 Welcome everyone to this extraordinary celebration of the 10th anniversary of the National Institute for Biomedical Imaging and Bioengineering. I'm Ken Luchin. I'm going to moderate the morning session. I'm the Dean of the College of Engineering at Bosch University and the immediate past president of the American Institute for Medical and Biological Engineering. Thought the morning rather than indulge in a long, time-consuming introduction of each of the speakers, which are highly well known. I'll just provide a very short vignette or personal vignette about who they are. Our first speaker, of course, is here to celebrate the nation's recognition of the need to invest in biomedical imaging and bioengineering for the good of the human health in our nation. And they did that by having the vision to create this wonderful institute and then had the vision to name as its first director Rod Pettigrew, who has been an extraordinary shepherd of this wonderful National Institute for Biomedical Imaging and Bioengineering. Please welcome Rod Pettigrew. Thank you, Ken. And good morning, NIH friends and guests. I am very pleased to welcome you to what promises to be an exceptional day of learning, courtesy of some of the world's foremost leaders in science and technology. We had anticipated also having Jeff Immelt, CEO and chairman of GE, here with us today. But unfortunately, he had an emergency and will not be able to attend today. But in every cloud, there is a little bit of a silver lining, and that gives us a little bit of a cushion time-wise today, so we're a little less pressed for time. And perhaps we can use that period for some questions as they arise over the course of the day. To the speakers, a big thank you. We're delighted that you have found it possible, despite the many demands on your time to share this day with us and make this celebratory symposium both informationally and scientifically rich. The legislation that established the Institute, N-I-B-I-B as it is known, was signed at the very end of 2000, December 29, 2000 to be exact. However, the first appropriation was 15 months later in the spring of 2002. And this is when the Institute became fully operational. The first council that we had was in January 2003. We have members of that council present, members of subsequent councils, and our current council members, many of them as well joining us today. And thank you for attending. I thought that you might be seated as a group, so I would have pointed to you, but I see you distributed throughout the audience. So maybe you can just sort of wave. All right. I would also like to recognize the leadership of the Academy of Radiology Research, Renee Cruey, and the American Institute of Medical and Biological Engineering, Jen Ayres, for their support of these events. Finally, I would like to acknowledge recent legislative actions, wishing us a happy anniversary. In addition to letters from Congresswoman Anna Eshoo and many health-based organizations, on Monday, Congressman Robert Andrews of New Jersey made a statement on the House floor honoring the 10th anniversary of the N-I-B-I-B. And I have a copy of that statement here and a personal letter from him. And on Wednesday, Senators Richard Burr and Barbara Mikulski announced passage of Senate Resolution 499, which they co-sponsored honoring the 10th anniversary. And finally, I would like to acknowledge the patients that you will hear from today, one this morning and one in the afternoon. Robert Summers, who is also featured in the final video segment of my presentation and who was the subject of a Washington Post article earlier this year, is here today. And we will hear directly from him about his experiences and how he has benefited from the research that we support. And in the afternoon, Robert Casano will also be here this afternoon to share with us his personal experience with health care and innovations that were developed by our researchers. At this point, what I would like to do now is to review with you some of the advances made by the N-I-B-I-B and the communities that we serve in addressing health. I'd like to do so on a fundamental level by focusing on precision, the pursuit of scientific truth, and the benefits thereof. This picture is, as it indicates here, of Galileo. At the beginning of the Scientific Revolution in the 1500s, the Milky Way was believed to be a cloud. It wasn't until the early 1600s when Galileo fashion his telescope pointed it to the night sky and determined that instead, the Milky Way was composed of a constellation of individual stars. This dramatically illustrated the importance of precision measurement and the value of precise scientific observation. More recently, Stephen Quake, the professor of bioengineering at Stanford University, who happens to also be a pioneer awardee and winner of this year's Lemelson MIT Prize. Also, in this rather coached statement he underscored the value of precision measurement. He observed that history has taught us that by measuring fundamental physical phenomena with increasing precision, one can make amazing discoveries and even sometimes stumble across new laws of nature. I would suggest that we would uncover new laws of nature. But the point here is crystal clear. When I arrived at NIB and held the first all hands meeting, this was a slide that I used. It comes from our archive. I posited a vision that circulated in these three points. The first item I'd like to draw your attention to in the first word, small or faster, different words, but this speaks also to precision. Small and faster is about increasing precision with the consequences that follow from that. And item two, convergence, the concept. You'll hear more about that from Phil Sharp this afternoon. And we're Francis here, he's on his way. I point out to him that item three, if you read it carefully, really is about personalized health. So I find it interesting that in this particular perspective taken from the New England Journal of Medicine earlier this year, that personalized medicine has been recast as precision medicine. The authors are discussing the concept of using multiple approaches to, as they put it, create diagnostic, prognostic, and therapeutic strategies that are precisely tailored to each patient's requirements. So how far have we come over the decade in this quest for precision and its application to the problems that we face