From DailyDoseOfWeirdNews.com, I'm Darren Marlar and this is your Daily Dose of Weird News. An unexpected passenger arrived on a Turkish Airlines flight after her mom gave birth. Crew members helped deliver the baby girl. That's a good thing. Children fly for free. A man in India was arrested for driving 158 miles per hour. That is impressive for a guy on a unicycle.  In fact, the artificial brain is so smart that it is thrilled that it's not human. An NRA employee accidentally shot himself last week during a firearms training session. The 46-year-old man was holstering his pistol when it accidentally discharged. The incident happened in Fairfax, Virginia, at the NRA's National Firearms Museum. And that, folks, that's my demonstration of what not to do with your firearm. Any questions? Chuck Norris has been named an honorary Texan by the state legislature.  One 7-year-old girl did not let her alopecia diagnosis stop her from participating in her school's Crazy Hair Day. Daniela Ride says that she was nervous when her daughter Giannessa came home from Salem Elementary School with details on their Spirit Week that included a day called Crazy Hair Day. Giannessa was diagnosed months earlier with alopecia, an autoimmune disorder in which the immune system attacks the hair follicles. While Daniela was hit by an idea after seeing some scrapbooking materials, decorate her daughter's head with adhesive jewels. It cost about $4 total, and it only took 10 minutes to apply. See, this, people, this is the way you deal with the world. This girl's mom, she could have gone all overprotective mom in the world and complained to the school about how Crazy Hair Day is discriminatory and unfair and should be cancelled. But instead, she stepped up with their daughter to face reality and decided to take it in stride and actually made it work for them. That is how the world should be. Take a lesson, liberal snowflakes. The study says that songs are becoming shorter because of people's shortened attention spans. Man, they must have been really short songs in the 60s, man. Boeing at JetBlue are investing in a startup that makes battery-powered planes. Hey, guys, if you want to save money on your startup, I hear you can get some really inexpensive batteries from the leftover Samsung Galaxy Note 7s. A 31-year-old artificial intelligence engineer in Hangzhou, China claims to have married a female robot that he created. Zhang Zhaizhe built the fembot last year and named her Yingying. He married the lucky piece of electronics in an informal ceremony.  You'll have a big hit with men all around the world. Last week on NBC Nightly News, anchor Lester Holt announced that Jupiter is now 415 miles from Earth. Holt, who just returned from South Korea, later tweeted, Okay, you got me, left out the word million in Jupiter's story, hanging that one on serious jet lag. Hey, honey, yeah, instead of taking the kids to Disneyland this year, how about we head to Jupiter? It's closer. The University of Utah has become the first major sports school to give scholarships for competitive video gamers. Why could this not have happened when I had the top score on Cubert back in 1982? More embarrassment for the Secret Service. Law enforcement sources say that an agent on Mike Pence's security detail was suspended after he was seen leaving a prostitute's room at a Maryland hotel last week. You know, for an organization called the Secret Service, they're not very good at keeping things a secret. If you liked this video, please give it a thumbs up and be sure to subscribe if you want to see more. And click that little bell next to the subscribe button to be notified when I post new videos. If you're already an official Weirdo, well, do me a favor and share this video on your own social media to help the channel grow.  Well, it is the official newsletter of Marlar House, and subscribers to the Marlar Sheet, you're automatically entered in prize drawings, contests, and promotions. In this month, one of my Marlar Sheet subscribers are going to win a Weird Darkness t-shirt and coffee mug. You can sign up for the Marlar Sheet free today at DailyDoseOfWeirdNews.com. For more weird news anytime, to sign up for the newsletter to download my free mobile app or to get DailyDoseOfWeirdNews t-shirts and coffee mugs, visit DailyDoseOfWeirdNews.com. I'm Darren Marlar and I'll see you next time. Weirdos.


Well, good morning, everyone, and welcome to what is the kickoff event for what will be a year-long set of celebratory events that we're going to have here in 2013. I'm Eric Green, Director of the National Human Genome Research Institute, and we are delighted to see all of you here and to start this 2013 year today with respect to what are going to be some pretty amazing things to celebrate, what we want to celebrate in 2013. Let's remind you what a historic year this is really going to be. We are celebrating the 60th anniversary of this Watson-Crick discovery, the double helical structure DNA in this famous publication in nature in 1953, probably more near and dear to our hearts at NHGRI, and certainly, as you will hear from the speakers today, we're also celebrating the 10th anniversary of the completion of the Human Genome Project, which will truly be at the 10th anniversary this coming April. To commemorate this historic year, NHGRI has programmatically planned a number of things that I just wanted to briefly share with you so that you're aware. And in fact, all of this that is showcased here on this slide is being led by my special thanks to Rudy Pazzotti and Brad Ozenberger, who have co-chaired a committee of people from NHGRI that have put together programs for the next handful of months to really celebrate this remarkable year that we're having. It really consists of two things that I want to make sure you're aware of. They're shown over here, and these are posters you'll see on campus. There are a series of three paired lectures. Today is the first of three. You can see there'll be a couple of other ones coming up in subsequent months. And then on April 25th will be a day long, and by the way, those paired lectures will be held here. And then on April 25th is a day long symposium over in the Nature Conference Center that will feature a number of very outstanding speakers to really have a day long look at the genomics landscape a decade after the Human Genome Project. These are the events we have planned immediately here on campus. I would actually point you to this website if you're interested in following these and more. It's at www.simpleurlgenome.gov.com which will also eventually have links to videos of all of these talks and the day long symposium, and we'll have other programming events that will be coming as the year goes on. So if there's one place you want to look to to sort of see a roadmap of what's going to happen, I would point you there. One of the things that is already described on this particular website, it's this very last link here, is the final thing I just want to tell you about. Those of you who have not heard, NHGRI has forged a major partnership with the National Museum of Natural History from the Smithsonian Institute to create a genome exhibition to commemorate these two important milestones in 2013. And this remarkable new genomics exhibit is at a very late stage of design, and we'll go to fabrication in the coming weeks. Pleased to tell you that opening in mid-June of this year at that museum will be this exhibition, Genome Unlocking Life's Code. This has been a remarkable partnership and collaboration with them. This will be resident in Hall 23. It's easy to remember because we have humans have 23 pairs of chromosomes. Hall 23 of the museum, and it's immediately adjacent to the Hope Diamond. So just follow the crowds to the Hope Diamond and take a left. And you'll find this. It will be there for one year from roughly June until the following summer, and then it will be touring around North America for probably four or five years. And we're expecting great things of this exhibition. I can tell you by reviewing the design, it's something you absolutely want to make sure that you see while it's here in the DC area. And in fact, nature also acknowledged it in their first issue of 2013. They gave a nice shout out as it being one of the hot tickets for 2013 in Science and Art, and that's this exhibition that'll be opening at the Smithsonian. And where we are is the kickoff. We're right here. We're at this very first event of what's going to be a series of events. And I can tell you that I couldn't think of two more appropriate people to kick off our year-long celebration of the 10th anniversary of completing the Human Genome Project than today's speakers. These genomics pioneers have truly shaped the field of genomics as we know it today. So one of the speakers is Dr. Robert Waterston, Bob Waterston, who's currently professor and chair of the Department of Genome Sciences at the University of Washington. In his role as the William H. Gates III endowed chair of biomedical sciences, he is currently leading research into the genetic control of development in the nematode worm. His recent research accomplishments have resulted in the development of a novel technology to decipher automatically the dynamic expression of genes with single cell resolution and minute time resolution. And as part of NHGRI's modern code project, he and his collaborators collected data that accurately defines the complement of both protein coding and many non-coding genes in the nematode worm. But prior to his arrival at the University of Washington in 2003, Bob established and directed the Genome Sequencing Center at Washington University in St. Louis for many years, partnering with the group headed by our second speaker, we'll talk about in a minute. The Waterston-Sulston combo completed the sequence of the nematode worm genome before turning their attention to sequencing the human genome, all part of the human genome project. Now, Bob's foray into genetics and molecular biology started under the tutelage of Nobel Prize winner Dr. Cindy Brenner in Cambridge, and there he worked to understand life at the molecular level through studying the nematode worms, the elegans, along with guess who, John Sulston. So turning our attention to Sir John Sulston, who you see on the screen up here, and I'll explain that in a minute, is currently chair of the University of Manchester's Institute for Science, Ethics, and Innovation, which was established with the mission to observe and analyze the role and responsibilities of science and innovation. The institute examines the ways in which science is used in the 21st century to evaluate possible or desirable changes and to consider the forms of regulation and control of the process that are appropriate or desired. Now, prior to his arrival at the University of Manchester, John was the founding director of the Wellcome Trust Sanger Center from 1992 to 2000, where he led a highly productive genome sequencing group that first sequenced the worm genome in partnership with Bob's group at Washington University and later contributed greatly to the sequence of the human genome, again, all part of the human genome project. Then in 2002, we co-authored the book The Common Thread with Regina Ferry, an account of the science, politics, and ethics of the human genome project. Sir John is also a fellow of the Royal Society and an honorary fellow of Pembroke College in Cambridge. Prior to the human genome project, John, like Bob, worked for many years in the biology of C. elegans, in particular, establishing the precise lineages of all of its cells. And for this work, John was awarded the Nobel Prize for Physiology of Medicine in 2002, jointly with Sydney Brenner and Bob Horvitz. But let me emphasize why