 Thank you very much, Mark. Good afternoon everybody. Welcome back. I'm Kevin Davis. The author of a few books over the last 10 or 15 years that have commented on progress in genetics and genomics and hopefully advances of this new technology, next-generation sequencing technology that we hope will drive medicine. We've heard from a fantastic range of world-class scientists and scholars today and you'll hear from more later this afternoon. I'm the black sheep of the programme. I think my greatest contribution to biomedical research was hanging up my lab coat about 20-something years ago and realising that the only way I would see my name in the likes of Nature magazine was if I snuck in through the back door and joined the editorial staff. So that's what I did and had the pleasure in 1992 to be the founding editor of the first Nature spin-off journal. We chose genetics largely because we were so inspired and so excited by the launch a couple of years earlier of the Human Genome Project. You see in the figure in the photograph shown here the very first article in the first issue of Nature genetics rolling off the presses, literally. That was the easiest decision I ever had to make, which was to invite Francis Collins to write news and views on advances in positional cloning, a technique that he not only established, but then, of course, put to fantastic use with the discovery of the gene-specific fibrosis and a number of other medically relevant and important genes besides. Then a year later, shown in this other photograph, he was one of the speakers at our first birthday conference here in Washington, D.C. and this was, I think, the first public admission to confirm the rumours that we're going around that Francis was indeed going to leave his nicely compensated perch at the Howard Hughes investigator in Michigan for a lower paid administrative job at the National Institute of Health, the new genome centre. I think we're all very grateful that he made that call. In addition, I'm sorry he's not here to hear this in person, but word will get back, I dare say. In addition to being a world-class scientist and physician and administrator, he's also, much to my chagrin, a very good author, a very successful author. He published, of course, a bestseller called The Language of God, followed that with a book called The Language of Life, and I can now reveal the third leg of the trilogy. The Language of Love will be coming out soon. I hear the CD that will compare, the company, the book is going to be fantastic. I think Francis is probably laying down some tracks right now. I would have gone with 46 shades of grey, but maybe that's just me. A couple of years ago I got a call from an agent in LA asking whether the rights to the book that I wrote to many years ago now about the genome project called Cracking the Genome, whether the movie rights are available, and I said no, I got really excited, and then the trail went cold, sadly, and the rights are still available if anybody is watching. It's a fun game to play, and you can play it this evening as you're celebrating DNA Day. Who would you cast to play Francis and Craig and the other key figures in the story? I spent way too much time thinking about that and decided to leave it, but I do want to give a quick plug, as I served a tiny role as a consultant on a new film that's just doing the rounds. I think this is important to try to get out to a much broader community, the importance of scientific medical genetic research and the implications, particularly for women with breast cancer. Helen Hunt, fresh off her Oscar-nominated role as a sexual surrogate in the sessions, turned to playing Mary Claire King, the brilliant geneticist who mapped the BRCA1 gene in 1990. This is the story of Annie Parker, a true story of a woman who was one of the first women in North America to be tested for the BRCA1 gene. It's now getting shown at different film festivals in the hopes of wider release later. I hope that perhaps there may be even people here in the audience or watching who may be able to support one of these early screenings to support the film and also to support cancer research and screening. I'm not going to spend too much time rehashing the key events of the Human Genome Project. We've heard a little bit about this already. Of course, the celebration in June of 2000 in the White House with my man Tony Blair beaming in via satellite from Downing Street, because the Brits, of course, did about one-third of the genome. The papers appeared about nine months later. Only one of these papers was republished as a coffee table book, brilliantly edited by my friend and fellow genetics editor Carina Dennis. We could spend a lot of time, and perhaps this isn't quite the right place, to rehash the friction. There was a book that came out a few years later called The Genome Wars. Obviously, if you scratch the surface from some of the participants, it doesn't take much to still rekindle old rivalries, shall we say. Tim Hubbard here from the International Genome Consortium making a point, a very important point, that the data is now open and I think few would disagree with his assessment that the public project won in quotation marks. But if you put a microphone under Craig Venter's nose, you're going to get a very predictable and very strong-minded response and I think it's important to say and acknowledge that if it wasn't for what Craig and Salera did all those years ago, we probably