 Our first speaker, the outside guest speaker today is Dr. Francis Collins. All of you know Dr. Francis Collins as the Director of the National Institute of Health. And as you also know, he had the vision to recognize the incredible importance of translational research as part of the portfolio of NIH. Now as President of the American Institute of Medical and Biological Engineering, when we heard this wonderful vision, we recognized that translation is a concept that's fundamentally in the bread basket of medical and biological engineers. That's what we do. We translate discovery to devices for impacting patient care and to drugs to impact patient care. So we asked to meet with Dr. Collins and his staff to talk about how AMB and NIH might work together to catalyze the maximum success of this effort. We had a wonderful meeting and that was followed sooner after with a talk at the annual event of the AMB to all of our fellows which was absolutely sensational in engaging us and making us understand how medical and biological engineering could have such a positive and important impact to the mission of NIH. It's my pleasure to introduce the Director of NIH, Dr. Francis Collins. Thank you very much. Good morning to all of you. It's an absolute delight to be part of this remarkable symposium celebrating the 10th anniversary of NIBIB and all the great science that is coming forward as a consequence of this really innovative and exciting aspect of what NIH is all about. I want to particularly give my thanks to the Director, Roderick Pettigrew, who has been such a visionary leader in this area of bio-imaging and bio-engineering and I think has, through the remarks that he put forward already, given you just some snapshots of the really remarkable scientific opportunities that this institute supports. It's a very exciting time scientifically and it's great to have such leadership and a component at NIH that really focuses on this and our interactions with AIMBE and other organizations only add to our excitement about where this whole field is going. I confess to being a bit of a techie myself so it is really delightful to have a chance to think a little bit about what I might say to you this morning and pick out a few examples of areas in this space that seem to be particularly groundbreaking and it's obviously a broad field of opportunity so I will pick just a few examples and please forgive me if I left out some of the ones that you might have chosen yourself that you might have actually thought were even more appropriate. But in my brief remarks I wanted to both celebrate NIBIB and to point out how this fits together in a broader sense with where NIH is going and where medicine is going. First of all, congratulations on this anniversary. Here's a representation of the act that created this particular part of NIH, 24th day of January 2000 and congratulations to all in this room and outside this room who have made this into such an exciting part of NIH. Congratulations to Dr. Pettigrew for having also made it possible for the Senate of the United States to make a resolution celebrating this achievement. You can see here that that happened just earlier this week with support from Senators Burr and Mikulski but wide recognition therefore about what's happening and lots of positive things said about NIH and NIBIB. NIH has a noble mission. It is science in pursuit of fundamental knowledge about the nature and behavior of living systems. That's our basic science component. And the application of that knowledge to extend healthy life and reduce the burdens of illness and disability. That simple sentence sums up what we are all thinking about every day when we come to this remarkable place and have a chance to work with some 19,000 individuals who have their sleeves rolled up trying to make this happen. And of course that's a small proportion of what NIH is all about since most of what we support is research going on out there in our nation's finest institutions and some abroad as well. And for me as the NIH Director it is truly a privilege to be able to stand at the helm of such an exciting operation and try to steer it a little bit here and there. But most of the really important scientific leadership comes from the Institute Directors of our 27 Institutes and Centers and hence the very important role that they play and again Dr. Pettigrew plays that role extremely well. I thought I would talk about four T's here. NIH investments in innovation, talking about the future and innovation is what we need to focus on to make those things happen. So I'm going to talk about technology, about translation, about talent and well yes indeed because we are at a challenging financial time. How do we also justify this in terms of economics because believe me I get asked that question a lot including at my house hearing yesterday in front of energy and commerce and I think we have a very good story to tell there as well and we shouldn't be shy to tell it. So let's talk first about technology obviously in the sweet spot of NIBIB with so many things that are coming out of the bioengineering, bioimaging approaches that are leading us towards new ways of diagnosis, prevention and treatment. I just mentioned one that is now actually beginning to take shape in the basic arena of technology development teaching us about how exactly the brain is really wired. This is coming out of the NIH blueprint for neuroscience research, a collection of institutes that are all interested in the