Good afternoon and welcome to today's meeting of the Commonwealth Club of California. I am Dr. Robert Mahley, the President of the J. David Gladstone Institute here in San Francisco. It's my pleasure to introduce our distinguished speaker Dr. Deepak Srivastava who is the Director of the Gladstone Institute. Dr. Srivastava was trained in pediatric cardiology and also in cardiovascular disease research. His heart disease research spans a number of disciplines, human genetics, developmental biology, congenital heart disease and more recently the whole topic of Stem Cell Biology. Recently he was honored as the recipient of the 2007 Mead Johnson Award for excellence in pediatric research, one of the oldest and most distinguished honors, given in this area of research in the United States. Please welcome Dr. Deepak Srivastava. Thank you Bob, it's a great pleasure to be here today to share with you some of the most exciting development developments that are going on in the field of Stem Cell Biology. And I will focus my comments in particularly on those related to heart disease, but as you will see, many of the same principles and paradigms apply to your the various different diseases. In addition during the course of the discussion, I will give you examples of how we are tackling this enormous health problem of heart disease at the J. David Gladstone Institutes. In the Gladstone Institutes which are located here in San Francisco, are about 28 years old, we have almost 350 employees in the new research building on the Mission Bay Campus Biomedical Campus just down the road. The Gladstone Institute is an independent medical research organization that is closely affiliated with the University of California, San Francisco Medical Center. In addition to the Cardiovascular institute where a scientist study both adult and pediatric heart disease, there is also the Gladstone Institute of Virology and Immunology focusing on HIV and AIDS research and the Gladstone Institute of Neurological disease involved in Alzheimer's disease and other Neurodegenerative disorders like Parkinson's and Huntington's disease. Now it's highly likely that most of you in this room have at some point been with a family member or friend may be talking, eating, having a good time when suddenly you see the a look of fear in their eyes. May be they start to sweat and then suddenly they clutch their chest in pain. What's going on? Is it this individual is having a heart attack? And unfortunately this happens over a one million times every year just in the United States. And it's typically the first sign that people have, that they even have heart disease. And despite major medical advances the outcomes for half of these individuals - there are about 500,000 cases the outcome for these is sudden death. This is what makes heart disease the number one killer in the United States. Now the other half that survive are often left with damaged hearts that slowly deteriorate over years because while they survive the initial heart attack, some of their heart muscle is lost and as I will get to a little bit later, the heart just is simply incapable of creating new muscle and regenerating itself. As a result there are now over a five million people just in the United States who have what we call heart failure, where their heart is just not strong enough to support their body. And many of these will ultimately require heart transplants. Now as I am sure most of you recognize it's unlikely that we will ever have five million hearts donated to address this need and have enough hearts for transplants for all these individuals. And obesity, we recognize which is an active area of research at Gladstone is an epidemic right now and we know that this is a major risk factor for heart disease. So we expect this problem to only get worse as time goes along. So it's clear that we have to do something different to address this major killer, and so that we are not in the same position that we are in today. Now some of you may have also had a friend, acquaintance or a loved one who has eagerly waited for nine months in anticipation to meet their new born baby. All parents have great hopes and dreams for their children and I think this begins very, very early before the child is even born. And you can imagine the devastation they must feel when someone like me has to sit them down in a cold impersonal hospital room and tell them that their child's life hangs in the balance because she was not born with a normal heart. I unfortunately have to do this. And I would like to tell you that it's a rare event, but the fact is its not. One out of every one hundred babies born, not in the United States but world wide has a malformed heart. And this is due to the cells in the embryo as it's forming very, very early, in the first few weeks, those cells not being told properly to become a heart cell. Or even if they are told to become a heart cell, they don't fashion themselves in the proper three dimensional organization to make a normal functioning heart. It is the most common human birth defect. And as a result heart disease in children results in more deaths than all cancers put together which is a remarkable number; and it's the number one non infectious cause of death in children in the first year of life. There are now one million survivors of childhood heart disease because of improvements in surgical approaches for such cases. Unfortunately