 So I'm David Valley, I'm currently the director of the Institute for Genetic Medicine at Johns Hopkins University, the McCusick-Nathans Institute for Genetic Medicine at Johns Hopkins University School of Medicine. I have been in that position since 2007. My background is as a pediatrician and then a geneticist, and I guess also a genomicist. I'm one of these people who was very early on captivated by something, and what I was captivated by was biology. So my earliest memories of childhood were roaming, I lived in the country roaming the fields and woods around my house and collecting anything that moved. And when I got to grade school, I literally began to count off the years until I could take biology in seventh grade. And I had a very good seventh grade biology teacher who gave me special attention. And then it happened, my family moved to a big city, Kansas City, and I had an opportunity to take advanced biology, which I did. And then I went to Duke University, where I advanced placed in zoology. And so I took in my first year comparative anatomy and genetics. And the genetics teacher in the spring of my first year of college offered me a job. And I took the job, and for four years as an undergraduate at Duke, I ran the fruit fly lab and worked on Drosophila experiments with Calvin Ward. And when I went to medical school, I got accepted into Duke. I did not, my undergraduate degree, my undergraduate performance was, you might even say, binary. I did very well in sciences and not very well in the rest of the stuff. And so, but I was able to get into Duke, which is a far better medical school that I could have gotten into otherwise. Once I got accepted at Duke, Calvin said, I'm going to take you up and hand you off to the human geneticists. And he took me up the street to the medical school and introduced me to Jim Sidbury, who was a pediatrician and trained at Hopkins and was interested in biochemical genetics. And I worked with Jim my whole four years of medical school. So I was basically hooked on genetics very early. And when I went to Hopkins to do an internship in residency, and I knew that I was going to do genetics and had the great good fortune of a number of, there were a number of senior faculty colleagues who were very helpful during those years to me. Jim Sidbury, who was irreverent and informal and funny, organized a weekly biochemical genetics rounds. And on those weekly rounds, the faculty included Jim Sidbury, Bill Kelly, who went on to be to Michigan and then to Penn, Jim Weingarten, who went on to be the director of the National Institute of Health, Stan Appell, who went on to be chairman of neurology at some place in Texas, I forget whom, where, and another medical student, Harvey Cohen, who went on to be chairman of pediatrics at Stanford and is still at Stanford, I think. Harvey and I were the only two medical students that went on these rounds, but we religiously went on these rounds with these guys who really were very, very prominent in their field. It was intellectually stimulating to see how the patients were approached, what was the thinking behind whatever the symptoms were and what sort of diagnostic workup was envisioned. And we saw lots of patients with, you know, rare and, to me, quite fascinating disorders. I always say that medicine is made up of two kinds of people, those that are interested in things that are very rare, and those that, by contrast, say, oh, that's so rare, I'll never see it again, I don't care to even learn about it. And so, in those days, the people that went into genetics were, by and large, interested in rare disorders, which could be recognized, rare Mendelian disorders, because they could be recognized by virtue of their pedigree, that was a key sort of diagnostic tool we had in those days. And Harvey and I, Harvey Cohen and I would, you know, walk all around the school just to see one case of whatever, something that we would be unlikely to see again. But during my freshman year at Duke, I was still considering, as an alternative to medicine, a career as a field biologist, basically, because I love biology. I can remember walking home one night from the zoology building where the Fruit Flight Lab was, and saying to myself, you know, I really would like to have a direct sort of humanistic reward, and so I'll choose medicine. And I also knew for some reason, not only would I do genetics, but I would do it in the context of pediatrics. I liked kids. I think pediatricians are like the idea that if you have a child who has a problem, if you fix that problem, then they have their whole life ahead of them, while if you're an internist, it's like patching up a car, you know, just patch this, patch that. And so in the one case, the patients are on the ascendancy of their life, and on the other case, the patients are increasingly on the descendancy of their life. So I actually much preferred pediatrics to internal medicine or other such things. So I loved medical school at Duke. It was fantastic. What I knew right from the beginning, I would do pediatrics. One person who really played a role in helping to make Hopkins as an interesting place for me to go was Mike Kbac. Mike Kbac was a biochemical geneticist. He's responsible for developing the Tay-Sachs screening test. And very energetic, very interested in biochemical genetics. And when I interviewed, he took me all around. I remember he drove me to the airport when I was going home and sort of gave me the sales pitch on the way to the airport. And then