 It's my distinct pleasure to introduce Dr. Dan Cooper, some of our faculty here. I'm in Brooklyn. He's 40. And I see some other faculty from other units. I mean, there are firms that go into the video and work from statistics. So Dan is a mover and shaker on UCI campus. But he's well known for building teams that do major research programs. He received his bachelor's at UC Santa Cruz and then went to UC San Francisco for medicine to get his doctorate of medicine degree. And he's done several residencies and completed three years of postdoctoral research in pediatric pulmonary medicine and that's at Columbia. And then came to UCLA and I think he's been in California since pretty much. And his professor of pediatrics here is the best name in pulmonary medicine and really, really passionate about children's health. One of the bright lights he brings to campus is to sponsor a photo documentary of children having fun and exercising. And it's an annual event now and it's always if you like to see the smiling faces of children engaged in really health activities. So that really is the focus of the research in this lab to do physical activity with health, disease, and growth in infants and children. And in his spare time as the Institute of the Accounting and Estational Science I will be hearing a little bit of what I think today. Thank you. Okay, so this is sort of modeled after a grand round but not necessarily about the patient but more about concept and the concept here being this buzzword that you're going to hear a lot about called Translational Science. And so I thought I would talk about something that I know about for a change which is something in pediatrics that's really a good example of Translational Science. So we call this the Grand Herd Round the World and how pediatric revolutionized critical care in the 1960s. Many of my colleagues throughout medicine view pediatricians as junior doctors and things like that. So I thought I would point out that some of the major advances in critical care throughout medicine were made by pediatricians. And we're going to talk a little bit about the story here which is a very interesting story which talks a lot about Translational Science and talks about how environments have created that permit Translational Science to occur and this reinvented Translational Research. So just to worry about this phrase so Translational Research has become a very important phrase recently because the NIH reconfigured how it would fund human-based research and the reconfiguration was focused around this phrase Translational Science or Translational Research. And the word has come, it's a very vague phrase as you can imagine and it now has many meanings. There are like T1 to T8 or something types of Translational Research. The one that I think most of us would probably ask anybody in this room what do you mean by Translational Science? You'd probably come up with an answer like well there's a PhD in Physics who's working in his basement lab and he comes up with a new laser that has amazing precision with very high energy and cellulose hormones. So the translation would be to say gee this wouldn't just be a great way to say deal with colon cancer where I could use this laser directed directly at a set of tumors without damaging any other tissues. So the translation would be I've got this basic science idea and I've got to get it to work within the clinical setting but that's not easy as you can imagine because you're not going to just take a bunch of people with colon cancer and start shooting them with lasers and discover that this thing was promising in the lab but ended up completely destroying somebody's colon whether they were sick or not. So you can imagine that there is a great gap between the ability to take a basic science idea and turn it into something that actually can be used in healthcare. So that's one kind of translational science. The other broad category of translational science is when in fact we have knowledge that is based on evidence and it's not being applied. So I'll give you a couple of really good examples. So if a woman is pregnant and she's let's say early in her third trimester she's 22 weeks, 23 weeks, 24 weeks pregnant and she starts having early labor and delivery. So you know that if you have a premature baby that premature baby is at risk for not surviving prematurity. If it survives is at risk for a myriad of diseases and disabilities ranging from cerebral palsy to cardiovascular diseases to failure of the thrive. So obviously what you'd like to do is either prepare this premature baby for a better course if the baby is to be born at 24 weeks or very early or try to stop the pregnancy. So it was known through really great clinical trials that began with animal models and progressed to humans that if a pregnant woman who was early several months before her due date started having premature labor that if you gave her a dose of antinatal, if you gave her a dose of corticosteroids you affected the baby in the following way. The baby's lungs matured rapidly over the course of a couple of days. You could see big differences. And so if the mom was to go on and have a premature birth the survivorship of those babies of the moms who got the dose of antinatal steroids was really improved. So that was medical knowledge that was known and it took about 20 years before it was to actually practice. So that's an example of what we call type 2 transitional research. The knowledge is out there but the folks aren't practicing it. Another area for example of this type 2 is management of pediatric pain. So if a child is having a surgery or has pain there are all kinds of good ways of using pain in children but the average practitioner doesn't use them and they assume it's okay if the kid's in pain it won't have any long-term effects which is not true. And so we now find ourselves in a situation where there's a gap, a translational gap between the knowledge about pediatric pain and the application of pediatric pain. So these are roughly the two kinds of translational science that we talk about both present and tremendous. So we're going to talk about a specific instance and then we'll talk about what we've done here. So let's talk about this case and this is about the grunt hurt around the world. Okay, so this is a disease that's called respiratory distress syndrome and it is quite common in prematurely born babies or even babies that are not so premature and what happens is that the lung is not ready for extra unit or not. And so these babies develop a great deal of respiratory insufficiency. Many of them need to be put on ventilators and I'll show you some data that before the modern management of this disease if you had a baby with respiratory distress syndrome and if it was severe then the baby had about an 80% chance of dying with it several weeks of being born. So it's quite a serious condition and this is what the chest x-ray looks like. You can imagine that in a normal chest x-ray you would see all of the lung this darkness of you you can see it's all sort of cloudy and not very well put together and this cloudiness looks like glass sort of looking through the glass and so this is called Highland Membrane Disease because of the pathology of it and this is what you actually see so this is one of the few normal LVOL which are those little poctets of air in the lung where gas change occurs and you