Stem Cells: Progress and Promise

[Music] good afternoon everybody my name is deep x4 Rostova and welcome to our spring symposium many of you I see or see many friends of the audience and are familiar with Sarah Gladstone and but I also see many new faces so let me just say we're gonna have a great program for you today on stem cells but I think it's safe to say that the topics that we're going to talk discuss are far beyond stem cells and really touch on the fact that as we sit here today in 2019 the convergence of multiple different technologies and approaches are finally allowing us to begin to really see and feel how we're going to address human disease in a different way in the coming years than we ever have been able to in the past and so we want to give you an inside view today of how that might happen over the coming years and what kind of steps are leading to that so before I introduce our topic today let me for those of you who are new to Gladstone let me tell you a little bit about Gladstone and what this symposium has been all about so we have a president's council at Gladstone that is many of you are part of that really are people who've been involved with us or committed to our cause and have been supporting us for many years and twice a year we put on pick a topic of interest to you all and dive deep into that sharing it to you where that field is at the moment and at Gladstone we focus on three major diseases of humankind we don't do everything but we do basic discovery in heart disease which remains the number one killer worldwide brain diseases like Alzheimer's Parkinson's Huntington's ALS a number of neurodegenerative diseases that collectively remain a vexing problem where virtually every clinical trial so far has failed to make significant inroads so it's a it's a it's a major unmet need it takes long term commitment and we're determined to overcome that and you'll hear about some ways that I think we finally can do that or have can envision doing that and then we've had a long term commitment to solving HIV and AIDS and other viruses and I'm glad to say that in 2019 this is an example of a disease going from being uniformly a death sentence to a chronic disease completely transformed that disease and we've turned our attention to other viral diseases and how that those viruses interface with the immune system and how can you leverage that information to engineer the immune system to tackle not only infectious diseases but inflammatory conditions cancer and many other areas where if you trained your immune system you could use that to your advantage to solve human disease now though all in all those areas the pace of science and pace of discovery and translation has markedly accelerated in recent years and it's done so not by chance it's done so because technology is advancing at a very rapid rate and that's what's driving the science and so at Gladstone we have recognized that and formalized our effort there by developing an area where we are recruiting talent in developing new technologies to address biomedical problems and using data science to be able to analyze that the information that comes from those technologies in using artificial intelligence and machine learning in ways that will give us insight that we could never gain before and so some of those technologies we've focused on in the last few presidents councils symposia including artificial intelligence last spring CRISPR gene-editing technology in the fall and some of you are aware that jennifer doudna who discovered gene editing technology is running a second lab here now at the Gladstone institutes and today you'll hear about another technology that is driving this which is the induced pluripotent stem cell technology that has allowed us to make stem cells from any one of you in this room and now we can make your stem cells we can edit them and engineer them with crispers and we can analyze those using data science in a way that alle allows us to understand human disease and you'll hear some from one of our speakers Steve Finkbeiner about bringing all of that all of that together and so before I introduce our speaker I wanted to acknowledge several folks that are here particularly those who have are now leading our President's Council will Evers is here is coach sharing that with Laura Dorman who's here also and Fred Dory couldn't make it here but is our third co-chair and so they along with the rest of the president council have become our ambassadors to get to let people in our community to know about the wonderful work going on here and my only request from all of you is you're going to get some wonderful information today and then when you leave here if you're excited about it tell your friends and that that'll be the most one thing you can do for us so let me spend just a moment then framing our topic today before I introduce Shinya Yamanaka who'll kick off our comments so Shinya won the Nobel Prize in 2012 and many of you are aware this and and it's commonly thought that a vision that he wanted for the stem cell discovery you're gonna hear about in fact what he received a Nobel Prize for is the conceptual breakthrough that if one knew enough about every different cell type in our body and how those that saw worked then you could control that cell fate at will and take any cell in your body and turn it into a different type of cell if you just knew the code that was telling that cell what it was gonna be and so Shinya figured that code out for embryonic stem cells and was able to convert a skin cell into a something that behaved just like a human embryonic stem cell obviated the whole ethical debate around human embryos but also for the first time allowed us to have access to human cells of brain cells heart cells liver cells that didn't require biopsy of your tissue but when he made that observation the natural leap forward next step incarnation of that would be well if you could tell a skin cell to become a stem cell by on cracking by cracking the code maybe you could turn a skin cell into any cell type you want in the body not just a stem cell but maybe directly into a heart cell or a brain cell or a liver cell and in fact we've been able to do that now and investigators here at Gladstone have done it for heart cells in my lab Cheung dings lab and others in the neuro area have done it for brain various brain cells as well as liver cells so I'm gonna show you a short video in a moment releases this so if you see these balls on the top of the hill imagine them rolling down into a valley those being individual cell types it used to be thought that those were could never go back up the hill that ball and be reset in time but in fact Phineas discovery showed that we could in fact introduce just a small combination of genes into those balls other cells and push those cells back up the hill so that they are now reset and can go down into any one of these valleys okay so that's the conceptual aspect of this and and what my lab and other labs here have done if you go to the next video is not just going back up the hill and then back down the hill but taking one of those balls one of those cells that's in a valley already and it's already determined what kind of cell it'll be introducing the set of genes that are it'll tell the cell what to be and rather than going back up the hill to be able to sort of jump over a valley if you will go over a hill and go into a different valley without having to get reset but all of this was made possible simply by the conceptual advance that every cell in our body has a key sort of code that only involves three