Rod Howell, who was another biochemical geneticist there, was a very good colleague and a very good person to talk to. I was especially close to the hematologist, Bill Zinkham, who was a good friend, so with Jim Sidbury, my Duke mentor. And it was very close, particularly after I finished my house staff training, to Saul Bursalo, who I think was, who developed all the ways we currently treat ureocycle disorders. And in my mind, it's one of the greatest clinical investigators I've ever seen. And then, of course, Barton Childs. And I will just say that my interactions with Barton really began a little bit while I was a house officer, but then when I joined the faculty, I can actually remember I was writing a paper not too long after joining the faculty. And for the Johns Hopkins Hospital Bulletin or something, it was sort of a local journal. And it was on some, a couple of patients I had with the homocystinuria, an inborn era of cysteine methionine metabolism. And I was trying, I was writing a sentence, and I was dealing with what fly geneticists would refer to as the wild type. That is the sort of normal. And at that point, we knew a little bit more about genetic variation. And I realized, the thought occurred to me that the wild type is not some sort of unitary thing, but actually if you could really know everybody who was currently wild type would have all kinds of variation in it. And I was struggling with how to say that in a sentence, and I walked out of my tiny little office into the hallway and bumped into Barton Childs. So I asked him, I said, I mean, I'm trying to write, I'm trying to indicate sort of normal. I want to say wild type, but I know that this is really not, that's a gross simplification of what's really going on. And can you help me? And he looked at me and he said, you're learning. That's all he said. He left me to struggle. I do know when I met Victor, precisely. So like all interns, I started on July 1, 1969. And I think most physicians, I'm not sure, sort of organize their life around their internship year, their sort of pre-internship and post-internship. And I love that internship year, so I have strong and positive memories of it. I took over the, I inherited a set of patients on the infant floor on my first day. Many of them actually were taken care of by Art Bodette, who preceded me, and left on June 30. And so I picked up Bodette's patients, and he went on to be director of genetics at Baylor for so many years. But my senior resident, Dick Kessler, said to me, this child is a dysmorphic child. In those days, a funny looking kid was the term that was unfortunately used. And you need to put in a consult to Victor McCusick. So on the second day of July, I think it might have been July 3, not July 2, I called up McCusick's office, and he answered the telephone. And I said, this is David Valley. I'm a new intern in pediatrics, and I have a child who's dysmorphic. And I wonder if you would be able to come by and take a look and tell us what you think. And he said, OK, I'll be there in five minutes. And five minutes later, it just happened I called him when he was taking his entourage on their weekly rounds. And five minutes later, this group of about 20 people comes walking down the hall. And I'm running around like mad trying to organize my thoughts of how to present this patient to Victor, introduce myself. We went in, and Victor in his clean, starched white coat looked over the edge of the high climber or crib with high things on it, and looked for about, I don't know, maybe 60 seconds at the most, and looked up and said to me, I don't know. And I was disappointed because I was, of course, looking for a diagnosis. Later on, I realized that was a very important thing for him to say, because if he had said, I don't know, but I think it might be this, then I would have immediately stopped thinking about the patient and just said, OK, this patient is an example of this disease. And in the olden days, that's the way it was done. The most senior clinician would say, I think it's this. And then we would all deal with that one entity rather than keeping our thinking caps on and saying, you know, trying to put it into context, you know, I mean, some people think it's this, some people think it's that, but it was very, again, it's, I think, human nature to try to organize and simplify biology, which is much more complex than our ability to simplify. So in retrospect, I appreciated very much that Victor did that. I was away for three years at NIH in the middle of my residency. When I came back, then John Littlefield, who was the chairman of Pediatrics, offered me a job. I didn't do any fellowship or anything. I just was a senior resident one day and assistant professor the next day. And I was to learn clinical genetics that I, in addition to whatever I'd picked up during my residency from a man named Thad Kelly, but Thad took a job and went to the University of Virginia a couple of months before I started. So I was a senior resident one day and then I was the director of the Pediatric Genetics Clinic the next day. And then I saw a lot more of Victor and about two weeks after joining the faculty, John Littlefield called me to his office and said, do you know anything about the Bar Harbor course? And I said, I don't know anything about the Bar Harbor course. And he said, well, it's a course that Victor runs, you should go. And he said, I'm going to call it Victor and see if there's still a chance for you to go this year. So he called me back