should all look completely wide open spaces and instead you see most of the lung is filled with cells and debris and so you can imagine that if we have this situation or this syndrome it's going to be very great. So this is my amazing graph, nothing. So this is sort of the translational part of it. So here's the mortality from respiratory distress syndrome. The high is for infant because there's also a respiratory distress syndrome in adults which we'll talk about in a minute. And you can see that the mortality of this was pretty high and again if it was severe enough 80 or 90% of the babies died but then something happened and you can see that there was this dramatic shift in the mortality of this disease it wasn't a gradual change I mean look at this right around here in the late 1960s something happened and there was some bit of translational knowledge and new approach that dramatically changed this kind of thing the response here you rarely see these kinds of dramatic changes in medicine I mean examples would include using penicillin for treating as antibodies another thing that we've noticed is that in the 1990s late 1990s we've seen this really dramatic reduction in deaths due to cancer and nobody understands what that is but from a public health epidemiological point of view it's a current and interesting question as to why we've seen this reduction it's been a screening better treatments nobody really knows why but this was something that we can probably explain in retrospect and that's what we're going to talk about oh there's some correlation that's sort of related so if we look at the National Institute at NIH National Institutes about funding for lung research something also happened at the same time that there was this huge increase in funding and again you'll see why that all happened but the two unfortunately are correlated in the sense that sometimes great discoveries depend on funding so what do we know about the 1960s? most of you don't remember five for a different reason so Chris you know this was the president in the early 1960s John Kennedy the kids are so you may remember that when he became president they had a baby and this baby had very distressed and died so there was a lot of interest and intense attention that hadn't been paid to that disease until that time this period began with great hope and expectation this is Sputnik anybody remember Sputnik? so when I went to Harvard in the Harvard UCLA in 1981 it was still a bar have you been out to Harvard UCLA? there was a bar there on the corner of the hospital across the street it was called the Sputnik Bar I think it doesn't exist anymore anyway that was the vestiges of that period of time there was a war in Vietnam we'll talk about it so here's the first lady she was seen this was Jacqueline Kennedy I remember what a remarkably powerful figure she was everybody appreciated her grace and beauty and this great young couple that was Jack her husband and her and of course it was a national tragedy first lady was seen a few weeks after the death of her newborn son Patrick who died on August 9, 1963 just 39 hours after his birth it was only five weeks premature which is not very premature but premature enough to have respiratory distress and the baby died from those complications his obituary in the New York Times pointed out that at the time all that could be done for a victim of highland membrane disease is quote to monitor the infant's blood chemistry and to try to keep it near normal levels which is what she couldn't do thus the battle for the Kennedy baby was lost only because medical science has not yet advanced far enough to accomplish as quickly as necessary what the body can do by itself in its own time in other words if the baby had been born three or four or maybe a week later the lung would have matured to the point where it could have we've stood breathing in the regular atmosphere without any problem and remember the context of this is a time when science is growing and we can do anything we can set a man to the moon and we solve this problem why did this baby so what did we know about this particular disease in 1965 and this is right from one of the major textbooks of diseases of the newborn everybody in neonatology and pediatrics read this book highland membrane would appear to result from excessive outpouring of fluid from the terminal respiratory sediments those are those little alveoli those little balloon-like structures even transitate from congested perhaps damaged capillaries just what is responsible is not known 1965 several years after the kennedy baby death we still didn't know what the cause of this syndrome was they go on to say cyanosis is seldom noted until later sometime after birth when this difficulty breathing becomes severe the disease progresses quickly in some infants they are seriously ill thereafter the infants gradually improve or respirations become weak the color becomes ashen gray and they die so in those days the principles of treatment have been accepted these are the use of oxygen, high humidity and antimicrobial drugs they treated them with everything they had they didn't know specifically what the problem was now interesting was the use of oxygen they couldn't get these babies oxygen this just shows and at that time we didn't have really good even ventilators this is a young girl with polio showing this is some of the techniques that they used in those days and I think I have a picture of an iron lung so this is a picture of an iron lung again, I'm sure that Bob remembers this period of the polio epidemic in the 1950s so polio was a disease that if it was severe enough affected your muscles of breathing that you couldn't breathe and so they developed these things called the iron lung here's the child's head and what they would do is this is sort of like a vacuum cleaner they create a negative pressure in this lung and it would cause your chest to expand and it worked but you had to be in the iron lung if you were to breathe so I still remember and I know Bob does that image was a powerful image of these babies and these iron lungs okay so what happened? how did we begin to solve this problem? so this is an article that came out in 1968 and it was about the significance of grunting and highland membrane disease and this is a very very important article because one of the things and it's really about translational medicine one of the things about these babies that was characteristic that nobody understood was that they grunted they made a very specific sound that was like a grunt and when you would see I began medical school in 1970 so the big change that I'm going to talk about hadn't occurred yet so I actually remember seeing babies who were premature, who had respiratory distress syndrome and I remember hearing this sound is a lot of people ignored it and nobody really realized what it was until this was and they were wondering so what is that highland what is that grunt? why are these babies grunting? maybe there's some information that we could gain physiologically from the baby as to why it was grunting because normal newborns don't grunt, they don't go what was this grunting? what did it mean? so in this article they did some really interesting studies I'll try to explain this what they found basically was that the grunt had a beneficial physiological purpose it wasn't just randomly that the baby was grunting and I think