or four proteins that are enough to tell that cell what it should be so the only hurdle here is figure out what that code is and fortunately now collectively in the world we've figured out what that code is for most cells and can now control cells almost at will and it's opened up a whole set of approaches for regenerative medicine and drug discovery and that's what we're gonna talk about today so with that let me introduce Shinya Yamanaka who had trained here at Gladstone as a postdoctoral fellow he's one of our alums went back to Japan where he was and he'll tell you a bit about his story we were fortunate to recruit him back to Gladstone in 2006-2007 and and I'll just tell this story because I think it says a lot about Shinya and it says a lot about how he thinks of this organization I had just moved here in 2005 and was building out a program in in stem cell biology as well as heart biology and we had talked on the phone I had flown to Japan I flew into Tokyo shinya-san Kyoto where he runs an institute there also he flew up to Tokyo we met over a sushi dinner for two hours and by the end of the dinner he stuck out his hand we hadn't talked about any numbers recruitment and he says this is what I want to do and we shook on it and that was that but that that's how this that's how this happened but it speaks to the trust that one can have between individuals and institutions and that's what we pride ourselves on here at Gladstone Shania's continued a pioneer in his in our field of stem cell biology he's served previously as the president of the International Society for stem cell research and goes back and forth between Kyoto and here but his only laboratory that he runs now is actually here at Gladstone so Shinya so thank you very much deepak good afternoon everyone I think I only have this microphone so I should sleep here so as you heard from Deepak I got my postdoc training long time ago actually 25 years ago when I had more hair so I was a physician before that but I really wanted to come us and I applied to as many Institute's in us as possible but I did not hear back from any Institute's but Tom Garrity Institute he gave me a positive reply so we talked or perform I was in Japan he was in u.s. he asked Tom asked me many questions I forgot most of them I only remember one question he asked to me he asked me Shinya do you work on Sunday and Saturday and I immediately answered yes I will and that was it decided to recruit me so as soon as I joined gladstone 25 years ago or Tom asked me to convert Mouse skin cells into stem cells which we designated IPS cells I presented this IPS cell generation for the first time in the meeting in Canada early 2006 as soon as I finished my talk a young scientist came to me I thought he was a postdoc or a graduate student he was trying to ask me a question but he turned out he was then the director of Gladstone and future president of Gladstone he was trying to recruit me it was Deepak so we met again as you heard from Deepak in Japan and it took only two hours for me to decide to come back to Gladstone I came back in 2007 and later that year 2007 we became able to generate human iPS cells so now we can make stem cells iPS cells from each of you all we need is just a small amount of skin fragment over a tiny amount of blood cells and the procedure is very simple in only a few weeks we can make your own IPS cells from each of you once yer cells become IPS cells we can expand IPS cells as much as we want up to a billion or even more and then after expansion we can convert IPS cells to many types of cells such as brain cells heart cells liver cells pancreatic cells or immune cells so now we can make human cells many types of human cells anytime when we want we are now trying very hard to utilize this technology to help patients we can use these cells in cell therapy by transplanting like brain cells into patients suffering from heart disease or a spinal cord injury and we can use cells from patients IPS cells in drug discovery importantly this IPS cell technology also led to yet another important breakthrough known as direct reprogramming which debug just described so now people can convert scar cells in heart after after heart attack back into heart muscle cells without going through IPS cells so now we really really want to help patients suffering from intractable diseases with these stem cell technologies it's we are still on our way but we will do whatever it takes to make this happen so your friendship and your support will be greatly appreciated thank you very much [Applause] with that I'm going to ask Kathy Ivey and Steve Finkbeiner to join us on stage and we'll have just a chance to have some questions and answers that I'll moderate and then we'll open up some questions from the floor so Kathy Ivey is the scientist who trained here and worked at Gladstone for many years and two years ago started working with a startup company called Taniya therapeutics in South San Francisco focused on heart failure and she'll tell us a little bit more about that they're using these technologies reprogramming technologies to try to address heart disease and Steve Finkbeiner is a senior investigator here at Gladstone and is doing beautiful work on neurodegenerative diseases and particularly using human iPS cells from patients with a whole host of neurologic disorders and as I mentioned combining CRISPR technology and artificial intelligence to really make breakthroughs so maybe Kathy and see if you'd say a word about what you're doing and then we'll go into some questions at Tenaya therapeutics where we're developing drugs to treat heart failure and the work that we're doing come straight out of the the findings from our scientific founders here at the Gladstone institutes and deepak and other cardiovascular researchers here and we are working on exactly what was just introduced so our two approaches at Tenaya for drug discovery are one using human iPS cells to make human cardiomyocytes that have mutations that cause diseases of the heart we can observe those diseases in this in the cells characteristics of those diseases in the cells and then look for drugs small molecules or other targets that can reverse those those disease characteristics and we're finding success in that so far I'm really excited to say just two and a half years in Intuit and progressing some of the work that originated here on the other side we're also using these directory programming approaches exactly what was just described to transform scars which form in a heart after a heart attack back into working heart muscle to restore function of the heart after injury and we're taking a gene therapy approach to do this and excited to say that we've progressed it very far since our origination in 2016 thanks Cathy and let me add my welcome to detox it's so great to see what a turnout thank you very much for coming so I'm a director of the Center for therapeutics and systems biology here at Gladstone and you know if you want to call it we celebrated our 190th consecutive failure in clinical trials in Alzheimer's disease last year if you want to call it a celebration and you know I think there's been a lot of hand-wringing about why it's been so difficult to treat brain disorders and move things from our lab out into the clinic successfully but certainly one of the big questions has been whether differences between the main model we use in science the mouse and humans might be a source of some of this failure and so I couldn't have been more thrilled when Shinya had made his discovery because I just have a really hard time getting people to