the next day and he said, I talked to Victor and there is an opportunity for you to go this year, which was like a week later. And he said, the only issue is that he needs someone to talk about Lysozomal storage diseases. So you'll have to give a one hour lecture on Lysozomal storage diseases, about which I knew I was not a special expert on Lysozomal storage diseases. So then I frantically prepared a lecture on Lysozomal storage diseases and those pre-powerpoint days preparing a lecture from scratch was not easy. And so I was up night and day getting that lecture ready, which in those days is all about just the clinical differences of the various kinds of Lysozomal storage diseases. And so I gave my lecture at the short course and in the first week of the short course, and Herschhorn, a very famous human geneticist, a terrific guy, was in the audience. So when I finished my lecture, Kurt asked me a question and I tried to answer it. And then Victor asked me a question and I tried to answer that. And then I realized that Victor and Kurt had some disagreement about some idea about Lysozomal storage diseases. And they were using me as a tennis ball to go back and forth, which was fine. It was fun. And the other thing about that first short course was that, which is, I think, 43 or 44 years ago, was that at some point in the first week Victor had a faculty meeting and he still had some holes in the second week. And we need someone to talk about the treatment of genetic disease. And the various faculty were, oh, I'm sorry, I'm going to be gone by then. So I ended up giving two lectures the first time I went. One was on Lysozomal storage diseases and the second lecture, prepared on the fly, was on the treatment of genetic disease. I continued to give that lecture to currently. So from that point forward, I went to every short course. And in 1990 or 1991, I became a co-organizer with Victor. And while our initial interactions were pretty junior-senior, once I became the co-organizer of the short course, we really worked together a lot. And he became much more informal. Victor was very much more informal in Maine and at the short course than he was at Johns Hopkins, where he was very formal by and large. I have the greatest admiration for Victor and what he accomplished. But he was a man of few words around Johns Hopkins. I mean, I had an experience where I got summoned to his office and I walked into the office and he was working at his desk. And I sat down and he said, I wanted to ask you something. I don't know what the question was. He asked me the question. The answer took maybe 10 seconds or 15 seconds. And then he returned to whatever it was he was doing. And I sat there and after about 30 seconds, I figured, well, I guess it's over, and I got up and left. So we had several interactions of that type. A very important part of my career, again, just happened by accident, was that you may know that Hopkins has close ties to the Peking Union Medical School, PUMC, it's called. And those ties were established by William Welch in 1912 or 13. And there's pictures of Welch sitting on a donkey in the Great Wall of China back then and stuff. And after the Cultural Revolution, there was a very wonderful man by the name of Wilson Low who had trained with Victor at Hopkins and then went back to China and was trying to develop genetics in China. But when the Cultural Revolution came, of course, he had to go to the countryside. And so as soon as the Cultural Revolution was over, Wilson got in touch with the people at PUMC and also with the Chinese Academy of Medical Sciences and came over and spent two weeks at Hopkins, reacquainting himself with all of his former colleagues. And he organized this trip for several leaders of Hopkins to go visit PUMC in China for two weeks. And so he asked six prominent faculty members, the Dean, Dan Nathan's, Ham Smith, John Littlefield, and some others, Dick Johns and Tom August. And at the last minute, and their spouses, at the last minute, Joanne Nathan's could not go. So a slot opened up. And so they called or they, I don't know what they did, they contacted Wilson. And he said, well, send Valley and Joanne Nathan's place because Wilson was trying to start a pediatric genetics clinic and he knew that I was running the pediatric genetics clinic at that time. So I went and with all these people who are very, very much more my senior, but we had a really fantastic time in China traveling around meeting Chinese physicians, seeing them rebuild their medical system and so forth and so on. But that was a chance for me to really become sort of on a first name basis with all of these leaders of Hopkins who are all much my senior at that time. And we had a lot of great experiences. The only thing I can remember is that my interactions with NIH, I think, aside from submitting grants, came when I was asked to ad hoc on the Malian Genetics study section. The Malian Genetics study section was quite a well-known study section. It was sort of like a club. And I ad-hoc'd. I remember I sat next to Carlo, what is Carlo's last name? Carlo Croci. I don't know if you remember, he has a big opera singer's voice. He was very valuable and everything. And so I ad-hoc'd. And then later I was asked, I guess I did OK on my ad-hoc, to become a permanent member of that study section, which I did. And when I became a permanent member of the Malian Genetics study section, Tom Kasky was the chair. And when Tom rotated off, I think he said to the SRA for the study