wouldn't be here today celebrating the 10th anniversary. I suspect that would be a few years down the road. The press release you've already seen, I get a kick out of this because it was just one line in a press release announcing the completion of the human genome project. I guess there was a press conference and a party afterwards and I think this is where George Bush got the idea because it was two weeks after that press conference that he was on the aircraft carrier with the mission-accomplished banner unfurled. Why that date? Because it was the 50th anniversary of the publication of the double helix in Nature, of course, but an even more remarkable, almost more remarkable publication was a few weeks earlier. You're a 12-year-old boy at boarding school in England somewhere and you get a letter from your dad and it's this. Your dad is Francis Crick and he's describing to you that Jim Watson and I have built a model for deoxyribose nucleic acid called Read It Carefully, he says, to his 12-year-old son and then on the next page he actually draws a model, the first rendering of the double helix. It was a good job that it was wife who drew the picture and the actual nature paper. He calls it a long chain with flat bits sticking out. He ended the letter, signed it Lots of Love Daddy, which is very cute. This letter just went on the auction block and sold for $5.3 million. A half of the proceeds went to the Salk Institute where of course Francis Crick spent many happy years later in life. It was six weeks after the nature paper before the New York Times got wind of it and saw fit to print the news. I love the very appropriately conservative, we need further studies, we need to confirm this to make sure it's right. Although as people have noted this morning on Twitter that the double helix paper flew into nature without peer review because it was so obviously correct. We're all getting our genomes off encyclopedias and servers and tablets these days but a group in Leicester decided there's no substitute for a good old-fashioned book is there. So they've actually printed the entire human genome to see what it looks like and for educational purposes and so there you have it. It's 130 volumes, tiny four-point font, double-sided and it's been shown in museums and things and this is obviously a day where we're stressing DNA education so I think I give them credit for this. He would not tell me exactly how much it costs to print this because he thought he might want to negotiate with the publishers and print another version down the road but I will tell you that it actually costs less to sequence the human genome these days than it does to print it, at least in the UK. So who is this reference genome that we are talking about and celebrating? Well this is the advertisement that Peter De Jong shared with me kindly that recruited the volunteers to build the DNA libraries in the late 1990s that would be used for sequencing. Peter De Jong, to borrow the vernacular of a popular television show he was the master, he was the cook. He was the guy, the Walter White of genomics who could build better DNA libraries than anybody else and so the advertisement appeared in a buffalo newspaper which is good except it's sort of I worry that the reference genome probably belongs to somebody like this but I'll point out to one particular individual in the front row there because we now know that RP11 which is the individual who contributes about at least 70% of the human genome reference sequence from the work of David Reich and Stefan Schuster and others is almost certainly African American which is something I didn't know but that's been buried in the literature for a few years and I think appropriate given some of the talks that we heard this morning. So work on the reference genome, the reason I thought it was mission accomplished a little bit is that the work continues, there are still some regions that are very hard to sequence. There are regions that vary astonishingly more than we expected in different people and people here at NIH at the genome reference consortium particularly Deanna Church have been coordinating continuing efforts to fill in the gaps. There's still medically relevant genes that are missing in some of these assemblies that need to be sorted out and if you look at the URL bottom right here that's an interview that we just posted this week with Deanna Church which tells you I think almost everything you need to know about the past, present and future of the reference genome and I urge you to look at that interview. Despite all the work on the reference genome and ENCODE and 1000 genomes and all that great stuff I still think the best genetic or chromosome map that we've had ever is the map of the Y chromosome that came not from massive high throughput sequencing but from the fertile imagination of a female geneticist named Jane Gitchia who science magazine first posted this 20 years ago because they saw a photocopy stuck on Francis Collins' door shortly after he arrived and you'll see. Although many of these are thought to be somewhat fictitious there are two loci that are real the one at the top which is obvious but there is a hearing loss locus that Chris Tyler Smith and others believe it or not that he discovered somewhere further down the chromosome. So what is the public making of the genome project? Well, popular science, at least we know what the readers of popular science magazine think of it, they thought it was