and the resolution of those problems? I'd like to review this with some examples in these three broad categories. First, observational science. By this I'm referring to information that is resolved in space and in time with the benefits from that outline and that second item on the slide. Using MRI as an exemplar of what has happened in the field of imaging, we see there have been tremendous improvements in resolution both in space and in time. These over-order magnitude increase over the decade with the consequent practical applications in the clinical arena as illustrated. A picture is worth 1,000 words and this really tells the story. Comparing an image from 2002, specifically stated as a high resolution image with one that is state of the art from the group at MGH, the improvement in the precise depiction of the anatomy is quite striking as is this image, 70 image also from the Rosen group. Different MRI technique contrasts reverse but striking as well for the remarkable detail. One of the people in my institute, a scientist, looked at this, thought it was a high definition photograph. It is not, it is an image of a person and the thin lines that you see coursing through the cortex that are dark are visualizations of venules and small veins consequent to the low level of blood in the veins. The contrast mechanism known as blood oxygen level dependent contrast, the same mechanism that is used in fMRI, remarkable detail. What is the practical benefit of this? Similarly, remarkable, we've known MS for years is a disease of white matter but also the gray matter but we've never been able to visualize gray matter lesions. It's been seen at pathology, pathologists indicate and visualize three different types of gray matter lesions. Now we can see them just in the last couple of years or so with this increasing precision and resolution. Each of those three types is indicated in these images with the double arrows, the different colors correspond to the different types within these gray matter lesions. This more complete picture of multiple sclerosis now allows us the ability to more accurately follow the level of disease in the clinic and determine the effectiveness of interventions. In the spatial arena we've just seen those advances. In the temporal resolution arena, similarly remarkable advances. This light courtesy of Dan Soddickson who has pioneered the improvement in speed, high speed MR imaging, who's in the audience today makes this rather elegant analogy with the way things were and the way things are. The way things were were similar to this. Like a typical photocarpier unit scanner, fax machine making an image as the light goes across one line at a time. Imagine if you had to try and make a movie with this slow imaging tool. The only thing you can make a movie of would be a turtle. But the improvement now is more like what is done with a video camera. This requires images from multiple lines comprising the image in parallel all at once and with that instant capturing of all of those data points at once in space being able to then visualize them in time. The corresponding hardware and software analogy is shown here going from a single coil in the old days to multiple coils now with the family of signals being obtained. But this is more complicated in simply adding more coils. This data set is a complex data set. One has to deconvolve the spatial coordinates from this data set. This involves some rather sophisticated mathematics involving series expansions, integral equations and trigonometric functions, but the payoff is dramatic improvement in speed. So what has that given us those improvements in spatial and temporal resolution and precision? This is a remarkable paper just published in the last couple of months from Van Widing and his colleagues at MGH in which they have pursued the question about the connectivity within the brain and deciphering the structure of those fibers. Now, a priori one might think that these connection pathways would come at oblique and odd angles. But what Van and his colleagues have discerned is that it is not as complicated as that. Surprisingly moving from the cortical surface these fibers appear to occur in a grid-like pattern in a series of sheets. Here is one sheet in which the connection pathways run along the X and Y axes. Here are two of those sheets color-coded differently but within each of those sheets these pathways running X and Y direction. And then looking here to the right, again two of those sheets in the third direction. Also orthogonal to the X and Y axes. Rather remarkable finding the first time this has been demonstrated could not have been done without having achieved the type of spatial and temporal resolution that we just talked about. Answering this question about the construction and the highways within the brain then proposes numerous other questions about genetic gradients that lead to this kind of development. About how the brain communicates the potential for plasticity. Amazing with this kind of observation. Analogous to Galileo deciphering the structure of a Milky Way in the 1600s. Now we move on to technological innovation and engineering and translation. Here is an area where again where precision engineering is absolutely critical in order to solve problems that we face. I'd like to show two examples. Both of these examples also illustrate the concept of convergence. The first is convergence of technologies. The second is convergence of sciences. We'll start with the first one on convergence of technologies. I thought it was funny. Well actually I have a better example than this. So here with convergence of technologies. The world's first MR guided high intensity focus ultrasound treatment for essential tremors. This merges MR as a diagnostic and imaging tool and assessment tool and HIFU as a therapeutic tool. Three important points. First we need to precisely identify the target that's done with MR imaging. Secondly we need to precisely engineer an array of high intensity focused beams so that they converge precisely at the target point and that they do so in a manner that delivers a therapeutic level of energy sufficient to heat the tissue to the point of destruction but only at that site. And the concept here is that these individual beams by themselves is below the threshold of energy but at the point of convergence it reaches this temperature where it