we wanted to kick off our celebratory year with these two accomplished genomics researchers. The historical accounts of the human genome project are already describing the contributions of the project as being at least two fold. First and foremost, of course, they generated the first reference sequence of the genome, the human genome, and those of model organisms, such as the nematode worm. But really, the second thing historians are already saying about the human genome project is how it began to change the culture of biomedical research, in particular with respect to the free and open sharing of scientific data. And I would tell you, and I was there, Bob and John are widely regarded as the icons of leadership that led to the second important contribution of the human genome project. And I think as you'll hear from both of them, they brought the social norm of open data sharing from the nematode research community to the more rough and tumble human genomics arena, persuasively arguing for free release of human genome sequence during its generation by the human genome project. I can tell you, their voices were influential in establishing the Bermuda principles on data sharing that you will hear about shortly. Well, in the past few years, Bob and John have jointly won numerous awards for their scientific work and their support for the scientific community, including the Gardner Award, the General Motors Prize, the Dan David Prize, and the George Beetle Medal in the Genetic Society of America. And Bob also received the Gruber Prize in genetics. Well, before I turn the podium over to Bob and John, let me just set the stage with a couple of additional things. First of all, I absolutely wanted these two to kick off this year-long set of events. I thought it was perfect to start that way. Due to some challenges, it was difficult for John Sulston to be here in person. But we're an HGRI. We don't let little things get in our way. We just figure out solutions. And the solution was let's just bring him in by video. And so John will be on the screen, and there'll be all sorts of heroic things going on back there to make sure that everything's being shown appropriately and each person is going to be talking. And we don't actually even know how all this is going to work necessarily. We were fortunate that Bob Waterston is here in person. So we're going to have this tandem of one speaker by video. By the way, video directly from the Sanger, what is now the Sanger Institute, seeming very appropriate, that we would directly link the Sanger Institute here with NIH for this paired lecture. So that's why one's in person and one is remote. But I also thought before I would turn the podium over, I also thought I would set the stage for what I fully anticipate you'll hear about. I'm a bit of an archivist myself, especially of photographs. And I dug and dug and dug of what I had and found a few photographs that I think in many ways capture some of the things you're going to hear about. So I'm just going to set the stage by just sharing a couple. We're going to hear about these Bermuda meetings that took place. And I just happened to find I had photographs. I actually couldn't find any photographs of Bob. I know he was there. But here, and John Sulston, you can't see these. But we have a very flattering picture of you, both individually, as well as in a group photo with some of the key people that were there and heavily involved in issues surrounding data release and data generation as part of the Human Genome Project. So that was 1998. And actually, one could easily conclude by looking at this picture and looking at John Sulston over on the video that he has not aged a bit since 1998. It is truly remarkable. The other thing I will tell you about John and Bob having been there on the front line of the Genome Project from beginning to end is they were also sort of the icons for reason and for advice. And this is a photograph from the Cold Spring Harbor genome biology meeting, or whatever it was called. It was probably called the genome mapping and sequencing back then in 1998. This was taken very late at night. In fact, chances are it was probably taken probably in the early morning, I suspect, right there in the dining hall of Cold Spring Harbor. I may see a lot of this. And I suspect Bob Waterston, and John can't see this photo, if they remember it, would see a lot of emotion in this photograph. First of all, there's a lot of alcohol being consumed. You can see that. But people didn't look particularly happy. And these were all senior members of the Genome Sequencing Center at Washington University. These were all people working with Bob. And it was 1998. Anybody who thinks the Genome Project from beginning to end, everything was simple and that everything was solved and that there was never any frustration or anger, apparently you weren't there. And this was one of those moments where things were tough, things were confusing. There was a lot of politics in the air. There was a lot of hard decisions about how quick to scale up the sequencing of the human genome, how to do it, what the right strategy should be. And these scientific, or actually all scientific leaders, including there's Rick Wilson with actually his head in his hand, who's now the director of the Wash U Sequencing Center. And these other folks have major positions, both in academic centers and at least one in the case in the pharmaceutical industry. And sat there talking to Bob and John. And basically Bob and John sat there and talked, all of us, I was there too, I was taking the picture, talked us off the ledge because the frustration was so high and it was just another example of their leadership of just sort of keeping the ship very calm even during turbulent waters at moments where it seemed like things were not going so well. Happier days did come as we all know. And this other photo, which has been widely shown, I know is a photo I happened to capture of the two of them looking much happier now. And this was actually the first meeting, what is now an annual meeting that takes place in Marko Island in February of every year. It was actually the first annual and they came and it was a much happier time with the genome sequencing efforts for human being well on track and nearing a draft stage and things were good then. And but again, they were looked to so much for leadership and for mentorship of folks that had really basically launched their careers by participating in the Human Genome Project and needed their guidance along the way. So with those three images in mind, let me now please join me in welcoming Bob Waterston and John Sulston and to thank them for their vision and leadership that has been so instrumental for making genomics the vital scientific discipline that it is today. So Bob, I think you're gonna start, right? Oh, well thanks very much for the kind introduction and I'll have to get a picture of, I'll have to get a copy of the Cold Spring Harbor picture. That was indeed a tense night. Okay, so as Eric said, John and I are gonna do a tandem here. I'll do the first half and John will do the second. We'll have more or less a worm's-eye view of the Human Genome Project that we're gonna share with you today. And my part will be taking you, looking back a bit and John will take us forward talking about some of the implications of what we did, especially in terms of data release. And if the technology all works, John will actually be able to talk a little bit during mine. John, can you see me? Yes, hi Bob. All right, excellent. So we'll try to comment a little bit on each other's talks. All right, so the main character today is indeed C. elegans. That's the star of the show. This is the nematode worm that Sidney Brenner, whoops, the one, it's not crawling, it's an inc mutant. Okay, this is the nematode worm that Sidney Brenner chose as his model organism in the 60s because of the great genetics and its simplicity. You can see on the left the egg developing. When it flips back, it starts at about the 16 cell stage and does all this in about 12 hours. And as Eric mentioned, John figured out the lineage of the worm, every worm goes through exactly the same pattern of cell divisions in the late 70s, early 80s. But it hatches and has interesting behavior. It crawls across the plate and sniffs and poops and eats and all kinds of interesting things. And it does all this with 302 neurons. The complete circuitry of those 302 neurons was worked out by John White and his team, also in the late 70s, early 80s. So all of this is known in great detail. Let's see, can I, anyway. So for all this, there were an increasing number of scientists trying to use the genetics to identify genes that affected the development, affected the behavior. And because the genetics were so powerful, the genes flowed. But the challenge became cloning those genes. The method at the time, there were really two options. One was transpose on tagging and that didn't always work and you had to find mutants all over again. And the other one was chromosome walking, where you started from one place on the genome and through a laborious and tedious process, you would find a series of clones and eventually hopefully end up at your gene. It doesn't want to advance at the moment, but we'll get it to. There we go. Our colleagues and rivals in the Drosophila community had a huge advantage in doing this kind of operation. They had polyteen chromosomes, where the whole genome is laid out for you, each chromosome in its linear order and big enough to resolve so that each band basically represents a gene and you could pick out where the genes were and in terms of chromosome walking, this was a huge advantage. Worm chromosomes, by contrast, are tiny. They're just little smudges and cytogenetics was very poor. Fortunately, large insert clones and genomic libraries came along at the time so that with Cosmids, they had a 40,000 base insert, 40KB, so that just 2,500 clones could represent the whole genome if you had the exact right 2,500 clones. And John recognized the possibility of this and in 1983 at the Worm Meeting discussed the possibilities and by 1984 here, spring of 1984, he announced his intentions. By this time, he'd been joined by Alan Coulson and they announced their intention of trying to construct a physical map of the worm genome. Now this is a cover of the Worm Breeders Gazette in which they announced their project to the worm community and this deserves a little bit of comment in terms of just the community. So the Worm Breeders Gazette came out every six months except on every other year when the annual or when the international worm meeting took place. And it was a vehicle particularly for the postdocs who from Cambridge who had gone off to start their own labs. I was in St. Louis feeling very lonely having left the nest at Cambridge and I'd look forward to getting my Worm Breeders Gazette every six months to figure out what everybody else was doing and especially there in Cambridge. The idea of sharing like this though and these were all pre-publication, you're not supposed to cite these. They were simply to share information. This is not a new idea though. This is quote from Ben Franklin quoted in Common as Air by Lewis Hyde and in particular this part he was talking about his experiments on electricity. I ought to keep them by me till corrected and improved by time and further experience but since even short hints and imperfect experiments in a new branch of science being communicated have oftentimes a good effect and exciting ingenious to the subject and so becoming the occasion of more exact disquisitions and more complete discoveries. So it was in this spirit of the Worm Breeders Gazette in this sense of sharing that Alan and John outlined