brain and has led to the formation of this human connectome project and part of that has been the support of a diffusion magnetic resonance imaging scanner which has very high detailed resolution and is faster than conventional scanners and if you have not seen any of these pictures or movies I would really encourage you to look at some of the literature. Whoops, let me see if I can get that movie to run, which has recently come forward in this effort because it is really quite a remarkable kind of image that one can achieve of this two-dimensional sheets of parallel neuronal fibers that cross paths at right angles as paper and science that will show you more of this and teaching us things about how the brain is working in the living individual that we probably would not have imagined we could learn about quite this soon. Lots of relevance for understanding normal and pathological development and again very much driven by clever innovative engineering approaches. In translation where we take the technology and try to move it forward into clinical applications that is obviously an area of intense interest across NIH and all of the institutes and centers. One of the new kids on the block is the effort to try to focus this in a way that would enable even more rapid development of therapeutics and one of the motivations for that is what you see on this graph which shows you what we have learned over the course of just the last couple of decades about the molecular basis of disease. This comes out of the compendium Mendelian inheritance in man which has been keeping track of what diseases do we actually know the cause of at the molecular level and you can see we are up now to about 4500 conditions. Most of them relatively rare and many of them caused by single gene mutations but look at the rate at which that has happened and this is about to go up I think even steeply again because of the availability of whole genome or whole exome sequencing that enables you to find the cause of disease even in very small numbers of individuals. The cost of DNA sequencing is a major driver of a lot of this technology. When we finished that first human genome sequence in 2003 it cost us about 400 million dollars to get that reference copy and now your genome or mine can be sequenced for about 8000 dollars so we've dropped the cost by roughly 50,000 fold in the space of less than a decade and there's no evidence that that particular drop in cost has reached any kind of limit. No laws of physics are going to be violated here. We can keep on dropping this down potentially to the point where a human genome sequence is down to 100 dollars or even less and that opens up all kinds of possibilities in terms of medical applications. Certainly also DNA sequencing has found its way into basic science in lots of applications not only in terms of whole genomes or whole exomes but just using it to count things like RNA expression for instance or epigenomics. It's been quite a revolution and the people in my lab over in building 50 actually can't quite imagine how we did anything in human biology before we had the genome sequence and the ability to collect this kind of data. That's all the good news. The bad news is if you look at this same diagram and ask how many of those 4500 conditions where we know the molecular basis actually now have a treatment. It's about 250. So we have this huge gap between what we know and what we can do about it and that clearly is an opportunity as well as a responsibility and a challenge and that's one of the motivations for trying to develop a better way to tackle the problem of developing therapeutics. Most of you know how that works but let me just run you through a little cartoon here. If you have a disease that you are seeking a small molecule therapeutic for you're faced with the challenge of sifting through the universe of shapes of small molecules to try to find the one that actually has benefit for that disease that hits the target in just the right way to result in clinical improvement. That means you're starting with a very large library of structures here cartooned and you are trying to pick out using some kind of assay which of those actually has some potential of hitting the target in a beneficial way and then you have much work to do to sift through that in the preclinical space to come up with something you might actually feel was safe enough to offer to a patient in a phase one trial. The problem is this is a terribly inefficient process with huge losses along the way. You start with maybe 10,000 of those compounds. You sift them down into maybe 250 in the preclinical and ultimately perhaps five of these make it into clinical trials but experience being what it is right now only one of those will actually achieve approval by the FDA. Notice the timetable at the bottom 14 years of the average time that head has taken over the last many decades to get to success and because of all the failures which are 99% plus you are also facing enormous costs because you have to pay for all those failures in order to actually have some successes along the way. So the estimated cost of each success is now in the neighborhood of two billion dollars. Well, that's just not sustainable with those thousands of diseases that are waiting for answers. Presumably we have to come up with a better way to approach this and we need to do so and do something fairly drastic in terms of the scientific approach because the experience here is truly daunting. This is