destroys the tissue. We need then thirdly a means of monitoring this heat change throughout the brain to assure that it only occurs at the intended site. And that's done by MRI performed in a temperature sensitive mode which it is capable of doing. This video works you'll hear from Billy Williams. My name is Billy R. Williams. I live in Fort Valley, Virginia. The tremors I have had for approximately 10 years and they progressively got worse. But now everything has worked out fine for me. Before I had the procedure I could not write. I could not eat without spilling stuff on me. I quit going to public places. Church socials and everything. I took medicine to start with. And every two or three years they would change the medicine because, you know, it didn't work any longer. So finally after 10 years my doctor in Winchester contacted University of Virginia. They contacted me and I came down and they started a series of tests which led up to the procedure that I just went through. And Dr. Lass started giving me the three options and I took this option. I didn't want a deep brain stimulation. And I'm just glad it worked out for me and I hope it works out well for other people because it will change the way you do things. I'm able to tee up the golf ball without help from a fellow golfer. I'm able to eat without spilling everything on me. I'm able to write and be able to read it later. Dr. Lass and his whole staff have done everything you could ask of them to get me through this. And I can say I just hope other people come and have this treatment. The second example that I mentioned is an example of integration of the sciences. This is a remarkable precision engineering feat comes courtesy of Don Ingerberg and his colleagues at the VIST Institute for Biologically Inspired Engineering. It is an example of an engineering of a functional lung unit on a chip which integrates all of the disciplines and areas shown here, including the influence of mechanical stresses and the variation of those stresses on the function of the lung unit and the cells contain their end. In fact, I can finally get these slides to operate properly. The lung on a chip is crystal clear, flexible and about the size of a small computer memory stick. But it contains tiny hollow channels created using microchip fabrication techniques. A porous, flexible membrane separates the two channels at the center of the device. The opposite sides of the membrane are lined by human lung and capillary blood vessel cells. This mimics the arrangement of lung and blood vessel cells in the air sac of the lung. Application of cyclic suction inside channels makes the entire flexible sheet and cells stretch and relax rhythmically just like our lung cells do when we breathe. In the lung on a chip device, air flows over the top of the human lung cells and a liquid medium containing human white blood cells flows below the capillary cell layer. To test how well the lung on a chip device replicates the natural responses of living lungs, we introduced bacteria into the air channel to mimic an infection. And we introduced white blood cells to the blood channel. We then saw the white blood cells penetrate across the capillary cell layer through the pores of the central membrane and into the airspace where they engulf the bacteria. Here's a video that shows this response in real time viewed through the device. The tissue cells are not visible here, but we can see white blood cells flowing freely in the capillary channel of the device just as they do in blood vessels of a healthy person. But when we infect the air channel by adding bacteria, the immune cells probably stick to the surfaces of the capillary cells on the opposite side of the membrane located directly below the infection site. Just like in a real lung infection, the white blood cells, which are now colored red, engulf and kill the clean bacterial invaders. Bio-inspired micro-devices that can mimic whole human organ function, such as the lung on a chip, could potentially replace animal testing and bring new therapies to patients faster and at lower cost in the future. So again, an example of precision engineering that is inclusive of multiple disciplines that help us to more precisely model the process in the body. In the final area of molecular medicine, we have advances towards precision medicine that simply did not exist 10 years ago. Two examples to follow. One is a point of care tool that is capable of precisely identifying cell and molecular markers. And the second one pertains to precision measurements that allow us to solve a pretty vexing problem that's been very important in the area of biology forever, actually. So the first example here is this point of care device that is capable of detecting a variety of markers of disease at the bedside. Those biological targets could be quite variable from viruses to bacteria to proteins expressed by oncogenes, et cetera. And you'll see, you'll hear about this in a video segment in this afternoon. But how does it work? Well, it has these three major components. The central component here is basically the biology and chemistry laboratory on a chip with microfluidic channels that contain reagents specific to the target of interest that tag those targets of interest with a nanoparticle that is magnetic. It can then be detected in this handheld size magnet. The magnet needs to be given instructions and powered by a computer. The computer is a mobile phone, as shown on the right, which also provides a quantitative analysis. An example is shown here when this has been used in a first cohort of patients to be evaluated who had unknown tumors. The tumors were analyzed both by this new device and by the conventional approach of open biopsy. The sample is provided for the MR device by fine needle aspirin. And in these individuals, all of whom had clinical follow-up. The improvement in the diagnostic accuracy is rather remarkable, as you can see, but also tremendous saving in time. One hour, 60 minutes, is what is required to do the procedure with the diagnostic MR in this portable form versus the conventional two to four days with biopsy. This accuracy was provided by way of assessing multiple and array of proteins associated with cancers highlighted in the blue here. And this final example is one in which the destruction function of GPCRs has been deciphered in the native state as this, excuse