 Okay. We're going to resume with our last concept presentation, and this is like the first. There will initially be a report. This is for the genomic technology development. There were two workshops that were held in early April, and first, Michael Smith is going to present the results of those workshops, and then go into the concept, which is based on the recommendations of those workshops. Mike? All right. Well, thank you for listening to this today and considering the concept. What you're going to hear about today is the workshops that we held, the overall goals of the concept, a timeline, two initiatives. I'm actually going to slip the timeline between the two initiatives to help break it up, and then an overall budget. And actually at the very end, I will talk a little bit about this budget versus the $1,000 genome budget because I know that's one of the questions that's come up. So we did hold two planning meetings. They were actually webinars, and we got a good turnout. We got pretty much very many of the people that we invited agreed to participate because we were able to meet their schedules, and I think they particularly enjoyed not having to come to Washington for a planning meeting. You can see that on April 10th, we had one of our council members, Joe Ecker, there, and on April 16th, we had Jay Shenduri. I'd also like to point out Hanli Ji, who helped us write the meeting prospectus. And just in general point out that we had a nice group from across both academia and industry. We felt like that was really an important thing to shoot for, given that technology development has to sort of perhaps start in academia, but also has to become something you can buy as a kit at some point to really have the kind of impact that it can't have. So we did hold these two webinars, and we charged the participants with helping us identify areas of really good opportunities, priority, and biology and disease. And you couldn't hit one of those three or two of those three. We wanted things that hit all three, right? So where are the best opportunities, priorities, and biology or disease? Where are those sweet spots today? And where are they going to be in the next five or ten years, more importantly? So I'm going to give you pretty brief workshop recommendations, because they're largely rolled right into the concept, into the initiatives. And we worked on this earlier, there was just no reason to keep repeating. So what we heard very strongly from the group was that there was a really wide area of technology development that's ripe in genomics today. And it's stretches across new DNA and direct RNA sequencing methods, but that there were also many other areas. And we needed to try to think about how we could help encourage those areas for the benefit of the field. Again, the details are in the initiatives. We heard also from the attendees that technology opportunities, we really wanted to give investigators an opportunity to tell us what their best ideas are, and you'll see I think the way that we're going to do that. And that the applications benefit both from dedicated review and from a solicitation in terms of getting them here and having them reviewed well. So getting to the concept, the goals are to facilitate development of new genomic technologies, not this year, but in five to seven years or longer time frame, specifically solicit new technologies for novel nucleic acid sequencing, both DNA and direct RNA. And just provide a new avenue of support for genomic technology development, which could really span a wide gamut of applications. And we'll get into what those are a little bit later. But clearly, there's a lot of opportunity in genomics these days. You think about how many pretty fundamental things have gone on in the 10 or 12 years since the $1,000 genome RFA came to this council before all of you were here, although maybe one of two were at that time. So the initiatives, a novel nucleic acid sequencing technology development initiative, and then genomic technology development awards. That's where we're going, and I'll describe the first one. So the purpose here is to develop revolutionary nucleic acid sequencing technologies. There are likely additional ways to sequence nucleic acids that we don't use today, that if they worked really well, would revolutionize the field one more time. And so if we can find those, that's really important. That's what we heard from the workshop, and that's what we're aiming to do here. The other thing we heard loud and clear, as part of that was, again, there was a revolutionary technologies that could really impact highly. We also heard that we've been sequencing RNA via CDNA for a long time. And we really ought to come up with some methods for direct RNA sequencing. So that's part of this concept. We'd like to have long read lengths, high accuracy, and low costs. Or if you know the old joke, you can only have two out of the three. But we'd like to have all three. In terms of support, we're looking at $2 million additional total cost dollars for each of the next four fiscal years, 16, 17, 18, and 19. That would put us at two to four awards per year. The RO1s on the order of, say, four years. R21s for three years would give people a little more time and a