sign up for brain biopsies so having having Shania's technique was really the first time I could ever make a human brain cell in the lab from patients who had a clinical diagnosis and it's still the case that 90% of patients with Parkinson's Alzheimer's ALS have those diseases for reasons we don't understand and so we don't even we can't even answer the question right now are those one disease ten diseases that all look alike we don't know and these are really critical questions for being able to understand causes and find therapies so as Deepak mentioned we've been working really hard to use these IPS cells we've developed a masked one of the largest collections of patient derived IPS in the world for neurodegenerative and psychiatric disorders and so we're creating models in the lab that we can use to understand what's causing the disease and then to find therapies and some of these have been really promising we've been able in fact last year to start a new company around one of the discoveries that emerge from these IPS technologies thank you Steve so I think what you can tell even just from hearing these brief comments is that at Gladstone I think our scientists work with the clearly a sense of urgency we have a large number of physician scientist here as well who take care of patients who are suffering from many of these diseases we've talked about and it's front of mind all the time that we've got to do everything we can to accelerate the pace at which we make discoveries because people are dying in the mean time and so Shinya along those lines I know that you've been very committed to seeing the IPS discoveries get into clinical trials and had some success with that it might be interesting to update the audience on where we stand now with IPS derived products being actually in a clinical trial and what's on the horizon so as I mentioned in my presentation there are two major medical applications of this technology one is cell therapy also known as regenerative medicine and the other one is drug discovery so ads for cell therapy many many applications are going on in Japan and also in u.s. in in Japan almost exclusively IPS cells are being explored whereas in us both ES and IPS cells being embryonic stem cells and stem cells so I'm more familiar with the situation in Japan in Japan at least two applications are already in clinical trial one is for eye age-related macular degeneration my fellow scientists muscle Takahashi she has conducted clinical trial on five patients already two years ago already and the other application is Parkinson disease another fellow of mine Jun Takahashi he performed on one patient last year and he's planning to perform six more in 2019 so those two are already in clinical trials in addition to that four applications have been approved for clinical trial or one is heart failure spinal cord injury and Konya disease another eye disease and freight rate transfusion from IPS cells so those four clinical trials coming in probably this year and we other applications such as type 1 diabetes joint disorder like cottage defect and also what is at risk to me that is very exciting is a cancer immunotherapy so we can regenerate and we can expand cancer attacking t-cells and other immune cells from IPS cells so they are very close to clinical trial as well as for drug discovery we have now performing clinical trial for patients suffering from FOP FOP is extremely rare disease we only have like 80 patients in Japan and 1000 patients worldwide in those patients muscles become bonds they suffered from ectopic bone formation in his or her muscles everywhere so in the end they cannot move but we found by using IPS cells from patients the cause of this ectopic ossification and we found one existing drug may be a helpful for those patients so we are testing by clinical trial and many more are coming we are planning to start one clinical trial for Alzheimer's disease and another one for our areas so it's been 12 years since human iPS cells so I don't know our pace is fast enough as dapat mentioned IPS cells are from patients so they have patients name on each IPS on I so we are always under a lot of pressure but at the same time by seeing those patients gives us a lot of motivation as well so it's very unique situation by using patient I think one thing that we're also excited about in this area is that unlike most types of medicines that that we are used to that accept the fact that one has disease and you work around that the stem cell biology and regenerative medicine changes that paradigm completely it says that we won't accept that we have this disease we get to the crux of why somebody has disease and we fix that problem once and for all and are not just mitigating the consequences of it and that's what's created so much excitement about at least regenerative medicine is that we're finally in a position where we don't have to accept the human can so Steve I know that you have taken some really creative approaches in working nationally and internationally with consort banks of patient cells generate them and then use artificial intelligence approaches to really understand what's going on could you say a few a little bit more about that so just as everyone in the audience is different than everyone else one of the challenges of working with IPS cells is that each line is a little different than the other one and so trying to really be able to study these lines and get information that we can work on and work toward has been a bit of a challenge and I don't know if there are any cooks in the audience now itself couple yeah good so you know it may take you three or four hours to make a nice beef bourguignon it takes sometimes three or six months to take an IPS cell and turn it into the cell that you want and it turns out that that very long process can contribute a lot to the heterogeneity that we get when we try to use these cells to answer some of the questions we're trying to answer so as Deepak mentioned one of the challenges in this field is really getting useful information from these very valuable cells that we generate from patients and how can we both get the information we want and maybe even really leverage some of the tools that are available to see new things so about four or five years ago Google came to us they said we generated enough data to be interesting which i think is a compliment so part of the reason we did that is we've built robots that help us to be able to acquire images of these cells on a scope and scale that most academic labs can't do and that's been very useful for us to be able to really understand the biology that's going on in these cells because we can study thousands and millions of these cells so much larger sample sizes than we can normally do and it was great working with Google because it really gave us an opportunity to work with engineers who can do artificial intelligence and deep learning at the highest level and it really blew us away we could see things in images that humans couldn't see we published a paper last year to show an example of that and it had such an impact on my group that now we've really developed a very large effort around artificial intelligence to be able to both see things in the data that we collect that we normally would have overlooked but I think even more importantly and this really kind of gets to some of the things we've talked about tonight to make connections between what we can measure in a dish and what we can measure in a patient because I think that's one of the most unique features of this tool is that this comes from a person a patient and