a paper from Nature Reviews Drug Discovery just published a couple months ago. These authors basically tallied up what the cost was in terms of drug development since 1950 and using inflationary corrections that they plotted here the number of drugs per one billion dollars of R&D spending and they plotted this out on a log scale and you can see it looks really troubling here. It almost looks like some sort of law is at work here and it's a law that's going the wrong direction. You're now down to sort of less than one drug per billion dollars where back in 1950 goodness there was more like 30 or 40 on inflationary corrected dollars of that same thing. So what's going on? The authors somewhat tongue-in-cheek decided maybe this needed a name it sort of looks like a law so they called it e-rooms law which if you notice is Moore's law written backwards because this is going backwards. So what's the problem? Well the engineers in the room I would probably say that's your pipeline that's the best you can do. What's going on here? Why all the failures? Why the slow progress? What could you do to choose your targets better to begin with? How could you figure out how to fail early instead of late? All of those are critical issues and science has come along in interesting ways in the last few years to enable us to tackle some of those questions in truly innovative fashions instead of continuing to do things the way we have which clearly from this diagram is not working so well. So this really was the motivation for us here at NIH after much consultation through many different venues particularly the scientific management review board and consultations with the private sector through my advisory committee to the director. We established the National Center for Advancing Translational Sciences just last December 23rd and it is not intended at any sense to be the place where all translation happens at NIH not at all. It's intended to be a hub, a catalyst to look at actual bottlenecks in this pipeline as themselves scientific and engineering problems not specifically attached to any disease or any specific small molecule or diagnostic or device project but looking systematically at the way the whole pipeline works or in many cases does not work. So the NCATS has already gotten itself deeply engaged in a variety of projects one of which fits rather nicely with one of the examples that Roderick showed you is to try to utilize what we're learning about tissue engineering to be able to do a better job of predicting whether a drug is safe or not before you give it to a patient in a phase one trial. And this has led to an unprecedented collaboration between NIH DARPA the Defense Advanced Research Projects Agency who are pretty good at wild and crazy engineering ideas and FDA and collectively here we're putting a hundred and forty million dollars into this over five years and the goal is to develop a chip loaded up with as many as ten different cell types human cell types in a fashion that is as much as possible representative of what happens in vivo so as you saw in the video a few minutes ago about the human liver that was being re-implanted in mouse in this case we'd want to have human liver in a three-dimensional organoid on this biochip as well as cells representing heart kidney brain and so on the places where you most would be interested in seeing a signature of toxicity if that was likely to be a problem and of course we need to wire this chip up with a lot of different outputs in order to find out everything we can about what happens to cells when they're exposed to that new test compound so that probably means looking at gene expression at metabolomics at proteomics and so on and here is where we hope the science that NIH is pretty good at and the science that DARPA is pretty good at can come together so there is between our two agencies now efforts to put together a consortium and this is be an interesting cultural experience as well bringing together staffs of NIH and DARPA to work on this awards are anticipated imminently next month where we hope to put together some of the best ideas about tissue engineering biology toxicology and so on to create a pathway towards generating such a biochip obviously the goal will be to assemble this in a fashion where you can then test it with compounds where you know the answer that they are safe or they're not safe and then develop the idea about what a signature would look like that would give you confidence that it was reasonable to go ahead with a phase one trial or not reasonable if this works presumably it should be much faster and cheaper than the slow expensive and not very reliable animal testing which is the current way in which you have to generate evidence that your compound is safe enough to get an IND from FDA so FDA's involvement here is critical because if this begins to work we would not want to see this as an add-on as an additional thing that you have to do to test for safety but rather as a substitute for the methods that are currently used that is an example of the kinds of things that NCATS aims to support and you already seen one part of this along on the chip I won't go through it again because you already even saw part of this video and saw it much nicer because it had some some a narrative to go with it I will show you another video quickly this is one I showed yesterday to the House Energy and Commerce Committee and it is work supported by NIBIB the work of John Donahue and others which is