the best way to explain this is to look at these are measures of airway pressure that they made in healthy babies and these are measures of airway pressure that they made in babies who were grunting so without going into the details of it you can see that if we look at the airway pressure up here and you compare it to this curve, you can just see that they're very very different so I don't have to go into this but you can see that there was a remarkable different pattern of what was happening in the airway pressure and what they discovered with this, this is reverse this is negative so when the pressure inside the lungs becomes negative air is going to move from the atmosphere into the lung now this is positive pressure, this would mean it's like you've got a balloon and you're blowing into it and the pressure in the balloon becomes greater than the atmosphere so here's the key thing when the baby who was grunting breathed out, here's zero notice that within the airway you develop positive pressure, you see this again this is positive is going down negative is going up and you can see that there's positive pressure developing this is the baby grunting we didn't do anything to this baby and one of the things that they discovered which was really disturbing was that even though we had ventilators I mean we could take a tracheostomy put into the baby's lung and you could do that and you could deliver oxygen better what they discovered with these babies with pilot membrane disease was that the babies got worse they didn't get better they got worse so you'd think, gee, if I can only put this tracheostomy tube or the ET tube, the end of tracheal tube into the baby's lungs and give it 100% oxygen I should be able to get some better oxygenation but it didn't happen even with 100% oxygen so the tools that they had they just weren't there so they looked at this and they said, Mike, this is really amazing what is this positive pressure why might this be important for the baby and how might we use this direct observation of what the baby is doing to fix the baby okay, so from this discovery from this observation, I should say came an absolutely remarkable discovery so as they were playing around with this and they were making these measurements and they realized that the grunt was what? well, to grunt, you need to close the glottis you need to close your vocal cords otherwise you don't make the noise and if you close the glottis as you're pushing the air out which is what the baby was doing you make the grunt but downstream you create positive pressure in the airway you're blowing out against your resistance so that did several things it tended to inflate the airways and it tended to inflate the lungs and as you remember in that picture that I showed you the lungs of these babies were collapsed for whatever reasons those little alveoli weren't staying open they weren't those nice open beautiful alveoli they were all collapsed so what these investigators realized was that what the baby was doing with the grunt was trying to keep its airway open as long as it possibly could because if your airways are open if the alveoli were open what could you do? you could get oxygen to the blood and you could get rid of CO2 because that happens down at the level of the alveoli it doesn't happen in the tubes it happens in that structure which is where the blood is flowing and the gas exchange occurs and if those areas are full of fluid and closed off you don't get gas exchange so breathing doesn't work so what the baby was trying to do was to keep the airway and the lung open for as long as it could within the respiratory system and it did it with the grunt so what these guys did was they said gee if in fact this is what seems to help many of these babies what could we do to enhance positive pressure within the lung they understood the physiology they got it from watching these babies very carefully they did it from making these elegant measurements they could then see clearly that the baby was creating this positive pressure which normally doesn't exist at all it was a normal cycle of respiration and now they turned it into an engineering problem right because they got a mechanism what could we do what would you do how could you enhance how could you make the baby have more time of positive pressure and keep the lung inflated what would you do so one of the nurses who figured this out so she said okay look when we intubated the babies they got worse why did they get worse because they couldn't grunt anymore you just put a tube in there and now the baby couldn't create that positive pressure so they figured that out how would you keep the lung under positive pressure at all times constant grunting what the equivalent of constant grunting and the equivalent of constant grunting was they took the end of the endotracheal tube and they put it under water so remember your basic pressure and stuff like that if you put it under one centimeter of water you have one centimeter of pressure in the lung and the baby has to the whole system will now be pressurized at one centimeter if you put it two centimeters it will be two centimeters if you put it four centimeters so now the baby there's that column of air is constantly pressurized and when you read these articles absolutely remarkable paragraph where they said so we took the end of the endotracheal tube and we put it in some water which is interesting enough when you look at ventilatory pressures on a respirator all the pressures except for this are in millimeters of mercury because usually when they invented ventilators they measured them in millimeters of mercury which is like what we do with blood pressure but because these experiments were done with just a tube in water they didn't want to put a tube in mercury for obvious reasons this thing which we call continuous positive airway pressure we'll talk about in a second this was done, it's still to this day CPAP and PEOPLE define them in a second are defined in terms of centimeters of water because that's how they did the experiment so when you read these studies it's just remarkable because they took these babies who were grunted they were barely surviving they intubated them, they got worse they then hooked them up to a couple centimeters of water and they oxygenated they now had PO2s that were in the normal range and this is an article that came out from the New England Journal back in 1971 and this work was done in San Francisco and it was done at a place called the Cardiovascular Research Institute and I was a student in those days and I kind of knew all these people and we sort of knew that this stuff was going on and it was kind of exciting to be there at the time and so this shows the PAO2 which is the partial pressure of oxygen and this is CPAP continuous positive airway pressure that's what this was this was the continuous grunt because it didn't make any noise but it was continuous positive airway pressure so the lungs of these babies were always pressurized they never got to close off they were always pressurized to stay open a little bit and look what happened you can see the remarkable increases in the partial pressure of oxygen the amount of oxygen and the blood and the amount of CPAP the amount of this continuous positive airway pressure this revolutionized the care of babies this was like remarkable now I'll show you what the mechanism why were the babies