recruited me here. I should have made him come to me. He did both. I did both, okay. I think that for the first set he went out and tried to call out people. So he was very busy and really did not get that involved in the bureaucratic aspects of running grant programs until he had the intramural program pretty much underway, at least to the point where Jeff Trent, the first intramural director could carry on. Mark, what were your immediate impressions? There was also a lot. And this continued really through his entire directorship of him. Saying, this is what we should do. And the staff saying, this is why you can't do it. And figuring out ways to do it, Francis was always a fount of ideas in a much more on the ground way than Jim had been. Once he learned how the government operates, he was very creative in using it, good knowledge. But by the time he arrived, it was really time where the project needed to get serious momentum. There were lots of issues about what the centers were doing, how many centers there were, issues around data release, issues around data quality. I mean, my memory of that time was that, I mean, Francis really started to be very hands-on in trying to write all of these issues and address them head-on, including some very tough decisions. What was that like? Was that mostly because of discussions internally or was he just being very responsive to some of the concerns of the community around these various issues? I think it was both. I want to go back to something Elka said about that original Banbury meeting. And that is, I think it, along with the background of the National Academy report, but it really set the tone of the way the administrators of the Genome Project interacted with the community and that there was this very strong dialogue back and forth and that really continued the whole time and Francis just obviously bought into that and ran with it. So it was- And probably because he used to be one of them and now, all of a sudden, he was like, right. So continuing that approach and he was constantly coming up with ideas and we would either spend our time trying to convince him that this couldn't be done or else figuring out how to do it. But that had another consequence that I want to ask you about, making it harder because one of the tough things that then had to happen sort of at the midpoint of the Genome Project was the recognition that you had started a whole bunch of centers. Some of them were doing really well and some of them maybe not as well and then it was really time to start ramping up considerably and it was very clear to get this project, especially the human sequencing done correctly, probably needed to consolidate it a little to a smaller number of centers and that meant making some hard decisions programmatically. How did that- I can say a word about peer review here. One of the things we had to deal with that was that peer review, as it was operating at NIH at the time, was really not prepared for genomic kind of research which was large scale, moving towards completion and all those characteristics. So we really had to train reviewers or convince reviewers to take a different kind of look at applications. And the reading out of centers really was, in large part, a peer review issue. Staff worked with the peer reviewers to get the criteria right. The peer reviewers eventually got it and they were able to distinguish those that might be successful from those that were not. I'm certain there was some unhappiness along the way. Did when that unhappiness came back to the Institute, was it most of the two of you dealing with that or did Francis jump in and sort of serve as the voice of the Institute? Or both? I'm sure Francis got a lot of calls. Right, that we didn't hear about. I think a lot of it came to Jane Peterson because she was running the centers program. One of the things that I think I at least was relying on through that process was something Jim had inculcated into us at the beginning of the centers program and that is as many centers as you start and you should probably start several, a number of them are gonna fail and you shouldn't be worried about that. As long as a few of them succeeded, the program was gonna succeed. And that is a great transition and so I wanna turn our attention to sort of, but I'm not sure everybody knows about it, especially the younger folk in the audience who weren't following carefully. Some of them probably weren't even born about this time. How sort of the actual leadership of especially the final phases of human sequencing and how it was actually really done and it is reflected by something called, affectionately referred to as the G5. I mean, this is the way that the end of the day, most of the human genome was sequenced. So Mark, maybe tell us about the G5 and tell us about the weekly phone calls. So we're now talking a few years later. Yes, we are. We're really into the- And just to fill in the beginning, the way the sequence, the human sequencing program got started. We were, so through the early 90s, we were supporting the sequence of E. coli of the worm, eventually Drosophila. Yeast was done much more internationally. I think it was in late 1994 or something. Bob Waterston and John Sulston came and said, the time is right to start sequencing. I was not yet convinced, but there was a meeting and the outcome of the meeting was that we needed to get a human sequencing program going. And so we worked hard and got this RFA out and ended up funding several sequencing groups. And what I can't remember, Chris, maybe you remember, was it the first RFA or the next one where the eligibility criterion was that you had to have sequenced a million bases, the second one. So at the first one, we didn't even do that. So then the second round, I think we funded the first ones for four years. And then the second round we did for five and then back to four as the groups were weeded out, the really prolific sequencers emerged. Maybe that's a better way to put it. And then the question became, how is this gonna get done? And this was