 Okay, good morning everyone. I think we're gonna go ahead and get started with this second session. I'm Bobby Robbins. I'm the director of the Cardiovascular Institute here at Stanford and I'm also the chair of the department of cardiothoracic surgery. So my day job is a heart surgeon and it's wonderful to have you all here. It's been a very exciting week here at Stanford, launching our campaign for the medical center. It's beautiful weather this week, great day today. Hopefully you're all gonna get well-educated and then go out this afternoon and enjoy yourselves. Exercise, yes. We were just two as I just talking with, Dr. Hanopy. Yeah, not only is exercise good in Howard, not only is exercise good for your heart, it's good for your brain too. I hear Dr. Longo, so how many people went to Dr. Longo's talk earlier? Wow, what about Dr. Abuse? Yeah, yeah, okay. I kinda want to give my time to Dr. Abuse because he was so incredible. But anyway, so I'll get started here today. We're gonna talk about stem cells, but before we get started, I just wanna give a happy Mother's Day to all of you mothers here in the audience and thank you for being here today. Yeah, big round of applause. Because it is the hardest job in the world and sometimes the most thankless job. So happy Mother's Day to everybody here today who's a mother. So I'm gonna talk about the possibility of using stem cells to repair a damaged heart. The Cardiovascular Institute at Stanford, there are several institutes, there's a Cancer Institute, there's a Neurosciences Stem Cell Institute and the Cardiovascular Institute seeks to bring together everyone across the entire university who has an interest in cardiovascular science and health with the goal to translate discoveries to improve the health of our patients and people in the entire world from the cardiovascular standpoint. So I'm gonna start with a story about what I think is one of the greatest translational discovery stories ever and that's heart transplant. This is the first animal of any type, first living thing as Dr. Shumway used to say. This is unfortunately, I wanna walk around but I'm being videoed and I don't have a laser pointer so I'm gonna stand here so the camera can see me. But this is Dr. Shumway and this is Ralphie the dog who is the first living thing, first living being to survive one year following the heart transplant. This was done over 10 years of dedicated, multidisciplinary collaborative work in the labs here at Stanford and it resulted in the first successful, this is Dr. Shumway doing the first successful heart transplant in the United States here at Stanford in January of 1968. This followed quickly after with the idea that not only could the heart be replaced but also both the heart and both lungs in an operation called a heart lung transplant, the first ever done in the world. You can see Dr. Bruce Wright's here who pioneered this operation and Dr. Wright's and Dr. Shumway doing the operation. So this is what we're talking about when you hear the word translational research. There was a problem at the bedside. People were dying from heart failure. There were no drugs, there was no other option and heart transplant was the only option to save a person's life. It required going from the bedside to the bench 10 years of hard work of discovery and then coming back to the bedside to translate that discovery and now as they say the rest is history with heart transplantation. This doesn't happen overnight and one of the great things that Dr. Shumway did then and we continue to have a culture here at Stanford today is one of collaboration. As Dean Pisa always says, we're a small research intensive school of medicine and we're very close to our colleagues and it forces us to be collaborative because we don't have thousands of people in a big university. We've got the great advantage of being on the campus of one of the world's greatest universities but it requires us to work as teams and I think all of the major discoveries, all of the things that are gonna change healthcare are gonna come from collaborative teamwork and this is just a picture of our heart transplant team that was taken around the time of the 40th anniversary of that first heart transplant that Dr. Shumway performed here at Stanford in 1968. So today I'm gonna just briefly touch on cardiac transplantation, talk a little bit about artificial hearts, left ventricular assist devices and then the most important thing is to tell you that we've built 10 years, a great internationally recognized team of cardiac stem cell researchers and a program that we're going to translate into humans we hope very soon. So the problem of congestive heart failure, it's the leading cause of death, just not just cardiovascular death but all death, all the deaths in the United States. More people die from heart failure every year than all cancers combined. If you look at the economics of it, $40 billion a year in US healthcare dollars are spent to treat patients with heart failure and it represents about 5% of the total healthcare budget that's expended in the nation every year. So this is another story that I think you'll find instructive and entertaining. So this is a young man who calls himself English Joe. His name is Joe