basically then developing this interface between the brain of individuals who have quadriplegia and allowing them through the process of connecting that interface with their own brain function to learn how to move a robotic arm simply by the thought process that the subject is undergoing I must tell you the members of the Energy and Commerce Committee were quite riveted by looking at this here is the example where the patient in this case is attempting by her thoughts to pick up this canister which has coffee in it and see whether she can bring it to her mouth and take a sip of her own coffee all of this being accomplished as you can see by the box mounted on the top of her head that allows her thoughts to be translated into that robotic arm and I think you can see by the smile on the face of the patient and the investigator that this was a pretty good day that this this really was a remarkable moment well it's great to have all of these capabilities but we certainly need not only to have great science and great ideas we need to have the talent of the individuals to pursue that NIH is intensely interested in encouraging the most innovative ideas to come forward and worry that in the current climate where our budgets are very tight that peer review sometimes can be a little conservative in terms of not taking as many risks because there's such great solid science in front of them as well and one of the things we have done in order to try to encourage that kind of innovative approach is a series of special programs the three you see here all supported by the common fund that aim at high risk high reward research the early independence awards which we've just started aim to take the most talented graduate students and take them directly from the PhD degree to independence skipping the postdoc and giving them the chance to show their stuff while they are still in that oftentimes most creative phase and not in a circumstance where they are following other people's guidance but allowed to put their own ideas forward we just made 10 of those awards in this first year the best day I think I had in the last six months was coming to listen to those 10 grantees talk about what they were going to do a truly remarkable and inspiring group of fearless young investigators who are aiming to do things that were quite bold indeed the new innovator award also aims to try to bring new investigators to NIH who've not previously received grants from us not requiring nearly as much in the way of preliminary data but demanding that what they put forward has to be a groundbreaking kind of approach otherwise they can't be evaluated as part of this program the transformative R01 and now called the transformative research award because it isn't really quite so much like an R01 also has to be transformative but can support a large teams and has less in the way of budget limits than many of the other kinds of formats that people are used to and the pioneer award which has now been around for more than five years which gives an investigator the chance to write a relatively brief proposal with some bold ideas and then to be funded for a five year period as an investigator and not basically allowing them to move in the direction that makes the most sense scientifically not particularly tied too tightly not to original plan very much like a Howard Hughes position and those also have turned out to be very much productive parts of our portfolio as an example I'll talk about an individual who's actually received a pioneer award and more recently a transformative R01 and who is a grantee of NIBIB and this is Sonny Shee this is a investigator at MIT who's a chemist who has actually applied some very innovative approaches to do single molecule visualization in single cells an area of intense interest in fact we're about to start a new common fund effort in single cell biology Sonny Shee using his skills as a chemist has been able to come up with systems that allowed you to look at expression of single protein molecules what you're looking at here from a publication in 2006 those yellow dots there are single proteins which are marked by a version of GFP called Venus and basically this is a circumstance where they've created a trans gene in this bacterial system that is only rarely expressed because it's actually repressed by the lack of repressor but occasionally one copy of the RNA gets read off anyway and that one copy then is used to make three or four proteins which you appear appear as bright dots in that particular bacterium and that is kind of fun to watch here you see the the solid static version we can run a little movie here now watch the yellow dots as they begin to appear they just sort of firing off there as an RNA was transcribed and then proteins are briefly made from that RNA in that same cell it's fun let's watch that again see that yellow dot now we'll pop right up there you can see oh must have made an RNA there now maybe four or five copies of the protein being generated from that transcript and teaching us a lot of interesting things it's obviously nice eye candy but it's also teaching us a lot about biology he has gone on with a colleague at MIT Xiaowei Zhuang who's been also a very creative individual in terms of figuring out how to see things at a resolution that you thought you couldn't do with light microscopy using this technique called storm and here is just one image here again of a E. coli system looking at a nucleoid associated protein called hns this is what