still at the time where we were very heavily influenced by the approach to physical mapping which was being done on a chromosome by chromosome basis. And it seemed that the right way to approach the human sequence was on a chromosome by chromosome basis. So a number of groups wanted to participate in the sequencing. Everybody was well aware that doing the sequencing was more than any one group or any one small countries could do by themselves. I think actually that was one of the keys to the success of the genome project was that until later, nobody came along thinking that he or she could do it all and needed to be interacting with people. We'll get there in a minute, but yeah. It's the next topic. And basically all around the world, there were 20 groups involved in sequencing either chromosomes or regions of chromosomes, but these were the five that were the largest. And when the challenge really came and we had to really focus on making sure it got done, it was these five that we relied upon. And every Friday was it at what time? I, some. Friday at 11. I don't know. We had to, what? Just in the morning. Because of the Sanger Center, we had to take into account the five hour time difference. This was it, right? I never would participate in one of those calls, but I mean, from what I understand, there was a whole staff gathered around phones at NHGRI and then at every one of these places and Francis sort of ran the show and was sort of the general, the field general and it got heated sometimes and it was cordial sometimes and it was hostile sometimes, everything. And the kinds of issues that we would be dealing with on a weekly basis was how many base pairs got sequenced that week and then. Quality? What's the quality? What's the quality? How many base pairs got deposited? Because there were clearly times when some group for whatever reason said they had sequenced so many bases that week and we went to the, to GenBank and we couldn't find them. So Chris got rewarded with the. And there's many notes. I mean, all, we have like huge numbers of documents from a lot of these phone calls that went on for what, a better part of two or three years? Oh, at least. Two or three years. So this was a rough and tumble group. But Elka, why don't you talk a little bit more about quality? Cause that was also a major, a major issue. You probably know more about that than I do. Well, I mean. It was a big issue. It was, it was, people were. I mean, there was a sort of the overall issue with Maynard Olson taking the position. Every seat, every base pair should be known in its exact location, which became unrealistic. But then there was also quality of, you know, the quality of each base pair that somebody had sequenced so that we knew how likely it was to be accurate. And with that many groups contributing, that we needed to have a way to know that each group's contribution was equivalent in terms of quality. What we ended up doing within the NIH program, and I can't, this was probably 96 or 97. There were still several sequencing groups around is that we did around Robin, where each sequencing center had to give, contribute some number of YACs, or some number of PACs that they had sequenced. And then we had it re-sequenced by another. It was essentially doing a double blind experiment. And there were a lot of sequencing groups that were very surprised at the results because they thought they were producing really high quality stuff. And it turned out that they were not. But the insistence on that became sort of assumption. We had Phil Green developing. Fred and Frapp. Fred and Frapp, and ways to actually quantitatively measure the quality. And so that became a constant issue, a constant theme. And of course the dilemma was it was trading off speed versus quality. And it was tense situation because they're milestones, goals, pressures, and so forth. And let's transition, by the way, so this is the G5, these are the five centers. And this is a slide I made a long time ago. And this is the, here are the G5 and Francis that is the ringleader of them on these weekly phone calls. But it was tense because it was hard getting a genome sequence for the first time was gonna be incredibly challenging. But of course there were other forces that were causing turbulence in the ecosystem. And of course that relates to the race. So let's talk about the race, especially without Francis here. We could talk about it. Of course this is this famous cover of Time Magazine. Actually at the end of the race when it was done, in fact Time Magazine declared the race is over. And here's this famous photo, I think from the White House, where Time Magazine came out and the two protagonists of this race were at least smiling. But they weren't always smiling. So tell us some things, again, without Francis here it's really easy. We could be totally candid. I mean, so the race had many angles but also the way it ended. It had a lot of mystery and intrigue because not everybody knew exactly how this was gonna get settled and a lot of it was done behind the scenes. So. It was behind the scenes. So the story goes that you guys really had no idea that there were these negotiations between. Oh yes. You had no idea. Oh we had an idea but we didn't participate in the details. And you didn't get updates. There was just something brewing and you didn't know. We would get. General updates. Progress for, we're pretty general progress reports. We knew things were progressing but we didn't know any of the specifics about what was being said. So I can tell you, I mean I vividly remember. You know about the meetings between Francis and Ari Petrinius, right? You didn't know if Craig was there or not or you knew he was there. No we knew. You knew Craig was there as well. Yeah. And we knew they were in Ari Petrinius. But in addition to dealing with that, you had to deal with the grantees out of the center and the G5 who are unbelievably unhappy about this time. You were dealing with staff who might have been quite nervous. I mean there was all this discussion about, I mean