section, I think he recommended me to replace him. So I went from being a member of the Malian Genetics study section to the chair of the Malian Genetics study section. I think I actually did that for a couple of years. That got me tied into genetics at NIH and so forth, and to know people. And I think probably that connection led to me being asked to become an advisor for the genome project. So I'm very interested in the genome project, but Hopkins passed on it. Didn't have a program there that was part of the genome project. So this was fantastic for me, because it was a way for me to be involved in the genome project, but not churning out the sequence or anything like that. One of the earliest things I remember was that Craig Venter, at that time, Ham Smith had just left Hopkins and taken a position with Craig Venter at the venture institute or Tiger, what's called Tiger then. And they came to visit Hopkins, and I had lunch with them. A small group of people, including myself, had lunch with Ham and Craig. And Craig, during the discussion at lunch, Craig was talking about sequencing the human genome. And at that point, he was a grantee of NHGRI. And so I could see from his conversation that he was very committed to sequencing the human genome project. And I also noticed that he was looking at Ham and winking, and Craig is not particularly subtle. And so I thought, well, this is weird. What is it? They've got some secret or something like that. And the next week, as it would happen, we, the advisors met, I can't quite remember how far along I was or anything. But, well, I can remember, because this must have been towards the end of the first round of funding, maybe the first three years of funding or something like that. Because I can remember Jane Peterson, who was terrific. Mark Geyer and Jane Peterson were there in Francis. And so Jane was standing up, and she was going over the various sequencing centers had been reviewed. And she was going over their responses to their reviews. NHGRI had asked them to respond to their reviews about what they were going to fix about this, that, or the other. And she came to Tiger, which, as I say, was a member of the thing. And she said, it's very bizarre. She said, we really haven't gotten a response from Tiger. They had a number of criticisms, and they haven't responded. And it's almost like they're no longer interested. And I thought, well, that's weird, because it was less than a week that I had had lunch with them, and I could tell that Craig was really hot on the sequencing of the human genome. I actually didn't put two and two together. But about three days later, then, Tiger sent back their grant and said they were going to go their own way and use a different strategy to sequence the genome project. And so then the race was on, basically. In those first few years, there was all this sort of lurking over everyone's shoulder was Tiger and Craig Venter, and whether their method was going to, were they going to do it faster, better than the publicly funded genome project headed up by Francis. And so that was in everyone's mind and everyone's discussions during that time. And I can remember, I think you probably know that when Craig made that announcement, he said he was going to try out his strategy on Drosophila to see if he could do a whole genome sequence of Drosophila. And if he was able to, using this sort of shotgun sequencing and then reassembly at the end, then he believed that would be proof of principle that he could do the human. And he made quite a bold promise of when they would finish the Drosophila genome. And I think we had conversations saying, well, I don't know if that's going to work. It seems a little difficult to imagine how it would work. I mean, in retrospect, now dealing with computers and everything, it was easy. I could see it would work. But anyways, and so I think for a while, we were sort of thinking, well, that's probably not going to work. We'll beat him. It's not that big of a deal. But then, I don't know how much longer it was, six months later, eight months later, and nine months later, he announced they had to sequence the Drosophila genome. And so that was proof of principle at his strategy of work. And now he was turning to the human genome. And so I can remember this meeting at Arleigh House, Erleigh House. And I don't remember the date. You probably can figure it out. I know Francis remembers the meeting. And everyone is sitting around the room. And I sort of felt like I was part of the genome project, even though I was simply an advisor. But I wasn't doing the work. I was just showing up periodically to give my two cents worth. But as I looked around the room, there's Bob Waterston, Eric, I guess Richard was there from Baylor. And everybody looked to me like they were exhausted. They looked, their spirits were down. They looked whipped in a way. And it reminded me, in part, I guess, because we were at Erleigh House, it reminded me of what it must have been like during the Civil War, where the generals would come in in the evening and they'd had a hard day or maybe they'd lost a battle and they were hanging on by their fingernails, basically. And so Francis presented a sort of a talk about how are we going to deal with this and blah, blah, blah. And he looked at me. And for some reason, I said, I'm always an optimist and I don't really shy away from a challenge. So I said, well, I can't even remember what I said, but I said something positive that sort of reinforced a little