as many of these children are getting older, they too are developing failing hearts because their hearts just weren't made right. When this happens, currently we have nothing more to offer them but heart transplants which unfortunately only last about ten years in the best case scenario. So that may not be such a bad option later in life at the age of 70, but it's not a great option for a new born. Now beyond the sobering emotional impact for heart disease, the economic burden is also and I'll use a term, a newly acquaint term, a newly sanctioned term, Giant-normous. Some of you might have seen the Webster report last week, this now an official word, so it's okay for me to use it. Heart disease accounts for over half a trillion dollars of our National Healthcare spending currently. It's an enormous number and it's only going to grow as I mentioned. So what can we do about this? We have to do something. One approach that we have taken at Gladstone is to try to identify the genetic variation between individuals that identifies those individual that are most predisposed to developing heart disease. And Dr. Mahley here has actually, over the last 15 years used a very interesting population Turkish population, that has a unique cholesterol profile to identify genetic variants that affect cholesterol levels which is a major risk factor for adult heart disease; that in fact he described many, many years ago. There are other risk factors for heart disease that we know that include obesity, diabetes, hypertension, and of course smoking. More recently my laboratory has discovered genetic variants in families with heart disease that cause abnormal deposits of calcium either within the valves of the heart, or within the vessels. And some of you might know those with increased calcium in their heart have to be much more careful about their cholesterol levels and other risk factors for heart disease. And so we think that using such discoveries, we can now begin to genetically pinpoint those individuals who need most need aggressive management at their risk factors of their risk factors. And so this is a preventive approach. And we are doing the same thing for parents now with congenital heart disease who might be at higher risk for having children with heart malformations. And this approach really is the future of personalized medicine that you hear a lot about in this post genomic era. But what about those people who already have disease? Prevention probably won't help them so much. And until a few years ago, I have to say there is little hope for those who already got disease. But now in the middle of 2007, I have enormous optimism that the revolution going on in science right now, particularly in the field of stem cell biology, has the potential to alter the natural fate of many diseases certainly including heart disease. And the ability the ability to generate replacement muscle or valves or blood vessels, could fundamentally alter the landscape for the treatment of heart disease and this is the sort of thing that really is the hope of regenerative medicine. So in the remainder of the talk I would like to focus my comments on the nature of stem cells, their potential and some of the challenges and controversies that we face in their use for the regenerative purposes. And while some of my remarks, as I mentioned earlier, will be specific to the heart, the concepts are applicable to virtually all diseases that might some day benefit from stem cells. Including these include one's that might affect the heart, the brain, the pancreas for diabetes, the skeleton muscle for muscular dystrophy and the list goes on and on. Now since its hard these days, to pick up a newspaper or a magazine without reading something about stem cells I imagine that most of you have some knowledge about these fascinating yet controversial cells. But I also recognize that there is a fair amount of misinformation out there and it's often delivered in a piece meal form. And so I would like to spend the next few minutes providing some context to the information that you might already have regarding stem cells. And the first and fundamental thing is clearly defining what is a stem cell. And there are two major features that really define what a stem cell is. The first is that it must be able to self renew and what that means is that as a cell is dividing into two, one of the cells has to be able has to be a carbon copy of the parent cell. That is what self renewal means. And the second feature is that other cell from the division has to be able to give rise to all of to many of the different cell types of the body and we call it a daughter cell. And the daughter cell has to have the potential to be not just the parent but many, many other things. Those are the two features that define a stem cell. Now to understand why a stem cell can not only form itself but can turn into so many others things, other cell types, is a critical feature of cells that I have to share with you, that will form the basis for this understanding. Every one of you in the room has billions of cells, not millions, billions of cells in your body. And they all have a unique job to do. Yet they all have the exact same DNA or genetic blue print. And that blue print encodes for somewhere around 30,000 different what we call genes. The genes are the blue print and they serve as the code for building proteins which are actually the things