little more money than you normally get out of our RO1s and our R21s to do this work. Because we realize that you've got to have different sets of expertise on any one project frequently. And that just takes more time and money to get it done. And then we would also work in the SBIR and STTR domain. And those monies are not indicated on this slide. But we would certainly be trying to find applications in those areas. Because I can also have an impact on the field. Along the bottom of the slide, you can see the, I'm not gonna. Along the bottom of the slide, you can see the dollar amounts in the fiscal years, you can see it ramps up as we issue $2 million a year and then it ramps back down as the commitments end. And then it's easier to think about this a little bit by what kinds of things might come in under this particular concept or initiative. So new chemistries or physics or instrumentation for really new ways of sequencing DNA. Some important areas include just fully sequencing all the nucleic acids in a sample. So not this, the luminous sequencer maybe you sequence 50% when you're doing really, really well. But fully be able to characterize that sample. And then very long reads, because we realize that those could be very important for de novo assembly. Direct RNA sequencing of full length transcripts without a CDNA intermediate. I already spoke about that. And then several orders of magnitude improvements to existing sequencing technologies. That's another way to get there, that would be fairly revolutionary. We all want to do all of that without paying too much more money. So I said I would break the two with a timeline. So you've seen the timeline like this that's very similar from ENCODE. Concept clearances today, FOAs released in the summer. Review in the winter, coming back to council this time next year. And then funding in that summer. But we would then have three more rounds, right? Because we're going to be issuing new money. We're going to have to be soliciting in FY16, FY17, 18, and 19. And that means anybody who comes in, say in FY16, and perhaps just misses the funding line or gets something really significant pointed out in review will have an opportunity to come back in. Maybe with some new data, whatever they do to make a better application. So this will be an ongoing process to try to make sure we get the best genomic technology development we can for those four years of funding. The second thing we would like to do is to have genomic technology development awards, this, and I should have said on this sequencing it was an RFA. I know it was on one of the slides, but that would go out as an RFA. This is going to go out as a PAR that just says we have an interest here. We'd like to see applications in this area. And the idea is to catalyze investigator initiated genomic technology development in that five to seven year time frame in terms of impact. And we think there's a wide area. I thought I would address, when I got to this slide, what that wide area was. That's what I'd like to do now. So really high throughput, high information content, functional assays. We should read genomically as one area. We think we might see some applications. Single cell methods for everything, anything we're interested in pretty much. You can do it on a single cell. We heard loud and clear and that that was a very high priority area. Foundational technologies, something as simple as extracting all the RNA, all the DNA, and all the protein out of a sample. Even better, a really small sample for analysis. Transcriptome analysis, other kinds of functional analyses. Down to dollars, three millions total cost per year. That's RPG funding. Again, for four years, FY16 to FY19. We're thinking three to six year awards per year. Same sort of timing and dollar amounts on the RO1s and the R21s, we're thinking of. And again, SBIR and STTR funds are something we try to use in this area. We already issue awards in the SBIR and STTR domain in technology development. So this is just an effort to sort of get more applications of high quality in those areas. Again, you can see that ramp up and ramp down of funds along the bottom of the slide. Here's some examples, some of which I've already mentioned. I won't read them again. There certainly would be room in here, for example, for some CRISPR-Cas9 type applications that were really genome wide and big impact. Scaling DNA sequencing to many, many samples. I think one of the things we heard from the workshop, and we just know, is that if you could sequence a genome for significantly less than $1,000, by several orders of magnitude, then that opens up a whole new set of experiments. In situ methods for everything, DNA, epigenome, RNA, protein, transcriptional, dynamics, and then generating sequence tags at very, very low costs. Some of the programs we're running right now spend a lot of money just getting the sequence tags. And so we could have a pretty big impact if we could get the costs of that down, and probably enable many things that aren't even being done today. So the summary of the money that we're talking about for these activities, 2 million ramping up to 8 million in FY19 for the nucleic acid sequencing technologies. 