 So why don't we get started, and we'll start with you, Tim, and I would like to know kind of what were the challenges that you faced? How did you get your job? The sort of thing that I would like to concentrate on today is the sort of thing we're not going to get from public documents anyplace else that you only have in your head. So I'm kind of curious for each of you, how did you first learn about the job that you were originally going to take here at what became the National Human Genome Research Institute? It really started with a phone call from Paul Byrd to me about our fourth company, 1986 Symposium, and Paul's suggesting that we have some special session where we talk about whether to go ahead with the genome project. So that was, I really hadn't thought about it. Bob Sinser, I've never had a meeting near Santa Cruz, and one knew that Lee Hood was trying to build a machine to sequence DNA, but it was really Paul's thing that then I of course went to it. And I think I was seeing Wally Gilbert's, you know, $1 base pair and realized it was only $3 billion, and that over 15 years, that wasn't that much percentage of the NIH budget. And I was already aware of, you know, the several DOE efforts to go for the human genome. You know, it was clearly, it could be done, so I didn't want to count on Lee Hood, so I visualized almost a genome city with thousands of technicians, you know, using the old-fashioned technology. It could be done. It turned out, of course, it didn't go that way, but I did it because I wanted to, I didn't want to be ahead of something that would fail. We could do, it was doable, even with the old technology. And so then we clearly had to follow up the code stream, and there was, President very intelligent man named Michael Witonski of the McDonald Foundation, and I don't know where he first entered in my life, but he came in supposing me, and I immediately thought it had to move to the level of the National Academy of Science, that is, we had to have some community to, in a reasonable way, look at it. And Michael said he'd pay for it. So often there's a real problem of finding the money, but we had the money, and then Frank Press, who was president of the National Academy, he was very available to that, and I remember going and talking to Frank about setting up the committee, and I was afraid of opposition from the good scientists. That is who was here, there's a, you know, Lee who had a hundred people in his lab soon afterwards, and no one wanted to give Lee any more money, because there's just something that he wanted to lead, and so Bruce Alberts had just written some opinion piece that, you know, no lab should be more than ten people in size. So I thought he's the person to be in charge of the committee, because, you know, it's a pretty good rule that ten is a very good size, and so now, you know, people would say twenty because you expect things to move faster. But Bruce was agreeable, the committee of Bruce, I guess, including probably both, I didn't look it up now, Lee, who is a Wally, and Wally soon after the meeting announced he wanted to start a company, and he had just, he had been a starter of biogen, and it had been, at one point, his chief executive, and wanted to do everything himself, and so they threw him out. I mean, it's had, but he was on the committee, the only woman was, we could think in a short tone. So whose idea was it to have an academy? Yeah, with enough medical, with enough medical people. So the, we weren't, didn't want to antagonize the human genetics. So there were two groups, there was a sort of, Modstein, Baltimore, the hardcore molecular biologist, who were, you know, quite happy with their current size, and weren't driven by medicine. I think probably Paul and I were driven by medicine, you know, and if you wanted to do you would have had to do that. So I was basically organized the National Academy Committee and found the funding. It was a member of what, that's what, then there was a. So that report comes out in February of 1988, and it comes out to a, kind of a, a community that's still a bit intermoil, there's still opposition. The National Research Council has done a really good job of reframing the project, include mapping and animals beyond the human, and came out with a budget. Yeah, it was pretty obvious, of course, but it changed the public dialogue, it made the project seem much more sensible. But one of the looming questions is, is NIH going to lead it, or is the Department of Energy going to lead it, and who is that going to be? So enter Jim Watson at that phase. How did that process work? The Academy report comes out at about the same time that the meeting happens in Reston. The Reston meeting. Yeah, the Reston meeting was important. It was. And I think that was chaired by David Bolton. I believe you're right. The wine garden was there. Yes. And Rachel had helped organize that. This is when I first met Jim Watson. Was that meeting? At the Reston meeting. I think it was really rather quiet at that meeting. You were. But I remember after the meeting ended, that wine garden pulled about four or five of us together. And I guess I was the token sort of junior human genetics person. And said, who could run this project for NIH? And we all agreed there was really only one answer to that. And that was Jim Watson. So Jim came to visit me and goes from the harbor. And I didn't say yes, but I didn't raise a lot of objections. So clearly I hadn't ever, even at the time of the Reston meeting, I didn't think of myself as leading them. So it wasn't a hidden agenda. Anyways, I think the key thing was a conversation between Jim and Bob Windham. Bob Windham was the assistant secretary of health and who had been appointed by Reagan. Bob, I think just totally ignored the illegality of the fact that I was the unit close from the harbor and for the national good just appointed me though. I should have, you know, when they fired me, they said, you know, they know we can arrest you. And that's what they actually said to me. So, you know, the sensitivity of government attorneys. So talk a little bit about that transition from Jim Weingart and approaching you and then you walk in the door or you do your first public lecture to introduce yourself to the world as the director of this new Office of Human Genome Research. What's going on behind the scenes in that window between March? I think, you know, Jim had told me Elka would run the office. So that wasn't my decision. So that's Elka Jordan. And Mark certainly came in early. So that's Mark Geyer. And we were over in the old library building, to start with. Well, my aim at that time was to try and get about 20 genomes under set up. You know, some mapping, some sequencing. And so we, I think I appointed because he was a friend and Norton Zinder, sort of the head of the advisory committee. This way, I mean, you know, it was hardcore. More like biology, Norton knew all the people. So there wouldn't be rumors that I didn't know about. But then Norton would, I think Norton knew. Because our original operation were our oppositions were our friends. So you walk into an office that doesn't really have budget authority yet. So I'm an advisor for a year, and then the institute will be set up during that year. And but it was more or less to try and have genome money go to as many people who wanted that. And the records would say whether we gave money up to 15 or 20 people. But, you know, there were Cox and Myers in San Francisco before they moved to Sanford. And it was, I don't know when you came in. Right at the beginning, one of the first centers at Michigan, one of the first six. So I wanted initially, you know, human genetic centers. I mean, I wanted to have the human genetic community part of the effort. I didn't want to have it as an alternative. And so I think that worked. I don't think there was ever any opposition from the human genetic community or not. So one thing that we haven't covered is the Office of Human Genome Research, as it's initially getting started is a coordination office. And then in 89, it becomes a national center for human genome research and actually can spend money and has a council. And that budget is carved out of the National Institute of General Medical Sciences, which is having its 50th anniversary this year. We haven't talked about Ruth Kirsting. And what's going on in the behind? And wanted to be controlled by General Medical Sciences. And I only remember a president said a meeting on the Hill. That was our OTA meeting in August of 1987, where it was about the cost of the genome. This is a meeting that Paul Berg chaired to lay out the budget for what would become the Human Genome Project budget in the chapter of the OTA report. And Ruth was at that meeting, Paul was at that meeting, and John Sulston was at that meeting, along other things. You know, I didn't have a personal dislike of Ruth. It was that she wanted to preserve her turf. And she had been sort of in charge of genetics with other General Medical Sciences. This was creating money that she wasn't under control. You know, it was partly, I actually think probably in Ruth's case, it may have, it was perhaps partly in turf, but I actually think it was also a philosophy of how science should be done with a very strong emphasis on it should be done at the R01 individual investigator, let it grow up from a thousand flowers. And here was a project that was almost being defined as being the opposite of that, of having a goal and having a set of objectives, and kind of an element of engineering and whiz-bang high-tech stuff. It seemed to be very natural because of the way the Manhattan Project had been organized. That was a big project and it was led from the top. It wasn't a series of small