Matthews and several years ago, I was sitting in my office and I got a call from the cath lab to come over. Joe Matthews was a 21 year old gentleman who was a professional rugby player. He's from the UK and he came over to the United States to play rugby and he noticed that some of the players were actually older than him and as you can see from the picture on the left with the baseball bat on, he was in incredible shape, strapping, good looking, very athletic guy and he noticed that some of his older teammates were outperforming him. When he tried to run, he was short of breath, didn't quite keep up so he's finally made his way to his local doctor who took an X-ray and his heart was massively enlarged. He was referred here to Stanford because people who have heart failure, whose heart doesn't work very well, are at great risk of sudden death. So he was transferred here to Stanford to get an internal cardiac fibula. And that's a device that is really quite remarkable in that it can sense when the heart is failing from an arrhythmia, either ventricular tachycardia or ventricular fibrillation and it can shock you like on TV when you see the paddles in the hospital and get shocked. This is all done in-planet and does the shock internally. Well, in order for that to work, you have to check whether the device is actually in the right settings and it'll work. So you have to induce one of these malignant arrhythmias, ventricular fibrillation or tachycardia. So in the cath lab that day, they induced Joe Matthews' heart to fibrillate, to stop so that they could test to see if the device was gonna work. Well, it didn't work and they couldn't defibrillate him. And so they called me and I ran over and we rushed him to the operating room and you can see him lying in the bed in one of these pictures there because he needed an artificial heart to keep him alive. There was nothing we could do. There was no other conventional operation we could do. So we put an artificial heart in and luckily because he was strong, he survived and went on to make it through his operation. A month later, he got a donor that was suitable for him and he got a heart transplant. He's now going on to be, you can see him here in this picture, a great outspoken advocate. You can go back to his website, EnglishJoe.net and you can read his whole story and he's quite the marketeer for organ transplantation and for Stanford by the way. He's a great ambassador. So he's now the fastest human in the world that's ever received any kind of transplant. He's blowing by even the guys who merely got a kidney transplant. And that's a great inspiring story. But it doesn't stop there. Why did this 21 year old strapping man's heart fail? There are two reasons why we do transplants. One is from coronary artery disease and I'll show you a picture later and hopefully not too close to lunch that it'll upset you too much of what heart attack looks like, a real picture. So that's about half of the people who get cardiac transplants have heart attacks. And we know the things that we should do to try to prevent coronary artery disease. The second group is called idiopathic dilated cardiomyopathy. Idiopathic means we have no idea why the heart fails. So in Joe Matthews' case, his coronary arteries look great, perfectly normal. His heart muscle looked fine. His electrical system was fine. His valves looked okay, but his heart failed. The muscle just didn't squeeze. It's true that your heart is about the size of your fist and your chest. And Joe Matthews' heart, because I put my hands around his heart, was the size of a basketball, this big, and it was failing. And how can that be that just six months before that this gentleman was playing professional rugby but his heart failed? So that's one of the great challenges and one of the things that the Cardiovascular Institute has really focused it on. Try to understand the mechanism of why the heart fails and come up with novel and innovative therapies to treat heart failure. One of which is gonna be stem cells. So in 2000, there was a paper published by these two gentlemen, Pira and Versa, who are now in Boston, and Don Orlik, who is at the National Institutes of Health. And they published a paper that really received a lot of attention and a lot of press about how cardiovascular diseases, particularly heart attacks and heart failure, were gonna be transformed by this work. This was work in rodents and rats that showed that if you take adult bone marrow cells and you inject into the heart, magically these bone marrow cells turn into cardiac muscle and the heart beats and that's gonna be the cure for all heart failure. So we've been working on this for about three or four years. Irv Weissman, who I'm sure is a familiar name to many in the audience, he directs the Stem Cell Institute here at Stanford. He discovered the markers for both mouse and human stem cells, hemopoietic stem cells. And if the world is fair, he'll win the Nobel Prize for this work. Well, Irv and I had been working in this area and I'd been pushing him and we'd been using skeletal myblast and bone marrow cells to try to treat heart failure and rats and when this paper came out and Irv and I live about a block from each other on the campus here, I could