their program here. And in particular they talked about how they were gonna map the clones and overlap them and so forth but importantly this was part of it. It is clear from the outset that the physical map will only become a reality as a communal project. In its final stages it will have to be completed opportunistically and in any case numerous markers will be required to align it with the genetic map. We therefore invite anyone who has genetically positioned DNA that is larger than 10 kb in length and available for distribution to collaborate with us by sending a sample for fingerprinting in comparison with the database. In return we can send you any flanking Cosmets that we find as well as any others you need. So it was not just simply telling the world but it was inviting the whole community to participate in this project. And I hope this slide gives you an idea of what was involved. So we're starting out with the whole chromosome, the DNA. And by comparing one insert to another John and Alan were able to get a series of overlapping clones, a minimum path through that represented by the clones in red here. So this is the physical map that John and Alan were working on. Meanwhile, the community was working on the genetic map placing a gene here with a marker here and maybe they had a gene of interest here, okay? They made the connection of gene one and the marker here so therefore gene X had to lie somewhere in between and indeed by test you could show that that was the case and so this joint effort between John and Alan and the community was producing the map. John, do you want to comment any more on that? Yes, I think we, although we'll go on quickly to the further joining. At this stage we had quite limited mapping. We had 700 gaps so these chunks on average were only just over 100 kilobases. And so we had to have rather a strong etiquette about whose rights were involved when people gave data because obviously if somebody identified the island by gene one then the person with gene X was very heavily dependent on them. So we had quite a lot of twoing and froing and this was one of the things that taught us how you have to have the right kind of etiquette to do these things. But I would just emphasize once again as Bob has the virtuous circle of the community and the central mapping labs going back and forth, back and forth between the two sorts of map. Over to you Bob. Okay, great. Yeah, the map was not perfect as John said. One of the problems was, oh so and then of course they were able to go ahead and sequence that. But one of the challenges was that they had fragments or islands of clones that they weren't able to associate with the genetic map because they had no markers on it but also because they had no linking clones. And as John mentioned, there were some 700 gaps at the time when I joined, when I came over on sabbatical and I have to confess, I don't know if John actually knows this but when I came on sabbatical I was nominally supposed to work on finding new muscle, new genes affecting muscle but in the back of my head all along I had the hope that I would be able to contribute to the map. For those of you who don't know, Maynard Olson was in the lab next door to me at Wash U. I was working hard and dedicatedly on the yeast map and so I was strongly inculcated with this with the mapping spirit and when I went to the LMB for my sabbatical John was kind enough to take me into his lab or because the main worm lab didn't actually have any space so I had to find a home and John provided me one. And so it was this challenge of trying to link up these bits of pieces and close these gaps that was confronting them at the time. I tried several things but actually about the summer before I left the solution started to emerge from Maynard's lab. I went and visited and there a graduate student David Burke had begun to develop yeast artificial chromosomes. And indeed shortly after I got back home I made a worm yak library. I think it was one of the first libraries made in fact it was made in parallel with the first human library. David was kind enough to take me along for the ride. And once we had those with Yuji Kohara's help who was a visitor in John's lab after I left we were able to position the yaks by hybridization against the existing clones in the map as well as tie in these flanking ones and the yaks indeed bridged the gap. The advantage was that yeast was a different system or you carry it and these were single copy. We're not fully sure what the reasons are but these bits of DNA that E. coli didn't like were certainly tolerated well in yeast. So this went on very quickly. Basically within a year after we had the full a good yak library we were able to tie things together came we instead of making competing efforts we joined forces with John and Ellen we did one set of hybridizations they did the other and by the end of by the end of our middle of 19 end of 1988 we had a much more complete map. And so here you can see the six chromosomes of the worm. There's still a few gaps here but you can see all the markers that have the community is placed on here. It's getting to be indeed a quite respectable map. And by 1989 at the worm meeting Ellen printed out all these things on the A4 paper eight and a half by 11 sheets basically pasted them all together. And so this is chromosome one along here. Chromosome two, chromosome three and you can see that chromosomes two, three, four, five are more or less fully complete.  There's a little piece of DNA sitting down here. So there's still a few pieces left but it was great fun at that meeting because everybody in the community was using these clones and all meeting long we had this up. People would come by they find their way along the chromosome and they'd start writing down the names of the clones that were in their neighborhood and then pretty soon they'd write for the clone. So, and many people, many of the talks had exactly had advances because they had been able to clone their gene through this. So, but we had a secondary reason for posting the map like this. By 1989, the human genome project was beginning to take shape. The NRC report shared by Bruce Alberts had come out recommending that action on this as well as the Office of Technology Assessment report. And so the idea of sequencing, the human genome had indeed taken root despite much opposition. The both reports, particularly the national calendar and the astronomy report, suggested the course of on human to start by developing maps and to save sequencing for a later time. But to use sequencing on model organisms with smaller and less complex genomes. Hoping that there would be more bang for the buck in those for those genomes. And this effort was gonna be run jointly by the DOE and NIH and by this time the NCHGR I think it was had been formed and Jim Watson, who was still the director at Cold Spring Harbor was appointed the first director of the center. And so for various reasons, we were hoping that we could talk to Jim during the meeting. We could get him to come by and see the map and interest him in supporting a joint effort between our two labs to begin sequencing. And Jim, of course, had been interested in the idea of a complete description of genomes for a long time. In his book, the molecular biology to cell in the first edition in 1965, he has a chapter called a chemist view of the cell. And then it has the whole section on the significance of a finite amount of DNA. And just as you saw in the polythene chromosomes, I mean, that's all the information. This is digital information. It's no longer analog and all its complexity. It's digital information. And if you have the order of the bases along those strands, you have all the information that it takes to make that organism. And in that chapter, Jim had already begun speculating about what it might take to understand E. coli completely and identify all of its genes. So fortunately, Jim did see the map at the meeting. And reportedly when he saw it, he, his comment was, you can't look at something like this and not wanna sequence it. So we thought, yes. So we did indeed have a meeting with Jim. It was John, me, Allen, and I think Bob Horvitz, met with him, I think, on a Saturday afternoon. John, you had the most bold proposal. Do you wanna tell people what you suggested to Jim? Well, we talked a bit about this beforehand, I believe, but I was the fall guy who said to Jim, well, look, you give us a hundred million dollars and we'll do it. I mean, that was the price that Wally Gilbert had suggested for sequencing the human genome a little while before, a dollar a base. So we thought, yeah, we could do that. And indeed, well, Jim replied, oh, that's not the way we do things here. So we did something that way elsewhere. And of course, he was right because in the end, we did it for a great deal less than a hundred million dollars. But anyway, we put the offer on the table to show he was serious. Jim didn't blink when John said, he said, that's not the way we do things. Anyway, but he did say that certainly NCHTR would entertain a proposal from us for a pilot project going for three years. And with the funding split, two thirds from the NIH and one third from the MRC. And indeed, that's how it went down. So with that, we were started. We were working closely as illustrated in this cartoon from the new scientist about 1961 or two or something like that. And our plan at the time was basically to double our throughput every year. And actually we did that for a very long period of time. The project attracted very talented people in both labs and at the same time, because this was obviously part of a much larger effort to improve sequencing, there were better and better ways to sequence. So we were constantly revising plans, tossing out something to be replaced by something else. And at the same time, trying to keep up the throughput. I've put a little note down here in the corner to remind me to tell you that while initially the map had been shared by this wormbreeder's Gazette as technology improved in the late 80s, we started sending around tapes and used the precursor of the internet bitnet to communicate with the community so that Paul Sternberg on the West Coast had tapes and we in St. Louis had tapes, Bob Horvitz or Marty on the East Coast had tapes so that people could access the map and John figured out how to send updates automatically to the sites so that the community could access the map. And as we began to sequence, we did the same thing. Basically as we generated sequence and assembled it, no matter what the state, we basically started posting it on the web. By that time, there was a web and the internet was much more sophisticated and we were fortunate to have Richard Durbin and Jean Thierry Migue develop a, what's close, C elegance database where we could display all this information for the community over the web. And so basically we had an, you know, almost live representation of this sequence for the community. They knew where we were sequencing and which direction we were going. And so we had people say, well, you know, that's on chromosome two, you guys aren't gonna sequence that until next year. We're gonna leave those genes, we're gonna study the ones on chromosome three where you guys are already sequencing. And so we kept up the spirit of collaboration between the central genome facility, generating the raw data and the community using it. And it was a great collaboration, sped up research enormously, I think. Our successes started to draw attention from other sources. At Washio, we were approached by Merck in the early 90s, mid 90s to do ESTs. ESTs at the time were being held privately. And Merck wanted to change that. They were willing to pay us to produce sequences. They