bit what Francis had said. And then Bob Waterston said, well, I think we can do this. It was like everybody got up and went back to their labs and went at it, basically. As I say, it certainly caused a lot of anxiety and a lot of increased pressure and so forth. But in retrospect, obviously it was great to have a competitor. I mean, that really drove things much faster. And then, of course, miraculously, both groups ended up on the same day declaring that they had achieved a draft sequence of the human genome. I made a slide of the New York Times headline, which is across the headlines on the front page, a draft sequence of the human genome. And then shortly thereafter, that was right around 2000. And the Clintons were having these millennial evenings, evening celebrations in the White House. And so I got an invitation to go to that. And that's where Francis and Craig were there. And Bill Clinton got up. And actually, we were all standing around there. And there was nobody there. And then the band starts up playing Hill to the Chief. And down the center aisle comes Bill Clinton and with Francis and Craig behind. Now it is said, I didn't actually see this with my own eyes, but others who were in the room said there was a lot of anxiety because it was so exciting to be here at the White House and so forth and so on. And Bill Clinton was standing in the wings with Francis and Craig. And when the band played Hill to the Chief, Francis turned and started to walk down the aisle. And Bill Clinton reached out and grabbed his shoulder and said, when they played this song, I go first. And so down they went. And then Clinton introduced them. And they were sitting on either side of them. There are lots of famous pictures of them sitting there. And the McCusicks were sitting just to my left front. And Francis was pointing out Victor to Bill Clinton. And the amazing thing to me on that night was that how quickly Bill Clinton seemed to catch on to what the genome project meant. And this business about we're all 99% identical and all this kind of stuff. But I thought, wow, that guy is quick because he may have been doing homework, but he seemed to catch it that night about what kinds of opportunities this afforded and what a real watershed moment it was. So it was very impressive to me to see him figure that out on the fly as it were. The other funny thing on that night were many funny things about that night. But one was I was standing in line to go in. And I think this was like two weeks or so after Harold Varmus stepped down from being the director of NIH. And each of us would walk up to the guards and they would say, what your name is? And they'd look and see, oh, you're on the list and everything. And so Harold was like about 10 people ahead of me. And when Harold got up there, the guard said, you're not on this list. And so he was saying how quickly they forget because two weeks earlier he'd been the director of NIH. But they did let him in. It took a little screwing around to make sure that he got in. But that was a wonderful event, basically. Well, I think that day at the early house was really one for me. And the other one was I just couldn't believe. I mean, I have great admiration for all of the people that were leading those labs and doing that work. But each one was quite different from the other. They had very different personalities. And their laboratories had very different personalities. Lee Hood was a major player at that time and others. And well, Maynard Olson was there. And Francis had a weekly call with that people, those folks. And talk about herding cats. I mean, just gearing up for and managing those weekly conference calls must have been an enormous strain. I don't know how he did it, frankly. And he was trying to keep many, many things in the air. First of all, he's a very accomplished scientist. So he could command the respect of these people because he understood the science. And they viewed him as an intellectual and scientific equal. But in addition, he had this poise that enabled him to think ahead where possible, avoid potholes, make sure we didn't insult this person or we didn't do this or that. And of course, that was a skill that James Watson did not have and he couldn't have done that. And I have scientific admiration for Watson, but he couldn't have done that part of it at all. But Francis did it, and he did it for a long time. And so it's a remarkable achievement on his part. I also remember a subsequent early-house meeting where Francis said, I think we should declare victory. I think we're done. And that was in 2003, where he said, we all know that we haven't sequenced every last base and we haven't plugged every little hole. But we're approaching an asymptote, and I think we should say we've got it. And then people said, well, we all want to make an agreement that we're going to finish every chromosome. And so then they came out one at a time thereafter. Another key time, and I'm sure you've heard about this as well, but this was very early. And we were at a meeting and Francis said, we become aware of a problem. It was very early. And the problem was that the guy who was making the YACC libraries, Peter Jejean, had in retrospect, I mean, these YACC libraries were this sequencing substrate for the genome project. And what set our approach apart from the Tiger approach. And he said, when Peter Jejean made these libraries, he did start with samples from a relatively small number of people, maybe 10 or 12 or something like that. And not