in the cell that dictate and tell the cell what to do. So this is a curious feature. Every cell on the body has the same blue print yet they all so different. How does that happen? And it and it happens because it turns out that even though there are 30,000 different genes, the set of genes that are turned on and turned off in any given cell is vastly different. So a skin cell has a unique set of gene that are all turned off and a few that are on. A muscle cell has a different set of genes that are turned on and most of the other ones are turned off and it's that set, that unique set that's turned on in every cell that makes one cell different from another cell. And very early as an embryo is forming, if you go back in time, as an embryo is forming, initially there are primary cells that sort of have everything turned on. And those cells have the potential to give rise to virtually everyone of the two hundred or so cell types in the body. This is what we call Pluripotent cells. And at some point in development of the embryo, these Pluripotent embryonic cells lose that capacity to generate everything, and the reason they lose it is that a very subset of their genes are turned off and this is a relatively prominent event. And the more genes that are turned off, you can think of it as the less potent the cell is to give rise to all the different cell types of the body. And ultimately the cells completely lose their ability to self renew and alter their fate and this as I mentioned is a permanent change and in the past has not been a reversible process. And this is the reason that most organs including the heart and the brain can't simply cannot regenerate themselves after injury, they are done. And they are permanently reprogrammed to be what they are. Now human embryonic cells, stem cells that you hear about are isolated from embryos just five days after fertilization of the egg. So this is well before any organs form, and these cells if you isolate them and put them in a dish they can retain their ability to be pluripotent. And so this is and because they can have that capacity and they can turn into all of the 200 cell types of the body, this is the reason they have generated so much interest and also so much controversy. Now this is in contrast to adult stem cells which also have value. But adult stem cells, as you can imagine, have limited potential. They are typically located within initials with in adult organs. And so they are capable of self renewing, that's why we call them stem cells, and they can give rise to discreet subset of cells, but usually just the cells of that particular organ. So if you isolate a liver and take it there are stem cells within the liver and they can give rise to liver cells, but not heart cells. And the same is true for other organs. There are few cells in each organ and they are rare, and obviously they are difficult to isolating you can't really get them, typically without harvesting the organ. So you can imagine why this is could have some therapeutic value but it might be limited. And of course a notable exception to the adult thing I just told you about adult stem cells, is those that derived from the bone marrow. And the bone marrow stem cells have been used to repopulate blood cells through bone marrow transplants and this is really a beautiful example of the effectiveness of stem cells therapy. It's not new; it has been going on for 30 years. Stem cell therapy has been going on for thirty years. It's been remarkably successful and in 2006 there were over 50,000 bone marrow transplants performed in the United States, for various disorders. And so you can for some purposes at least, adult stem cells can be very valuable. However for therapies outside of the blood area pluripotent cells provide the best hope and currently that means use of human embryonic stem cells. Now this is a very young field and it only began in 1998, only nine years ago. And that was when the first description the ability to grow embryonic stem cells derived from that five day old embryo and grown in a dish. And that it was the first description in just in 1998. And much like In vitro fertilization 30 years ago, growing human embryonic stem cells immediately raised many ethical concerns across the country and across the world. As a result federal support for research on such cells was initially banned, awaiting further information. And over the next three years as the therapeutic potential of this discovery became clear many constituencies across the country clamored for a revaluation of this initial federal position. An on August 9th 2001, President Bush declared that federal support on existing human embryonic stem cells lines that were created before that date would be allowed. But no new cell lines could be derived or sudden with federal dollars. Since the National Institutes of Health, the government arm of biomedical research, funds the vast majority o medical research in this country the dozen or so sanctioned stem cell lines are the ones that the medical community can use currently. As a result some research has moved forward, but the policy has had a remarkable dampening effect on stem cell research on a very wide scale on this country. I will just give you an example, the National Institute of Health budget; annual budget is about $30 billion. Of that the amount that goes to may be, arguably one of the promising areas of biomedical research