knew about our reputation of putting everything out online. And they were perfectly happy with us to generate these ESTs and deposit them. And so that's what we did. And by, I can't remember, we generated hundreds of thousands of ESTs speeding the discovery of human genes and not incidentally making all of this information public instead of having to subscribe to a private database. We also learned a lesson for the, that as Eric said, it's a rough, it's a human community is a little more rough and tumble. Ventures EST paper used all of our ESTs and they equaled about what they had from their own. And so we hadn't published on them yet, but they were out there. So it was probably fair use. But when we tried to publish our paper, nature said, well, we've already published them. So it was a little frustrating. Nonetheless, what? Anyway, at the same time, the success of the, of John's group led to interest on the part of the welcome trust for expanding their effort into human sequencing and eventually leading to the creation of what was first the Sanger Center and now the Sanger Institute just south of Cambridge. So with this, we started thinking more seriously about how we could extend our efforts more systematically to take on the human genome. And by the fall of 1994, we presented our plan our ideas for how the human could be done at both the NHGRI and to the welcome trust. There are some stories there. We can go, we can do those later. But I think the end result was that the community finally started taking seriously the idea that Sanger sequencing might be up to the task of sequencing the human genome provided that there was continuing improvement of this kind of incremental two-fold a year kinds of things. It didn't need a revolutionary breakthrough in technology. And the plan that we outlined at the time was remarkably close to what was actually followed with in the end, although there were severe swings back and forth between that and where we finally got there. But that eventually led the NHGRI to fund several pilot projects. And across the world, in various, in many countries, efforts were begun at sequencing the human genome. So that led the welcome trust and the NHGRI to convene the first Bermuda meeting in 1996 to coordinate these growing efforts across the world. And coordination was indeed badly needed. There were about as many ideas on how to sequence the genome as there were groups present in the Bermuda meetings. Lots of different ideas of how it would work best in one form or another taking advantage of Sanger sequencing. And there was also, because people were focused on, I don't know, impact, I would say, there was a lot of interest in trying to sequence the few genes that had been discovered in the last year. Our group in fact had sequenced exactly the same clone that Andre Rosenthal had sequenced in Germany just before the meeting. And this was, we found this out. This led Francis Collins to describe this as sort of the likelihood of a car wreck in the Sahara. But nonetheless, it was a challenge. So we had all these different groups all pursuing different agendas. And there needed to be some heavy coordination. So, but there was another important topic beyond that. And that was how to deal with the data. There, human sequencing, human sequence had already been patented. The tradition in human genetics was not what it was in the Bermuda community. In fact, even after publication, sequence was often not released beyond what was necessary to support the publication. And so how could you organize and coordinate an effort to sequence the human genome when people were not releasing their data even to one another? And so we had, in one of the last sessions, we debated all these issues. And it's important to know that it wasn't just scientists at the meeting, but there were government representatives there as well. Some of the projects had support from their governments basically with the idea that they were going to hold turf, that they were going to have intellectual property. And so it was a tough discussion. But in the end, we agreed to the following principles and this is actually a photograph of the whiteboard of the things as the group discussed them and you can see it was a work in progress. But the important points are that there was gonna be automatic release of sequence as long as it was greater than assembled sequence, greater than a KB. Any finished, annotated sequence was gonna be submitted immediately. And the idea was agreed to that all the sequence should be freely available for both research and development to recognize its benefits to society. And at the bottom, the funding agencies are urged to foster these principles. Obviously, this is just a group of scientists getting together talking. We didn't have any real force and so it was important that the funding agencies go along with that and put their persuasion behind it. I should say that while there was agreement among the scientists, the government representatives had to be more reserved. Several of them had to go back to their countries and indeed in one case it took a couple years before the policy was adopted. But it was and as Eric said, it had a major impact on I think both policy long term but also in terms of how the genome project was perceived by the community. Even in the mid 90s there was still a lot of skepticism about the value of the genome project and how it was gonna benefit people and I think this helped to allay the concerns. And John's talk is gonna pick up and explore some of these issues more. Anyway, we kept sequencing and by 1998 we had the first worm sequence and it wasn't quite complete. There were still some very sticky regions but it was about 97 megabases of the 100 megabase genome and we knew those that last 3% would require highly specialized efforts and indeed the last gap was completed, I think, in about 2002 with Alan Colson, the last person still working. But it was done and I think today it's probably because it doesn't have highly centralized center mirrors with all that stuff in between. It remains the only animal genome that's complete from telomere to telomere. It's highly accurate, we're proud to say and we've been able to validate that in the last couple of years in my lab. We've sequenced 2000 worm genomes and with different technologies it's just amazing to think that we spent eight years sequencing the first genome and in the last two years we've done 2000 with two people. So it's a little different operation today but the result is that we have 32,000 X coverage of the worm genome and we've been able to find the few remaining errors and these are now being corrected. So we think we have a highly accurate reference sequence but the accuracy was roughly on the order of one in 40,000 bases or so. At this point, we had done that. As Eric said, 1998 came with its own challenges. I'm gonna skip over all of that because it was just lots more and lots, lots, lots more. Many groups joined. I think there were 13 different groups across the world who contributed. We like to think that because of the Washu-Sanger connection, anchoring it as an international project made it easier for groups across the world to join and as Eric said, by 2001, we had a draft sequence. That was followed quickly by the mouse, a draft of that in 2002 and then the chimpanzee genome. And of course, those are all draft sequences. Importantly though, while all this was going on, the groups continued to sequence the rest of the human genome, trying to make it in high quality. You can see that people were not so interested in the final version as they were the draft version. We didn't even get top billing in this issue of nature. It's down here. Going the last mile. And even that still had problems. There were still gaps. Evan Eichler in my department constantly reminds me of the shortcomings of the map in complicated regions and to their credit, they are sorting those out. It's an important source of variation. So this is 2004. I guess the 10-year anniversary is an anniversary of the announcement of the completion. I was, when we heard about the 10th anniversary, I was trying to figure out what anniversary, but in the genome project, we've learned that there's an anniversary any year. So anyway, importantly, all of the sequences out there in the public domain, and as I said, John's talk is gonna explore the consequences of having it out there for everybody to use.  So with that, before closing, I wanna thank all the people, many, many people who I've been fortunate enough to work with through the years. My colleagues at the University of Washington now, Washington University before that. Most people don't even know those are different institutions. People at the Welcome Trust and the Sanger Institute now, especially the Worm Community, for working closely with us throughout the years. And providing the model to convince our colleagues in Bermuda that it was the right thing to do. EMBL, the EBI colleagues, and John's colleagues at the University of Manchester. But as it says, opinions are our own. So with that, I'd like to thank you for your attention and I'd be happy to answer questions and John can join me for the questions for sure. I think we can do questions. We can do some questions now and then more questions after John finishes. Yes? You gotta go to a microphone. So Bob, was there any resistance in the Worm Community to your data sharing model? Were there any bad behavior that you had to deal with there and provide a model for what might happen for human genome sequencing? I don't think there was resistance. It was voluntary. You didn't have to, if you wanted to share clones with the mapping group, that was fine. And if you did though, you had to expect that it would be published. But there were some, as John indicated, there were some sticky issues because there were competing efforts. Certainly I was involved in one where there was information that we had to share and wanted to make sure that people were playing fairly. There were, and when we got to sequencing, there were some issues as well. It was an unfinished sequence. There was one publication that thought there were several pseudogenes because they hadn't checked with us to make sure that the sequence was actually fully correct in those regions and those were just sequencing errors. They thought they were pseudogenes. So there were hiccups like that. There was not, in terms of the sequencing effort itself, there was many people in the worm community thought that we were taking resources from the biologists and this was not a good thing to do. But that was a common reaction across the whole community. Yes. But that, Bob. Oh yes, John. Can I join in? Absolutely. Yeah, quick comment on that. Yes, I looked it up. I mean, in 1991 at the worm meeting, a lot of people were coming up and complaining exactly as you said about taking resources. In 1993, it was quite the opposite because by then the sequence of the worm was being exploited and making the worm more powerful in the areas of sequence than the fly and people were actually getting, beginning to get grants on the basis of having the genome available. So we actually saw in a couple of years or so that switch around from not seeing why resources should be spent and not seeing the point to realizing how valuable it was. Yeah, that's a excellent point because by 1991, we had a few cosmic sequenced. We hadn't impacted on almost nobody. But by 1993, we had a couple of megabases and even that was only a couple percent of the genome but people were able to do this. And I remember a story about Bob Horvitz and his competition for postdocs with Jerry Rubin and the tide had turned. Yeah. If you look back on these past projects that got you here, is there anything that you wish you did differently that may have changed the outcome of the timing? Oh, there were lots of things I would have liked to have done differently. I think it's, do we know where this is coming from? Do we're working now? I don't know, I mean, there were many things that we could have changed and done better. I don't think there are, I don't have the sense that there are any major snafus that we would have done. I guess one thing I would wish is that we had a more disciplined response to Craig's challenge, but it worked out. Rudy? I'll go ahead. So when you were describing the early days of building the physical map and then overlaying a genetic map on that, I was sitting here and I couldn't help but think if we were doing that now, there'd be a data coordinating center, there'd be a requirement to deposit it in NCBI that everybody would have ready access to it through that. And so what did you do in the early 1980s? Somebody was writing this out in a notebook. Were you using carrier pigeons to get information back and forth? Can you talk about the challenges of just exchanging the information in the absence of an internet? It was 1990, well 1985, not 1885. But I also saw the pieces of paper at Cold Spring Harbor. So, I mean, there were challenges.   