3 million ramping up to 12 for technology development awards. Five ramping to 15, and then you can see it ramp back down. In the next slide, just shows a little bit of where we were with a $1,000 genome. So in FY6, 7, 8, all the way out to 17, you can see the commitments. The $1,000 genome was sort of in the 20 to $15 million range for a while, and then it's been ramping down and ramps down in 15, 16, and 17 because we made no awards in 15, 16, and 17. And you can see it's ramping down by about $4.5 million a year for the next two years. So that's at least gonna help pay for the first two years of this concept. And I should say a few thank yous. Bianca, Katia, Chris were really helpful with the webinar. Bianca with many things she was key to just helping pull the webinar and other parts of this together. Elise, Mike, Adam, and Betty, this is my first time I brought a concept up here. Helpful for knowledge and feedback and everything else and many others. Jeff, I mean the $1,000 genome is his baby and I've learned a lot from him about genomic technology development and how the NIH works and he had a lot of input into this. His name could have been on the first slide. Hanley, Joe, and Jay have helped in developing this concept. And we had 21 other people in the workshop and we also had a follow-up server I haven't talked about that was useful in all of this together. So with that, I'm ready for questions. Go ahead, Joe. One thing that was in the report that you didn't mention was that because essentially the funds for the $1,000 genome were being split into these two areas. And there was a, let me first say your summary was very accurate regarding the webinars. And in thinking about what the sequencing part would do, there was a consideration that the new technologies would not over a lot much with industry, given less money, but yet still a great desire to attack these areas that there would be. So that would be worked out how with by. I think the best we can do is be aware of what's currently in industry and we try to do that our reviewers are usually pretty darn aware of that also. So I think that's in reality at $2 million a year compared to what some of these companies are spending, but they're probably working on things that would be more immediate than we would think this DNA sequencing or nucleic acid sequencing initiative would go to. I'm going to move us back to that slide because I can tell that's what we're going to be talking. I should have done that earlier. Okay, Tony? With the increased mandated funding for the small business pot of money, is there any way of cutting this back and forcing some of that mandated money to be small businesses in collaboration with academic groups to develop new technology, rather than it all being new money? I believe the increase is around $500,000 a year that we've been saying. And so, it's been going up by 0.1% every year. I thought we saw an increase of several million. Those numbers are all over the place in part. The numbers you saw earlier are showing new spending in a fiscal year. So anytime we issue, say, a phase two that has two years of support, then we've committed money next year. And so that's a large reason why those numbers will bounce it around like that. I didn't say anything at the time, but. Sorry, that must be thinking of the wrong slide. I saw a large increase in funding for small businesses in one year mandated. I don't understand why some of that can't be put to this. Yes? I thought I'd probably go from like four to eight or it doubled. But our small business dollars, I happened to coordinate the small business program at about $11 million a year. And it's been going up by about half a million dollars a year for the last couple of years and will for the next year or two. 0.1% of the budget. Why can't some of that be used to get small businesses to collaborate with academic youths rather than- Well, in fact, we just came back from the genomic technology development grantees meeting last week and we had many small businesses there that were doing DNA sequencing and other things like that. And they were funded out of the SBIR pool last time. So when $1,000 genome we were funding SBIRs there, that's what we're talking about. I thought what I was hearing Tony suggest was a mandatory linking as opposed to wouldn't it be nice if they came and they spent some of our SBIR money. I'm hearing and I don't even know all the legalities and the policy. But what I thought I'm hearing Tony put me wrong is some sort of a requirement or I mean a designation that this is the way SBIR money is going to be spent. So we use more of that money for this and less of our colorless money. Thank you, Eric. Yeah, okay. But is that legal and is that possible? I just don't even know the feasibility of it. It doesn't, the legality is hard to know but it could be encouraged in some way without saying, well, you wouldn't be selected against if you didn't. But having an academic partner is something that's encouraged that you could include that in the description. I think what I'm hearing is sort of a suggestion to invest less of our undesignated money and force better use of SBIR money in a way that might be a win-win. Especially if you feel the scores on the SBIR grants are not up to the same levels of- Can