doing this oh yeah we'll get to that so the reason that the babies couldn't keep the alveoli open was because they lacked this substance called surfactant and surfactant is detergent and when you guys take a bubble bath do any of you still bathe or YouTube isn't deli you can go take a bubble bath if any of you take a bubble bath what do you notice about these bubbles they're stable you pour that stuff in which is soap and they form these bubbles and those bubbles don't go away these bubbles are surfactant one of the qualities of surfactant is that normally if you have a sphere and as it gets smaller and smaller it tends to collapse the surfactant, the detergent stabilize it so your lung is kind of like those bubbles without the surfactant it collapses but with the surfactant that's produced in a mature baby's lung it doesn't collapse and surfactant is indeed a soap it's a complex soap but it's a soap so at the same time that CPAP was discovered as a treatment people began to understand that the immaturity of the lung the reason that many premature babies went on to develop this disease was because the cells that produced the surfactant in the walls of the lung had not yet developed well enough so if the baby were born premature they had lacked the surfactant and so the lungs collapsed and you got all these problems then if you could just keep this open it was exactly what the guy in the New York Times said you know with time there's some developmental schedule that we are just beginning to understand those cells start producing the surfactant and the lungs start to stay open what is interesting is that at the same time that the discovery of CPAP was made the folks many of whom were at the CVRI at the Cardiovascular Research Institute many of whom were here at UC Irvine by the way who were real pioneers in this were discovering surfactant and the molecular biology of surfactant and how it worked so nowadays we actually treat infants with CPAP that keeps them alive and we have gotten to the point where we can make surfactant that is artificially made and you just literally squirted into the baby now there's complications with that but the point is is that the dramatic change dramatic change in the treatment of these babies came across it came about because of people making observation and translating those observations from physiological measurements into therapies so this is one of these great leaps forward it doesn't happen all the time it's rare but this is a really good example of it and here's the implications of it so at the time the war in Vietnam was going on and military medicine had advanced to the place where many more things could be done in the field to a wounded soldier to keep him alive whereas in World War II for example the availability of IV fluids and things like that that you carry around that were sterile was much more limited so there were many soldiers who would be injured in the field have lost a lot of blood and they were kept alive and then when they went to the they were transported back to the hospital they developed an x-ray that looked surprisingly similar to what I showed you from the baby in other words you get this really this is an adult and you can see this cloudy lung with all these patchy infiltrative pattern and they also were having a hard time ventilating these adults and this became known then as Benang Lung from Benang which was where the US one of the biggest military hospitals was and it turned out that the same approach to have continuous positive airway pressure was enormously successful in getting these individuals through that period of time again you can see here's one little normal alveoli and the rest of them you can barely see because they're so full of fluid and debris and cells and it also was because of the shock through a very complex process these lungs for a while were unable to make surgery so here we go back to what happened to the mortality of IRDS and actually the stress in Roman adults it was this singular event now you'll notice that from this period down to the 2000s there is continued improvement and this continued improvement is probably the result of using surfactant better use of antibiotics better use of nutrition etc but this was really the big break here and we haven't been able to gain as dramatic a success story in babies born prematurely even though we can certainly say that we did now here's the discouraging figure and that is if you look at the incidence of chronic lung disease so you can imagine that if a baby is born and has respiratory distress syndrome and is on a ventilator and has infections and is not having the normal third trimester of life and it's immune systems alter the change that there might likely be a tendency to develop chronic lung disease and there is somewhere between 10 and 15% of babies born prematurely they will go on to develop some form of chronic lung disease so we can now save a baby born at 21 weeks that's less than 500 grand and I was an intern in pediatrics in the late 1970s we could maybe save a baby that was 24 or 25 weeks and was greater than 500 grand that's a pound of ground ground that's a really small little baby if you've ever seen these people with their babies it's really a remarkable technological feat that you can keep any of them alive so we haven't been able to lower the level at which you can save a baby but we haven't really changed the incidence of chronic lung disease so even though we can save the baby we've probably now identified a population of babies who are more immature and therefore even though we can get them through that initial neonatal period some switch some developmental switch or some insult that occurred early on in the development of the lung is potentially perhaps irreversible and so these babies will go on to develop chronic lung disease so the number of babies who are born prematurely who go on to develop chronic lung disease unfortunately hasn't changed so this is again one of the unexpected consequences that you get this is kind of interesting but okay so let's now bring this back to here at UC Irvine so I mentioned to you that support for this kind of research has changed dramatically in the past four or five years people who did translational science were always had a hard time finding a home within the academic community because it's clear that if you're a basic scientist and you're discovering something in a very narrow field you fit well into the model of what had traditionally been expected to be your role as an academic that is you develop your own area of research you wrote papers that didn't have more than a couple of authors it was identified as your work you were able to get funding for it etc when you started doing the kind of work that you do that's translational it's rare that one or two people can put together a project that involves addressing a clinical problem the problems that you find in clinical medicine tend to be more complex than the problems that you would find in pure biology where if you're a PhD student for example and you're in biology and you say I'd like to discover the cure for cancer which may motivate a lot of people to go into biology your advisors if they're good will say ok that's a great question but before you get there you need to define an area or a set of experiments for which when you do the experiment you get an answer so the question becomes more and