So that was part of the point. Certainly, John and Alan were making computers were central to keeping track of the data and John can comment more on that. And we did have BitNet by the time I got involved in it. I think for the first couple of years, John, it really was through the Worm Breeders Gazette that you were and mailing back and forth. But by the time I got involved, we really did have places across the country where you could access it. And you can describe that in more detail, I'm sure, John. Well, yes, I wrote a program which came to be called Contignine, which was just a graphing program. But it also included an element of automation for joining things up. We kept it somewhat under manual control. It wasn't something where you just threw in all the fingerprints and it would assemble. But it helped you. But the important thing were the graphics. And having got it digitized in that way, then, of course, I could devise mailing programs. And because BitNet was very slow, even that graphic that you see on the back of the hall have taken a very long time to send. And so what we did was to send update files to the centers and then they distributed them further. So we took advantage of the gradually growing power of the connections. And I would say exactly the same thing happened with the sequence. We tracked, I would say, the power of the sequencing machines. And in some ways contributed to them during the 90s now, jumping from the map to the sequence. That was the limitation. It was how much sequence we could get out per day and we were doing all we could with it. And that was the doubling of the speed each time was us keeping up with our wet chemistry and the software. Yes, but we were absolutely dependent on the growing power of the sequences themselves. And so it was with the map and the internet. Yeah, just in terms of the BitNet, I would send John an email. I mean, this is not, you know, this is five sentences or something. And I would watch the echo come back on my screen as it went to North St. Louis, to Champagne or Benna, to Indianapolis. Then it would sit there for a couple hours. And then it would finally land in France before it got to England. And just a simple mail like that might take overnight. Yes. Thank you very much. I wanted to just ask you about your perception historically about this, the good of sharing. Which I think it really has created this concept of the positive. Sharing is a good thing. And when you first made the proposal in the Worm newsletter, it was about worms. And I just wonder if you could just speculate if you think there would have been a different uptake if it had been sharing about humans rather than worms. Back then. I mean, the ethos was completely different in the communities. And part of it was that the worm community was small. There was nothing at stake. Right. And basically all of us had a shared experience. We came through Sydney's lab or in the later years we were, people were the intellectual grandchildren or great-grandchildren of Sydney's lab. And so that sense of community was strong. There was also a sense, I would say, of us against them. There was the much bigger and much more robust fly community. And so there were all of these things contributed to a very strong sense of community within the group. And in large part because of that, combined with the early use of the Worm Breeders Gazette, there had developed an etiquette of sharing so that you would put things in the Worm Breeders Gazette and you would not expect people to take that project up and publish on it. And if you did something like that, you were shunned. And so there was, the ethos of the human genetics community was just polar opposite, I think. I remember going to meetings where people were talking about doing mapping and the probes they used and they were all without information. There was just no way that anybody could, the talks were given in a way that there was no useful information provided. I mean, people, I would urge people in the human genetics community to counter me on that, but yes, Eric. Bob, let me ask one more question and then maybe we should transition to hear from John. But I was there, I was a postdoc in the department down the hall from you during much of this era. I should remind people, and I don't remember, I don't actually know the answers to the question I'm gonna ask, even though I was there on, I was within yards of all of this. I mean, when the Genome Project began, the first genome centers were set up and one of them was set up at Washington University under David Schlesinger's leadership. I was a participant in that, I was a postdoc working in that.  But you guys were heavily focused on worm, were heavily focused on the goals of what you wanted to accomplish and then you made your play as successful to get the worm sequenced as part of the Genome Project. There was some moment in there where both of you decided to stick your toe in the water and get involved in human genome sequencing. You didn't have to do that. You both had fantastic careers. You had gotten what you wanted. You had made your contribution.  But somehow, and you weren't part of the human genome center, but somehow both of you just kept finding your way into this rough and tumble world. I'm just, was there a moment where you said we're gonna go for this? Or was it that you wanted to have your sequencing groups have longevity and therefore saw that the human sequencing was it? And so that's sort of part A of the question because I don't remember what that moment was. Part B is what would you have done if the Bermuda meetings hadn't gone well and that you couldn't bring the ethos of the nematode community into the human community? Would you still have participated or would you have said to heck with this, let these human genomicists figure it out themselves? That's my two part question. Okay, John? No. No. No. Hit a minute. All right, on the first. I think you couldn't be doing all the sequencing without thinking about the human. John and I were having, we're in preparation for this, we were having an exchange of males just trying to think about when we first started thinking that sequencing the worm would be possible. And it was there from the start. It was just, it wasn't a realistic possibility but thinking about the genome, the map had an end in itself and was important in and of itself but somewhere in the back of Maynard's head and doing the yeast and I think in the back of John's head was that there was sequence behind this. And so that was part of it. Part of it was that there was, I would say a great deal of pessimism in the community that what we were doing in the worm would be applicable to human. And so we wanted to try that and we did and showed that it could do it. And then there was this aspect of the outside, Merck coming to us, getting us involved in the dirty world of human genetics. And on the other end, the Sanger, or the Welcome Trust coming to John, we wanted to see, we needed money, resources to finish off the worm. And it wasn't immediately forthcoming. There was a lot of money to be committed to getting the worm finished. And so we explored various possibilities to do that. And I think John's deal with the devil was that he could get resources if he committed to sequencing the human. Is that fair, John? Yeah, no, I think you've put it exactly. It's a Faustian contract in my case. And I think that probably led it. I do urge people, I hope you agree, Bob, to read the Common Thread. I was looking through this again last night and it really has laid out, we're all in there, you are all in there, everybody who's involved in this is, and we detail these little stories. There was many more than we have time to go through now. And it is a fascinating road that was traveled. But I was in the end offered that deal. It wasn't that the Welcome Trust would finance the sequencing of the worm, but they would provide the space which the MRC didn't have. And then the MRC was drawn in to finish the sequencing of our half of the worm. And I would say, coming back and linking this to the previous question, that we were quite intrigued to take it forward. This level of cooperation on the mapping, I think was unique to the worm community when you think of all the other organisms, the people in the position of Bob and me and other people involved in the maps all fought. They all tried to have their own papers. You know, you had separate papers about yaks and about cosmetics and about every other kind of clone. We were the ones who brought it together. And it was partly because of the community, but also we made it happen. Every worm meeting, there was quite a tense meeting with all those who were interested in the genome. And we would argue through cases about how to handle the awkwardnesses and so on. And then I mentioned already the thing about the resentment from the sequencing. And we got through that because everybody persuaded. But it did take work, I think, to make it come together. We had a good start with the worm community, but it was made to work. And so going forward into the human, I think we did, as well as the fallacy and contract, have a level of optimism or at least a level of determination to translate these feelings because we thought this is the way humans, you know, make sorts of go as well in the end. And it did, thought of. And sort of. And in answer to your second question, fortunately it didn't happen that way, but I think what we probably would have done is go back and just release the sequence ourselves. It would actually have been easier than trying to get it into GenBank. I mean, GenBank wasn't happy about accepting incomplete sequence or draft sequence. And we would have just posted it on the web on our own and made the community see what could happen. And if not in 97 and 98 or 99, I think we would have won the day. Just a little historical footnote relevant to that. I was looking a little while ago at the 1990 report from NIH DOE on a human genome project. And it turned out, I'd totally forgotten this, but there was a data release policy there for physical mapping, that all mapping information had to be released within six months of generation. But that didn't galvanize, that didn't create the ethos. It was Bermuda and it was the push by you guys and the example of the worm community that really got it to stick. And I would guess that that six month wasn't fully honored. All right, should I just turn it over to John? Okay, John, you're on. I'm gonna