efforts coalescing. It was started from the top and stayed that way. And so, you know, some things are big and some are small. The genome was big and it wasn't going to be done by an R01. But Ruth actually came around. Yeah, actually to her, very much to her credit, she would talk to my students and basically said, I'm really glad that they didn't follow my advice. She was pretty straightforward about that. It was never a deep cancer. I mean, it never really occupied any of my time. You know, it was just, Jim had given me the power and there was that. So... Did you have any idea how long you'd likely stay? Did you have any sort of plan? No. Day at a time. So that, those crises are hitting it precisely the same time as you're trying to launch a new federal initiative and fighting your political battles for control of the human genome project. After Bernadine fired me in 1992, in 94, I resigned as director and created a new position as president. I think I'd done that just from, you know, my observations of how universities function. That you need one, you can't have someone raise money and build buildings, et cetera, and be a scientific leader. So when you departed in March slash April of 92, did it feel like it was the right time to go? But I didn't miss coming down to Washington. You know, my evenings when I was down here would be, a lot of them were with Max Collins, who was the scientific director of Howard Hughes, or with Bob Gell, which was fun. And Bob, you know, it was just a big crisis. Who had found HIV? Yes. So, and... So Jim, can you talk a little bit? No, sorry. I think, you know, and Cold Spring Harbor was always... We had celebrated our 100th anniversary in the 1990s. And it had built a new building, which I especially designed a sort of president's office. And I moved into that in 1992. So, I was doing something new that I hadn't done before, I mean, it was... I think one, you know, word slightly about whether Craig Mentor would be chosen by Bernadine. I think I knew, you know, there was just no future for me with Bernadine as the boss. Because we had a rather nasty argument when she was at the White House. She was for regulating plant-by-technology. And I was just totally opposed to any regulation. But I just saw her as a government wanting to regulate, even though she was, you know, Republican. And I more or less said to Craig, you don't know what you're doing. Probably a little more than more or less, yeah. So I didn't do her with much respect. But, you know, I had gone through that period in the late 70s of recombinant DNA. And suddenly Bernadine was, you know, once you... Monsanto was beginning to, you know, really prosper the plant part. So did you ever have any thoughts that if you stuck it out for an extra six months, it would have been okay? I insulted her when she was in the White House science hall. Then she's my boss. And, you know, so... But I didn't, you know, I wasn't neurotic about it. I didn't, you know, every day, when am I going to be fired? And in fact, it was totally surprised. The one thing which was a seedy character, and Bernadine really used it as a basis of our... It was that there was an effort for poor venture by a man named Frederick Burke, who had married a Ford, and who wanted to hire John Solston away from England and set up a lab in Seattle. And somehow someone arranged for Burke to come to the Benbury Center. And Burke and Norton Zinder and I were sort of talking. And at the end, I just didn't like Burke at all. And, you know, more or less, they gave you a no-raw of the digital project, because I saw him as killing it. He had been supported by Lee Hood, who should get a copy of the letter from Lee to Bernadine, urging I be fired for not supporting industry. My take. So this is going on at the same time as you are publicly also disagreeing about DNA patent policy and the EST patents that... Yeah, but Lee wrote me, it was about Burke. Burke, you know, ended up going to prison. Yeah, he was convicted of sub-financial. And... He was a very smooth character. He was a smooth character, but I think I want to come to Benbury to see that I also know rich people. You know, you're not impressed. Well, that'll do it. Yeah, I remember being at the library of the Robertson House when Burke did. But anyways, that letter from Lee, which I somehow saw. But she was by Bernadine when she's, you know, it was the patent thing. Right. In the allegations or conflicts of interest. I was really, you know, all I didn't want is patents on nonsense DNA. You know, the DNA was... EST. You know, I wasn't trying to break the patent system at that time. I wasn't, you know, there hadn't been myriad of, you know... Right. In case where I thought the public was losing. Yeah, took 20 more years to break the patent system. Yeah. But... So Jim, basically you've done... So I think Bernadine probably, the letter from Hood gave her the ammunition. And I don't know who told me or all I know is I met with the attorney and then I had to hire a attorney. So you go from an office, a coordination office to a national center for human genome research. That is funding the beginnings of the human genome project, starting to get maps, genetic linkage map, physical mapping effort is starting, technologies for doing... I was trying to run, you know, through advisory committees. Because I remember meeting Venter. He was going to his lab and liking him and encouraging him to apply for money. He was then turned down by the committee, which I think was then sequenced. The committee was chaired by Joe Sandbach. Because the money went instead to Lee Hood. And so Venter didn't get any money from us but I would have given them money. Was that when Craig was here in the intramural program? Yes. So he applied as an intramural scientist. So what happened is they did a study section. It was a very odd arrangement but they did a study section that in the morning reviewed a whole bunch of extramural grant applications and in the afternoon they did a review of the intramural proposal. Which was one proposal. Which was one proposal that involved Tom Kasky and Craig and Steve Warren and a bunch of other people. But Craig was the only one in the intramural program at that time. But the money was going to be channeled through... Got it. And that review didn't go well. To say the least. You can talk to Tom Kasky about that. But he still remembers that review of the committee. All the sequencing. And then in Craig's lab was done by Dick Montgomery. And who I hired afterwards. So Craig had good people working for him. So that's what happened. They funded John and Bob to start on the nematode. And they funded Lee. They didn't fund Wally. I can't remember all the results. But they did fund Fred Blatner to do the coli. Which took a very long time. So now we have a National Center for Human Genome Research. Jim has resigned. We have an inner egnum. Bernardine Healy is the director of NIH. And is in charge of a very high profile search to find someone to take the reins of this National Center for Human Genome Research. And enter Francis Collins. So tell us a little bit about the process. There was then a temporary head. Yes. Don't forget Michael Goddisman. Thank you for doing that. Great. So tell us about that. Well Michael would say he got a call from Bernardine the same day that Jim was being asked to leave. And basically called in and said you will do this. There was not a are you interested. He said he was willing it was you will do this. And Michael being a good scientist and somebody who I guess thought this was good for the country and good for science didn't object and took this on hoping that he would have a short stay in that role. But he actually had about a year. Yeah. And his role up until that time was being an intramural scientist and at that status and being a laboratory chief in the cancer institute. Exactly. So it's not that he had a major NIH leadership role up until that point. A thoughtful dedicated wonderful human being. With fabulous political skills and a fantastic network and highly respected by almost everybody which is exactly what was needed. So I had been a fan from the beginning of the importance of doing the genome project but did not in any way imagine being called upon to take on this kind of role. I was at that rest and meeting. And I remember it well. I was at a meeting here at NIH where Ruth Kershstein stood up and said that this should all be in GM all the things we've just been talking about. I remember Jim standing up at that meeting and saying everybody I've talked to at Cold Spring Harbor is opposed to the genome project but I'm for it. I remember that very clearly. Yeah, sure. That was actually in this building on the top floor. It was. Yeah. The conference room 10 probably. So as the project began to have real opportunities for getting going. Yeah, Michigan was one of the first centers to apply and get supported. And ours was much more a medical genetics. What was Tom Kasky the second? Tom was one of those first six as well. Washington University. Washu was one. Boy, with the other three. I couldn't at this point tell you. Stanford. Yeah. I was in the first half that then became Stanford and then David Botstein had a center. Yeah. Okay. Okay. So this was exciting trying to set this up. And this was at a point where I was also the principal investigator on a gene therapy program project. So life was pretty busy and I was a huge investigator and had a fair amount of clinical and teaching responsibilities. But I was having a great time. Jim's leadership in recruiting talent into this area because Jim hasn't really mentioned this, but the genome project never would have succeeded without his skill in convincing the best and brightest that this was a project