more focused I mean it's no longer I'm going to find a cure for cancer it's going to be ok a gene that's expressed in certain white blood cells that are associated with certain cancers and when this gene is expressed a little bit differently because it has some you know SNP or something it produces a protein that's a little bit structured differently and it may contribute to downstream to the development cancer later on and the question I want to know is you know one of the SNPs with another will that cartoon still work and you get your PhD if you can figure that out and one of the things I noticed throughout the year is having been on NIH study sections is the huge difference between grants that were submitted by MDs and grants that were submitted by PhDs so what would happen is your MD training is very inclusive I mean you're sitting there on rounds as a medical student or as an intern and the attending you'll have a patient with high blood potassium and the attending will say to you what are the 123 causes of hypercaline and you're supposed to know all of them because you are taught that you have this huge responsibility that if you miss something this patient's not going to get well because you missed it because you didn't know what the answer was so you think of everything or you think of things that probably aren't related and you go through this process of trying to narrow down and focus down on the things that really count this is one of the reasons why there is still to this day despite the argument that it's all legal it's not all legal is there is over we do too many lab tests and you do too many lab tests because you don't want to miss something you know and everybody the lore of clinical medicine is the person who had some rare disease that everybody missed and then finally somebody picked it up those pictures I'll actually show you is sometimes it's the medical student who picks it up picking something up but nobody else has thought of but the problem is in terms of how you write a grant and how you get funded this is a very different culture all over the place okay there are 50 possible causes for tobacco related and I'm going to study all 50 and I'm going to do it in 3 years and it's going to cost $150,000 and so the people judging the grants are going to that so there is this wide cultural difference and a lot of people began to recognize that there should be medical centers a sort of special place for people who do this translation or clinical research and originally there were clinical research centers so the first the NIH began a clinical center in the 1950s have any of you seen this over in Bethesda at the NIH yeah it's really worth a visit I mean this is a remarkable place it's a hospital in the centers of the NIH in Bethesda it is where to this day people with rare diseases diseases that are not responding people willing to subject themselves to the most out of the box kinds of experimental procedures go to the NIH clinical center and it's still thriving and I think under the new leadership of the NIH will continue to thrive in the 1960s the national center of research resources which is part of the NIH created things called the general clinical research centers so what the NIH realized was that in the period of this huge growth of the NIH after World War II a lot of people were a lot of individual investigators were asking for the same things even from the same medical center like I need a nursing report for a clinical project that I'm doing I need a place to do the research that is separate from the clinical area you can imagine that if you're doing research and it's patient oriented it's not always a good idea to have the clinical activities and the research activities in the same place I'll give you an example let's say you're doing a study on diabetes and you're testing a new drug and to test the new drug at those levels every 20 minutes and you've set it up with your pharmacokinetic people so that you have to obtain a sample every 20 minutes or else you can't fit this model correctly that would describe the pharmacokinetics so you put this individual in a regular patient award and next to him is a regular patient who comes into the hospital because of asthma and you have a nurse assigned to these various patients and everything's going well the nurse is getting those samples every 20 minutes and then the patient with asthma starts wheezing and having difficulty breathing what do you do you know even by the this is 2 a.m. by the time you call in somebody else you've missed four or five of those critical to you as the researcher those critical samples that you had to get every 20 minutes but you're not going to go through all those samples and let this person die of hypoxemia because well you know Dr. Cooper told me I had to get these samples every 20 minutes it wouldn't work so it was understood that there needed to be created these centers places where you had staff that was devoted to research and so these general clinical research centers developed throughout the country and between 1960 and 2004 and these were places and UC Irvine had one where you had resources from the NIH to create infrastructure that would support human-based research and they became very creative they were responsible for some great work the work on cholesterol metabolism that was done at the University of Texas for which the Nobel Prize was won was done at GCRCs a lot of the human genome project at GCRCs for example so there was a great deal of productivity it was a very dedicated group of people this is our own little history this is our when we were first making the case to the NIH to get one of these centers we had to disabuse a lot of the reviewers that Orange County was sort of this homogenous race so I had this great picture from the UCI early childhood she's now 15 now we love so this helped us get from so this was again our it's actually worth going over what we did so we originally applied to become a GCRC in 1999 we were mostly outpatient this gentleman over here was our leader in biostatistics does everybody know Dr. Newcombe so Bob Newcombe's been at UCI for since 1979 1969 he's also the founding coach of UCI men's volleyball which in the last few years is one of two NCAA champions and he's a great guy and a great supporter of all of our efforts he's still I don't think we've paid you a nickel or anything that's a talk to you about what you tried to create from these clinical research centers was court facilities so you created entities that a lot of different investigators could use that it would be difficult for you as a single or even two investigators that for example we have a human performance we have an exercise laboratory so a single study could probably not support something like that we have a metabolism biometrician which we still have for diets we have a grain imaging court and then we thought we were doing pretty well because our first competitive renewal was back in 2004 this is a great score in those days and we thought we were home free these are just some of the stuff we did exercise lab DEXO which was a way of looking at body fat we had a bio nutrition metabolism core our own GCRC has been involved in hundreds of different projects one of which we're very proud of which was Project Healthy which was a study that was a school based study to prevent obesity and type 2 diabetes and lower SES kids this was a large