this would look like in phase contrast for recents of a conventional sort would look like that look at the level of resolution showing where that protein is in these individual bacterial cells so lots of exciting technology being supported through these grant mechanisms the pioneer awards and the transformative are ones I wanted also to mention something that N. I. B. I. B. is doing which I think is kind of exciting bringing young scientists undergraduate level into the realm of competing with each other for this debut challenge and this is basically N. I. B. I. B.'s opportunity for people to compete for prizes the deadline for receipt of the applications was June 2nd so presumably there will be some announcements before too long diagnostic devices is one one approach therapeutic another or technology to aid underserved populations and low income circumstances or individuals with disabilities so very much an innovative way to try to drum up excitement in undergraduates they have to be submitted as teams and as you can see there is money involved which tends to get the attention of undergraduates finally there is this issue about how we need in the current climate to be sure that we're making our case for the value of what biomedical research is doing not only for the future of human health but for the economy and again I think as all of us are are called upon to defend the investment of taxpayer dollars in this activity we should be prepared to say why this is a good investment we need to make that case because we are not at the present time enjoying a particularly favorable environment for the support of biomedical research through NIH you can see here in this series of bars the purple bars tell you what the appropriations have been to NIH over the course of the last 13 or 15 years you can see the doubling that happened between 98 and 2003 which was a wonderful opportunity for growth and for new investigators to come into the field but you can also see that we flattened off pretty badly after that and if you look at the yellow bars which take account of inflation we are actually losing ground and have been since 2003 our purchasing power now is down by about 20% over what we could do nine years ago and obviously with the current focus and appropriately so on our difficult financial circumstance and deficits there is certainly no indication that this is going to get any better and presumably it could even get a lot worse especially if those sequesters that are being talked about happened to kick in on January 2nd of next year if that were to happen we would in one fell swoop lose 2.4 billion dollars of the NIH budget we would have to cut back our grant awards for FY 13 to unprecedented low levels about 2,300 grants that we wanted to give would not be given so there is a cloud on the horizon and we need to be defending this as I tried to do yesterday in the hearing but as all of us I think are called upon to do from time to time why this is such an important investment for our economy for American competitiveness but for human health is our number one approach if you're looking for evidence to cite about that there are a number of really remarkable analyses that have been done by credible economists that make this case every dollar that NIH gives out in a grant results in more than twofold return on investment in the first year in economic goods and services to the local community our grants support about 432,000 jobs high quality jobs and the spin-offs from what NIH does probably results in multiplying that number by a factor of 20 in terms of employment through pharmaceutical and biotech companies and we are major driver there for the American economy and cutbacks at NIH will have ripples that will be really quite severe again there's lots of information about this if you go to our homepage NIH and look for the button that says impact you can see a long list of documents that go into this issue about economics and the evidence that supports the value of what we do and I think this is a particularly moment then as we are facing this potential challenge to the future of our enterprise to emphasize that return and to do so in a fashion where it's clear we're all speaking together it's one thing to have somebody stand up with one voice and talk about the value of medical research even better if that's a part of a symphony with a chorus and we also kind of have the same song sheets in front of us basically arguing what we are about is a noble mission to try to improve human health we have a remarkable track record in terms of what's happened in the last few decades with for instance heart attacks and strokes have been reduced as a cause of death by more than 70% in the last 40 years HIV AIDS no longer being a death sentence but consistent with lifespan to age 70 and beyond and a variety of other really remarkable achievements and we shouldn't be shy to sing that song to people who are interested in asking the question about whether this particular part of government investment is worth the dollars it is more than that as far as where you're going in terms of this symposium and the future of NIB IB and the rest of the NIH and all the disciplines that we represent I have a hard time imagining that very clearly and I'm fond of this quotation from the guy who wrote the little prince of the petit prince if you read it in French Antoine de Saint-Exupéry who says as for the future your task is not to foresee it because that's too hard but to enable it of