sit down, but I'll be able to comment together. Okay, I hope so. So you're going to lose me now. You're gonna get the slides instead. So bye-bye. I hope you can't see me. Well, it doesn't matter whether you can or not, but you can hear me all right, yes? I would just like to start quickly by saying thank you very much for setting this up, the video link. I appreciate it's a lot of work for many people, at your end as well as ours. And I do have particular, I have family reasons why it's difficult for me to travel this month, so I'm grateful for that. However, I'm also very pleased that we can, as it were, try out this technology because after all, I have saved a jet fuel seat going to and from across the Atlantic here. And I think it's something that we should be mindful of that where we can usefully do this kind of linkage, and of course technology will improve, we should do so. And that sort of relates to some of the things I'm going to go on to say. So I thought it was reasonable to pop that in. But thank you above all for doing it. Now this slide shows you the situation you would have if the human genome, as some people wanted, had been entirely proprietary. It will be locked up in the little green circle there with a barrier that nobody could access it unless they had money, helps the dollar, dollar, dollar research, researchers at the bottom, those without the dollar dollars can't get in. And furthermore, the dollar, dollar guys have to make a binding contract with the proprietors of the database that they will not redistribute the data. Otherwise, of course, the data would simply leak out and there would no longer be a business plan. So they have a limitation, those guys, the privileged researchers, they have a limitation on publication because they are not allowed under this sort of model to tell people exactly what they're doing. They can talk maybe about the little tiny bit but they would not be able to show the entire genome and the map and when you think about it, an awful lot of the work in investigating the genome requires you to look right across it to look at, for example, families of genes. So basically not only is it something that is inappropriate for all the reasons that have come through so far but it is not good science because you cannot communicate. What is the way to do it is to make the central data public which is what, of course, we strove for and succeeded in, then everybody has access without hindrance, everybody can communicate and yet you can see the arrows going outwards on the outside, people are not inhibited from doing whatever they like with the data. What they cannot do is to block access to the central data. And so this is absolutely the right way to handle all kinds of pre-competitive data which is both useful in the long term and useful to many people far beyond what you can immediately do at the time. And so this is, I think, the answer to the question of why has this been influential? Well, it is because it works. It's actually good science and it's good business and many people will tell you this that had the human data remain proprietary like this, people in industry say this, it would have been a disaster. Anyway, it was not. Now I want just to very quickly talk about a couple of justification to that. One is comparative genomics. Here's an old slide showing the alignment of promoter sequences in four vertebrates and you have a tremendous power when you can look at a number of genomes like this, line them up and look for common features. So beyond the things you can recognize as coding for protein and so on, you can see things that are retained in evolutionary time and those black boxes show the items that are identical and indeed in most cases they turn out to be essential. That's why they haven't drifted apart in evolutionary time. Whereas the other areas have drifted and are not essential at least to making a vertebrate. Though of course among those you will find the reasons why human is human and mouse is mouse and so on. Then again, you can use the genome going ahead, far, far ahead for exploration and so you can make an inventory of elements. You can look for the things you know about already, the protein coding genes, you find the whole lot as you explore, you can look for other sorts of genes but then you find whole new families of genes. I mean the story of the discovery of the microRNA genes of which I think until the end of the 90s there was just one example known in the worm as it happens and that was an unusual biological curiosity and it turns out of course that there are hundreds of these genes in the human once you have the sequence available to search properly for them. And so it goes on and we now have come to the big program which I'll get Bob to refer to in a moment, the ENCODE program, the Encyclopedia of DNA Elements which is the drawing together and the continuing elaboration of all the things that can be discovered in the genome. So these are reasons for having it public and going on from the attainment of it being public, this is a little slide from the IBI and I rather like it, it just illustrates the cascade of other sorts of data which grow out in some sense of the genome in that that carries the basic information of biology but also the etiquette, the habit of sharing, we have preserved the three great public databases which were under direct threat back in 2000, they would be directly threatened that there was a better way to go that the whole thing would be a corporate entity. We have kept those public databases and they have continued to grow and prosper. As you go down the cascade, you find areas like for example protein structures which are much nearer the possibility of commercial exploitation and there of course you find people being a little more iffy about what can be done. I want to just go to this one slide before I come to Bob and not last but I mean the next slide before Bob. The first thing you do of course and it was even growing out well before the human genome was finished is to start looking for variation among individuals. These are medically important. You can make correlations. They're used in forensics so on the whole slightly different markers are used there but it's all there in the genome and you can above all as I see it understand development. Being a series of major international projects, the HAPMAC, the general system of genome wide association studies, the discovery of copy number variants which was another great unexpected item that came out of the genomes and now the thousand genome studies as next generation sequence goes forward. Bob would you like to comment on where we are because you unlike me have been actually working in all these areas for the last 10 years? Well I've been doing worms but I've been watching people in my department and others carry on these studies and obviously as this group knows the GWAS studies have been an enormous investment and success in terms of identifying hundreds of genes involved in pathways behind common diseases and that's fueled lots of research. Copy number variants I hear all the time about and their involvement in autism and schizophrenia and other diseases. These things while as I alluded to in some regions of the, these are the really nasty regions of the genome if we hadn't persisted to push things as far along as we could, this would have been even harder to do and just having the sequence makes things possible with short reads. The higher the quality of the sequence, the more meaningful these short read sequence projects can be. So all of these have been key and just back to John's point about the promoter and the other regions of the genome, in the early days it's hard to believe but there was a big effort or a big community that thought it was actually all we needed to do was sequence the protein coding genes. And because that other 98% of the genome was worthless. So it's a path not taken for good reason. Yeah, it's a very good point Bob. It's a gamble that really paid off doing the whole thing. We were suspicious that we might need it and so it is. Now all of this leads one to the possibility of medical advances beginning straight away with diagnostics and the possibility of personalized treatment simply from the correlations without understanding them of the genotype with the phenotype. We're going on, of course, this is the basis for looking for drug targets where we can actually do therapies and although in very early days yet because of delivery problems to gene replacement therapy. So we have a cascade of prospects for that. And now I'm going to sort of move towards a couple of issues which are really coming towards the social effects of these advances and the openness that must go with them because what Bob has just been talking about it's very important not only that the sequence is there but it's available to everybody. Now one thing discussed come to prominence actually as a result of the work at MIT looking at the possibility of identifying individuals as part of the 1000 Genome Project and also particularly as a part of genealogical databases in which their family history and their names are listed. And it's because of these combinations of databases that actually as genetic data becomes more commonplace and it will soon be affordable of course to complete genetic data from everyone, data will leak out. We cannot stop it. We shall constantly find that data will leak out. I'm not going to say much about this because George Church will certainly be talking about this in the next paired seminars but I would simply make very clear that in my opinion and I think this is a view that everybody is coming to that society needs a principle of genetic equity in some way or another. Genetic information should not be used, must not be used to limit the equality between human beings. We are taking some steps in this direction. In the US, you have the, you have GINA, the act that prohibits people from using genetic information and adversity for health and employment. And in the UK, in the UK actually we didn't need that because we have the National Health Service and so we automatically protect it as far as health is concerned but we have not taken the formal step about employment and it may be that the UK will have to do that in due course. So there are practical measures you can do. This equity is not just a philosophical term, it actually means statutory provision so that people cannot be disadvantaged. Now of course, that's not to say we should not be confidential at all, it's a matter of human dignity that one should not, you sort of spray people's genetic data all over the place. But as people are finding for example, even things that they would like to have private like for example, exactly which children you've fathered in some cases is not really realistically going to be a secret thing in the future. So for number one, genetic equity, number two, get over it. And so the future generations will not be sort of so concerned about these things. And now I'm gonna spend the next few minutes going to an aspect of data release which concerns me very much and this is what I've really been involved with in the last few years in thinking about and to use this little cycle, this diagram to illustrate something about the way science operates. Now up here, if you can see my little marker going round, this is what I would call the cycle of science, so we discover stuff, we build up knowledge and if we put it together in a sense a clever way, we can get understanding and that feeds back to more discoveries. So science wants to do this sort of thing. Science has to be funded, it can be funded either in a not-for-profit fashion or a for-profit fashion. And the output of science is important. We often forget that