great. Indeed, they awarded it in a survey last year the most important invention of the past 25 years beating out a whole slew of things from Google Maps to seedless water melons to Wi-Fi, Viagra I really couldn't disagree with any of those. I think the Burj Khalifa was a little hard done by but maybe that's just me. What about the economic impact of this? Well, I think as you've heard from President Obama put this survey which had been somewhat ignored front and centre in his State of the Union speech a survey from an organisation called Battelle it was funded I believe by the Life Technologies Foundation in which this remarkable figure which has come under some a fair bit of scrutiny since the report was publicised by President Obama that for every dollar spent on the human genome project and that's with a very lofty denominator of $3.8 billion we've received back $141 for every dollar spent. That study may need some peer review I suspect but I think we will all agree that there have been some tremendous benefits and those benefits have come largely as Eric mentioned in his opening remarks from the technologies that have culminated over the last decade in search of a sequencing technology that would succeed, sang a sequencing the brilliant venerable technology that saw us right the way through the genome project and still has important roles in forensics and clinical validation and other arenas. I give Craig credit again for if not inventing the term the thousand dollar genome at least really putting it out there in a symposium that he organised in Boston in 2002 we reported it as did new scientists and other media and he invited six young scientific entrepreneurs to show off their next generation sequencing technologies and said we need this so badly I don't think people realise how badly we need to kick on because one genome is not going to do us any good we're going to need hundreds, thousands, millions it was a fascinating evening and I suspect that the one talk that actually didn't stand out in my mind that evening amidst US genomics and George Church and others was from a young British company called Selexa the two founders of Selexa are professors of chemistry at Cambridge University, Shankar Balasubramanian and David Clennaman having a celebratory pint in the Pant and Arms and I asked Shankar when I interviewed him for my book The Thousand Dollar Genome Why didn't you go to the Eagle? Surely that's got to be the pub in Cambridge that you go to for momentous landmark occasions in genomics and he looked at me and sneered and said no, no, no that's the biologist's pub this is the chemist's pub this is where the real serious drinking gets done although I should add they have no drinking policy if you're going back to the lab in the afternoon to do experiments The reason for the celebration is that this it was at a group meeting in the late 1990s that the technology that would become Selexa that would eventually become Illumina sequencing platform was hatched they had to go to the pub, Shankar swears because the offices and the seminar rooms were so small and cramped and decrepit at Cambridge University's Chemistry Department that they literally had no excuse to no other option but to go to the pub You won't belabor the technology obviously coloured fluorescent dyes each tagging a specific nucleotide and Selexa's girl wasn't the thousand dollar genome or personalized medicine it was really to study the physics of DNA sequencing it was to engineer a sort of a stop-start approach that you could see how one base is incorporated at a time and do it across millions of molecules so the reads were very short to start but the technology continued and grew and in 2005, Clive Brown who was head of IT and Informatics Selexa sent an email to the brain trust announcing that they'd done it sequenced the first genome of course a very small genome but nevertheless an important landmark at the time now most people in that situation invented a new sequencing technology what would you do? You would down tools well you go to the pub first if you're British and then you down tools and then you write a paper for nature or something Selexa said no, we don't care about that we don't care about publishing papers we're tunnel focused on one goal which is to get this machine optimised and get it out and launched commercially by this point they'd merged with an American company a Sydney Brenner company called Lynx they had a Nasdaq listing and so they were on their way but in a very stealthy manner and so a few months later when 454 burst out onto the public scene everyone thought including the founder John Rothberg that they'd won they'd certainly won the race to get the first commercial next-gen sequencer out and because Britain was quite I think he thought that success would be longer lived than it actually was that was the paper in nature in the summer of 2005 we won the race Johnathan told me that the eve of that publication everyone may not be happy with that but we are, of course they were Rothberg is the most colourful character in my book it's not every day that you meet somebody who has built we're not talking spinal tap stonehenge here we're talking a real monument of stonehenge proportions 700 tonnes of Norwegian granite shipped across the Atlantic for exactly what purposes I'm not entirely sure his wife said she just wanted to put a soccer pitch in the back yard and Johnathan had other ideas when it came to sequencing