all the parts of NIH that I think is really focused on that remarkable task and opportunity of enabling seems to me NIB IB is right in the thick of that I congratulate all of you for the progress you've made and I wish you another wonderful decade to come thank you very much you know I think at this point it's still the health argument that gets people's initial interest because everybody has concerns about themselves their loved ones their constituents in terms of health issues that need more attention but as soon as you get that part of it oftentimes their then responses well yeah but can't the private sector do this better or why are we giving you so much money couldn't you do this for a lot less then I think you have to be prepared to come right right behind that with the economic argument which is a very compelling one as well now you're you're quite right the major source of cost that doesn't get us anywhere is in failures in phase two and phase three because by that time you've invested tens or hundreds of millions of dollars in a compound and the major cause of failure is efficacy the compound turns out to be safe but it doesn't work so another effort and I didn't have time to go into this which we're deeply engaged in right now with industry as major partners is how to do a better job of target validation right at the front end of this development how do you pick the right targets so that you don't go down this path very far and ultimately discover you've got a drug that just doesn't work there are some exciting potentials there again because of the ability to use tools like genomics we have a chance to do target validation in humans instead of perhaps in cell culture or in animal models in ways that we couldn't have before we have a human knockout project that's underway right now nature has been at that project for all of human history and now we have a chance with things like exome sequencing to detect the consequences of that take an example like this gene called PCSK9 which Helen Hobbs and colleagues in Texas discovered carries knockout mutations in about two percent of people and those people have very low levels of LDL cholesterol and very low risks of cardiovascular disease she even found a few homozygotes who have no functional PCSK9 at all they're entirely well their cholesterol levels are like 12 and their risk of heart disease seems to be extremely low now talk about a great way to validate a target that tells you that if you built a drug that's an antagonist to PCSK9 and you actually hit the target you should provide substantial clinical benefit with a reliable biomarker and it should not be toxic because the people who don't have this for life seem to be just fine that was a great example but could we do this more systematically by identifying such loss of function human knockouts for lots of other genes and focus on the ones like PCSK9 where the loss of function actually seems to provide some advantage those would be perfect targets then to mount a campaign to build a small molecule against that target that's kind of the thought process that we're going through right now with industry is our close partners because they need this too they're aware that the way in which targets have been chosen has resulted in a great deal of failure oftentimes very late in the process yeah Dr Collins in terms of the dollar amount or so the time being taken for drug development shouldn't we include a general statement that apart from trying to be more sophisticated the problems remaining are much harder to solve therefore it is taking more slides and effort both in money and time to achieve the goal that's certainly part of it and people would argue that the low-hanging fruit in terms of developing drugs has already been plucked and that the targets that we now need to go after are going to be tougher less well understood perhaps less easy to hit with our particular small molecule or biologic approach that's certainly in there that's part of erooms law undoubtedly but it's not the whole story and if we have a chance to stop that downward curve or even start it back up again with new science facing the fact that we may have more difficult science in terms of the targets themselves we should put lots of energy into that the future really depends on that i very much oversimplified all the factors that go into this but i do think we have an opportunity here if we work together to try to do something fairly interesting one of the thing we just announced which is a way to shortcut all of this which i'm pretty excited about is to take those compounds that got all the way to phase two or phase three but failed to show efficacy but we're shown out shown at that point to be safe and figure out okay so it didn't work for diabetes might this drug have worked for schizophrenia or cancer we've seen lots of examples where that kind of repurposing actually works out pretty well whether it's the lidomide for myeloma or whether it's goodness AZT for HIVA it's AZT wasn't developed for that it was developed for cancer there are now eight companies that have agreed to open their freezers and make 58 compounds available for investigators in academia or in small businesses to look for new uses and if that turns out to look promising one could go almost straight to a phase two trial with compounds where a lot of that investment's already been made that won't work for everything but if it works for a few it's well worth the effort thank you very much thank you all