science is the greatest cultural activity of our times and I mean that. Science drives culture in a way which is sort of unprecedented because we learn so much and science is used or the products of science are used all the time throughout the arts and really are a major part of humanity's exploration altogether now of itself and the world around. But we could also use science and most people think of science this way as providing useful applications. We hope that they're mostly good. We occasionally manage to use harmful ones which we have to try and suppress a bit and these applications anyway can give some revenue which can feed back. So this is a very good cycle and looks great and that's the way we operate. Now what's been happening in the last 50 years in my career, in biology in particular is that because other sciences were in different states of this development, in biology after the beginning of molecular biology became more or powerful and more and more there were possibilities of for-profit applications which are driving the cycle rather strongly in this fashion, sorry about that. I didn't mean to jump which are driving this cycle rather strongly in this fashion and we are finding that there is relatively less not for-profit revenue now compared with the for-profit revenue in many areas. Now up to a point this is grand. I mean this is really providing a lot more resource to science, we are learning a lot more and we are doing a lot of very beneficial things with it but we should examine a little bit what we're doing. We are securing revenue more and more through the exercise of intellectual profit, the intellectual property. Now I call this relatively easy money though anybody who's written the grant proposal might beg to differ but the fact is that people don't much like paying taxes and they do rather like a flutter and so the idea of investing with the possibility of something money in your pocket afterwards is more attractive and so that makes, that's why it's somewhat easier to get hold of, it's also free essential control and so somebody starting a company, a startup company has a very large measure of freedom to do what they like but of course there are investors in that startup and they want to return and by the way we are all investors through our mutual funds this is a point that I shall come back and emphasize. Now that means that the R&D gets channeled into profitable markets as I've indicated on the previous diagram and this sort of tends to exclude or inhibit some of the other needful things we should be doing so we change the balance between different kinds of science that we are doing and that is to our loss if we miss out on things that are either immediately socially beneficial or we need for the future and we put a little bit of a downer on scientific communication that we'll come back and talk a bit more about that later on. Now, intellectual property is driven or is based on the exclusive rights patenting of things that are discovered and in the early days although we have the genome free and in the public domain this was not true of genes that could be identified with particular medical conditions and so people would identify these and they would say, look, I understand this gene is causing or the mutant is causing a particular medical condition and I know how to diagnose it so I'm going to have a patent and of course that's entirely reasonable that one should have a kit that is patented one might think is perhaps a little less reasonable is to extend that kind of patent filing to cover all ways of diagnosing the gene. You sort of begin to think, well, I seem to have patented the idea of a mousetrap not my own particular version of it which is actually at variance with the history of patenting as it's been but what was much worse and because this went through very rapidly and people weren't setting the bar appropriately is that that same sort of information was used to exclude all other uses of the gene including pathways into the future and much longer more difficult pathways to therapy and possibly pathways leading to new functions. So we've really patented in a way which is not based on the correct definition of patents as being novel and inventive and useful we've only taken the sort of something of novelty and extended it to cover everything else. Now this is not manufactured, this is in fact, it really happened and the notorious case which I'm going to talk briefly about because it's in the news again now is the case of myriad genetics and the two breast cancer genes BRCA1 and BRCA2. I call them breast cancer genes because certain mutations in these genes give women a very high chance of breast cancer and indeed men too in some cases. These are only a small proportion of all cases of breast cancer but if you have these genes in your family, these variants then you have a very high chance and so you want to be tested but because myriad has the complete America US portfolio in these genes it's able to charge an exorbitant price for what is actually a very simple bit of sequencing of the DNA of these people. Now these patterns were or challenge was raised back in 2009 by a consortium of women's groups led by ACLU lawyers. Many of us were involved in this including in due course an amicus curiae statement from some of the national institutes of health but initially they were actually ruled invalid on the grounds which the general grounds are given that you cannot own a human gene or pattern the entire human gene in his fashion because you don't have the correct perquisites for doing so. They were ruled invalid by Judge Sweet in the New York district court and then they went to the appeal court where myriad's lawyers were able to overturn them. From there they went on appeal to the Supreme Court they came back to the appeals court which once again overturned them and now ACLU has got the rights or the agreement that they can go back again yet again to the Supreme Court not for this case alone but for considering whether or not it's appropriate to patent human genes in that ring fencing manner that I described. So you may patent, they have processed patents on human genes obviously for particular things you can do but not to take a whole human gene on the basis of a small amount of knowledge. There's one other thing before moving on I want to point out because I think it's extraordinarily revealing about the whole system and that is the three appeal court judges were in great disagreement. One actually agreed with the original judgment of Judge Sweet and said yes that's right the patents are invalid. A second judge said no that's not true at all the genes once isolated and put in a test tube are different from nature and so can be patented. The third judge was very interesting Judge Moore said well I'm not sure I can see the arguments but the PTO has for a long time approved patents of this kind and industry has relied on them and so the patents must stand. Now that is not a good reason for going forward what it would say is that any patent no patent can ever be overturned because people have got used to it you very poor way of developing patent law so I think it's very important I recommend that you look at this case it's not an interesting because of the details of that kind that I've outlined and you can see on the ACLU website and follow that up. But now coming back to our cycle the consequence of this kind of continued pressure has resulted to some degree in a sort of short circuiting of the process so that the main thing that science is driven for in certain areas and pharmaceuticals unfortunately is one is that the applications are mostly for profit and the result of that is that we cannot work by the for profit mechanisms available for R&D on things that matter. The consequence is that we work on masses of molecules that can be potentially bought by the richer communities of the world but not at all on treatments that would be or very little on treatments that are needed for the greater part of the disease burden of the world and so we have this notorious issue of the neglected diseases. A little bit of change in that but not much and not enough and it's a defect you see of having a system where people can own knowledge you see how it relates back to what we were doing with the genome and how we handle that. Looking further around the cycle we see that what we are doing through all this not only making applications mostly for profit but very curiously the way the process operates looking up over here is that the vastly greater part of the revenue goes into profit and marketing and lobbying. Only about 15% actually comes back to the scientific process. So those who say as many do that oh we must have this system we see it's imperfections we must have this system because this is the only way we can get revenue for doing or for curing diseases. Well I think 15% of drug revenue is a pretty inefficient way in my view of doing biomedical research so I think this is not very satisfactory but I keep on saying we are doing this because we are all shareholders in this business. It's not there is some bunch of people doing it we are all shareholders through our savings our pensions our mutuals we are all part of this process and if we don't think it's a very good way of doing it we should get down and change it. Now I talked about the problems for the less developed countries of the world the poorer countries who are not getting treatments as they should in a more equitable world but we also have problems near home and that's the excesses of marketing that are applied which are distorting our medical systems. The lobbying in Congress and in Brussels the incentives to physicians to prescribe certain drugs rather than the others patient groups are when funded are pressured to use particular products the whole testing procedure is very inefficient because it's too adversarial the medical journals are full of ghost publications written by marketing departments and signed off by academics sometimes and the bottom one refers to the extension of particular drugs beyond their immediate utility into novel or inappropriate applications. Now this actually despite the example I gave you the myriad patents are quite near their end a couple of years to go but it's important to think about these things because we have an awful lot in the future and that's what I'm going to turn to. Pharmacogenetics is a word which we throw around a great deal and it's beginning to come into practice not as fast as we might like because there's obviously huge potential here but we need to have some sort of more equitable treatment of products of pharmaceuticals coming out some sort of more open treatment in order to exploit these ways in which we can use genetics so that for example some drugs like Warfarin that are used for anti-clotting very important to tailor the dose according to patient's needs and we can do that to some degree by genetics or by other kinds of testing but what it means is that there should not be a pressure to sell more of the drug it should be simply used in an appropriate way because of the adversarial climate many drugs are thrown out because of rare adverse reactions but this may well not be necessary if we can find genetic correlates of that adverse reaction and use it only for patients who are going to respond properly and so we begin to find cases like that as septin is an example where you genetically test people in order to see whether they'll be responsive or not but you can see that having a patent of strongly IP patenting landscape where everything's siloed is going to make it much more difficult to cope with these in the future another very important example is multi-gene testing this is an old slide this goes back to 10 years