their first human genome Rothberg was talked out of sequencing himself by some of his advisers including Richard Gibbs from Baylor and they opted for a more logical and guinea pig and that was of course Jim Watson and in May of 2007 the first digital genome by next-gen sequencing was presented to Jim in a ceremony at Baylor College of Medicine because it was Gibbs and David Wheeler and colleagues that were doing the informatic analysis the cost of that sequencing programme project Jim as it was codenamed about a million dollars it left about not much in the budget for GIFRAP but you see a little bit there so what did Watson learn from his genome in truth not a lot and I think for most people who've embarked on this if you've looked at a 23andMe scan or something that's probably the reason you think well really that's all I got we still have a long way to go in terms of linking a genetic variance with common disease traits he did learn something of pharmacogenetic benefit he adjusted the dose of his blood pressure medication he learnt about the importance of false positives for a while he thought he had a BRCA1 mutation that might be of importance for some of his female relatives until Mary Cleckin advised him it was nothing but more than a benign Irish polymorphism but I think what stood out was that in his desire and willingness to share his entire genome publicly posted on this Cold Spring Harbour website there was one gene he wanted left off the list and that was the ApoE gene which in the E4 variants which can be found in two copies in a small percentage of the population can infer a pretty strong an increased risk of Alzheimer's disease and Jim just didn't want to know what his genotype there was so that was all well and good that gene was left off until the site went live and a couple of groups including Mike Careas so at Snipedia noticed very quickly that you could infer the ApoE genotype by the genes flanking that gene and so the Cold Spring Harbour guys quickly had to go back to the servers and wipe out or redact about a million bases so that to my knowledge the world is supremely unaware of Watson's ApoE genotype. So 454 was dominating the headlines for a while and then in November of 2008 an issue of nature appeared. I remember the days when we were cock a hoop if we published three papers describing disease genes in the journal and here now we had three human genomes each paper very significant in its own right you had the first major genome paper from BGI which put them really on the map the Beijing Genomics Institute you had the first cancer genome from Lane Mardis and Rick Wilson colleagues at Washington University and you also had the guys from Selexa publishing their paper so they finally got their nature paper three and a half nearly four years after that 5x174 landmark except by now the Selexa sequencing machines now had the Illumina logo on the box because Illumina had swooped in and bought them for about $650 million and boy wasn't that a bargain. The first woman's sequence was a Dutch clinical geneticist named Mylein Kreek chosen because her last name sounds like Crick it was really that simple and she's enjoyed her 15 minutes of fame even though the paper has still not been published she's had statues, she's had art exhibits and commemorated in I think this is the Dutch equivalent of Doonsbury which I will not attempt to pronounce but you can see even her comrades were somewhat bemused that one of their compatriots had been selected for this great honour and at ICHG some 18 months ago Crick finally met Watson so that was nice at this point there was sort of a rush of news stories about oh my god celebrity genomes only the wealthy and the famous are going to get their genome sequenced and that quickly dissipated John West shown here was the guy who engineered the sale of Selexa to Illumina he must have done quite well from that transaction because he decided a little later to have his entire family of four sequenced using Illumina's new personal genome sequencing service and his daughter has been given some fabulous talks and had articles in the Wall Street Journal describing her experiences trying to sort out her genome using little more than an Excel spreadsheet and if you've never seen a prescription for a human genome sequence may I present to you a blood and saliva for personal genome sequencing by Illumina from 2009 Illumina thinks sensibly at the time deciding that you would need a doctor's note in order to get your genome sequence now why did they do that because there's an increasing scrutiny and concern in some quarters that the director consumer genomics companies offering genotyping to the public were giving people more information they could handle of course there are several companies back when this started in 2007-2008 23andMe got most of the press because of the Google connection Anne Wojcicki is of course married to Sergei Bryn they won Time magazine's invention of the year which caused a volcanic eruption in Iceland in one particular location because decode had really pushed this very heavily and they had a new term entered the lexicon the spit party found in various glamorous locations like Davos, Switzerland and New York although 23andMe were not the first to learn that you cannot hold spit parties in New York because of very strict medical laws and as the health czar in New York State reminded them you should go have your spit parties in Connecticut it's not that far it's