we have information from them and as I told you we've had really lousy luck in the past moving things from the lab to the clinic but what if we could use these artificial intelligence deep learning tools to discover connections between the patient and the cell that we can study in the lab that would guide us and help us make better bets when we move things into the clinic so that we can be more successful and just as you got a sense from both Deepak and Shinya you know I see patients or seen patients and really feel the sense of urgency around a lot of these disorders that patients are suffering and so the better job we can do to accelerate this process and make it more successful overall the more we're going to have to offer patients and that while we what we do at Gladstone is a very basic discovery trying to understand the underpinnings of human biology and how that goes wrong in disease as you see the tag line there science overcoming disease is what we're here about and many years ago particularly after the 2008 financial crisis it became clear that the landscaped had shifted but right below us where if we just kept making great discoveries and then made the next great discovery in the next those unless we were proactive about getting those to the next step to help people those were gonna sit on the shelf the capital markets just shifted and we decided we had to be more proactive and so at Gladstone the last many years we have been quite entrepreneurial to try to bridge the gap so that our discoveries can get into the commercial sector and to the extent that we they in our sweet spot of discovery but can still facilitate that next step we've been very active in doing so and and that's meant in many cases launching startup companies that might be incubated here at Gladstone with and ultimately get venture funding and then branch out on their own and our scientists continue to say involved to some degree to help with the their scientific knowledge and judgment to push those and Kathy here represents as I mentioned earlier one of those efforts in what's now tonight at therapeutics that was housed initially here at Gladstone but Kathy I wonder if you could share with the audience what that's been like to be in that setting going from coming from the academic setting to that and how they interface between the two entities has you know made a difference for the discovery in the translation how having experienced both environments I can say I I love them both but they're very very different and I think that the interface that you referred to is really key to success certainly on the industry side and I think we offer something also to the academic group that we interact with so that I would say that the the real difference is here at Gladstone there's such a energy around discovery and an enthusiasm for making advances that change how we think about possibilities right but that's not the ideal environment to move things toward the clinic the environment to move things toward the clinic has to be a little more has to be much actually more linear we have to be have our sights on a specific goal and not be distracted by what could be the next great discovery the kind of things that happen here at Gladstone every day so I I've learned a lot by being in this environment and I value the continued interaction with with the scientists here from Gladstone who are still working with us very closely we need their guidance and their they're thinking on on scientific aspects but then at Tenaya our scientists are embedded along with clinicians who think about how to transform scientific discoveries into actual therapeutics people who think about regulatory paths how to get things approved by the FDA and then also groups who are thinking about how we manufacture drugs because how we manufacture how we make therapeutics for academic research purposes it's very different than how we make them for putting it into a person and so we have to have our our sights on on those differences in making sure that the the quality of both is is similar thank you so going back to the IPS technology and the transplantation we talked about when Shinya first made his discovery it seemed like it would be the ultimate personalized medicine because we could take a small blood sample from any of you if you needed more heart cells or brain cells convert those into your stem cells and and then your brain cells and Transplant them back into you that way your body wouldn't reject those cells because they'd be your own that was the hope that we all had that it would really personalize your own stem cells it's turned out that the time it takes to make those cells and the cost at least currently is prohibitor prohibitory to everybody having their own stem cells to be able to use because you have to get a FDA approval for each one of those and Shinya went through this and found I think maybe it cost over a million or several millions of dollars to get a cell line once aligned to that stage so so Shania's lab has been working on a solution to that and she needed you and if you could say something about how your group is approaching this problem of rejection if we can't do that is there some other solution so that you could transplant cells without having to suppress somebody's immune system yes that's very important from a practical point of view so once again my friend Masao Takahashi she conducted the very first IPS cell based treatment for M D age-related macular degeneration five years ago already in 2014 in that case he used patient on IPS cells and surgery went very well or the patient is still very happy right outcome of the first transplantation we were happy to some extent but we are not so happy in terms of the money we spent and time we had to be used in preparation so as you mentioned it took more than 1 million u.s. dollar equivalent for just one patient and it took almost a year to prepare cells from from that patient so it's not practical there are many many millions of AMD patients worldwide so now as an alternative we are making IPS cells not from patient's own cells instead we are making IPS cells from so-called super donors so super donors rare one out of like five hundred we may have one super donor in this room maybe ten so those super donors had very specific immunological types so that even when their cells are transplanted to somebody else it won't cause massive immune rejection it may cause some small immune reaction that the degree is much much sort of like an O blood type exactly you might be familiar with you can get don't a donor who's o-type can give you blood and you won't reject it uh-huh but other than blood transfusion our cell transplantation is much more sophisticated and complicated so each person has a different mineralogical type we have more than like ten thousand different mineralogical types none of you should have the same in neurological type on this we have identical twins in this room but those super donors are very useful or we have generated IPS cells from four super donors in Japan and those four IPS of lines alone can cover up to 40% of all the Japanese population well Japan Japanese population is less typist in the case of the u.s. you need a lot more in each ethnic group we calculated we would need 100 lines to cover 80% but it's not one thousand ten thousand lines one hundred so it's more affordable but still we need 100 lines it's a lot work to make one line it still cost almost 1 million but thanks to Jennifer and CRISPR technology we can now make super donor IPS of lines by ourselves we don't have to identify those rare super