I address that directly, please? Which is this year the scores are pretty much right at the same level as our R01s and our R21s. So they are very competitive this year. They were a little less competitive in the year or two before that. But I think they're going to continue to be competitive going forward and I could talk about the SBIRs for a while, but that's. So we have a practical question and I confess I don't know the answer to it because I don't do SBIR reviews, but I'm looking over at Betty. Can an SBIR applicant have an academic collaborator and if so, what are the budget splits that are allowed? Okay, so what are the budget splits? Is it 50, 50, 51, 49 or 99? I can answer that question also. Okay, so on an SBIR, it's up to 30% can go to academic partner. And the vast majority of our money is SBIR. So in the STTR domain, it's between 30 and 60%. It has to go to the academic partner. But I would take STTRs largely off the table because the budget amount is like a million dollars, it's so small. Sorry. Can you change the distribution between SBIR and STTR? That's congressionally mandated, the percentages are. Because I was going to say that the STTR program is a way to do this because up to 60% can go into the academic domain, which would be great because then it could do, I don't know, an RFA around that. But if it's a million bucks, it doesn't really help. And there are a lot of other restrictions we haven't gone into. Go ahead, Jay. Mike, can you comment on the difference between the practical consequences of setting up the second part as a PAR as opposed to an RFA? I think others probably can comment on that better than I, but I will try. In an RFA, it's more dedicated dollars, which is what we were talking about earlier on. And then with a PAR, we're telling you and others that that's how much we plan to spend there, but probably our hands are a little less tied. Betty's raising her hand. She's going to have a better answer than me. So the RFA is dedicated money and it comes through concept clearances. The PAR is really a program announcement with the review being done at the institute level rather than CSR. So it's just a program announcement. No set aside, you're just saying, this is what we're interested in. And by the way, it won't be reviewed by CSR, but it'll be reviewed by G. Which is what our segs in. So it looks like a set aside up there, but it's not really in the practical sense, meaning you have more flexibility. Planning target number. I see. Jeff, go ahead. With respect to the SBIR, there's one real challenge of trying to do this all by SBIR, which is you have to have a business plan for an SBIR grant. And a lot of these projects are way too early to have a business plan. You don't even know if the technology is going to work. If we're in the space that we would like to be in to explore new technologies. So we want to use SBIR to the extent that we can and bring additional dollars. But I think it would be a mistake to try to do this mostly with SBIR, just because we're trying to stretch. The other point with the PAR is it's sort of an aspirational goal, but we do need to talk about whether we want to try to in some sense set aside funds to be able to do that, versus have that compete with all the other applications that we get. That's a discussion for later on probably. Yeah, just about. So from a non-technology development person at the workshop, you've got what seems to be a pretty lofty goal here of getting these three pillars. Did the panelists actually feel that this amount of money would move the needle? We asked them that and what we heard was they thought we would get high quality applications, which is one of our concerns. Was it so little that we wouldn't get a quality applications? And I think we heard it would move the needle some, but like a lot of these things, there's more need than there is money. So we're trying to fit in. The money's better than none. So you'd expect that response. I was just curious if you really expect to make much of a dent here. We've made, we think, significant dents in the past with this amount of money. Yeah, so I mean, at least as I recall it, for the $1,000 genome RFA, the response was pretty vigorous over the years in terms of applications for basically the same amount of money. I mean, you're funding individual investigators for projects that aren't super sequencing driven. And so five million bucks actually goes a pretty long ways, especially when it's, you know, it's every year. It's another five million. So I actually think there's a, I mean, there's a community you could, you could pretty effectively fund here to try out a lot of ideas with this amount. I think one thing that hasn't been mentioned along those lines, and Jay asked the question on the phone earlier was, could this be a place where someone who was interested in a SEGs, but maybe didn't have enough to turn in a SEGs application, could sort of get their feet wet? And I think there are a lot of good ideas that aren't big enough for a SEGs. And this is a good, would be a good place for it. Yeah, we were calling mini SEGs. And, you know, for the, at least for the second objective, that the money is big enough and you could potentially have several collaborators