just ship samples out of state without a doctor's note for people like doing a spit test is pretty tricky it's not as easy as it sounds if you're from where I come from you just say and you're good to go so that is what I'm on I think 23andMe this is not just about giving individuals information that they can choose to do whatever they wish with we now have a database of 250,000 genotyped individuals pushing towards a million later this year and papers such as this one exciting demonstrations of sort of in-silico genome wide association studies map finding and identifying important loci not just for things like whether you're allergic to cilantro or whether you have upper back hair but important disease traits like Parkinson's disease and whether they are able to sustain a business model of course is another question for another time as I mentioned I think the concern about the worried well is something that you've heard a lot about from editors at the New England Journal of Medicine to the American Medical Association which pleaded with the FDA to clamp down on this industry because people couldn't handle the genomic information that they might receive I see no such evidence for concern I see no data line specials with thousands of 23 and me customers confessing to some journalists that they weren't able to handle their information and the empirical data that's been published from Robert Green in the Reveal study and more recently from Cinnamon Bloss at the Scripps Genomic Health Initiative just published in the Journal of Medical Genetics provides some very solid evidence that people are very able at a psychological level to handle this sort of information but the reason I think most people are trying to push genome sequencing is for medical benefits Leave I later this afternoon we'll talk about cancer I'd love to talk about that but in the interest of time I'm just going to focus on this notion of ending diagnostic odysys a term you've heard this morning but you haven't seen I'm surprised you've not yet seen a picture of this child Nicholas Volcker who in many ways has become kind of a poster child for what exome and whole genome sequencing can mean for a patient suffering almost indescribable torment medical procedures by the scores gene tests ad nauseam to try to get to the root of a particular genetic disorder In 2009 Nicholas's pediatric gastroenterologist emailed Howard Jacobs shown here really as a last straw to ask whether we could sequence whether they could sequence the genome of Nicholas this has all been published not only in peer review literature but in this Pulitzer Prize winning series of stories and the Milwaukee Journal Sentinel which I refer you to and I think the story is fairly well known now they did exome sequencing they had a list of 2,000 candidate genes they found nothing of note in those but they found a very intriguing point mutation on the ex chromosome and that led to a specific diagnosis that prompted a bone marrow transplant they finally had something they could put in the medical record and the results in a further newspaper series from last year is that Nicholas is now not only home and eating solid food but back at school and trick-or-treating and it is it's a story that whenever you meet any of the team from medical college in Wisconsin you know how much that means to them but they didn't just stop there what was impressive is that they said that's great but we were going to continue to do this so they now have a system in place they review cases on a monthly basis and exome and whole genome sequencing now continues for many patients weighing the benefits of a whole genome sequencing approach to find the disease gene in question versus traditional sort of trial and error let's do this gene or let's do this gene panel and racking up the costs Nicholas's medical care was put it over a million over a million dollars and many academic centers are now following the same path Baylor College of Medicine is one I will mention Jim Lovsky giving a DNA Day talk recently of this month mentioned that Baylor College of Medicine is now doing something like 200 clinical exome sequences a month so this is not just sort of esoteric anecdotal medicine this is rapidly becoming in some quarters at least a sort of a mainstream endeavor and I could give many examples from I'll just show I think three this child was diagnosed as a result of the clarity challenge the Boston Children's Hospital organized ending an 11 year diagnostic odyssey this is a story that my colleague Alison Prophet broke in Bio IT world the URL is in the lower right the Allingham family from Sacramento ending a three or four year diagnostic odyssey in two of their children with a rare form of baton disease there are clinical trials doing enzyme replacement and gene therapy that they may be eligible for and Jeffrey Trent formally of this parish of course now at TGen has a remarkable YouTube video on the case of a charming vivacious young girl named Shelby Valent who is now up and walking and healthy thanks to the genome sequencing results the cost we've talked a little bit about the cost we're not quite at the thousand dollar genome even though people predicted that 2013 would be the year not just of the thousand dollar genome we had the 15 minute genome we've had the 30 dollar genome one of the people predicting we'd have the thousand dollar genome any day is shown at the end here is Daniel Franklin who happens to be the nephew