we're showing pictures from the end of the race but what about in the middle of it? Or the beginning? I mean the whole Solera thing caused immense amount of tension in the community. And I was living on the intramural side of the center, I guess at that point, Institute at the time. So I, but I'm aware of, there was a lot of hand-ringing even among the staff. Yeah, I think, I wouldn't, there was a lot of unhappiness on the part of the participants in the genome effort, the sequencers. A huge amount of unhappiness with Craig. There wasn't unhappiness with each other. I think everybody recognized the challenge and sort of decided, we're not gonna lose. We're gonna maintain our standards of what we're gonna produce. We're gonna end up with a complete high quality sequence. And especially, I mean there was one point where Craig testified before Congress and basically said NIH shouldn't be, or the public effort shouldn't be sequencing human DNA. He was gonna do it, let the public effort sequence the mouse. That, people didn't take easily to that. Who was more difficult to, which was a bigger issue managing in terms of being unhappy about this, or the center directors or the staff, the extramural staff, or was saying. The center directors really, they had staked their life on this. So I think they felt it more than the staff. They felt it more, were they harder to sort of keep corralled and morale up and so forth? But again, I- They were very dedicated to getting to this goal and the importance of having the sequence public rather than private patents for Craig Venter. So I think it actually stirred them on to greater effort. And I think because of this relationship, this really collaborative relationship between the staff and the center directors, I think the emotions were high all around. No. The outcome obviously was good from the point of view of, at the announcement at this level, obviously then the finishing of the Gino project. But this does relate to even the previous couple of slides. And I wanted to, I mean, you two had a first work for Jim Watson. That was a challenge for reasons. But then you also had to work, as did I in this case, have to continue to work for a rock star. I mean, having this guy as your boss is interesting. This is something I think from Time Magazine and here this is from Vanity Fair at the base of the Metro escalators at the NIH campus. So he's not here, so you can be very candid. What was it like having Francis as a boss? Again, bullet form. What was the most pleasant, wonderful thing about having Francis as the helmet? What was the most frustrating? Lee has a very- They only allowed one of each because when it comes to both of them, the frustration list, no, I'm just kidding. Go ahead. Well, Francis has a very genial personality. He's really easy to deal with. Now underneath, sometimes there may be other things going on, but at least on the surface, it's easy to work for. And the frustrating part? He's always doing a million things at once. And then delegate some of them down, right? Yeah. I would say the best part, again, was the ease of working with Francis and the contact he kept with the staff. We had weekly staff meetings of the entire NHGRI at that point staff, which was only about 30 program directors plus review staff. And Francis would come every week or three out of every four weeks. And that really set a tone. People became very devoted, both to the project and to him. I'd say the frustrating thing was that his ideas came too fast and too assertively. And we had to deal with where's the money gonna come from or how can we convince him that this is not the right time? So I sort of characterized my role with Francis sort of holding the reins and keeping him back. And when he comes up with a crazy idea, he also doesn't forget it. So if you don't do anything about it, I'll ask the next week and the next week and the next week. Yeah, okay, I know that feeling. But I know both of you admired Francis tremendously. In fact, you were both inspired by this photo and all you wanted to do was to be like Francis. So here's a picture of the two of you with big sunglasses. Because that was clearly the in thing then was to wear big sunglasses and look really cool. And the two of you do look quite cool. So I'm sure that's Cold Spring Harbor is my prediction. One last topic or second to last topic before we wrap up but ending the human genome project. So here's a photo, I think it was after the draft announcement, so major center directors in the US there's a picture of Jim, but it showed a celebratory time. But I also remember vividly that when it came time for sort of finishing the human sequence, there were discussions about should you know the genome project was originally 15 years, not 13 years that we're gonna have done the human sequence. Should we end the project or keep this good gig going? Let's move the goalposts and declare some new goals. So what's your memory of that decision? The other day the decision was declared over and move on and have the institute move on to other things which we've done. But what was your memory of how that decision played out? Well, I remember that Francis was very strongly in favor of keeping it going. He felt like finishing the sequence was just the beginning, not the end. So that's how it turned out. But nowadays when you talk to historians and people who sort of have a broader perspective about it, they do seem to feel like the genome project is finished. And now we're doing something else. It's related, it's an outgrowth, but it's something else. I don't have very strong feelings about that. It's a matter of semantics. Yeah, I think the question really wasn't so much whether the genome project should continue per se, but whether NHGRI should continue. And I was of the opinion that NHGRI should go away because I thought it would be fantastic to have worked for a government program that set goals, accomplish those goals, and then went away. But I didn't win that one. And I vividly remember arguing Francis quite strongly that the idea that we should