walk to my house in about 15 minutes. And so this paper came out on a Friday, Saturday morning I'm at home and the phone rings and Irv calls me and said, did you see that article in Nature? I said, yeah, isn't it exciting? I told you, you know, they beat us to the punch. We were almost there. He goes, it's complete rubbish, not possible. Cannot be possible that a bone marrow cell, an adult bone marrow cell can magically differentiate in a heart cell. So we began working, trying to re-duplicate this work. And in Nature in 2004, we published a paper that was published at the same time. This is a picture of Irv and one of my postdocs, Eric Balsam, who did this work. We published this work in Nature along with a group in Seattle led by Chuck Murray that confirmed what Irv said, that adult cells cannot magically turn into other types of cells. The only cells that we know that can do that are embryonic stem cells and now IPS cells, inducible pluripotent stem cells. And I'll talk about that in just a second. So that really changed the world because in that intervening three to four years when Inversa and Orly could publish their paper, it became rampant that people all over the world were taking cells and they were claiming that any kind of cell with a catheter injected into the heart would heal heart failure. I think Don, what was the guy from Hawaii? Don Ho went and claimed that he was magically cured. And so an important thing happened. Once our paper was published, I think it stopped all of this unrealistic hype about what biology could do. And also importantly, the FDA stepped in. And for the first time, a biologic cell was regulated by the FDA. And so now you have to apply for what's called an IND and an investigational new drug permit to be able to do stem cell injections into humans. So when we think about injecting cells into the heart, there are a couple of factors that one must consider. One is the patient population. They're basically two. One is the Joe Matthews heart failure needs a transplant. The other population are those patients that have an acute heart attack, acute myocardial infarction that cells going into the heart hopefully can prevent damage. There are different cell types that can be used. I'll go over a few of those. Cell survival factors. A lot of the work that I'll talk about today is in collaboration with Irv Weissman and Joe Wu. Joe Wu is really one of the leading stem cell, cardiac stem cell biologists in the world. And we're very fortunate to have him here at Stanford. One of the things that we have a tremendous advantage over all the competition is our imaging facilities here. Sam Gambier is speaking in the next room and luckily we get to watch our colleagues in their talks because these are being filmed. But Sam brought Joe here with him from UCLA and we really have an incredible advantage because we have a molecular imaging core in the Clark Center that is second to none in the world that allows us to follow the fate of these stem cells. And it turns out that most of the cells that are injected in the heart within the first week or so have died. So that's gonna be an important thing. Are there things that we can do to make the cells survive longer? Then the imaging I talked about and then what the mechanism of action is. There is some controversy about, well, can some of these adult cells cause the heart to improve transiently? But the mechanism of action that we seek is really growing new heart muscle and having that heart muscle, this new heart muscle, connect to the heart muscle that's still in the heart that works well, the viable muscle that's not been damaged. And so that's gonna be an important mechanism of action for us. So here's sort of a current list of the type of cells that can be used. We've covered bone marrow cells and there's still people who are injecting bone marrow cells. I'm not really sure why they're doing that but they're modifying these bone marrow cells but just to be clear about it, everyone realizes from the work we did originally here that bone marrow cells will not turn into new heart muscle. Then their skeletal myoblasts, even though we started with these cells, I never quite understood how that was gonna work. What we were thinking is that the skeletal muscle would grow and prevent the heart from dilating and maybe that would help. It turns out that it caused arrhythmias in the heart and that's basically been abandoned. Then there are so-called mesenchymal stem cells that are adult cells. Again, some people think that there's a possibility that these cells could differentiate into a heart muscle cell but there's no great evidence for that. There is a new area. I'll talk mostly about embryonic stem cells and IPS cells but there is some new interest in is it possible that in our heart there are cells, a small number of cells that are able to divide. We're taught in medical school that the brain and the heart, the cells in both of those organs don't divide. You're born with X number of cells and they don't divide. We're beginning to realize, certainly for the brain, I know Irv and some of the neuroscientists have discovered that there are cells that divide. The heart is still controversial but it's possible that there are cells at least in the