they just didn't want to miss. They had to be part of this and pulling people like Lander into this who might have done something totally different as well as many others. And that was fun to see the way in which that community began to develop. I was also a charter member of the advisory council, the NHGRI, then called NCHGR. So I had the chance doing those first couple of years. Do we know what was up? Yeah, I knew what was up. And certainly participating in a lot of those discussions, those were fascinating times. And by the way, there was already at that point, even before I got here, a discussion about, well, maybe there should be something intramural that had a focus on genomics because you could look at intramural and say, boy, they're good, a lot of stuff. But other than Benter and his sequencing effort, not much you'd call genomics going on there. And that doesn't seem like a good thing. The strength of NCH was never genetic. It was always biochemistry. And they were very good. They're very good at that. But they sort of weren't ready for this next generation of ideas. But I thought, okay, this is where it's going to be. I will hope that my genome center at Michigan can remain competitive, recognizing this is not going to be easy because Jim made it very clear we're going to start funding but we're not guaranteeing that you're going to stay in the mix for 15 years. And then all of a sudden, there was this earthquake and phones rang and people said, Watson has resigned and we were all in deep gloom about, my gosh, this is like a project that's still a baby in the crib and suddenly daddy has left and who's going to take care of the baby? And a couple weeks later, it was Rick Clouser who called me because Bernadine, I didn't know Bernadine and Bernadine didn't know me. And I guess she asked Rick to make the call because Rick and I were scientific colleagues. They got along very well. And Rick called and said, hey, Bernadine asked me to call you and there's a search getting ready for this and she wants you to apply. She thinks you would be appropriate for this. And I said, well, gosh, that's really flattering but that's not my life plan. So maybe you better let Bernadine know that I'm probably not going to be a candidate. Now, Rick called me another time or two and said, well, at least put your hat in, come down, do an interview, at least find out what the job's about, let people talk to you. So I really went through the motions on that and showed up on a very hot day in August of 1992 to be interviewed and I think the search committee was chaired by Shirley Tillman. And I had not prepared anything. I just sort of walked in wearing cowboy boots and carrying my guitar because I had just been at a folk festival and I didn't want the guitar to sit in the car because it was too hot. So I'm sure I made a really good impression. At least you were on your motorcycle at that point. Walking into building one, like some country yokel. But it was an interesting conversation and it did intrigue me that this was shaping up to be a pretty interesting opportunity but it still didn't feel right for me. I got shown around the lab space because I was running a lab that was very productive. I didn't want to give up being an active scientist. They showed me Craig Venture's lab space because he might have done brand new lab space. But it just didn't feel right at all. A government employee, really? I don't think so. So I actually did have some discussions about is it possible to do this and keep my lab and myself in Ann Arbor. Do what Jim did. Try to stay at a distance and they would have none of it. That model was the longest of it. They were right. So ultimately I did get offered the job in probably September, October and I said no. It was not sort of fitting with what I thought I really could do. Did your salary go up or down? You know, I don't remember. Maybe not even been smart enough to ask the question. I think it was fairly sort of neutral in that regard as opposed to later on when it became very negative. And Washington then wasn't hopelessly expensive? Not hopelessly, but... It was expensive. Compared to Ann Arbor, it certainly was. Yeah. So I was actually speaking of personal issues in the midst of going through a divorce and my kids had just reached the point of being just about launched. My youngest daughter was a senior in high school. So maybe it was sort of a moment of thinking about being more geographically portable. But again, scientifically I just couldn't see walking away from what I had been doing. And we were in the throes of trying to actually find the Huntington's gene, which we found a couple months after that and trying to find the breast cancer gene, which Mark Skolnick beat Mary Claire and me too a few months after that. So I was intensely involved in other things and I said no. And the search got started again and there was an effort to identify the candidates. Frank Ruddle emerged as a possible choice. Mary Claire emerged as a possible choice. And I came back, I think it was for a study section and Bernadine asked to see me and I thought, oh boy, here comes the hard sell and this must have been like late, maybe November of 1992. And yeah, she brought me in and she had Lance Lyota in the office, Lance who was the director of Inframural who was making all sorts of inappropriate comments about how great it would be to be at NIH which I had no real interest. I was there to say no again. But Bernadine kind of took over the conversation and she got me right in this vulnerable place. And she said, I can tell I'm not getting through to you. She said, and she was right. She said, I had this vision, Francis, that we're both somewhere in an old age home and you're walking down the hall with your walker and I'm walking down the hall towards you with my walker and we come up next to each other and you turn to me and you say, damn it, Bernie, I should have taken that job. Which was the dumbest thing anybody ever said to me in a serious job interview, but it totally nailed what was bugging me, that I was about to walk away from maybe the most significant scientific opportunity anybody of this era could dream of because it didn't happen to suit my timing. And it really shook me up. I mean, isn't that stupid? So I went away and thought about it and two days later I called her and said, okay, I'll do it. So she did have some of Lyndon Johnson's political skills? Ah, something. I don't know. Or maybe I was ready to give in and I just hadn't admitted it. Yeah, she could be charming. She could be. She could also be really charming. She was really charming. Difficult. No, but she didn't charm the people of Johns Hopkins. They couldn't stand her. Oh, and she terrified her own staff. I mean, boy, once I got here and began to see what happens when there's a meeting and building one, we made a decision about looking devastated and white tearing their hair about what they've been asked to do. So there it was. Francis, what was your, how important was constructing the intramural research program? How was that involved in these negotiations that were becoming director of this still center of human genome research? Yeah, again, the council had already sort of made a conclusion that there ought to be something going on intramurally. And I felt like, okay, that's something with because it was clearly going to have to be built by recruitment. There was virtually nobody on the campus other than a couple of very junior people like Dave Boudin that could be recruited into this. Otherwise, I'm going to have to convince other really good scientists not to come and work in this environment, which many people were skeptical about. But I thought I could do that. And I thought in the longer term, that's a contribution I could make. But I never had any misgivings about whether that was the main job. The main job was to get the genome project to succeed in that rather arbitrary 15-year timetable that Jim made up at some point along the way because it sounded like something you could sell to the Congress. Where did 15 years come from anyway? Generally, you don't propose anything more than 10 years. But I knew 20 would mean the project would be finished by people who didn't start it. But I just didn't see it being done in 10 years. But I didn't see the machines taking it over. So it was the machines made 10 years possible. Well, and I think there was another element to that. And that was when the NRC committee was meeting. And David Botstein was in charge of the subcommittee that was supposed to come up with budget numbers, where they did the famous go around the table and vote. And they'd gone around the table once, and they had ranges from 50 million, 100 million, and 200 million. Jim intervenes and says, no, I want to propose 500 million a year. Because if 200 is the high one, everybody's going to go for the middle. That's very important. So the budget had come out at 200 million a year, and everybody had agreed to that. Well, how do you get to 3 billion from 200 million a year? Through the math. 15 years. So that's part of the origin of that. 15 years also. But there wasn't much disagreement. I think it didn't put much pressure on us to start from. You know, we had 15 years. Yeah. And just thank God for those machines. Yeah, that just in time came along. So you step in. And what are the problems that are facing you as you're taking the reins of this National Center for Human Genome Research? Well, there were lots of them. It still seemed like this project was barely sort of beginning to get itself organized. And I mean, it's only three years into a 15 year effort. And frankly, most of the centers hadn't really gotten started for that first year and a half. And it was clear that there