end this, I didn't like the idea, I remember Alcott that he was saying, maybe we should consider moving the goalpost a little. I thought this was an awful idea. I argued very strongly just to clear it over and move on and create other project, which is what we did. I think he was wrong in this case. I think we were right. But again, he took that up pretty quickly once the decision had been made. And people started to use the term we're now in the post-genomic era. And Francis didn't like that at all. He said, we're just at the beginning of the genomic era. And that's the way we should approach it. And immediately started a whole bunch of new projects and we've been running full speed ever since. So last question, and then if we, yes, and then people want to queue up, they have want to ask questions. I'm gonna ask one more, and then people can go to microphones if they want to ask Mark or Elko questions before we totally wrap up. Just the future. The two of you are icons of the Institute, your icons of the field of genomics. You've seen a lot. You've been involved in a lot. You've contributed greatly. I would be curious about your perspective, especially about the Institute. And we're not fishing for compliments. But mostly I just want to, so having watched, I mean, Elko, you've been away from the Institute for a number of years, Mark. You're officially away, maybe a year or something like that, but you're still quite involved in many of our programs. So you're not told, but sort of, if you were gonna look sort of out, what do you think this Institute is gonna become 10 years from now, 20 years from now? And it's interesting that we're having that discussion because we were just talking about, and Mark's gonna say we should close it because he already told us once. He thought we should shut it down. But just with your perspective, what do you think about, and you wonder what NHGRI might look like in its director beyond me, and the one after that and so forth? Well, when we first started, there was a lot of criticism of the project because it was going to change biology forever. And we said, no, no, it's not gonna change biology. This is just a project and we'll finish it and then we'll go on. Of course, I think we didn't completely envision how much it would indeed change biology and that's certainly been borne out. So to me, this Institute represents sort of the edge, the moving, future edge of biology, medicine. And I think it's had a profound effect on the NIH. Without the genome project, this place would look quite different. So I would certainly argue for continuing it. What it will be doing in the future, I don't know. But I'm sure there will always be something. It's a new way of thinking about research, database, large scale, that just wasn't around. We spent an enormous amount of energy getting people to understand how to do large scale research. And to embrace team science and consortium and data sharing and bioethics. Data sharing, all these things. All these things, innovations at the time. So all core values that I think we certainly continue at the present time and want to in the future. Mark, any last thoughts on the future? No, just a lot of uncertainty. Clearly one of the futures is in the area of genomic medicine, whether you define it narrowly or broadly, I think clearly genomic approaches are gonna have a lot of influence. But I don't really quite know how, see how it's gonna play out if, because there are the arguments, for example, that if you can stratify diseases very finely, then the population of people with each disease is gonna be so small, is there an economic effect in developing therapies and approaches? I would like to think really that the major contribution that genomics is gonna make in medicine will be in preventative approaches in helping to form strategies for preventative approaches. And I still, and I think a lot of target identification with the consequent development of targeted pharmaceuticals. I would agree with all that, and I certainly agree with Alka's notion we should stay on the edge. That's what I think we continue to wanna do, stay on the cutting edge. So let's just take a couple of questions and then we will let everyone go. So here's somebody at the microphone. Thank you, thank you both for that fascinating oral history. Just a question about paradigm shifts, which the Human Genome Project certainly was, and it seems like the next paradigm shift we're facing, as I speak, is the CRISPR germline gene editing debate. And I wonder if what your thoughts are about NHGRI's involvement or role in that debate and what it should be. You were to take that. I'm just the moderator. I'm not taking hard questions, go ahead, Mark. I don't know, is NHGRI actually doing anything with it? The short answer is we're not doing anything, actually in our intramural program, there's some things we're certainly doing that are quite relevant. The intramural program at the moment, not so much, but the one thing I would say that I think we, and actually in some ways you guys, as some of the founding creators of this, the fact that the bioethics discussion is sitting there in parallel, highly integrated with the technology advances, and the fact that even this week there's a major meeting going on where, again, a lot of this is the bioethics discussion, I think represents a very important development that we all deserve a little bit of credit for. And we will continue to sort of drive the bioethics discussion and the bioethics research. Yeah, I mean, I think it can be argued, I don't know if I'd win the argument, but I think you could argue that one of the effects of the genome project was, one of the paradigms that changed was the technological imperative. Because you can do it, you should do it. And that probably is unlikely to result in something ever stopping because you shouldn't do it, but the idea and the conviction that you really ought to think about what you're doing before you get too far into it, I think is another paradigm shift. Over here. Yeah, thank you again for the