donors and by modifying the actually I mean you know in logical or type all we need is just a few like 10 lines will cover most of all the population worldwide not only for us or for Japan but worldwide all we need is recent 10 right so it's getting more and more affordable feasible and at the same time we making IPS technology even faster even cheaper more affordable so that we expecting in like five years we can make your own IPS cell line with a very affordable price less than one small car and within one month so that's our ultimate goal to make your IPS affordable affordable cost and very quickly so it's going this is this is an example of the power of bringing two different technologies together so having Jennifer's lab here and Shania's lab here with the sort of founders of CRISPR technology and stem cell technology and how marrying those two can allow efficient alterations engineering of the genome for the immune system and for many other purposes to study human disease and it's one of the strengths we have here at Gladstone is that we've been able to be at that at that forefront so let me open up the questions to the audience I'm sure many of you have questions here Sharon and if I could ask you to use the microphone we are we are live-streaming this and recording it so that as I understand it an issue with cloning is that the cloned creature like if I wanted to clone my dog I talked to Deepak about this a few years ago my old dog there would be a puppy that would be the result of the cloning but it would have the age characteristics of the donor dog so in other words I wasn't really gonna get like a new younger little puppy do you have these issues with the cells in other words when you take a skin cell and turn it into a heart cell does it have the vigor and strength of a baby's heart cell or does it have the possibly disease characteristics of the person from whom that stem cell was made very good point so for example or now there are two ways to make neurons from patients suffering from neurological diseases one is to by going through IPS cells but the other way is to utilize direct reprogramming if two new ones if we go through IPS cells we rejuvenate cells so even when we make IPS cells from like 80 years old patient IPS cells the age of cells is zero or close to zero so it's rejuvenation but if you directly transform skin cells from eighty year old patient to you neurons those neurons are still 80 years old so it turned out it is easier to use direct reprogramming to the capture rate in robotic our disease which is affected by H but if you go through IPS cells we may be able to observe the process of aging once again so there are pros and cons on those two projects probably Steve you should have just like Shinya said for some of the diseases we study aging is the number one risk factor so trying to understand how that contributes to disease is really important in addition as far as we can tell some of the mechanisms by which your cells age are similar to how environmental exposures may contribute risk to and that's a big unanswered question also so I mentioned earlier that only in about 10% of cases of Alzheimer's Parkinson's ALS can we identify a gene that patient has that accounts for the disease so we think that there probably are other influences genetic or environmental so being able to retain that information from a cell from a patient could be really valuable as well to be able to study that interaction and to study that mechanism the first one has to do with converting the HIV virus to a cell because they're remodeling it and removing the HIV portion because apparently this virus is very fast in moving through the body and and I just read some things about that so I'd like to hear a comment number one and the other one I've read about recently about modifying the LEC which in the brain we've talked about the other part of the brain but the LACC portion of the brain and working on those brain cells and there been some work on mice who has been that's been apparently very successful to help with memory I just wondered comments thank you let's see I see Melanie in the audience or his Warner leer here warner wonder do you want to comment on the HIV questions Warner Warner is in our director there are fire ology immunology Institute and as a studies HIV Thank You Deepak so the CRISPR technology in the case of HIV has been a bit disappointing in terms of there have been efforts to try and go in and molecular lee remove the virus but it turns out that the virus rarely rapidly evolve and change in me and make the make repairs etcetera so that approach has not been as effective we are much more interested in using a dead a nuclease dead version of the crisper so trying to bring recruit to the to the site of the virus enzymes that will put that virus into a deep sleep make it completely inactive in dormant hopefully permanently dormant but so it uses the CRISPR backbone but there's no cleavage there's no editing of the DNA it's it's epigenetic we're making DNA methylation and histone methylation etc so that and that seems to be its that has worked beautifully with various somatic genes but it mentioned early that the FDA would not okay individuals stem cell solutions to people's pop their own stem cell solutions well what is there in the law or in the FDA technique for being used in other words a standard technique it was used on everybody I don't see quite why they wouldn't permit that to be a standard technique similar to what you might have is a patent so I think if I could answer that the the it's not that the FDA wouldn't approve the use of somebody's personalized IPS line they would but they would require that every person's cell line be sequenced in its entirety evaluated for whether any mutations might have arisen in the process that could be say cancer-causing and so there's a tremendous amount of effort they would have to be go into each one of the cell lines being approved for use clinically so I think that technique would be approved you've experiences in Japan 10 years of if you can oh we are still in the early stage those regulatory people or PM da here EMA in Europe and PMD in Japan they are very conservative so they want us to test each line in animals prior to human clinical trial and it takes very long but in principle they are ok with the technology itself it's just each cell line it's different maybe different so that's what they want to double-check but I'm hoping after like 5 years or 10 years after 100 patients are treated by this technology and if we don't see any major side effects it won't be necessary anymore so we could apply this technology to many patients without animal testing but we are still in very early stage that's why PMD I mean FDA is very conservative and we should be conservative too because safety is number one priority for us some of you may remember in the 90s there's a lot of excitement about gene therapy and there was a thought that that could cure so many human diseases and then there are a few cases where people died in the process of the use of gene therapy and it completely killed the field for almost two decades and there was so that so the stem cell community has been very careful to not let that repeat that history repeat and so I think even the regulatory agencies certainly have been but even the scientific community has been rather conservative in moving these things forward to not have any negative outcomes that would just set the field back for many years so that's part of part of the concern I should say that the Japan's regulatory agency has been very progressive