all of them yielded very good back libraries. And so the number of successful back libraries is actually quite small. And we've become aware of the fact that at this point, I think we were 12% there or something like that, that the bulk of the sequence so far is from one person. And this raises LC issues because we're essentially undressing this person to the world and without him, him or her, it was him, signing consent for that kind of scrutiny. And so here are our options, we think. One is we can discard all the sequence we have so far and start afresh and do it in a way that we have learned would be a better way to do it. Or we could, I only remember two options, or we could rapidly ask Peter Jejean to make a bunch of new libraries and mix those in with the existing libraries and dilute out this individual back clones by these new libraries. It wouldn't erase the sequence that we've already gotten, but that would only be, let's say, 10% of the total or something like that. And I think we voted on it. And of course, we all voted to the latter because we didn't want to, we were in a race and we didn't want to take that progress and put it in the trash. We have learned that genetic information is very powerful for lots of different reasons. And we all of us want to make sure that we reap the benefits of this powerful information. And we all have learned that there are also many problems that one could get into with this information. And it would only take one really bad problem to derail the whole effort or to give us the whole effort of black eye. And so I think that's also part of Francis' genius that he, I'm thinking, he spent a lot of time sleeping at night or laying in his bed at night trying to think of every possible problem we could get into and avoid it. And I think that was a good example of where we were close to really getting into something that was a bad situation and it was avoided. Yes. So I did the genome project advisory committee and then that committee sort of morphed into something called the sequencing advisory panel. And Rick Lifton was the chair and I was on that committee. I think we were on it for maybe 10 years or something like it, quite a long time. And that was interesting because basically what we would do is we would go around from sequencing center to sequencing center and sort of do a site visit. And so that was interesting because as much as I had been involved in the advising, I had not actually seen much of the actual place where the work was done. And so in the course of those site visits, which also included the intramural staff, Jane and Mark and Rudy Pazzotti and the intramural staff was really a terrific team. And so that was quite interesting to go to the road and to Wash U and other places to see that tiger. We went to Tiger. But that was fun. And then we did the sequencing advisory panel. And then at some point, I can't remember for sure, but now I know almost about 22 years ago. 22, I think it's when Cider came along. I was actually the acting director of the Center for Medical Genetics at Hopkins. I couldn't be the director because I was a huge investigator and huge wouldn't allow one to take a large administrative position. And somehow we got wind of the fact that the idea had been hatched at NIH, that it would be good to have a center that would provide high throughput genotyping for investigators in a bunch of NIH institutes. And that NHGRI was going to take the lead on that. And they didn't have enough space, they thought, to do it on the Bethesda campus. And they thought it would be best served to be on an academic campus. And so they were looking at Maryland, University of Maryland College Park. And we got wind of it and we quickly fired down, hey, don't forget about it. Because it turns out, of course, you take the tunnel under Baltimore, the Bayview campus is really a pretty easy get from Bethesda. And so that moved very quickly. And we were able to convince Francis and the others that this would be a good opportunity. And I was very excited because, frankly, because I saw this as a chance for us to get in as a participant in genomics and that this would build genomics at Johns Hopkins, which we had passed on, not me, but others before me, had passed on at the start of the genome project. So we were thrilled to get that contract. And it continues to be very successful. I think we're now in our 22nd year. And the first person I hired was Kim Doheny, who is the current director, who's terrific. I couldn't have found anywhere in the world a better person to do that job. And she's a graduate of the graduate program I run at Johns Hopkins. So I knew her well because she had done her PhD actually with Phil Heeter of East Genesis. And she was interested in coming back to Baltimore. So she was a perfect candidate to start this new venture. And she came in and for a while, Allen and I sort of ran things. We tried to hire, we tried to recruit a senior person but then we had several people close to signing but in the end they didn't sign. I finally went to Bob Nussbaum who at that time was a contract officer. And I said, well, I knew very well. And I said, Bob, we're now 18 months or two years in and we're both sort of learning on the fly here. But if you're comfortable with me taking the directorship, we'll quit spending our effort trying to recruit someone and we'll just do it. And that's what we did. That's been very, very good for Johns Hopkins. I think Seider has done a terrific service for the community