wonderful history that you've gone over today. I'm kind of struck, my own take home as someone who, I was originally in Craig Ventures' lab when he was here at NIH, I made a conscious decision to stay at NIH when he departed, but I've never, while I've been involved in sequencing for a long time, I was never really connected to the genome project itself, but I did attend a lot of the meetings and whatnot. But to me, it's kind of an untold story or underappreciated story. What I, and please correct me if I'm mischaracterizing this, but it seems like applied biosystems made a brilliant decision as a business strategy to basically give Craig Venture a whole lot of money. And then, well, the only thing Craig was gonna do with that money was turn around and buy machines from applied biosystems. And, but in doing so, he then in turn forced the public effort to do exactly the same thing and to buy a whole lot of machines from applied biosystems without which the project never would have been done because we were still using gel machines instead of the capillary machines. It, you know, it, we'd probably be talking now about finishing it instead of, you know, having it done 12 years ago. So please, you know, any comments you have about that, I'd be curious to hear. Well, I have always felt that Craig made important contributions. And, but because of his attitude and the way he spoke about them, kind of turned people off. And so there was much more controversy than was needed, I thought. Yeah, I would agree with that. I think Craig did make contributions, Solarer made contributions. But the major effect was to galvanize the public effort into looking at itself and coming up with this idea of first do a whole genome draft and then finish it rather than producing finished sequence as you went along, which was the original strategy. So there is, there certainly had an effect. And in terms of the economics of applied biosystems, yeah, I don't know, probably. Yeah, they weren't stupid. They were probably pretty shrewd in how they're doing. One last question, then we'll wrap up. Yeah, thank you. Thank you very much. I had a question. A little louder. Let me get closer to Mike. Can you hear me now? Yeah. All right, I was wondering about, because nowadays here about all of these other omics technologies, I was wondering what are the relation with the human genome project with kind of the conception with all the other with the lucidity, the proteome, the microbiome, all the other omics here about nowadays. You mean going forward? No, from the human genome project. So the sort of the, that the genome project sort of gave rise to this omic movement that now has led to the microbiome, metabolomics, proteomics, and so forth. Yeah, so how did that differently before? No, the genome project too. And that's only now we kind of are interested in the whole center things whereas before, was there more individual parts that weren't quite linked? So how did that happen? There wasn't a design for that either at NHGRI or the genome project. Was there sort of the other omic things would grow out of the genome project? No, yes and no. I mean there was a sense that if we did it for genomics, we should be able to do it for proteomics or something like that and yet NHGRI wasn't gonna do it. There's a lot of discussions all along at NHGRI which always came back to the conclusion that NHGRI was really grounded in nucleic acids and that there was enough to do in nucleic acids that we shouldn't spread ourselves too thin by going into other molecules. At the same time we thought, many of us thought that there should be an effort and tried to help that along to some degree but there was never emerged a strong champion for a human proteome project in the same way as Jim and the founders of the genome project became champions for it. It's also possible that genomics, at least the human sequence or genomic sequencing is a special case because each of the things it's dealing with is finite and therefore you could complete it whereas with other omics that's not true. Nevertheless the point of validating and recognizing the role of technology development, the critical role of technology development in making however much of the data generation you can afford making that doable and driving the cost down and things like that is I think something that is another lasting legacy of genomics. I'm dealing with all the data, I'm dealing with it. Okay so thank you very much for your patience. Before you applaud let me just do two things. First of all I really want to express my incredible appreciation to Elka Jordan and Mark Geier. You've now heard a story for the past hour and 15 minutes not only of their contributions to NIH and to NHGRI in terms of leadership but you can see how intimately involved they were in some pivotal decisions regarding how the human genome project was conducted and you can just imagine the legacy they're leaving behind because of the success of the genome project. So thanks to both of you for telling the story. Thanks to all of you for joining us this afternoon. Let me remind you now for each of the next five months will be an additional and we'll switch over from panel discussion to lectures in January. As I mentioned earlier Maynard Olson will be here and you'll hear a very visionary perspective at times controversial and quite provocative of somebody who really helped be an architect and to some extent a participant in the genome project but a great advisor all along the way and after that we'll shift gears because the last four by design are people who really made their careers come out because of the genome project and most of those cases they were postdoctoral fellows like myself during the genome project and they're gonna have stories to tell how they built their career by having early involvement in genomics and the genome project. So again we're really trying to showcase stories of what has come out beyond the base pairs of the genome project and I hope you come and join us for the next five sessions as well. Thank you very much.