today is less than $50 million. Other countries have aggressively moved forward in the phase of this scientific vacuum in the United States and have often been able to lure passionate US scientists that were committed to pursue this type of research. And those scientists have some times gone overseas. The California Institute of Regenerative Medicine or CIRM, which is founded by California tax payers through the Prop 71, is already transforming this landscape. And other states fortunately have developed similar models that facilitate broader human embryonic stem cell studies. All three of the Gladstone Institutes are currently engaged in stem cell research for various human diseases and the CIRM support we have already received is allowing novel avenues of science that really would not have other wise been possible. Now that we can actually began to study human embryonic stem cells with some rigor there are many potential ways that we can through which we might be able to harness this new and exciting technologies. First, human embryonic stem cells that could be generated from patients with specific diseases like neurodegenerative diseases or heart disease could be used actually to study the mechanisms by which that disease actually occurred in the patient. And we have never been able to do that before because obviously we can't study the individual with disease in that isolated fashion like we might do in a cell that has the gene mutation that causes disease. And it's that understanding of the disease mechanism that is really the prerequisite for the development of the future therapies. Our lab has identified the genetic cause of heart disease in several families and we are now attempting to generate those types of disease specific embryonic stem cells from the affected family members to understand why they even get the disease and I can tell you that the families who have these diseases are very excited about giving their cells and the DNA to generate stem cell lines because they want to know why. And we want to tell them. And secondly cells derived from human embryonic stem cells could be used to test pharmaceutical drugs for potential toxic effects and for their therapeutic value. This has never been possible and it's not some thing you hear about because it's not some thing the industry has even thought very much about previously. But now this might be possible if we can generate cells from human embryonic stem cells for such studies. And as an example, Bruce Conklin, an investigator at Gladstone studies the effects of various drugs on the beating rate of heart cells derived from human embryonic stem cells. So you can make heart cells from these stem cells, they actually beat in the dish. And he can test various drugs to see if they alter the pattern of the beating or the rate of the beating. And you can imagine that these types of efforts could increase the safety of drugs as they reach the market and before they actually tested in humans. And may be of the greatest potential are the efforts to coax human embryonic stem cells into either becoming neurons or muscle cells, pancreatic cells, liver cells or other cell types. And these are the types of then cells that could be used to replace diseased tissues or organs in patients some what as I described earlier for those types of cells in the heart. And the scientific challenge here is to be able to efficiently guide a pluripotent embryonic stem cell into the cell type that you desire and then to expand that cell type into sufficient numbers that you can actually introduce it into a patient and do something of therapeutic value. And this is not a trivial challenge. But at our institute, my laboratory and Dr. Benoit G. Bruneau's lab have found new ways to both generate and expand these cardiac precursor cells and this effort involves the use of what we call sort of master regulators that can execute lots of different events in a cell all by themselves so that they in themselves become sufficient to take a pluripotent cell and not take it a little bit towards the heart cell but all the way towards a cell that can beat and function in every way like a heart muscle cell. It turns out that these master regulators are the same regulators that are required to build the heart in a developing embryo. And in fact this is what my lab has spent the last dozen or so years studying as to unravel the intricate steps that are going on in an embryo that cause a heart to form normally and because of my interest in children who don't have normal hearts, then are the ones steps that have gone wrong in setting of heart disease in kids. So essentially what we are doing is that we are using nature's own tools, to make heart cells in a dish from these human embryonic stem cells. And based on our results so far we are very encouraged that at least for the heart we will in fact be able to generate cells that could be tested in hearts after their damage. Now the problem is that is even if we are able to efficiently make heart cells we have recognize that there are still many challenges that lie ahead that have to be addressed before we can even think of clinical therapies. One of those is how do you deliver these cells to the proper place. So delivery to the damaged organ is going to be a technical and biomedical engineering challenge that is critical to solve. And particularly for the heart we can imagine that the direct injection