and continues to provide fantastic service to the community. I would argue that we are the best high throughput genotyping lab in the world. So we didn't develop our sequencing as much as that but we certainly provided great genotyping. Remember, I think in the first five years the goal was to be at the end of five years to be able to do one million genotypes a year. A year. Now we do billions in a week. We don't do billions in a week but we, I mean, when they're cranking, it's amazing what they can do. One other thing that you should, that I'm very, in retrospect that I can't take complete credit for but I certainly helped was I came on and was president of the American Society of Human Genetics and I don't remember what year that was but it was around the early 2000s maybe. And at that time there was almost no genomics in the sort of scientific platform of the American Society of Human Genetics. And I felt, I thought, well, come on guys, genomics is booming here. We gotta, it's gotta be incorporated in ASHG. And so one of the, I guess I would say the major goal of my presidency and the president serves on the board before and after so I sort of able to influence things for a while was to bring as much genomics into ASHG as possible. Now of course the whole meeting is filled with genomics and the sort of interaction between genomics and genomics is very synergistic as it should be. And but one of the things we did is I remember I asked Francis to come and give a talk there which is sort of like the first talk about, at our annual meeting, which is sort of like the first talk about the genome project and what would be expected, what would be the benefits and so forth with all this new information. For me, the person that really mattered and that was Barton Childs again. Because Barton said, look this is great that the specialty of medical genetics has grown up and their boards and exams and journals and all of the accoutrements that a specialty in medicine should have and that's a great achievement to have medical genetics be a recognized specialty. But Barton said, just stand back and look at the biology. Genetics is important for all of medicine and victory, you can't declare victory until we've integrated genetics and now genomics into all of medicine. So I have this two slide thing where I show what I call the medical pie and medical genetics is a tiny slice of the medical pie. Again, people who like, who are turned on by finding rare things. But then what the future is and which is that medical geneticists should be the leaders to integrate genetics into all of medicine. Some medical geneticists felt threatened by that and didn't want to do that. They didn't want to keep that area to themselves but it's too big to keep to yourself and it's too small minded to keep to yourself and we should spread the wealth and we're the ones that should be able to lead that spreading because we know lots of examples of how genetics affects health and disease and so we should be the people that lead the integration of genetics and genomics into medicine and I think now we are. And it hasn't hurt the specialty of medical genetics doing just fine. So we shouldn't have been threatened by it. Well, so human genetics really was almost equated to Mendelian genetics for a long time. So Mendel was rediscovered in 1900 and then progress was slow. There was this sort of Mendelian ancestry and debate up until Fisher in 1918 and then it sort of became a plotting recognizing Mendelian phenotypes and the actual, the inheritance pattern was the key part in recognizing the Mendelian nature of the disorder and people who liked rare things would be just thrilled that we had figured something out and what happened was then the Genome Project came along and then GWAS was developed and attention moved way away from Mendelian genetics. Mendelian genetics was pretty much situated in the American Society of Human Genetics and the Genome Project came in and just sort of overran everything and then all the young people were going into genome-wide association studies and that was all the rage for about 10 years or 12 years and someone who's doing Mendelian disease couldn't barely get above the water line and there were a couple of papers, there's an important paper written by Stelios Antonorakis and Jackie Beekman on something to the effect of don't forget Mendelian genetics and I don't, I'm not sure of this but I know that I was at a meeting at Cold Spring Harbor something to do with the Genome Project and there was a breakout group, there were these typical breakout groups and Jane, I was the chair of the breakout group and Jane Peterson was my sort of intramural partner and Bob Waterston was in the audience of our breakout group as a participant and the idea was hatched that in addition to the large-scale centers, perhaps there should be some sort of intermediate level centers that were good at sequencing but they also brought in people who are good at phenotyping and who were nimble enough to do small jobs whereas the large-scale centers were really all geared to do massive jobs and small jobs that required a lot of back and forth with a submitter and everything but was not really very efficient use of the large-scale centers and I don't remember who suggested that idea but I do remember and it might have been Bob, I do remember thinking, this sounds like a great idea to me and it's, I did think, I'm not supposed to think of these things but I did think this could be real opportunity for us