were some that were starting to catch some real momentum. And it was already clear there were some that were going to be struggling. And so part of what I would have to do is not only give money to people, but take it away, which is not going to be that much fun. Fortunately, at that point, a new NIH director arrived on the scene. Just six months after I arrived, Harold Barmas arrived. Harold and I for the first six months lived in apartments in the old nurses dorm right here on campus and a cockroach infested facility. But it was great because we had many evenings after struggling with how to make things work in the government, which was foreign to both of us. And neither of us had ever really run anything very big. And we would meet in Harold's apartment at 10 o'clock over a glass of wine and try to figure out what the hell we were doing and how to make the whole thing succeed. And that was really helpful. And he was enormously supportive. So this was as a Clinton presidency? By this time, Clinton had been elected. And Donna Shalala was the secretary who was enormously encouraging to both me and to Harold. So yeah, the environment for supportive science was very, very good. And that helped a lot. And I did have good fortune by recruiting not just one at a time, but sort of a whole cohort of really excellent extramural scientists to come and start this intramural program. People like Bob Nussbaum, Eric Green, David Leadbetter, people that I always thought, boy, it'd be great to work with them. And they all sort of made the same conclusion. What happened to Clouster? That's a long story. Yeah, we don't want to get into that. No, I know you were just saying. Yeah, we'll take that offline afterwards. I went to the Howard Cancer Institute. Then he went to the Gates Foundation. He is now... Case Foundation and then Gates. And then Gates, right. I forgot about Steve Case was in there. Then Gates. He is now the chief medical officer for Illumina. He's out there pushing DNA sequencing. Oh, boy. He's on top. He's doing well. He's doing just fine. So, Francis, you've been involved at this point in very high-profile gene hunts. A couple of questions for you. One is, what's the first time you ever testified in Congress? Ha. So, it was in front of Al Gore and a Senate panel about the genome project. Other witnesses being Jim, Nancy Wexler. This was the ethics. This was the ethics thing. And the poor guy from DOE, Benjamin Barnhart, who was basically saying DOE didn't have a plan. And that didn't turn out so well. You remember that? And Gore was very well primed because I think somebody had helped him think about these issues. And that was my first appearance. But the DOE decided to do education. Whereas we were going to do ethics. And I went into... When I was appointed into that press conference, knowing I should say something about ethics. Because I was afraid of being attacked this way. So, the first thing I said is we're going to have an ethics panel and we're going to spend 3% of the money because 1% some are like the token. And then Gore said you're going to spend 5%. I remember sitting next to Nancy. Yeah. That was a moment. Jim, just to put that in context, you're talking about the press conference when you were announced as the head of the Office for Human Genome Research in September of 1988. That's what you're referring to there? Yes. Okay. Yeah. And that was... So that's in many ways, that's the origin of what became known as the ethical, legal and social implications research program. And I think we had made the same, but it was basically premature until you had the genome. There weren't that many ethical issues. So I'm conflicted on this issue, but what do you guys have to say? Yeah, I bet you are too. No, because... And now we have real ethical issues, but we can't solve them. Beginning of life and end of life issues. Should you encourage life of someone who'll have no future? And then how do you define, how do you know someone will have no future? These sort of things. But I think there's no point discussing them because it'll get nowhere. But back to the sense of having a program in this area, it's a truly distinctive feature of it's been in so-called kind of in the DNA of this institute from what became an institute from the very beginning, from the press conference where it was announced. The ethical things were largely taken over by mediocre people. I have a slightly more positive view, although I do think there were some of the LC activities that had very little long-term impact on anything. Certainly, the more specific policy-focused efforts, like how do we begin to think about what is appropriate to be publicly disclosed and what's not? Something we're still arguing about, of course. Things about, you know, if you're going to sequence the human genome, whose DNA should it be? And is that somebody whose identity should be known, who's going to be the reference standard? Issues such as genetic discrimination, which became a personal passion of mine, because I was really quite worried if we didn't deal with that, that the public would stay away from involvement and utilization of all this science. And we had to have some pretty good, serious, legal sort of deliberations about how do you solve that, which ultimately, after 12 years, struggling with the Congress resulted in Gina being passed. And I think, while the LC program was not the only reason that succeeded, it provided a useful scholarly foundation upon which you could build a case. So Eric, how do you think of having an LC program being integrated into your institute? I think it's valuable. One of the things I would immediately say is you go talk to members of the general public, you go talk to a high school class, you go talk to a PTA or any of these public outreach efforts, and you explain genomics. Their questions inevitably are heavily enriched to ones related to ethical and societal issues. And so I think it's irresponsible not to then immediately say, it's very important that we study these things because these are clearly concerns people have. One of the surprises I would certainly say I had when I became director was when somebody came and told me that our LC research program is the largest program in bioethics in the world. In the history of the world. History of the world. That's a block of funding, which I admit I hadn't realized. I mean, I knew it was distinct. I knew there weren't very many of them. I just didn't know it was the largest because I feel like everything we do is an institute relatively small because the size of our institute is only 5%. And so that with that comes sort of a lot of responsibility in terms of trying to prioritize. In the time since I've been director, I've tried to broaden the discussion around sort of the broader societal issues, not exclusively focused on ethical, legal, and social. I also think the LC brand has sort of accumulated some baggage. You can hear some of Jim's comments, the kind of baggage that's accumulated. So part of the reason I even wanted to sort of change the focus to a broader label was also to sort of give us more flexibility to think about what are the societal issues we should be studying and thinking about general advances. I think now I'm much more libertarian than I was when I started the LC program. And just my just so arbitrary is to what answer you come to that I prefer no regulations and no one telling you what to do or not to would be healthier than our current one, which I saw the ethicists as people who fundamentally hated genetics. And so they were really trying to block us. And that's what I but I saw no alternative, but at least what I started to have them. But then it was that we're dealing with problems which don't have obvious answers. And so we were giving money so we could have discussions. But it wasn't going to change how humans behaved. Well, just one very practical thing you alluded to it in passing, Francis, you might dilate on it a little bit is if the sequencing effort had built on the resources that were available from the one individual from chromosome 19 studies that had been selected, the world would have been a rather different place because our reference sequence would have been to a person who could have been identified. And as I understand it, the reset button was pushed at one point precisely because somebody thought, ooh, maybe it's not such a good idea. I don't know if that somebody was you or a group. I was part of that. But I think so that seems like it's a very practical thing that changes because you're thinking about these issues. It may not be the research program per se. And it's not really regulation. It's a fateful choice that you make in light of having thought about something you might not have otherwise. Stimulating a dialogue. But I think, you know, we don't spend lots of money talking what to do about medical records and how are they secure. And we were sort of saying genetics are more important. I don't think they are in a practical way. In fact, whether you should have a job or something like that. And I don't know so far of anyone who's yet been damaged by release of genetic knowledge. I mean, you can, but it seems to be just minor problems compared to the very major problems of genetic disease. That's all I'm trying to say. But I think I wouldn't recommend you guys get rid of LCU or just get into trouble. But I'd give the program about half percent. That is, you know, because I'd have to compare the alternatives which ways you use the money. Right. Jim's very interesting because right now as we're starting the brain initiative, this very ambitious effort, which many people are comparing to the genome project because it's a 12 year program to try to understand how the circuits in