and that's why many of the first trials have been done there the FDA in the u.s. in the last few years has I think had a palpable shift in its risk tolerance and Scott gottlief who has been the FDA Commissioner of the last few years says I think done a remarkably good job and the pace of approvals is increased and there the twenty-first century cures Act many of you are familiar with that the Congress passed last year has tried to make it easier for many of these novel therapies to go forward so I think there's hope there from a regulatory standpoint as well yes I was really intrigued by your therapy that you talked about turning creating t-cells from IPS cells and I guess I'm wondering how do you deal with autoimmunity so my understanding is during normal development t-cells are kind of exposed to self and any t-cells that bind to self get killed but if you're turning like a skin cell into a T so how do you deal with so they can fight cancer which is great but how do you I guess prevent it or how do you know if you put that T cell into a patient if it's going to go and bind to something that it should not it's also a very good point so actually autologous transplantation there's no problem such problem but when using allografts we have to consider that aspect so even making key cells we may need we receive much HEA immunological type between donor and recipients or as I mentioned earlier we can utilize CRISPR technology to get rid of immunological presenting in immune presenting molecules on IPS cells and T cells so that they won't be recognized by donors immune cells so at least in animal model it works but we need to wait for the result of clinical trial like cod T therapy is available it has been approved in this country and will be approved in Japan for leukemia it's very effective but it's very expensive almost a half-million for each patient we really want to reduce the cost one-tenth yes by utilizing interesting features of around the T cells is that we can now make IPS cells from T cells and when you do that you make a stem cell that has the same code if you will for recognizing self or non-self as that original T cell did so now you've got a stem cell from that T cell that when you turn it back into a T cell again it retains that and I think that's one of the solutions but Shinya you raise the point of the expense of this and so many other treatments err unlike a traditional pill that you might take for 30 years and a drug company then sells it to you and until you take every day for 30 years and they make their money that way many of these treatments are a one-time treatment and you're done so the pharmaceutical that's invested billions of dollars in developing that drug now is going to treat you one time you're going to pay them one time and so one of the challenges that many in the the community are facing is how do you reasonably price that product and some of you are familiar with when Gilead a few years ago developed a remarkable amazing drug that literally cured hepatitis C curative there aren't many cures in our field cured it and they charge ninety thousand dollars for it for three months treatment which is nothing compared to what somebody with hepatitis C would cost our system yet they got raked over the coals for that being so expensive so now you're going to talk about five hundred thousand eight hundred thousand dollar treatments and I think the we have is a field to figure out how to price that how to explain that and amortize that maybe over time but I don't know you have that come up in Japan or others in our audience we have many experts in our audience from Pharma who I know think about this I would love to hear from any of you as well it's a very important point the cost of you know fashion okati is very expensive opdivo is very expensive but its effectiveness is remarkable but in beauty we are going to see more and more these very expensive innovative treatments in the very near future so the question is right here each country has different insurance system all patients can all patients access to those innovation or only those rich patients can access it's a huge issue you are right many diseases can be treated by just one treatment so in total it may be cheaper comparing to you like 30 years life long treatment but you have to pay even though only once you have to pay that amount of money and some many patients cannot do that so that that's a problem we we have to think about we we want to bring our technologies to all the patients but we may end up bringing our technology only to small number of patients so that's what we we have to discuss so huge I know you're very concerned at the ethical and political solutions around a lot of these things and it's something we all struggle with well this is a little different topic Steve this might be for you several years ago there was a presentation here what around the protein that dr. Miele was working on for Alzheimer's what's the status of that research yes the question was about a protein called April lipoprotein II and I mentioned to you that in most cases we don't understand why people develop Alzheimer's disease but depending on which flavor of a pony you happen to have it's the number one risk factor for Alzheimer's disease besides aging and so the particular flavor that raises your risk for Alzheimer's disease most is April 4 and you can think of it a little bit like eye color you know we each have a gene that either determines whether we have blue eyes or green eyes or brown eyes and depending on the variant that you have you may be at higher or lower risk for Alzheimer's disease so there's a lot of discussion now about why you know what is it about that flavor that confers the risk of Alzheimer's disease or a number of ideas about how that might work and whether it's something that we can treat or develop a drug against and one of the one of the spin-out companies from Gladstone has really been focused on trying to develop therapies that might target that risk factor for Alzheimer's disease and research here continues on that score of really trying to understand what it is about apoE that confers risk there's some thoughts that the protein itself may miss fold and form structures that are directly toxic to cells there's another thought that it may get truncated and affect the sort of energy producing organelles in cells called mitochondria another thought is that it plays a really critical role in the immune and inflammatory system in the brain called cells called microglia and there's certainly been a lot of evidence from genetics lately in Alzheimer's disease that those cells play a really important role in determining our risk for Alzheimer's disease and for clearing some of the proteins that can miss fold in that disorder so I'd say it's a very active area of research and because it's so important I think it's gonna be a really exciting direction for the future and yeah dongwon's group here with and Bob Bailey's group have made IPS cells from a number of patients with the apoe4 mutation and used that to look for drugs that might correct that some of the problems there and just reported last year some success with that and identifying a potential therapeutic that could convert the bad form of a poly close better to the good form man so that's also moving forward a question for dr. Finkbeiner Steve that's there's been some really elegant work that's come out of your group recently and I want her to follow up on a point you made earlier and that is specifically many a common theme of neurodegenerative diseases tends to be poorly soluble proteins