or so ago but I remember this appearing in nature and being tremendously excited although this is not the most powerful way of testing now in these days of RNA-seq but this is a chip from the company Rosetta which shows how in the... you can distinguish to some extent between breast cancer tumors that allow them to spread and those that aren't according to the patent of expression of genes and the patent of expression above this dotted line roughly speaking these are good, very few people will experience metastasis and go out of remission whereas they probably don't need or didn't have very aggressive chemotherapy whereas those down here are very likely to have spreading cells and will need further treatment and there are now kits things are going on, RNA-seq is being used and more and more genes are being looked at in more subtle ways but now this can be completely impeded as Bob Cook-Degan and his colleagues warned us a few years ago that if we have extensive patent tickets so that every gene is owned quotes by somebody and has to be licensed separately and so at this point Bob, may I ask you to comment on how serious you think this problem is and indeed actually whether it is a problem or if as some say that intellectual property and licensing of genes is actually a positive thing for going forward in these ways. Well, I can certainly chime in here. I mean, in terms of just whole genome analysis maybe if you're a company and you wanna just study particular genes you can not report on the breast cancer gene but from our standpoint doing either whole exome or whole genome sequencing the idea of blocking off parts of the genome and not being able to look at them either not sequence them in the first place or not analyze them or not tell the patient just seems to me to be a non-starter and the overhead of trying to get all the rights to communicate all this and to pay all the fees is really not tenable but I think in another aspect if we're really gonna harness the information in the genome we're gonna have to be able to amass large numbers of genomes with lots of clinical information about them and if we don't have the full set of information about each of these genomes if parts of them are blocked off if the use of those genomes has to be it has to go through IP issues for everybody it's just not gonna work. We want to be in a situation for variation like we are with the genome so that if you're a high school student in Kansas you can get access to this information and make discoveries so anybody can figure out what's going on. Back to you. Thanks very much. Yeah, that's great, thank you. So ideally then we would like to rebalance the cycle. It requires that we don't drive discovery quite so hard with full profit there's nothing wrong with a full profit it's great where it's appropriately gained but we need to have enough not-for-profit coming in to make that healthy cycle where everything can be done we can do the important cultural things after all what is the human journey really other than culture going forward? What are we doing all this for? I would suggest that we are doing science at least in part to understand and in fact I would say entirely to understand but we can maybe get a few little widgets along the way but the important thing is the journey and we do not want to have that inhibited by this short circuiting of the process but of course then we do need to go on doing medical research so what's happening? Well this rather complicated list of slides is just to indicate the broad range of ways in which people are tinkering with the process these used to be called public-private partnerships they now are some sort of euphemistic way of being called product development partnerships but basically they're using not-for-profit money partnered with companies in order to unblock for example malaria or drugs that were stuck in the system because the marketing department wasn't willing to fund their development any further and so you have this idea of partnerships you can also have various ways of changing the licensing landscape patent pooling for example is something which is being talked about quite a bit at the moment compulsory licensing is being used by some of the developing countries but it's being strongly lobbied against by the pharmaceutical industry the other systems have been discussed global treatise prizes special incentives and I haven't got on the list here but I'd want to allude to of course the NIH's own National Center for Advancing Translational Sciences which is a very exciting experiment that's being set up now but in all of these cases I would bring you down to the bottom line here if we use intellectual property on a level playing field as a way of people doing good trading with one another in a fair way then it's a good servant if we use as we are intellectual property in a global way in which those who have most dominate against those who have least then it becomes a bad master it's setting actually human ethics human medical practice in a way which is utterly inappropriate for this commercial tool and so I think we need to watch out for intellectual property good servant, bad master and it's getting in the way if we allow it and I would go further and I apologize for the way I'm moving here I've had quite a strong experience sharing the Royal Societies report People and the Planet which is broadly the impact of people on the planet and the impact on us on our well-being as a result and it's come to my realization and our working groups realization of how these are not solitary issues this is not just about biomedical research it is about the way we run global economics it's about the limitations of gross domestic product as a measure gross domestic product is just the sum total of financial transactions it comes very strongly to my mind that this dreadful oil spill in the Gulf of Mexico that the UK and the US were sort of jointly involved in through their various companies and their regulatory apparatus that oil spill cost an enormous amount to clean up meanwhile doing huge amounts of damage to the environment and to the fishing industry around the Gulf and all of that money got added to the GDPs of the US and the UK that doesn't make sense does it should have been subtracted so I just point out GDP is a mindless financial transaction we need alternative sorts of indices if we can make them work we need ones that account for natural capital so we actually cost what we're doing to the environment directly and that measure real wealth including the effect on human well-being it'll be extremely hard although people are experimenting with these things to change because GDP is the currently accepted standard and we're all implored by our governments to go out shopping to get out of recession to go for more competitive growth but what we're doing as we do that is to drive material consumption, to drive emissions now you may feel I've come a very long way from the DNA and yet I hope you can see that this is really turning back to the beginning because we're talking about the way we use knowledge the way we share the benefit of knowledge and of science and that should be done by everybody having access by having equitable trading, openness, opportunity we don't have brain drains just of taking the world's best scientists and concentrating them in the richest countries but rather giving them opportunities as countries level up and have more possibilities of doing the very best research in each of them so everybody has good career prospects if we can do that, we are expanding justice and when we think about the planet we are thinking particularly about justice for future generations consuming too much now governing economically in the wrong way now is doing an enormous disservice possibly a fatal disservice to our children our grandchildren and their children and we are not building a sustainable world so I want these messages to go forward in the broadest way we understand where they come from and we've described to our history with the worm and the human and the sequencing but they are much broader than that these are principles of life for an equitable world thank you ever so much you should come up and we can just sort of pick up on anything people want just in the last five minutes or so I guess I'll start, John you had so many great things to say I'm curious especially in some of this later work who in the United States in particular are you working with or you think if you're not working with directly you think of sort of a thought leader in similar ways of your thinking well it's Bob of course and I mean just to I mean there are so many people who are involved in these things but one particular person I point to who is on our working group for the Royal Society studies Joel Cohen at Rockefeller also at Columbia and he is a terrific guy who's he's written a very fine book on the human carrying capacity of the Earth and he is a very wise figure but above all I look to everybody I look to I'm very excited by this by President Obama's second term I don't have the privilege of working directly with him but I do hope that he will feel the opportunity to make some progress in these matters in climate change in particular so I think this is something for everybody not just for a few collaborations Okay Any other questions from the floor? If not John that was spectacular Bob as I knew it would be spectacular I think this has been a terrific session I've learned a lot and it's just been just wonderful to hear from both of you so I thank both of you greatly for your willingness to do this thank the audience for participating and stay tuned we have more of these to come thank you very much Thank you Thanks John Thanks John


The study presents monthly global land evapotranspiration, ET, synthesis products based on satellite and or in situ observations or land surface models driven with atmospheric re-analyses. The merged synthesis products for the shorter period of 1989 to 1995 are based on 40 distinct datasets, while those for the longer period of 1989 to 2005 are based on 14 datasets. The study provides statistics for four merged synthesis products and shows that multi-annual variations in ET display realistic responses to changes in precipitation and other factors. The global mean ET from the merged synthesis products is estimated to be 493 mmHg-1, 1.35 mmD-1 for both time periods, which is relatively low compared to previously published estimates. The study also estimates global runoff to be 263 mmHg-1, 34406 kmHg-1 for a total land area of 130,922,000 km2. To reduce uncertainties in current ET products, the study suggests improving the accuracy of input variables, especially precipitation, as well as the parameterizations of ET. This article was authored by B. Muller, M. Hershey, C. Jimenez, and others. We are article.tv, links in the description below.


Upperclass said the whole like he wanted you and Maya and Kenzo to do the sexy thing Mm-hmm the snippet that you put out after he said that did you already have that in the tuck or you made that after he said I did that like a day before he said that Wow That's why that's why and it's crazy cuz I wasn't I wasn't even gonna put that snippet out like no time soon Mm-hmm, and then he just pissed me off.   Now you did that now you look dumb now He asking me to be on his podcast, right? I feel like especially with you I think that it's super interesting because I always felt like out of all the drill girls You were Like you did talk that hot shit, but I feel like you was talking your I do a little thing in a year about niggas like I just said that I'm gonna act bad on the niggas Like I feel like you're you've always done that so it was interesting to me that he would even yeah He missed it.