of cells in to the muscle or injection into vessels that feed the heart muscle might be useful and we have we and others have in fact tried these and they appear to be fairly effective, but they are invasive. Now even if we managed to both make the cells and deliver them, then the cells that we introduce have to get properly incorporated with the rest of the organ. Otherwise they function in isolation and that likely will be ineffective. And this is particularly important in the heart because as you can imagine all the cells in the heart have to beat in synchrony, the heart always has to beat like this, not like this and like this. And so all the cells have to be electrically coupled with one another for that to happen. And so if we introduce cells into the heart it's absolutely critical that they are electrically coupled with their neighbors so that you don't have isolated cells that are beating with their own rhythm because that likely will cause fatal arrhythmias or rhythm disturbances within the heart. And finally even if you can do all of those things and you introduce the cells into an organ, just like organ transplants can be rejected there is potential for these stem cells, if they are not derived from the same person's own DNA, to be rejected. Therefore modulating the immune system of either the cell or the patient but even better the cell will be critical to prevent this. And fortunately one of the Gladstone Institutes is focused on virology and immunology and so they have begun to bring their expertise to this problem in an effort to avoid this complication. Now those are some of the challenges that we have in front of us and we are addressing. But imagine for a moment what if we are able to make replacement cells that have the exact same DNA and genetic code as the patient who needed those cells. Clearly this would obviate the issues concerning rejection. And what if we could go a step further and the required pluripotent cells that we need could be derived without even creating that five day old embryo, that would then have to be harvested to make the human embryonic stem cells. If we are able to do that many of the ethical concerns surrounding the destruction of embryos would be moot. So in one of the most exciting breakthroughs in years, a very creative scientist named Shinya Yamanaka at Kyoto university in Japan has managed to do exactly what I just now described. By introducing a handful of these master regulators into an adult skin cell, he was able to reprogram the DNA of that cell which had, as I mentioned, turned off most of it genes and he was able to reactivate all of the genes necessary for that cell to go back in time and once again become pluripotent. We call this reprogramming but it essentially means that all those DNA changes I described you earlier on are now erased the cell is once again where it was after the first few days from fertilization. These pluripotent cells functioned just like embryonic stem cells in every sense. They had the same genetic code as the adult skin cell from which they were derived and they were generated without ever having to make an embryo. This is truly a remarkable advance that not surprisingly was highlighted last month in Time Magazine, the Cover of USA Today and in The New York Times. It is now been reproduced by several other laboratories and represents a major advance for regenerative medicine. Dr. Yamanaka, who trained at Gladstone over 10 years ago has done this work in mouse cells so far. But now he needs to see if the same approach can work in human cells. Now because of the stem cell friendly culture created by Prop 71 and CIRM and the strong scientific environment of the Bay Area, Dr. Yamanaka will be trying to reprogram human adult cells into embryonic stem cells with us here at Gladstone and will be moving part of his lab here next month to begin this effort which is critical for the future I think of many diseases. We believe that this approach could revolutionize the stem cell field and open the door to patient specific stem cells lines that could be used for therapies. So I think you can see why I am so enthusiastic about the prospects of stem cell based therapies not just for heart disease but really for most of the major diseases of mankind. And to be sure many breakthroughs will be required in the coming years and rigorous resting of clinical therapies will take time, and they will have to be safe. But we should have tremendous confidence that by focusing the resources and attention of passionate, creative and dedicated scientists and physicians; the key discoveries will be made. This is what we were trying to do at the Gladstone Institute with our many colleagues at UC San Francisco and beyond. So in closing, I have to admit that I have a very selfish motive. As a physician, there is nothing no worse is feeling than having to look at my patient or their families or their parents in the eyes and to say to them, "I am sorry, there is nothing else we can do." It's the same feeling that drives me as a physician scientist and will not let me rest until we achieve our goals. But as you can tell from my comments, the goals are achievable, they are there. We have to focus, work hard, and be creative. And I am confident that we will attain them. I appreciate your interest in this topic and for being here today and having your attention. And I would be happy to take any questions at this time.