of Roslyn Franklin I suppose we should we should I suppose I know we should remember the contributions of Roslyn Franklin on a day like today that what is the actual cost I think Eric was pretty close in his introduction so these figures are from David Bentley who's the chief science officer of Illumina if you do a batch run on the latest Illumina high seek 2500 you can sequence five genomes simultaneously in a run in this particular mode the list price for the reagents is $25,000 so that's $5,000 list for a human genome right now but obviously you can get discounts and that was his words not mine so you can negotiate less than that and the cartoon on my opening slide had the $2500 genome so I think that's sort of where we are now okay that's not including informatics and all that sort of stuff and we will come to that where does next gen sequencing go from here well of course there's a lot of hope for new technologies and I want to also remember the work that NHGRI and Jeff Schloss and Adam Felsenfeld have done to support the whole community, academic and startups alike to foster these new technologies one of the ones that shows the most promises from Oxford Nanopore this incredible device the Miniron it's literally a DNA sequencer on a thumb drive was unveiled a year ago and this is the same guy Clive Brown shown here who sent that email during his Selexa day so you're not going to see a peer review paper about this anytime soon they're going to follow the same model how would that work when the last iteration that we heard you would take a bacterial nanopore a bacterial enzyme with a hole in the middle you would attach a DNA helicase something that can unzip DNA a single strand will go through and then this will make me sound a lot smarter than I am you run a hidden Markov model with a Viterbi algorithm which is easier for me to say you can use the sequence by measuring the incremental block or resistance of current as the DNA sneaks through the pore if you engineer a hairpin loop at the end of the molecule you can do one strand and then brilliantly you can do the other strand there a little behind schedule that was apparent from this year's AGBT but companies like this and Genia suggest that we're going to take the $2,500 genome or wherever we are and see some remarkable further breakthroughs of that I have no doubt in the coming years so that leaves me in some closing remarks to talk about the other half of this and I think one or two other speakers will have much more to say on this which is I love this quote from Bruce Corff past president of the American College of Medical Genetics who says okay I buy it I was a skeptic before but we're going to have a $1,000 genome it's the million dollar interpretation that worries me and that's not the cost of doing a genome interpretation per se but it's the whole effort to integrate this into health care and we've heard little smatterings of this earlier from educating physicians the health IT infrastructure that's going to have to be built to make this to work regulations, CPT codes reimbursement and so on but insurance is covering this the Medical College of Wisconsin report that several insurers are reimbursing their work and it says that at the Baylor College of Medicine something like close to 90% of their clinical exam cases are being reimbursed there's a whole ecosystem of fantastically high thoroughbred startups trying to get into the genome interpretation space but some of this is already here so this is a sample from Foundation Medicine Levi Garroway you'll hear later is a co-founder of this company this is how tumor biopsy DNA profiling data are being presented to oncologists and physicians a list of mutations in a tumor a list of drugs that potentially fit the profile, fit the pathways that are disrupted in that patient's tumor and the clinical trials of that patient may be eligible for we can debate whether we use the term personalized medicine or precision medicine but we're starting to see real exciting really exciting advances in that space and it leads even a very conservative and respected medical geneticist to sort of drink the Kool-Aid and say it will be sequencing once and reading often if the price gets cheap enough we'll be sequencing many many times closing sort of just where are they now just two slides to close earlier this year Shankar about a supermanian in Cambridge made the press back in the UK for a discovery that was published in Nature Chemistry a new structure for DNA a quadruplex molecule found in cancer cells in certain environments that could be very important for cancer research also noteworthy I think is that he commissioned this painting which is hanging in his office I'm very pleased to see that he actually finally got a decent sized office for his for his troubles and of course the irrepressible James Watson I found this on Twitter and I wasn't sure whether to show it but you know it's good to know that DNA day celebrations aren't just some tedious black tie celebrations in some crusty Cambridge College this was in New York just a couple of weeks ago the person who posted this on Twitter described his four companions as his four nucleotides I have no idea what that means but I thought that was kind of cute so I want to wish Eric and Francis and everybody involved to hear NHGRI a very happy DNA day and I look forward to 10 more years if they're half as successful as the past 10 we're in for a treat thank you very much indeed