the brain work. Very challenging imagining. And we're getting a lot of pressure. Well, you need to have an ethics program because this is going to result in the opportunity to manipulate. I think the chance of the ethics program, you know, we're not going to understand the brain. Well, understand. We have to decide what we mean by understand. I think we don't understand it better than we do now. That's safe. But we better. Right now we have not solved any big problem. And we need to do that. That's all. So Francis, back to you. And it's very hard. You walk in the door and you're trying to put the reins in. Maybe just walk us through. What's going on with the genetic linkage map? What's going on with the physical map? Where are you in sequencing? Give us a segue into this move from laying the foundations for the ultimate goals, the reference sequence. This is happening on your watch. And also you go from a center to an institute. So tell us a little bit about what's going on on your watch or the structural features of your institute. So it's fascinating. It's a bit chaotic. It's up and down. The interactions between the centers are not always as smooth as you would like. The genetic linkage map is coming along using microsatellite maps, which is finally sort of really beginning to produce reasonable quantities of such markers so that people can start to do linkage much more efficiently. The physical maps are starting to take shape as well. Backs and yaks are making it possible to do things across long distances. Sequencing is pretty much devoted to model organisms, the E. coli effort taking forever, yeast coming along. But C. elegans really becoming the place where you could see this is how to organize an effective program between Solston and Waterston. This becomes our model of what we hope ultimately could be scaled up, but not without a lot of very hard work and something that in many ways doesn't look like it will be very scalable to a genome the size of the human. So I have many anxious moments in that first five years trying to figure out how am I going to give the speech when we basically miss our deadline and we don't have the genome sequence at the deadline that Jim had promised. Fortunately, I never had to give that speech. Fortunately, things really began to connect. But I depended a lot on these various, some small, some large gatherings of advisors. And the fact that we did this, what sounded rather Maoist, a series of five-year plans was very valuable for this program. And of course, there was one in 1990 and then there was another one in 1993, shortly after I got there. And then there was another in 1998. So we kept refreshing and those plans incorporated the best ideas of 200 or 300 people in various ways in order to be sure we were on track. You know, it's interesting, you talked about this was a top-down project. And of course, it did have to be in a certain way. But it was also bottom-up. I mean, we basically set here the big goals, but then we didn't tell Bob Waterston what particular strategy he should use to achieve those goals. And ultimately, when we got to the point of being ready to really scale up human sequencing, it was those five centers that we referred to affectionately as the G5 starting in 1998. Every Friday morning, 11 o'clock, I still, Fridays at 11 o'clock, I have this anxious moment about, oh my god, am I ready for the G5 call? Because I had to set the agenda and you never quite knew. And some of those were pretty prickly at the beginning before we finally really all gelled the whole thing as a team. But those five were very much bottom-up making this. When did Vendor appear at Cold Spring Harbor? May of 1998. 1998. Yes. And that was a month before I got married. Yeah. And that was quite the experience because he was going to appear at Cold Spring Harbor the next week. And he already had talked to Nick Wade. And Nick Wade already had his story ready for the Sunday New York Times. And I was on my way to California to talk at some meeting. And I was asked to meet Vendor and some surprised person in the red carpet lounge at Dulles Airport. And I walk in and there's Vendor and there's Hunkerpillar. And then I know what's going on. And so they sort of drew up. And you got in wind of what became Solarra by then at all? We knew something was up because Vendor's Tiger, a genome center, which was doing chromosome 16, had suddenly, well not suddenly, over the previous year sort of seemed to have slipped into the doldrums. Whereas usually he was so aggressive and driving and just like it was coasting. And you had to think, something's going on here. Craig's got another plan, but we're not being told. When was Tiger founded? Oh gosh, 94, 95, somewhere. I don't remember. Maybe in 93. But when Craig left, it was when he left the intramural program. And when was human genome science? Same time. Same time. Yeah. So basically the human genome science funded Tiger. Exactly. Tiger was their sort of action. And that's where through sewing at the right time Bill Hazel team became rich. He did. He did quite well for himself. Yeah. So Craig was hired to do Tiger. And then Bill Hazel team was hired to direct human genome science. Right. And human genome science, they finally did produce some drugs. Yeah. A drug Ben Lista for Lupus, which has been moderately successful. I don't think anybody would say it's turned into a blockbuster home run, but it's been a drug. But Bill certainly left the human genome science under a cloud. I think people felt, yeah, he was ready to move. His daughter had built a really very nice sculpture on protein, which was that human genome sciences. And suddenly we were offered it at Cold Spring Harbor. And that's the one that's up there on top of the hill? Yes. That was made by Hazel team's daughter. Yeah. It's very good. It is very good. I didn't know that story. Of course, his brother is like a big fixture at Disney. Did I ever tell you the story about calling his brother? This is a good story. Go for it. When we were getting ready, this is after the genome of the human is done. And it's time to sort of try to finish off the mouse, because everybody's clamoring. Can we hit the mouse? Can we get the mouse? And we didn't have enough money. And I was tin cupping all the institutes, asking them to donate. And they were giving little bits and pieces. And I got some money out of Perlegion, because they were feeling like they needed this too. But it still wasn't enough. So I have this great idea. Okay, what's the most famous mouse in the world? Well, it's Mickey Mouse, of course. So maybe Disney would like to contribute. So we could hurry up and sequence the genome of Mickey Mouse. So I called Eric Hazel team, who is Bill's brother, and made the pitch. And he said, well, I have to think about that and talk about it to the board. And he calls me back the next day and said, well, I've discussed it. But I'm sorry to say we're not going to support this. Mickey Mouse is magic. He doesn't have a genome. They thought it was going to ruin their brand, you know, Mickey with DNA. No, I can't do that. That is a good story. So back to you're trying to construct this. Tell us a little bit about the shift to sequencing the Bermuda principles, the consolidation around the model of C. elegans as the way to do science, right? Yeah. So tell us a little bit about your role as the NHGRI director. weren't there two Bermuda? Oh, there were three, three, at least three. Yeah, three. But 1996, sort of the signal moment of gathering together the sequencing centers, to see where are we and what path are we on. And I still have my notes from that meeting. Which you kindly shared with us. That's right. You have the archives. You have seen those. That's the one where we said they did ask to place in front of the public. Exactly. So there was a session. In fact, it was sort of came up twice. There was an initial session that John and Bob kind of led. And there was a general sort of sense of this is probably the right thing to do, but we hadn't actually reached a conclusion. And then we came back to it at that point, by the way, Benter had left because he was clearly one of those who was not particularly positive about this Bermuda rules proposal. But he left early. We came back to it at the end and everybody agreed. Although most of the people in the room had no authority to agree to this representing countries whose intellectual property they had just given away. But oh well. But it had a great effect. It had exactly the right effect. And when everybody talks about the race for the human genome between Solera and the public project, it wasn't about the technology. It wasn't about who had which machines or which software as much as people try to make it then. It was about what is the model? Is this a public domain deposition of our shared inheritance? Or is this a commodity? I wish they had gotten that message a little more clearly as people began to argue about which model was right. Because so much of the focus was really there when Wally was going to form his company and own the genome. And it was certainly there when Burke was going to form his company. And then it was there again when Solera was going to do the same thing. Although I think they tried to mask the intentions in a fairly clever way so that if you weren't paying attention you might thought oh they are going to give it away. No. We all knew that didn't we? They're not going to give away their founder's sequence. Meanwhile in that mix of course we had that very awkward moment when DOE pretty much came back close to signing a memorandum of understanding with Solera on their chromosomes that they were going to make a partnership because they felt under pressure to work with the private sector. And