which accumulate over time gradually come up the works and cause disease how do you approach that in the context of stem cell technology newly created for example neurons how do you recapitulate that model yeah so thank you for the questions so it is true that one of the remarkable common threads of neurodegenerative diseases is that in almost all of those examples Alzheimer's Parkinson's ALS Huntington's if you look at patient brains you see abnormal deposits of protein either inside cells or outside cells or both and so it certainly has been a prevailing view in the field that that probably plays a really important role or it's least a sign of a mismatch that patients may have between the propensity that proteins have to miss fold and aggregate and the ability of the body has to clear it and so as you mentioned a big focus of our work or what we discovered as we observed cells was that there are a couple different clearance pathways in cells and if and we discovered some small molecules that stimulate one of those clearance pathways and they seem to be really helpful for a number of those disorders and for clearing those proteins at least in our laboratory experiments and so we're trying to push those forward it's really interesting in the stem cell area because as Shinya mentioned one of the remarkable features is that if you try to determine so we now have a way that if I took a cell from your body I could measure a few things called methylation marks on your DNA and I could tell you within 99% accuracy you're age and so yeah it's remarkable and just like Shinya said if you reprogram those cells you erase those marks and the cell looks like it's a newborn cell and we we've discovered I would say that one of the consequences of aging that some of the systems that cells have for keeping proteins in good shape and for clearing miss folded proteins declines with time and so what we find is that in stem cells those systems are really really good in fact it's really difficult to make proteins miss fold and deposit in stem cells so in fact one of the ways that we've tried to model these cells is that is sort of directly reprogramming cells to retain those those aging marks so that we can make sure that the environment is similar to what the environment might be like in cells from patients where the miss folding occurs so we can understand that and make sure that whatever we develop that might help boost some of those processes and patients is likely to work in a patient cell and not just a stem style but I would say that I think there are huge unexplored opportunities kind of to Shania's point that maybe we can use this technology to also understand better that aging process and are there ways you know we believe that those marks that get placed on cells are things that emerge from pathways that we might even be able to interfere with or modulate and so maybe there might be a way to even go after some of those mechanisms that are involved with aging and tackle not just neurodegenerative diseases but other diseases of aging including diabetes heart disease and things like that so I think there are some really exciting opportunities there as well Steve you've often used the analogy of a flight recorder I think maybe not maybe maybe I have you said enough keep it going do you have let's see hope it's not a 737 max flight recorder but the the notion that when a patient presents let's say with Alzheimer's or other diseases there that disease has often been brewing for decades and so we're only seeing the end stage of that process disease process but that one benefit of going resetting the cell and then is that you might be able to actually observe the disease process that might occur have occurred over a lifetime but in fast for and stimulate it and actually catch it early in this age you know with the equivalent to decades earlier in the patient and actually see what went wrong early on because when we see the patient ultimately and it's already happened maybe we're not gonna learn from that you know how it started and what you really want to know is how did it start so you can stop it there and that's I think one of the benefits I meant by the flavor flakes I think it's a really good point I just add one more thing and that is the really good news is that although you know we think about these diseases developing you know when we're late in life in fact you probably have amazing coping mechanisms that exist in your brain that stave off those symptoms for many many many years and so I see that as sort of the glass half-full because I think that as we understand what those mechanisms are and I think that's where some of these technologies can inform us that may give us new opportunities to boost just our natural mechanisms for staving off those diseases because if we can stave off Alzheimer's for another 10 or 20 years that's almost as good as a cure Oh deepak is two amazing astounding things that you're doing and the progress you've made and everything but we've also here understand how much money it costs so what is happening in terms of funding for example a government funding federal government and IH type of thing state of California I think had some biotech funds some years ago spectacular things that you can do but it's it's a really good point and the sad part of that story is that just at a time where our opportunity to understand and address human disease is unparalleled just at that time our funding for biomedical research at least in the United States has in real dollars been declining so if you look over the last decade when all these remarkable things have occurred the real dollars that are being spent by NHS are down by about 25% and and the opportunity is enormous and so you know institutions like ours we we do disproportionately well in our scientists being able to compete for those funds from NIH but the the real dollars that make a difference actually have been for many in this room and hopefully others in the future that allow us to in our investigators to take risks and to seize some of these opportunities that are in front of us quickly and make discoveries so we utilize its really been philanthropy in large part that's been able to meet that difference that the need of where the need is and we use those dollars to recruit new talent to provide seed capital to take risks and do the really important initial experiments to make discoveries and to stay at the cutting edge with technology and the equipment that we need so those are three areas where we can't get funding from the NIH and that's where philanthropy steps in and the other is our interact interfacing with the commercial sector we as I mentioned at the beginning we've been more entrepreneurial then I think most and out of our 80 million dollar annual budget at Gladstone now every year about five to six million is coming through our commercial relationships and that used to be zero ten years ago and so between that and philanthropy and our NIH grants we that's our formula for being able to be as aggressive as we can be but it's critical we can science is expensive and funding it is a major challenge and as president that's one of my biggest challenges is ensuring that we have the capital to to drive the science with the sense of urgency that we need we know we need to and thank you for your support in making that happened and many others in the room question here so I work with stem cell transplant here in the city and I have noticed me and the doctors there the clinic that we have a greater results utilizing umbilical stem cells as well exosomes even though