large national study and the results were published recently in the New England General Medicine we had a core laboratory and you know if you're a clinician and you're sort of focused on a clinical disease it's not necessarily expected that you'll know how to do every kind of inflammatory analysis inside of time and as the genetic and epigenetic interest in public health and individual health grows unless you have core facilities to support individual investigators you're going to be too far behind to be able to do modern research that's competitive one of the things we did was we established a center at the Hewitt building I think some of you have been there we really should make sure that everybody gets a tour of what was nice about the Hewitt building is that it was on campus and we put this image in here because this is before the stem cell building was built by the way which is now right here across the street is that by having a facility on campus we could enhance the interaction between basic scientists and clinical scientists and you know one of our success stories is with engineering so for example I'm going to show you some pictures of this in a moment when I came here in 1999 in 1997 David Rankinsmeyer had also joined the faculty now David is in mechanical engineering and he had come to this school from the Chicago rehabilitation institute which is one of the most well known rehab facilities and he studies robots so what do robots have to do with medicine well what he was working on was ways that you could improve the rehabilitation of people that had strokes and brain injuries so one of the problems with having a stroke or a brain injury is you can get the brain to reroute its circuits you can actually cause new neurons wrong but you have to stimulate the brain and the way you stimulate the brain in somebody who's had a stroke is with movement now if the person can't move beyond a certain degree because of the stroke it's sort of a vicious cycle you can never get those neural tracks to regrow so what David is interested is using robots that you know the person would begin to do a movement you look on the screen for example they're called haptic robots they give you a sense of touch and feel and you'd say keep going and then the robot would take over and your arm would move and you could guide your finger on the computer screen to touch something that was distally positioned and you could do this but to get the brain to regrow you had to do this hundreds of times so the only way you could do this is if you had a physical therapist sitting there with this individual for hours and you don't have enough physical therapists to do this and you don't have the ability to pay for it so the use of robots to do this kind of rehabilitation was something that David was interested in so when we first set up the GCRC David had people with strokes coming up to the engineering gateway you know when signing a man there was no blood pressure there was no consent so we were able to talk to David and say why don't you do that and this really blossomed into a really phenomenal collaboration here he's now doing inventing wheelchairs for children with cerebral palsy just a lot of really wonderful work has gone on for him here's some of his stuff he actually has a treadmill that can help people walk I don't know did anybody see the news today about the this is a really big area of people who are paraplegic where you use robots that are attached to the body and there was someone this morning who was actually someone who had a spinal cord injury that was ready to be paraplegic and she was walking because they had these robots haptic robots and she used her arm to signal to the robots and she was able to walk around so there's a lot of really exciting stuff going around this field and this is an example of where you can create structures that really bring basic scientists and clinical scientists together and other stuff that we're working on looking at physical activity and premature infants this is an average accelerometer you know these babies as I mentioned were terribly small where would you put this so here we will bring you baby and here's an accelerometer that our engineers invented that's a human hair that's a micro accelerometer and we actually use this to create some accelerometers that we can actually put on newborn babies and you can now use these things to predict for example if a newborn baby is going to develop a neuro motor disease like cerebral palsy and the reason that that's worth doing is that it's really clear that earlier you can identify neuro motor diseases the brain is quite plastic early in life and the more you can do in terms of therapy early on you can mitigate and attenuate some of the long-term effects so that's what we're doing this is another example of translational research here, who's this anybody know should all know who that is so that's Sherry Rowland who's one of UCI's Nobel Laureates and he discovered the mechanism for the ozone hole and he studied the chlorofluoroparbons and his laboratory was really good at looking at organic gases in all quantities that are in the atmosphere now what is the source of organic gases in the atmosphere of all the organic compounds mostly biology mostly the results of biological effects so a number of our investigators thought gee why don't we look at the human breath and see if you can't begin to use some of the things that have developed in his life and this is turned into a very fruitful collaboration now where we've got people who can measure glucose concentrations and insulin concentrations in the blood from breath analysis and we've got somebody working on identifying bacteria from their gas signatures using these techniques so you can imagine if somebody came in with a pneumonia if you could get a breath sample and identify a bacteria that was growing in the person's lungs from the gases that had produced quite different from any human cells can imagine then this could be a real step forward in making diagnosis so this was a project that they're working on making these breath samples out in a community mobile band that's called the breath mobile that goes out to the schools and looks at it last month I'll finish up we've got time so what have we done there is a point to this story so we created this GCRC we got funded back in 1999 we had about 10,000 visits at the time we were averaging about 3,000 or up to about 4,000 visits per year we have about 100 now active protocols we've been instrumental in the funding now there's been about 50 of these and there's been about 300 articles this was a couple of years we've supported medical students this is something that's really exciting that we plan on continuing this is Dana Graven who's now a fourth year medical student so she took a year off to do research and her research was supported by the GCRC at the time and what she actually looked at is that infant accelerometer that I showed you in this is a device now that she's written a couple of papers about and we hope will actually become marketable as a new tool for assessing these things early in life and then all of a sudden everything changed so we were doing pretty well we had gotten our GCRC in 1999 we got the grant renewed in 2004 and then a huge GCRC NIH Bob and I thought we could retire together we'll put a long surf for the rest of our lives so this guy this is Eli Serboudi