heart that would be capable if treated with the right genes to differentiate into new cardiac cells and I'll talk a little bit about that at the end. And then there's embryonic stem cells and inducible pluripotent stem cells. So this is where we've done a lot of our work here at Stanford is using the mouse here with the green ears and all the cells in this mouse express a green fluorescent protein which is a marker for us to be able to use the molecular imaging I talked about to follow the mice and it's been a very valuable tool for us to gain new knowledge into whether these cells stay where they're injected and what the fate of them are. So embryonic stem cells, when an egg is fertilized, there's one cell and then that cell divides into two cells and those cells divide into four, eight, 16 and at a certain point, up to the time of about 64 cells, all of these cells, if you take a cell from this inner cell mass of this blastocyst which is at about the 64 cell state, these are embryonic stem cells. So the question is why does one of these cells, let's say cell A, become skeletal muscle and cell B become heart muscle? Unknown, there are certainly genes that we're beginning to understand how to differentiate these cells. So the embryonic stem cells can develop into any cell in the body and will but at some point they go down a path of differentiation and there are certain signals that are turned on and certain signals turned on that causes the cells to either become a heart cell or a brain cell or a liver cell. So that's an important point. The second is that if you take these cells that are undifferentiated, then put them into a human that will try to become every cell in the body and the problem with that is that there are tumors that are formed called teratomas. That's why there have only been five people in the world ever that have gotten embryonic stem cells, three for spinal cord injury, two of which were done here by Gary Steinberg in collaboration with a clinical study that Geron sponsored. Unfortunately, Geron stopped that trial and got out of the stem cell business and then there were two patients who received embryonic stem cells to treat macular degeneration, but that's it. We believe our group has an application in and we've been given a lot of positive feedback and we learn next month whether the California Institute of Regenerative Medicine are gonna award us $20 million that if we win that grant it'll allow our group to be the first group in the world ever to put embryonic stem cells into a heart. And I think that is a great translational story just like heart transplantation. This is an example of how big thoughts and big ideas can be accomplished at a place like Stanford. I just wanted to put this slide in because this shows you what a human embryonic stem cell transplanted in the heart developed into cardiac tissue. This is exactly what a cardiac muscle looks like. It was an embryonic stem cell, a human embryonic stem cell that was injected into a mouse heart that had a heart attack. You can see the striated bands that look just like cardiac muscle. These red areas are expressing protein called connexin 43, which means that this new cardiac muscle is connecting to other viable cardiac muscle that's left into the heart. And that's gonna be an important part of any therapeutic approach for treating heart failure. Now, there are problems with embryonic stem cells. I covered with you the problem of teratomas. So the way we get around that is that we know these protocols that we can give genes to these cells and differentiate them until this embryonic stem cell develop into a heart cell. And then we purify those cells and put into the heart. The problem with embryonic stem cells is that they come from embryos. So there are certain ethical and moral issues that have been well publicized. The second thing is that the embryo has a genetic code. Now we heard a tool butte talk in the last session, those of you who were in that session about the genetic code. But suffices to say that the embryo has a certain group of antigens that are different if I'm getting those cells from an embryo and my immune system will try to reject those cells. So that's the second problem with embryonic stem cells and then the teratoma is the third. So there's a new type of cell that was discovered in 2005 called inducible pluripotent stem cells, IPS cells. And so these are cells that the way that this works is you can take any adult cell in the body. The easiest thing to do is to take a biopsy from the skin called a fibroblast. And then there are four important genes that can reprogram these cells into pluripotent stem cells. They're just like embryonic stem cells except they're your cells. And then those can be used to go on to differentiate into cardiac cells or neuro cells and then they can be used for therapeutic approaches to treat heart failure or Parkinson's disease or diabetes. Moreover, every drug that you consume is tested by regulation by the FDA, but it's tested for toxicity in a very rudimentary hamster cell model called the choce cell. And it's simply whether the calcium channel works, yes or no. There was a drug called sysopride back in the 90s that was given for gastric motility. If you had reflux