I think quite naively thought that this memorandum of understanding had no consequences for Bermuda rules. And it clearly did. And only at the very last minute did this get realized. And I and Waterston and Lander and Michael Morgan basically said you can't do this. And that was a very bad awkward moment for Ari, for everybody else involved at DOE who thought that they were kind of trying to do something to make peace and realize that the terms of the peace agreement were not what anybody really would have wanted to live with. So this is going on at more or less the same time as you're just now an institute. So talk a little bit about the process of going from center to institute. What does this mean? What does it matter? Well, frankly, the difference in terms of the mechanisms that an institute can use compared to a center, there are pretty small differences there. So while I made the case that we needed to be a full-fledged institute in order to have the same capabilities as all the others, it was really, I think, more about recognition that this is here to stay, that this is not something that's maybe going to just be absorbed in some other way. But this is really serious, that NIH is making a long-term commitment. And so when I first agreed to take the job back in 1993, I wanted NCHDR to become an institute then. And Bernadine said she would support that, but it didn't fly. It was late in the process of NIH's reauthorization, which happened in 1993. And it was already pretty much a done deal. And nobody wanted to open it up again and do something that might be controversial. And frankly, the human genetics community was not supportive of that at that point. You said human geneticists always supported the genome project. Not all of them did. Some of them were threatened, thought it was going to take money away from their R01. But every year that this would come up again, I would make the case. And it was Donna Shalala who really got that, supported that, saw that this was something she wanted to take a role, and she had the authority. It did not require an act of Congress to elevate us to an institute. The secretary could do it. So who did figure out that you had to change the acronym order? That was not hard. Substitute I instead of C and then try to pronounce that you don't want to go there. We have many other arguments about what the alternative should be. And it's not unprecedented. I mean NHLBI, N-E-I, there's lots of institutes where I is the last letter. So why not NHGRI? Took us a while to say those letters without tangling our tongues up. But we got it. How did Santa Cruz get started? That's a good story. Lander recognizing that while we were winning the battle in terms of data production, we were not getting anywhere as far as data assembly. And that the gurus that were supposed to be helping us, many of whom were at NCBI, were working hard, but they were not really creative about solving the problem of this large-scale assembly. So this was an opportunity that UC Santa Cruz was just emerging with David Housler who clearly had both the smarts and the drive to make that happen. And with Jim Kent, remember Jim, who's this guy with hair out the here and he would basically be a video game programmer in his garage, kind of put together the algorithms that started to make the assembly work. And now look at UC Santa Cruz. I mean, they are the powerhouse of large-scale representations of genomes. How much money did you give to Santa Cruz? A lot. I don't know the exact figure. I mean, you know, more than one million, but say up to 10? Yeah, probably in that range. But Lander personally got Housler engaged, correct? It was at Cold Spring Harbor, Jim. It must have been 1999 Cold Spring Harbor meeting in May where Housler came. He had not been known by most people. And Eric had brought him there, and we had this long conversation out on the lawn about what needed to be done. You were around for that, too. And it was pretty compelling that this was a solution to a problem that we had only fairly recently begun to appreciate could have ruined the entire promise. I assumed that Lander would do it, but he couldn't. Couldn't do it himself? No, no. And he didn't have anyone else there who could do it. And so one other thing that you haven't touched on quite yet, Francis, is this change of politics with the emergence of Solera. We've mentioned that Solera comes on the scene in May of 1998, but that kind of changes the politics of how you're going to go about your job in two respects. One is you have to defend your project suddenly in Congress that July. And also, you now have a common enemy that unifies your troops. Can you do it? I don't want to do too much counterfactual what would have happened, but for if there'd never been a Solera, but how do you balance thinking about the presence of a private sector, basically a private sector competitor that enters your space? That was tumultuous, to be sure. And of course, Venter, not lacking in confidence, was certainly making it quite clear that from the perspective of anybody willing to listen to him, the public project should probably just step back. And as he said, you can do mouse. We'll take care of the human. That was a very stupid statement. It really mobilized me. Well, right. So this was the famous meeting at Cold Spring Harbor shortly after that, where I remember Jim coming up to me in the cafeteria and saying, so are you going to be Neville Chamberlain or Winston Churchill? It's pretty clear what you meant. That we couldn't lose. We could not lose. So there was a lot of tumult in terms of, okay, should we stay the exact course that we are on, which was finish as you go, build the physical maps, then sequence those backs as you are sure that you have them in the right order. And then you've got the assembled sequence and you don't have to go back and fill in many gaps later because you've already done that part. Or is it time to say our sequencing capacity has now started to really increase. Machines are coming on board that have high throughput. We're having trouble keeping up with the machine capacity with the backs that have been mapped. Should we go into a different mode? And that's the big debate that then raged in the course of the summer and the fall of 98 at one point, resulting in a very angry email from John Solston, the subject line of which was Friendly Fire, where he was very upset that the U.S. seemed to be deviating from this. Instead of starting with a random back strategy, which would keep the machines busy, but sort of abandoned the process that, particularly, Sanger had been very much devoted to and were very well prepared to do, that was a bad moment, that sort of big uncertainty. We fixed it pretty quickly. I think, Jim, you got involved in helping a little bit, sort of calm down the British emotions. Yeah, I mean, Solston has... It's like a preacher. I mean, he's really... He got very righteous. He may have come out of a Methodist background, but there was a certain... He's a Baptist at heart, yeah. I don't know what it was, but he was so clearly wrong. Yeah, he was in that situation. But he was powerfully excited. He was not a mathematician. He didn't understand it. And so he wanted to say something that he could control. And he felt he'd put a lot... And frankly, there was a little bit of, hey, we did this part already, guys. You over there in the U.S., you didn't build your maps this nicely. Don't look to us now to say you have to change strategy because you're behind your schedule. But he was wrong. So what's it feel like to manage this kind of army in rebellion against a well-greased, well-oiled, well-funded machine? It was a wild ride, but it was good fun. The White House appearance was in the last year of Clinton's term. So it would be in 2000, and we all went to the White House. We all did. I remember a particular meeting in Houston, sort of February 1999. We had had this discussion about, are we going to shift more into random back strategy? And I, on the way out there, I'd been looking at all the throughput numbers from what the centers could do. And at that point, we were still saying, we're going to finish the genome in 2003. And looking at the way in which machine outputs had been going up like this and what you could do if you decided to really pull out all the stops, it looked to me like we could get done in the spring of 2000. And I hadn't talked to Elka and I hadn't talked to Mark. I just decided, okay, let's lay it out there. And so at the beginning of that meeting of the PIs, I basically laid it out. I still have the overhead because, of course, we used overheads in those days that went through the tabulation of how that could be possible. And there was a furious discussion at that point because the Genome Center directors were really tired of having the plan changed almost every couple of months, just when they thought they had their teams organized, we're going to do this. And now all of a sudden Collins is saying, no, we're going to do that. But ultimately by the end of that two-day meeting, people said, okay, let's pull out all the stops, let's go. And it didn't hurt that Salera was breathing down our necks. This was by now February 99. Craig was making all sorts of noises about how much he has done. And of course, nobody could tell because none of the data was public, but made you nervous. So February 99, it was just then 16 months later, the draft was announced as being done. So most of the genome got sequenced in that last sort of 16 months. We were only 10% done in February of 99. Then we had our billion base pair bash. No, it was the only thing that mattered were the machine progress then. That's what made it possible. We had to do 1,000 base pairs a second, seven