so I was really hot on the idea as well and then maybe 18 months or two years later out came the RFA for the Centers for Mendelian Genomics and I said to my colleagues at Hopkins, look if we're gonna go in on something, we can't, we cannot say no on this and because we have 50 years of Mendelian Genomics sitting here so that's how that came, I think in part how that came about and it's been terrific for us. I mentioned Art Podette earlier but I got a call from Art Podette as we were struggling with getting our application together and he said they were gonna write one and what would I think about joining forces and so we discussed it for a couple days and then we decided yeah, we like, we have good colleagues at Baylor, why not and so that led to Baylor Hopkins. The biology and the progress of the Mendelian centers in my opinion, obviously I'm quite biased but in my opinion it's been really remarkable and it's exposing all kinds of really interesting biology, just really interesting biology and all of that biology is essentially following the paradigm of you have some human or some set of humans who have some interesting problem and mother, I always say mother nature is trying to tell you something and we just have to learn how to be smart enough to understand what she's saying and so what we're learning is that by unearthing the Mendelian component of those interesting phenotypes all of a sudden we enter into some new area of biology that has been overlooked and it turns out to be fascinating and important for human health and so it just happens over and over and over again and so I'm very pleased to be part of this. One of the centers for Mendelian genomics and I think we've done great work but there's a big job ahead. I actually think that there should be, I was thinking this morning, there should be a project or an effort, I've been pushing this for a while now, an effort to hook a phenotype to every gene in the genome and I would call that the human gene to phenotype project or the HGP squared and right now we're at 20% of the genes and other people think, well there must be some genes that will not have Mendelian, will not have variants that cause Mendelian phenotypes. I don't think that, I think if we look carefully enough every gene in the genome will have a Mendelian phenotype associated with it. In order to do that you have to look around, you have to look at a big population i.e. the world's population and you have to have a lot of good phenotypic data. Yes, I think the idea of a reference sequence is naive. Again, it's another example of our desire to simplify things to help us organize things and I think it's served its purpose gangbusters but come on, we should have the complete sequence and we should have the complete sequence from lots of representatives of our species and they should be sampled across the world to maximize diversity because from the diversity we're gonna learn what's important and what's not important and so forth and so I think this effort to develop what's come to be called de novo assembly and de novo complete assemblies is something that was prominent in the strategy meeting I was at a month or two months ago, and I think that's quite a reasonable goal for NHGRI myself and I think the technology, NHGRI is the institute to do it number one, genomes are our business and I think the technology while not perfect is much better now than it was a while ago to do that kind of study and so I think we're bound to learn stuff from that and we should do it and it will help other areas of science, it'll help the Mendelian projects because we'll have the right reference for the right person we're interested in understanding and it will tell us about evolutionary biology, what the history of a species is and all of that good stuff and I have a colleague at Hopkins who's done a Steven Salzburg who's done extensive analysis of all of the RNA seek data he can lay his hands on and he looks for transcripts that look like they are messenger RNAs from genes that are not annotated as genes and so I don't think we have all the genes yet. I don't know how many we're missing, I don't think it's a huge number but I think we're missing some. It's also confounded by the fact that we can't really get a definition of a gene that everybody agrees to but if your definition of a gene is something that generates a transcript and that transcript has a function then I don't think we have all the genes and since I believe that we can find Mendelian phenotypes for every gene in the genome I want a full list of the genes and when I can't tag a phenotype to a particular gene one of the things I think about as well maybe it's. You don't have the gene yet. I don't have the gene yet, that's why I can't find it. I'm not looking there, I'm not, you know. One of the things my interest in biology entailed early on was I would go out in the woods or the meadows or wherever and streams and I would look around and I would very often spend a lot of time turning over rocks to see what was underneath the rocks and that's what I think, you know, going after Mendelian disease genes is you turn over the rocks and sometimes you don't find anything but sometimes, you know, you find something really amazing, it was a salamander or a snake or some sort of centipede or all kinds of interesting things and so you wanna be as efficient in that process as you can be but it's always exciting when you turn over that rock and you see something new and novel then it's really, it's great.