esophagitis or reflux disease, you were given sysopride and your GI system moved forward. It was a multi-billion dollar drug. It was screened through these choce cells and deemed to not have any cardiac toxicity. However, that drug had to be pulled from the market because there were over 80 deaths from a condition known as prolonged QT syndrome. If you look at the QRS complex from an EKG, it's a prolongation that causes these deadly arrhythmias to the ventricular tachycardia fibrillation. Just imagine, and what we're doing here at Stanford, we're developing 1,000 IPS lines from people that have a variety of different cardiac diseases. Artery disease, dilated cardiomyopathy, atrial fibrillation from all ages, all ethnicities. And just imagine that before you take a drug to market, you could test in a petri dish whether this drug had an effect on the QRS complex because these IPS cells in a dish can be beating, you can measure an electrocardiogram, and you can determine whether that drug would have toxicity and produce this disease called prolonged QT syndrome. So those are three areas that I think IPS cells will be used, one for therapy, one for drug screening, and then to understand mechanisms. Think about, we just had a major publication about mechanisms of how aortic aneurysms form in Marfan's patients. And to be able to test this, instead of doing a big clinical trial that costs a lot of money and can be dangerous, you could develop IPS cells, cardiac cells from patients with Marfan's disease, and basically do clinical trials in a petri dish. Think about that, and we can get to that in the question and answer session. So coming back to the forms of heart failure, I think that stem cells hold great promise for treating certainly both dilated and ischemic cardiomyopathy. Here at Stamp, we've got the great fortune to have not only great basic scientists, engineers, imaging experts, but also clinicians and patients that have heart failure. Because of that worldwide recognition and heart transplantation, we get patients from all over the world with heart failure. And we're able to come back to this idea of translational research, having problems in the clinic, taking them to our labs, working together in teams, and coming up with innovative therapies that we take back and treat our patients with. So this is a picture from the inside in the operating room of what a heart attack looks like. This is the inside of the left-sided pumping chamber, the left ventricle. This is normal muscle. This is the mitral valve. Blood flows through the mitral valve into the left pumping chamber. The left ventricle comes through the aortic valve, which you can't see, and it's pumped out to the heart. It took from the heart to the body. So this white area is scar tissue from a large myocardial infarction or a heart attack. One of the coronary arteries was blocked. And so the idea is, how do we treat this? Today, we have some conventional operations that I'll show you here in just a second. But the other is transplantation. Our idea is that we would replace the scar tissue. We would convert this damaged heart muscle that doesn't beat anymore. We could replace that with stem cells and reproduce and regenerate new cardiac tissue and cause the heart to beat stronger and more normally. And I believe it won't be just injection of cells. It'll be a tissue engineering approach. And this just shows you an example of a cardiac tissue on a matrix to produce what's called artificial myocardial tissue that could be re-implanted. In an operation, first, this is how we treat this area of heart attack. You can see this is thinned out. This is the picture I showed you from the inside. This is all thinned out, non-functioning heart muscle. And we simply go in and cut that out and put a Dachron patch. It's like a piece of cloth that stays with the patient. But it's rigid and doesn't beat. Think about that artificial myocardium that I showed you. And could we make a patch to treat this area of the heart such that these cells would be beating? Just like we're doing in the lab today and we've treated many mice in this way. I think that this is the hope of the future that first we'll do it by surgical approach. But I believe that eventually we'll have a tissue engineering approach that would be used through a catheter in the cath lab to be able to repopulate this area of damaged heart muscle and restore cardiac function. Just in the last couple of minutes, I wanted to just show you another pioneering effort and tell you a little bit about heart failure, treat official hearts, LVADs. In 1984, Phil Orrier, who's cardiac surgeon here at Stanford, implanted this device which was developed in our labs called the Novacor device. It's a left ventricular assist device, a heart pump, into this gentleman. It was the first time that any person had been kept alive with an artificial heart and survived to get a transplant. It's what's even more remarkable to me about this is that this gentleman, the first person ever in the world survived for over 20 years with his transplant, all work done here at Stanford. So I think that it's gonna be a combination of both transplantation, stem cell therapies and artificial heart therapies. We're to the point now where these