days a week, 24 hours a day to get this done. 1,000 base pairs a second was so far out of range of the previous version of the machine. But this made it all possible. So Francis, to your knowledge, has an NIH Institute director ever stood beside the President of the United States with a press conference that's going on in Downing Street and at the U.S. White House simultaneously? Probably not. Probably not. So tell us a little bit about that moment, what that feels like. Well, it was, it was a little odd. I mean, of course, only a month before that was there an agreement about how to do this sort of announcement so that there wasn't going to be sort of competing claims from the public project in Solera about who had done it. I mean, it was pretty clear that they were moving along. Of course, they were using all of our data plus adding their own data to it. So if we had A and they had generated B, they really had A plus B. So how could they be behind, right? And it was pretty clear by about that time, we would all be able to say we have 90% of the information. So let's call that a draft. But it was getting really nasty. There was all kinds of claims and counterclaims. And I will say after one of those really difficult times, I went to Ruth Kerstin, who at that point was, because Harold had stepped down and said, you know, Ruth, I think I want to try to broker a piece. But I can't do it myself. I just want you to know I'm going to ask Ari to help with this, because Ari had said all along, hey, if you need a peacemaker, maybe I can be. You mean that led to the White House meeting? That did. So Ari convened Craig and me in his basement over pizza and beer. And I felt very awkward about that because nobody knew that was happening, including my British colleagues. And I sort of felt like I'm negotiating for people without their knowledge. But it just seemed like we had to come up with something that got away from all the tawdry accusations about who was telling the truth. Did the institute staff know at the time? Your senior institute staff? No. Just you alone? The first meeting. I told them. Then we met again the second time. And basically, and to Craig's credit, he agreed that this was the best outcome as well. And I'm sure he didn't mind the idea of standing next to the president either. And so then there was this furious arrangement about the timing. And when was the president going to be in town? And then ultimately, there on June 26, we all arrived. And so we all arrived in the blue room and stood around waiting. And the president shows up with his Diet Coke. And we've all gotten our instructions about who's supposed to stand where and how you're supposed to walk down the carpet to the east room. And I did have a embarrassing moment there, one of many in my career, where the guy who was doing the stage managing said, now you're going to walk on the left hand of the president and Ventra's going to walk on the right hand. And we're in the blue room. So we have to walk out into the hallway. And I'm thinking, well, if I'm on the left, that means I need to be here and the president will be next to me. So I better kind of go out there first. And they start playing hail to the chief. So I head out onto the red carpet. And Bill Clinton's arm is on my shoulder. And he's saying, no, no, I go first. Oops. He had a point. I'm just trying to follow the directions. So, you know, as Solston said in his book, we were all phonies that day because we didn't have a publication. We didn't have the usual scientific standard for having something that you could really look at and say, wow, look at this. That came, of course, in February of the next year. But it was the right thing to do to get the word out there. And my gosh, the way in which that electrified public imagination was far beyond anything, I would have guessed. That's what changed the topic. Changed the topic. We're not doing a race anymore. Now we're going to figure out, what do we do with this information? We cross the threshold into a really exciting place. So Francis, one of the other things, so you're finished in a way, you're not really finished, but you have a lot of momentum to finish in 2002 years later. And you celebrated that moment on April 14th of 2003. It happened to be my birthday. But that was a pure coincidence. And of course, the other wonderful thing about April 2003 was this 50th anniversary of the double helix. I mean, talk about having something in perfect poetic alignment to have those things spanning by exactly 50 years to the month just seemed... Yeah, that was nice. That was really nice. So Bob, your question about sort of what's next, I think Francis mentioned two critical things that happened in April 2003, completion of the Human Genome Project, celebration of the 50th anniversary, discovery of the double helical structure of DNA. But there was a third thing that happened on that day for the Institute, that was publication of a new strategic plan, which followed in the footsteps of what Francis talked about earlier, this culture of always renewing your vision. Yeah. So I think Francis should say some things about what led up to the end of the Genome Project. It wasn't as if we weren't thinking about what's next, because he had put in place a planning process that led to that 2003 strategic plan. And that was a vigorous process, to be sure, extending over about 18 months. I think we had two major meetings, nine topic-specific workshops, input from all kinds of people with bright ideas, and ultimately resulting in this piece in nature that laid out what we hope we could do in the next five years. Pretty much all of which we did. And of course, a lot of that was okay, let's learn about variation. So HapMap, which I think became a very important next step contribution, which has opened up all kinds of windows into understanding genetics of common disease. Projects like ENCODE. They gave us GWAS. Gave us GWAS, which has been, I think, actually undervalued for what it has told us about mechanism, but overvalued in terms of what it's told us about predictions, because the things we have found have relatively weak contributions, as far as risk. Things like ENCODE, really, an organized effort to bring together dozens of laboratories to understand what are, what's the parts list of the genome, and what do those parts do, how does the function work? And technology investment. And technology investment in a big way. And lots of other things, the knockout mouse project to try to system-manage. Can you really compete with private investors? In technology development? Yes. You know, not at the sort of end point of getting something hardened and out there, but boy, at the front end of coming up with a new idea. I mean, if you look at sequencing technology, the stuff that Jeff Schloss has made possible is one of the reasons why we have an almost $1,000 genome, because of all those academics and small companies that were boosted by NHGRI support to take a risk. They would otherwise not have taken... Well, so just to... I think that's worthwhile. Recording is a serious document. There was a nice beautiful article in Nature this year that had a wonderful shout out about the Institute saying that a major part of the credit for the rapid decline in DNA sequencing costs go to the grants program out of NHGRI. And documenting the reasons why they say that. Yeah. Yeah, so it has been done already. Well, it's been done in sort of a news article. We're in the process. That's not sufficient. Within the Institute, there's an effort to document exactly how it is that our grants program has led. You want to do a scholarly discussion? Because Congress will be inherently against the idea of wanting private. So I'm just curious what the truth is. So I was going to double click on that. Do you think that pyro sequencing or ph sequencing or nanopore sequencing would have happened but for having an NHGRI program? Maybe eventually, but not at this pace. We would have lost many years if it weren't for that source of support to have people pursue those ideas on a shoestring when they weren't at all sure they were going to work and they would have had a hard time getting funds. Where did the luminous ideas come from? They were Selexa. The original Selexa came out of, I think, private money. But if you actually look at the current machines that illuminous cells, there's a number of technologies that were acquired and cobbled together to help refine the original technologies. So I think NHGRI fingerprints are on that can be found in places on the current instrumentation. Yeah, that's true. So back to 2003, you've fulfilled your goal. So we have this grand next vision. And this means then setting up in a similar fashion perhaps to the genome project teams that can accomplish this next round of goals that are sort of big science and that are somewhat top down but you're encouraging all of the participants to come at this in the most creative way and invent new ideas and technologies as they go. And that's wonderful to watch that emerge, whether it's ENCODE or the HapMap project or knockout mice for every single genetic locus. All of those assemble together with some support and begin to go and take a lot of my time. And so I found the time I spent between 2003 and 2008 was not that different than what I had spent in the previous five years. A lot of it was being sort of a project manager for very large projects with excellent staff and so much credit should be given to people like Mark Geyer and Jane Peterson and Jeff Schloss and Elaine. Jane is now running the Keystone meetings. Keystone. She's scientific officer for the Keystone symposium. Okay. Yeah, just moved there a couple of months ago. So I had a great team to work in. Something