me, article earlier from Nature underscores. This problem has been one of the most important and challenging questions in biology with tremendous implications from the standpoint of the rational design for drugs. This problem has eluded scientists up until this year, specifically when one wants to determine the structure of this protein without alteration in the membrane, without extracting it from the membrane, without crystallizing it, and without subtracting or adding residues. How has this, and is this done now? Stan O'Pell and his colleagues here use MR spectroscopy to do this. The basic idea is illustrated in this slide. In the case of the GPCR, the structure of which they've been able to identify and elucidate CXCR1, that structure contains 350 residues. The problem boils down to determining the angular rotation of the molecules in each of those residues. They have two degrees of freedom here indicated by these angles, phi and psi. So one has to determine those two angles for each of those 350 residues. This is provided by MR by virtue of the fact that the bond axis subtends an angle with the main magnetic field. This angle results in a shift in the observable frequency of the MR signal. If one is able to precisely define that signal, a shift, one then can also precisely also define these angles, phi and psi. And that is what was done by his colleagues. This has been a project that has been in the works over the decade, and just this year, they now announce the structure, the first structure of a protein of this class in its native state. That is, in the membrane without alteration. Here's a ribbon diagram of that structure shown from the side, the bottom, and from the top. This also, I think, is analogous to the first example I led with, which was Galileo in the 1600s deciphering that the Milky Way was actually composed of individual stars. Here we have solved this problem of the structure of G-protein couple receptors. So in summary, the NIVIB has been working toward our overarching aspiration to have, as an institute, the biggest impact that we can on the nation's health care agenda through technological innovation, scientific discovery, and advancing precision measurement. Precision medicine through precision measurement. I hope this presentation has given you some indication of the progress that we have made. Two additional examples follow in the brief video segment. These examples are from two of our investigators. You'll hear from each of them. One in a more basic laboratory setting and the final one in the clinical setting. And I also mentioned that the patient that you will see in the final video is Robert Summers, the patient that you will hear from this morning just before we break for lunch. So I'd like to tell you a little bit about one of the exciting new developments in the tissue engineering and regenerative medicine portfolio from MIT from Dr. Sangita Bhattia. And the problem that she's trying to address is the fact that when we try to evaluate new drugs it's often very difficult because the best we have right now is to use an animal model system. The responses are not often typical of human responses and so therefore they don't give us the information we need. So what Dr. Bhattia and her colleagues have done is to make a construct that is made up of human hepatocytes or liver cells and mix them with supporting cells as well as a matrix to support this and wrap it all up in a protective hydrogel so that they're able to generate a little miniature liver. Once this little liver is transplanted into a mouse the product of this is a mouse that can provide both mouse liver function as well as human liver function. So there's been this interest in understanding human specific liver responses in particular how human livers metabolize drugs and are susceptible to the toxicity induced by those drugs. So when making a new compound it's really important to understand those species-specific responses that typically don't show up until clinical trials and patients. The hope of the field has been to make mice that could somehow help predict these human responses. Our idea was to make a tissue engineered human liver and implant it in a mouse, engineer it so that the human hepatocytes would be stabilized that they would express all their human-specific functions and that they would be engrafted into the mouse and then the mouse would have its own liver but in addition a little human liver organoid. So essentially through tissue engineering what we've done has made a very robust technology that allows us to make large cohorts of animals with human liver responses that can be used for testing. Our hope is that this will really be the use of tissue engineering to create a drug discovery and development platform. So ultimately our long-term goal of course is to create livers that will implant into patients but in the near term we'd really like to be able to make this tool to transform biomedical translational research. It's been shown for many years actually that epidural spinal stimulation in combination with motor training facilitates recovery in complete spinal cord injury in animals. This NIBIB project demonstrates for the first time that epidural spinal stimulation also works in humans with complete spinal cord injury. Now this is very exciting. The significance of the results that we will be reporting is that we found a new avenue to apply to individuals with very severe spinal cord injury that will help them to improve their motor function. That is they will be able to stand and to step and be able to improve perhaps their voluntary control based on our initial results. We've known for some time that the spinal cord has pretty sophisticated neural networks within it. Well what we're doing here is using epidural stimulation to increase the excitability of this network but a very important point and what's really different here is we're not actually stimulating at an intensity that will induce the movement. We're just modulating the background activity of this network. We've been able to achieve a level function that has not been demonstrated before in an individual with a motor complete injury. That is this individual can stand for several minutes independently. Now several minutes may not sound like a big deal but several minutes of standing for an individual that has not stood for several years is quite important.