devices can last for up to five, seven years. The devices are getting smaller, much easier to implant. This is the size of about a D battery that's placed right into the left ventricle, sucks blood out of the ventricle and then pumps it out to the aorta and to the body to support our patients. And indeed, if we get this CERM grant, our is gonna be patients that require these left ventricular assist devices to get them to a transplant. We're gonna inject the embryonic stem cells. We think it's a safe model because we can mitigate the possibility of these cells going out to the body and having teratomas. More, this is a chance when we take the heart out to do a transplant, we can look under the microscope and look and see how many of these cells survived and if indeed they turned into new heart muscle. So I'm incredibly excited about that. I just put this last slide in here to show that not only does cardiomyopathy happen in 21 year olds and 80 year olds, but it also can happen in newborns. And this is a child that Bruce Wrights and I put an artificial heart in and about two weeks later got a transplant and is alive and doing well. So just in summary, I think that transplants have been remarkable over the last 40 years. We've saved thousands of lives. That effort started here at Stanford and is now spread around the world. Additionally, the first successful left ventricular assist device was done here at Stanford. And I believe that will be the first place in the world to inject embryonic stem cells and demonstrate to the world that stem cell therapy can also be a novel and innovative treatment for heart failure. Thank you for your attention and I look forward for your questions. No questions. Wow, okay, there you go. With a large area of infarct and injecting stem cells, there must be a time frame before they can become active. Are you working on what's the right size area to put the stem cells in and at what point you really can't wait for the stem cells to take over those logistic plans going on? So that's a very good question. The question had to do with how big an area and how you target the area and can you wait for the stem cells to start taking effect. That's a very good question. It turns out that this first study that we've planned would be a safety study. So if you or someone who needed an artificial heart and we came to you and said, in addition to the artificial heart, we're gonna put these embryonic stem cells in because it gives us an opportunity to study the biology of them, to see if they're gonna be safe and then we take them out and look at them under the microscope, as I said. But one of the things that we've thought about and we can't make any problems, but as the patient is recovering, it's usually about three months from the time that you get an artificial heart until you find a suitable donor that's found for you to do a transplant. So after about a month, our plan is to turn the pump down and look under echo guidance and we know the area we're gonna inject those cells to see if the heart's functioning well with the idea one day that someone who's in an emergent situation needs an LVAD, we can put the cells in at the same time and then slowly wean the LVAD away as the cells start to take over new function. Now for people that aren't in that dire strait, I believe that earlier on, so there's a spectrum of heart failure that at one end is an LVAD in a transplant, but there are signs and I think genetics are gonna be able to help us predict who has headed down the pathway of failure and we wanna start to inject those cells earlier so that they can start to divide and incorporate. So we don't know how much time that'll take but we think it's probably gonna be several months. But it's a good question, yes. Yeah, so what I've described to you so far would be sort of a proof of concept in first step and you would need a big operation for the direct injection or to put this tissue engineering patch in. But I certainly believe that these therapies will be done through a catheter. You'll come in, you'll have a catheter go into your heart, we've got sophisticated imaging and locating devices that allow us to find the area of damage and inject cells now. This has been done with these bone marrow, adult bone marrow cells. Now there hasn't been much utility because as I outlined before they don't really work to form new heart muscle but we believe that embryonic stem cells and I think more importantly IPS cells because we can take your own cells and use those. So I think that this is all gonna be done minimally invasively. Whether we can do it to prevent damage is still up in the air but that's the idea behind a big heart attack so that you have your artery closed and instead of having a big scar and damaged area that results from a big heart attack then at the time you're having chest pain you come into the hospital, this goes on now and usually in less than an hour if you come into the hospital your artery's opened up in our cath lab and there's a stint in your artery and then to use stem cells at that point to prevent damage. The areas of the infarct that occurred acutely if you get the stem cells out to try to prevent damage and mitigate any scar and damage to the heart muscle because it's a