like that. Maybe more. No, not more. I don't think that was enough. So that was great fun. But after a while I kind of felt like I've done this. I've been doing this for 15 years. It's time to think about doing something else. But I didn't know what it was going to be. So hence May 2008 decided, okay, guys, three months more and I'm going to step away into the white space. And I don't know what that's going to look like. I want to write a book about personalized medicine. And I can't do that as a federal employee, at least not if I want to ever get a dime of royalties out of it because that would be a conflict of interest. So if I'm going to write a book, I got to quit my job. And I really wanted to write the book. So did the rules change between book one and book two? Well, see, book one was not about personalized medicine. Book one was about science and faith, which was not considered to be part of my official duties. So I could write that book without it being a conflict. Can you define personalized medicine as starting with your genome? It's in there, but it's not all that's in there. It's genome. It's your environmental exposures. It's your lifestyle. It's the whole package. Yeah, but the genome gives a reference. A very critical one. Probably the most sort of fundamental reference that I can imagine. Yeah, that's what... But this is why I think, I'll just argue, you've got to get more genetics in the medical schools and not just in terms of research projects, but real practical as part of medical practice. I'm with you. Well, so maybe both of you could actually comment on that because you're at UNC and Michigan for part of your training. Eric, you're at one of the places that's one of the ground points of ground zero for medical genetics. It's certainly the medical technologies in your career. So maybe you guys could talk a little bit about medical education and what was unusual about your backgrounds that suited you to your later career compared to what you would have gotten if you'd been at other places. Well, I think Eric and I probably caught the fever early of seeing how this fundamental science of genetics was the way that you were going to really understand answers to all these mysteries about disease and how could you not get compelled by that? But most people don't catch that fever and they get channeled into other sort of more traditional ways of approaching medicine or at least ways that are not tapping into this. And medical education is pathetically slow in changing curricula and emphasis. And it's very frustrating. You know, back what, 15 years ago, I helped form this thing called the National Coalition for Health, Professional Education and Genetics. Nichepeg, we were going to solve this problem because it was so compelling and so much need was out there and we couldn't get traction with any of the major physician societies. They just didn't see that this measured up on their list of things they needed to know more about and that's still where we are. It's very troubling. I mean, these challenges really around genomics are quite new. I mean, the story I like to tell is I graduated medical school and graduate school with my MD-PhD in 1987. In 1987 was when the editorial came out in the inaugural issue of the journal Genomics that told the story about how genomics, the word was actually sort of created. And that was 1987. I mean, that's why when I think back on my medical school and graduate school, I never heard them word genomics once, nor shy of because it didn't really get put into existence until 1987. So when I think back on what I learned in medical school was like a two-week elective in medical genetics. I mean, it was so minimal. Fast forward to today and there are some examples of some medical schools that have infused more genomics and genetics in the curriculum, but there's just a few examples and it's not nearly the extent that I think is needed. What is needed is for genomics to emerge as being a central part of the need that a physician must have in order to take care of a patient. And I think most physicians aren't aware that that need has arisen yet, but it's really happening, particularly in the field of cancer. They're not going to be able to stay away from this space for much longer. And then there will be a deluge of requests for how do we learn about this and give me some decision tools everything that the average physician needs to become a genomic medicine practitioner, but until that sort of critical moment arises, people are too busy to spend their time learning something that they're not convinced is going to help them with the patient they're seeing right now. So if I'm sensing a theme here, there may be a theme of build it and they will come. And sensing where the puck is moving technologically, scientifically, and is this a characterization of your jobs as the head of this part of NIH that one of the distinctive themes is you do things big and you do things that are technology-intensive and data-intensive. And heavily managed. And... Heavily managed. And tail a fair amount of central management. Right, I think you've got to though just get into the medical curriculum and practice more. And I think you only do it by offering them sort of five million dollars each and they'll do it. So talk about your Mendelian centers because that's kind of the model. Part of an example that would be in the discovery we have a program now to focus on the remaining two to four thousand rare disorders where thought a single gene is involved. And we have set up a series of centers, about three of them, to focus on really industrializing the process of going from a remaining example of a disease for which we don't yet know the genomic basis to get in sequencing patients, analyze it and quickly getting the information out. That's one of the discovery side. I think on the more applied side, which I think is also what Jim is implying, we have set up also a series of exploratory centers to look at what is it like to take genome sequencing out for industrialization. I regard the... So Congress, I spend a lot of time now as the NIH director talking to Congress. In fact, I'm going to have to go in about five minutes to go downtown and talk to Congress. I've met probably 300 members of the current Congress in the current term, one-on-one, just to talk about medical research and the exciting ways that that's changing things. Yeah. Well, do you want to... I don't know. I think we're... We've done our job. Jim is declaring. Yeah, well, yeah. No, I'm not speaking to people. I'm just giving my own... Because I was the big fighter of comprehensive cancer centers. That's why Bennett Spritt fired me in 1974. I said we didn't know enough to actually deliver any medicine on the basis. But I think we are reaching the point where we really can deliver something to the public. And ironically, a lot of it's in cancer now too, Jim. Because that's maybe the place where we are most actionable. I mean, if I had cancer today, you think I don't want to get my tumor genome sequence? Yeah, I was darn sure I do. But the chief value would be to learn that you have a RAS gene, in which case you just don't take any medicine. Right now, we need to fix that too. I actually want to hear... What's your plan? Well, you can if you're in that 25, 30% where you have an accident mutation, you have an EGFR, you have an ALC. Yeah, but you know, ALC, I know... There'll be ALC, and I'm so... Jim, I would like to just declare this as the informal end, but I do want to hear... I want to hear about the changes in congressional relations, and I actually want to hear your perspective on this. He has to go. So, okay, that's fine, but let's hear it. But I can also answer. You know, I think medical research, whether it's genomics, whether it's heart disease research, whether it's Alzheimer's, is an incredibly compelling story. And it doesn't matter whether you're a Republican or a Democrat or a Libertarian or whatever. This is something that you have to care about. And so I have no problems, I think, when I meet with a member, convincing them that this is one of the most critical things that a government can do is to support research. And it's not something that just the private sector alone can do. They get that, that this is an ecosystem where you need the basic and you need the applied and you need all these partners to work together. So I don't have a problem convincing congressional leaders about the value. The problem right now is that we're at this gridlock of making any decisions about what's in the discretionary budget which happens to include NIH and everything we're talking about. And until that gridlock gets resolved, we're stuck as an innocent bystander with gradual erosion of all of the capabilities that were built up over the doubling and which are now many of them been lost over the last 12 years now with more than 20% of our purchasing power going away. I don't think we lack for congressional enthusiasm. We just lack for congressional fiscal decision-making. So one other counterfactual that I just wanted to ask about is if, I mean, so the Human Genome Project got launched at a time when budgets were incrementally increasing year by year. And would it even happen in the current environment? The idea of the Human Genome Project came along in 2014 with something similar? It would be a hard sell because of the fact that budgets everywhere are either frozen or going down and to argue for starting something new. We're trying to do that with the Brain Initiative. I don't know how it's going to go. I think it's a compelling scientific opportunity. But will it be possible in the face of declining support for everything in medical research because of this gridlock? I don't know.