on something like this, but not a full blown SEGs. So it's kind of in that intermediation here. Maybe this is all in the same lines as Long was asking, and maybe this is incredibly naive, but sort of at the end of the day, you know, one outcome might be the development of some the $100 genome, some blockbuster technology. And my concern is that NHGRI, by making this sort of little investment at the beginning, won't get any credit for it at the end. I suppose that's always the danger or the sort of the frustration of being the sort of initial funder. But where, you know, it's a philosophical question late in the afternoon. What's the role of VC? What's the role of industry? What's the role of NHGRI in the development of these, the new technologies? I mean, I understand the single cell sequencing, for example. That probably needs to start here. That's not going to start somewhere else. But fundamentally, you know, we run the risk of creating a new industry that we then end up paying for, you know, five years from now, because we don't have a stake in it. At the beginning, there's no way that NHGRI is going to get a stake in a new company, I guess. But how do you approach that kind of, how did, I mean, did Illumina come out of thin air? Did the high-seq come out of thin air? Did the high-seq come out of investments early on in a thousand genomes? And Illumina came out of a chemistry lab at top. No, that Illumina actually did, but I think Jeff's about to tell you, if you look at the instruments that Illumina now sells, there's what, about four, five, six patents that came out of NHGRI grants that cobble together to actually make the current suite. For Illumina, the my-seq platform depended a lot on technology that we supported for several years. But what we've heard over and over again at these grantee meetings is that even relatively small NHGRI investments of $250,000, $500,000, $750,000 have been leveraged many, many fold. The fact that people could get an NHGRI grant then allowed them to get additional funds to do additional development. But without the NHGRI funds, they couldn't try out those initial ideas and they couldn't demonstrate to others that they had an idea worth further investment. So, maybe I'll just leave it there. Industry generally won't start at the very beginning of these projects. I mean, it's anecdotal, but I would say when I've spoken to the Illuminas and the similar companies, I talked to their CEOs that, I mean, they say that the kinds of things that we are supporting, the kinds of things that we're proposing to support, they have almost no interest in doing. It's way too upstream. And so they absolutely think that the field has been stimulated by some high-risk things that we have done traditionally and would love to see us continue. And obviously, it's their best interest to see that happen. But within the ecosystem, I mean, I think they're being pretty blunt. This is not what they're going to be doing. So the other point to make is we jumped immediately to Illumina. And so for one Illumina platform, NHGRI support made a big difference. For their basic chemistry and so forth, they didn't have NHGRI support. For the sequencing technology, for the Illumina bead technology, we were absolutely critical, but maybe that's another conversation. On the other hand, there are a couple of other technologies out there. The single molecule technologies received a tremendous amount of support from NHGRI over a long period of time. And I have no question in my mind that they wouldn't have gone anywhere near as far as they've gone. Now, I understand they're still too expensive for the routine sequencing that we'd like to do, but we're seeing them being adopted more and more and having the potential to once again change the field. Whether they will reach the costs and so forth that people would like, we don't know. But if anybody who was at AGBT and is reading the literature has seen these new technologies emerging in a very important way. I just find it incredibly frustrating that we are sitting here trying to find $10 million out of our budget. When early seed money from this institute and others have made such a huge difference to companies that are large and getting larger. And I wish there was a way to sort of transmit that to the people who provide the money so we wouldn't have to scramble around looking for those $10 million to state the obvious. Nonetheless, this is our role. I would just, Dan, I'd say the problem, let's wish that the problem you pose comes to pass. Right? That's exactly what... The history says that it will. This is what NIH is supposed to do. It's not, the problem that you pose is not unique to sequencing technology, right? It's all of NIH is doing what pharma will not do, for instance, right? If only we could get big pharma to actually declare that to be the case, right? Show Lon some love here now. Other questions for Mike? Okay. So Council understands we're asking for approval of the initial concept. The second one is a PAR and we're not going to take a vote on that. So this is for the initial concept for DNA sequencing and direct RNA sequencing. Can I get a motion to accept? And the second, all in favor? Any opposed? Any abstentions? Thank you. Thank you, Mike.