that we get less umbilical stem cells than adults themselves from from the surgery my question is would you utilize Bullock au stem cells as a super donor to avoid the rejections that you mentioned before yes we do we have been collaborating with Japan Red Cross so that we can utilize cord blood cells and we now make IPS cells from both called blood cells and adult blood cells they look the same but when we sequenced the entire genome of a doubt derived IPS cells and cord blood you know IPS cells we see a huge difference IPS cells derived from adult cells they have many mutations whereas IPS cells from cold blood cells they had much fewer very small number of mutations so we we are making mutations every day in a bad whereas called blood cells they are very cream so in that sense cold blood is a better source coming back to this idea of rejuvenation at least in IPS cells we know that one of the other diseases that's affected by age really precipitously is cancer and also that one of the concerns about safety of IPS cells and the transplant is that they would cause tumors but it would seem from what we're saying here is that there's actually reduced risk because they're rejuvenated and also that implication is for nerd generative diseases that there would also be a reduced risk at least as far as the cell autonomous properties of these cells as neurons so I just wondered if you could would like to elaborate on this as a as a benefit of going through the reprogramming to IPS cells as you said cancer formation is probably the number one risk of IPS cells and ES cells transplantation there are two types of cancers or tumors after transplantation one is caused by mutations in the genome but we can avoid that risk because we sequencing entirely prior to transplantation if we see any risky change we don't we won't use that cell line but there is another risk which is a contamination of undifferentiated stem cells we don't transplant undifferentiated IPS or ES cells only after differentiation we transplant we transplant like brain cells heart cells into patients but if there are very small or number of contaminating undifferentiated cells they keep proliferating and after a year or two we may see tumor formation so that it's probably the most important point we need to avoid we have been spending a lot of time and money how to prevent that contamination of undifferentiated cells so one way is to improve our differentiation protocol so that we won't get any undifferentiated cells the second way is to purify differentiated results removing all undifferentiated cells by like cell sorting and third way to prevent that kind of formation is to develop a specific chemical that will kill undifferentiated cells but not differentiated cells so we have like multiple layers of protocol to prevent such risk but still we are not free from such kind of risks that's why we very careful in each trial Kathy one of the things that in the field we've often thought about is that if many human diseases that we give different names and have different features might the problems might funnel down to some common problems we think this in the neuro degenerative field where it's just a different neuron that's affected but they all have the same problem and so that if you find a drug to one disease it might apply to many others can you comment on what what's transpiring in that realm it and I am yeah so um at Tenaya we are focused on developing drugs for a condition called dilated cardiomyopathy which can arise from mutations in a variety of genes so there's a whole bunch of different ways that someone can end up having dilated cardiomyopathy we have now at Tenaya generated a panel of IPS cells that are identical to one another genetically except that they each carry a different mutation that causes dilated cardiomyopathy in humans and so this provides a great model for us to as I said identify disease characteristics in addition look for ways as to ways to reverse them what we have for with these tools in hand what we have been able to do for the first time is identify a small molecule that could reverse a disease characteristic caused by a specific mutation and then see if that small molecule is also effective at correcting the disease if it's caused by a completely unrelated mutation and this was something we had hoped would be true because it really changes the game for drug development and in fact that's what we've seen so we've been able to find small molecules that can correct the disease characteristics and cardiomyocytes in the majority but not all of the genetic backgrounds that we've tested and this allows us an opportunity then to move toward precision medicine or personalized medicine where if we understand the genetics underlying the cause of an individual's disease we can then hope to tailor a drug to them that would have some promise of working in their genetic background and this was a big effort one of the early demonstrations of this notion that a cell actually can't that doesn't have that many things they can do when you stress it and so it's possible that for many diseases there will be a discrete number of responses that a cell has that leads it along a disease pathway and so if you can figure those out then you drug those then you could solve many different diseases and Steve's work is leading to that as well for neurodegenerative diseases and so I think it's my great hope that that sort of approach will simplify the problem for so many human diseases and we'll be able to find some drugs that affect many things I think Steve uses the term common threads along many different diseases great well thank you so much for your attention today I hope this has been an interesting program I'll leave you with the thought and the vision for where we're headed as a field so I don't think it's unreasonable to look forward in the next few years next five to ten years to a day where every child when they're born has their genome sequenced right now we can sequence the coding part of their genome for only $250 that's probably not that different than getting a you know your blood count done in terms of cost so it's not inconceivable that every everybody when they're born will have their genome sequenced we'll know all their genetic variants we'll be able to utilize gene editing technologies to manipulate those codes we'll be able to use stem cell technologies to be able to understand what that genetic variant what the consequences are and maybe even in some cases correct that and all that is now not just pie in the sky it's going to take some time it's not around the corner but it's something that is tangible now that will alter the way that we address human disease and so that's where the field is headed that's what the those are the types of things that we're trying to do here and doing that in in great collaboration with many others including our colleagues across the street at UCSF and much beyond science fortunately works as a web where we interact deeply with one another and that's something that we value here at Gladstone quite a bit so we have some wine outside there's some foods for reception so please join us there and as I mentioned earlier we I hope you've enjoyed the program and my only ask for you is to go spread the word so thank you very much [Applause] [Music]

Channel: Gladstone Institutes

Views: 13,071

Rating: 4.8983049 out of 5

Keywords: Science, Research, Stem Cell, Cardiac, Neuro, Virology, Immunology, UCSF, iPSCs, Stem Cells, iPSC, Shinya Yamanaka, Gladstone

Id: N8RiYT2CDhA

Length: 82min 51sec (4971 seconds)

Published: Wed Mar 27 2019