and he became the head of the NIH in 2003 so this is how things changed he basically announced that the GCRCs were finished that this program that now there were 90 or 100 of them that they were fatally flawed and he created this thing called the roadmap for research accelerating medical discovery so there's a fair amount of politics here and I think he got a lot of things right there was a growing sense in congress that you have this money for the national institutes of health so this is really influencing people's health this is where you guys in public health become so important and you know it's easy to criticize NIH research I mean if you go look through the titles of the grants you'll find a lot of stuff that are about fruit flies and rats and so on and so on and if you want to take cheap shots it's easy to do that but there is also the side of it that Serb says okay what are you doing with all these millions of dollars that we're giving you to benefit people's health you know and even if you can make the case that a particular area of research is scientifically you know really important unless you fully believe in the concept of science for science sake and eventually great discoveries will translate into practice there is a case to be made well maybe there's something we can do to speed up that process because after all this is what the taxpayers are giving their money for they're not necessarily just giving their money to do science for science sake they're giving their money to improve health that's why it's the NIH and I think Serb who knew red congress I think he read congress right and he said we've got to accelerate medical discovery to improve health he added this we're not just medical discoveries great but to improve health and this is something that really did revolutionize everything he wrote an article I don't know is it on their reading list though everybody should read this this came out in 2005 and he talked about translational and clinical science time for new vision and he outlined these total new entities and he pointed out some things that were really really critical tell me you want to shut up am I doing all right it is more and more okay I've got the five minute one it's more and more difficult to recruit, mentor and retain a critical mass of clinical and translational scientists profit training and mentoring of scientists capable of conducting truly innovative patient oriented research require dedicated time away for the escalating pressure of clinical service demands so let me translate that so if you are a typical physician at UCI medical center even though you're at a university hospital the average physician here is in what's called the health sciences clinical research series and how critical is research in that series for your promotion it's not you know and it's not because the finances aren't I mean the medical center most physicians throughout the country are barely making their salaries from clinical work so yes you can say physicians should earn less more like the rest of the world but you know it's just logical that if you have a family and you're trying to support them and your salary is one half of what it would be if you were out there practicing that it becomes unfeasible to pursue a career like that you know you kind of look at yourself and the people at your family look at you and they go what are you doing so in order for this to work there was a time when there was enough money in the business and the medicine to support physicians who predominantly did clinical work but also did some research now having said this the UCI medical center the most altruistic physicians around because they don't make as much as they could if they were in the private world they are dedicated to the research and the time in a very real way and the complaint that they have is we don't have enough time to do the academic side of the program and so what Zerhouni thought was maybe we can begin to restructure how we support clinical research so that the people who are doing patient oriented research have more backing and more you know support so he put hope that the intention of this new program would be focused and make a significant commitment to the creation of the new vital and reinforced academic discipline and home for translation on clinical science along with an explicit effort to maximize the effectiveness of NIH resources directed to this area of research and will ensure that extraordinary scientific advances of the past decades will be rapidly captured translated and disseminated for the benefit of all Americans so this was the new vision that I heard about in 2003 and 2004 and that basically what happened was Zerhouni said there is no more GCRCs all 90 of them are gone there's a new program you got to start from scratch reapply and now let's fast forward five long years in which we made four applications and with the most competitive places in the United States because everybody had to apply for this new entity the Harvard's, the Johns Hopkins, etc so I can tell you guys that we have a National Science Award here it just began in July and we're hoping to do some of the things that are outlined here and I'll end this talk with something that I heard this morning it was an interview with Marlowe Thomas who's the daughter of Danny Thomas who was one of the great spokespeople and great fundraisers for St. Jude's hospital now what is illustrative about St. Jude's St. Jude's is a children's cancer focused hospital in Memphis Tennessee and they call themselves the St. Jude's cancer and research hospital because they understand that for parents who have a child with cancer you want to know that you're going to a place that's also doing research and she said something that I thought was absolutely stunning and something that we should make as part of our efforts in our CTSA which was so when a child is admitted to St. Jude's the issue of insurance is it's not an issue there's no one has ever turned away because of their own insurance and then she said and every child is assigned a physician and a scientist a physician and a scientist now I don't know if you can operationalize that but I love the idea it's really something that we should be thinking about because it really talks about the integration of the clinical process and the research side which I think you saw from my example of respiratory distress syndrome and how we make great strides and I'll stop there I'll talk too much thank you I have a question please feel free why is this any thoughts discussions I'd love to so this issue of bringing this valley of death is one of that one of science policy's main problems these days and you mentioned that earlier how sometimes there's issues with translating research to the actual application of that research so what do you think is a solid and sustainable way to overcome that at least in the helpful well so I sort of agree with one is training we need to train people I'll tell you what often happens so if a clinician says you know I could cure XYZ disease if I could use drug A that hasn't been used for this disease I think it would work so that person has a great deal of enthusiasm and energy and then he's confronted or he's confronted with a mound of obstacles to do that IRB's grants and contracts review boards committees I mean it's overwhelming so if you don't know how to handle this or how to manage it 9 