spectrum. You get the cells die and then the heart starts to thin and the heart gets bigger because it's failing. So acutely the idea would be to try to prevent any further damage by injecting those cells down the coronary arteries or directly into the heart muscle at the time of a heart attack or earlier on in this spectrum of heart failure but it'll be less invasive for sure, okay? Those are the bone marrow cells. Those are adult bone marrow cells. And then the other question was related to, you mentioned the FDA and I'm in the biotech industry and a lot of the issues, I mean, the FDA deals with small molecules and has not come around to cell therapy. So how do you see them kind of getting to a point where they understand what? Well, for us to do this for us to do this cell therapy study we have to have an investigator initiated IND today with the FDA. So we've got four years. We find out in June from CIRM, if we get the grant we've got four years to get to humans and there are tranches of money that come to us depending on the benchmarks that we hit but one of the early benchmarks is and as part of our application we've had to have pre-pre-IND meetings with the FDA. So they're regulating cell therapy today. Certainly if you, because we believe that I didn't have time to cover all this and this gets into a little more detail but we believe that because these cells most of which don't survive we're gonna need to genetically modify the cells to cause them to differentiate but also to help them to survive because you put them into an environment where it's sort of hostile. There's inflammation, it's in an area where there's not enough blood flow. So you're gonna have to have gene therapy in addition to cell therapy and the FDA gets really concerned about that. So they're definitely regulating them and the CD34 cells are these adult bone marrow cells that we used in that first study. I will say that there is some, there's some suggestion that there's certain paracrine factors, not that the cells will develop into new heart cells but that there are some factors that can help to grow new blood vessels into an area so that the area around that heart attack there's a rim of tissue called the transition zone and to help that area function better by growing new blood cells. So that's why people continue to use adult bone marrow cells inject into the heart. Ann? Do you envision the stem cell therapy being more useful for one of the types of cardiomyopathy versus the other? The ischemic cardiomyopathy obviously blood supply is the problem. So when you put new cells in the blood supply may not be optimized but with an ischemic, with an idiopathic cardiomyopathy it's a much larger area. Do you envision one being better than the other and more useful than the other? Yeah, that's a veteran question there from Ann who's our chief of staff by the way and one of the best doctors I've ever known. If I get sick I won't hurt taking care of me. So that's a good point. I think that everybody has gone and that's when I said at the patient selection side acute myocardial infarction done in the cath lab down the coronaries, chronic disease which is either ischemic from a heart attack or idiopathic cardiomyopathy that Joe Matthews. I see that cell therapy is gonna be directed toward the ischemic first because that's a defined area that we can see on this device called a Noga device in the cath lab. You can test and see the area that's not moving and using echo. We can direct cells into that infarcted area. You're right. I think that's why it's gonna be a tissue engineering play with pro angiogenic factors and pro survival factors, anti-apoptotic genes. But I believe that's gonna be the first place. Now, I didn't have time to really talk about the resident cardiac cells and whether there are gene therapy strategies that can convert those cells into new cells. I think that's gonna be more applicable because those cells are gonna be throughout the myocardium and I think those are gonna be more important for these dilated cardiomyopathy. I think the dilated cardiomyopathy's though the real thing, we're clearly, and you've probably heard this across this week, we're clearly moving from an era of diagnose and treat to one of predict and prevent. Predict through the genetic code and try to prevent these diseases. And we really don't know, there's been some suggestion that these dilated cardiomyopathy's have to do with viruses, coxsacky B virus. And so just imagine if you could find a gene that said that one person was more susceptible to a cardiomyopathy, a dilated cardiomyopathy, if they got coxsacky B virus and you could develop a vaccine, you could basically eradicate that disease. But for the dilated cardiomyopathy's, a stem cell play, I think it's gonna have to be resident stem cells that are stimulated to grow new cells. So I'm getting the time's up. I'll be happy to stay around. We have 15 minutes before we go back to the plenary session again. Again, thank you all for being here today. I really enjoyed being with you and I'll stick around and answer any questions you may have. Thank you. The preceding program is copyrighted by the Board of Trustees of the Leland-Stanford Junior University. Please visit us at med.stanford.edu.