out of 10 people are just going to say you know what, forget it I'm just not going to try because it's so overwhelming to me when it's literally often a catch-22 like they'll tell you okay we want you to do this study but it has to go to the XYZ committee and then the XYZ committee says we can't review it until it goes to the ABC committee and then the ABC committee tells you but it has to go to the XYZ committee so this is the classic so one is training people like yourself to understand what these obstacles will be so that you're not surprised by them and how to manage them I often say that the approach towards the regulatory stuff sometimes it can be made easier there's no question about it but there's always going to be regulatory stuff there's always going to be IRB's it's not going to go away human subjects, applications not going to go away it's like treating cancer in many cases the goal of treating cancer is managing the disease rather than curing the disease and there are many examples asthma, cystic fibrosis cancer you do a really good job of managing it it requires time and effort so training is important two, creating a home for the translation of science so that when these obstacles come up and these impediments that seem so stupid come up you can go to a group of people and whine and complain beyond whining and complaining you can value their experience somebody may say hey this is how I handle that problem this is what happens in the basic science lab right? somebody is trying to do western blood and some new can't get it done somebody said hey did you try a PH of 6.3 instead of 7.1 so creating a home for people who do this kind of work becomes effectively very very important addressing the issues of compliance and stuff to ease the burden and we have great examples even in our institution where seemingly unovercomable obstacles have been changed for example Ayaka which is the animal review committee so until about three or four years ago everybody in this institution complained about animal research because you sent your stuff to Ayaka and they sent you back five volumes of problems with your stuff and it just you know so Jim Hicks who is a biologist took over that committee and he said I'm going to make this better and he instituted some really concrete things like pre-review so before you so this is psychological in other words before I say no to you the committee is going to point out some stuff that you ought to change now you feel much better they take you the same time but you feel much better if you don't get said no to but somebody says hey why don't you fix ABC and D before you submit then you submit and now 95% of their Ayaka submissions go through so even if it's just psychological as an investigator you don't feel like you've been you know insulted just by getting your stuff so addressing those issues is another important creating core laboratories we mentioned this before that include for example the statistical consulting center one of our great deficiencies at UC Irvine is the relative non-availability of one of the absolute life bloods of clinical research which is statistical consulting we don't have enough biostatisticians Bob has struggled here for a generation first to establish a department of statistics second of all to create a statistical consulting center which is open for the public so our center now with its funding will promote this and we're promoting this sort of stuff so it's not hopeless there certainly are things we can do to make it work better and then there's all these novel and creative things that you can do for example there's an emerging science of team science the science of team science how do you get people from different disciplines to actually work together if you have a disease often it involves social, psychological, physiological you know elements and you get these people from these different disciplines who really think differently about stuff you know what's important to the behavior list is not necessarily important to the physiologist right how do you create environments that actually work to create a cohesive team so that these people really are talking together the essence of the discovery of CPAP was that all these different people spoke to each other the nurses spoke to the respiratory techs the respiratory techs spoke to the physicians the physicians spoke to the parents and they were all watching the baby very very very carefully how do you create that environment it's really interesting George Gregory who was an anesthesiologist at UC San Francisco during the times of the discoveries wrote a great essay which I'll send to you and everybody should read and when she talked about the history of the discovery of CPAP she said why didn't we discover this earlier why didn't we figure this out all the pieces were there we knew that babies were grunting we knew that when you put a ventilator in take hours it's not like we didn't have this information ten years before one of the things that we had at the CVRI at UC San Francisco was a team where people talked and his quote was an inquisitive environment where everything was questioned and there was no status quo an inquisitive environment where everything was questioned and there was no status quo how do we create an environment like that where people really question stuff and feel free to talk to one another about their ideas you know so that's an abstract concept but I think there are ways of getting at it in functionally effective ways you start about the, this is a little weird it's on my mind you start about the presentation by alluding to the advances that we've made in pain control for children I think this weekend I was reading Newsweek or some article about how my primary source for medical how there's been a huge increase in drug addiction especially among these kids who had cancer and they were doing all this pain control so it just got me thinking that perhaps our NIH model of five year grants where we study people for two and then they kind of fall off the radar we don't know exactly what happens so I just thought maybe you could this is on my mind this is a real problem especially as we understand that there are critical periods of growth and development where certain acute events occur like in the life of the newborn giving antinatal corticosteroid is a moment to occur in a very short finite period of time can have lifetime impact the NIH isn't here to study that and I don't know that that'll change in the near future because funding is so crappy at the NIH right now people who ask for five year grants and aren't getting 12 percentile are not getting funded so they're not going to put a lot of money into the suburbs so it's a problem the national children's study will provide mechanisms so there's this new study it's called the national children's study which is a huge study that will study kids from preconception I can explain that through the time they're 18 years old and that there is a fair amount of money separate from the regular NIH budget that's dedicated to that so maybe some of these problems could be addressed but we're not used to getting at these longer term loans we're much more a typical scientific model if things happen quickly I'm looking at something a fast event and you address a great issue which is that in the real life of human beings the time scale may be a little bit beyond the five years