Welcome everybody, this is Harvard Medical School's Ethics and Research and Biotechnology Monthly Consortium Series. I'm your host, Nsu Ken, I'm the Director of Research Ethics and a faculty member in the Center for Bioethics at Harvard Medical School. I'm also Professor of Bioethics at Case Western Reserve University School of Medicine. This monthly consortium explores issues at the intersection of ethics, technology, and bioscience, with an eye toward practical and ethically responsible approaches and policies. Just a quick reminder, next month on November 20th, we have Madeline Lancaster from Cambridge, UK, and she'll be joining us to talk about how human brain organoids can help advance COVID-19 research. So again, that's next month, November 20th. Now I'd like to turn our attention to today's session, which is with Lorenz Studer. Lorenz Studer is the Director of the Center for Stem Cell Biology and Memorial Sloan Kettering Cancer Center in New York. He's a pioneer in stem cell-based approaches to Parkinson's disease and other diseases of the central nervous system. In 2015, he received the MacArthur Genius Grand Award for much of the work that he'll be presenting today. So I'd like to at this point turn it over to Dr. Studer. We're going to present, for about an hour, go through a slide deck, I'll be interacting here and there with some questions and some comments, and then we'll have 30 minutes at the end for Q&A. So the instructions for Q&A are up here on the board. You simply type into the Q&A feature your questions, and we'll get to that as many as we can at the conclusion of the formal presentation. If there are any technical issues, you can use the chat function, send a message to the panelists and the staff members. So with that, I'd like to welcome Dr. Studer. Thank you so much for this great introduction, Enzo. I really look forward to talk to you about my work and we'll share the presentation to make sure. So I hope you can all see that now. Yes. Otherwise, let me know. So what I really would like to do is to tell you a little bit about the journey or actually nearly two decades on how we went from the idea of developing cells therapies for Parkinson's disease to actual implementation to do so. Obviously still at the early stages, but I think the journey might be helpful to give an idea of some of the challenges both on the scientific side, but also obviously challenges that come up, thinking about problems that maybe intersect with Essex and research regulation and so forth. And I look very much forward to the dialogue within this presentation and to all your subsequent questions you might have. So just to start off, I want to give you a little bit of a background about Parkinson's disease so we are all on the same page. So Parkinson's disease was first described, as you could imagine, by James Parkinson's actually many, many years back. He was basically walking through the streets of London and noticed that there were patients that have very unusual gait and actually astutely described some of the symptoms. Now the more scientific description of the disease came really from Jean-Martin Jarcault and he particularly noticed a very, very stereotypic features that these patients have with regard to movement problems. And for example here, if you can see my cursor, you see these different scribbles that he recorded, where in one case that's actually a shaking that you have when you have a problem in the brain that affects the so-called cerebellum has nothing to do with Parkinson's but below here you can see specifically the shaking or tremor in the Parkinson's patients. He already also described how these patients have this peculiar gait and position changes, how when they write, they write smaller and smaller, which is another feature of the disease. And these are still some of the main symptoms obviously that we use today to actually diagnose the disease and so primarily Parkinson's disease is considered the movement disorders and the movement disorder component of the disease is caused by the loss of a very specific cell type. And that cell type is called dopamine neurons or dopamine nerve source and they are a relatively rare cell type in the brain, so you have only about 300,000 of those on each side of your brain. You can say 300,000s a lot but actually if you think that in the brain you have about 100 billion of those neurons it's a very very small fraction and so it's maybe more a little bit of a you can think of it as a lego piece now that's missing in a bigger structure and once those cells die off once the lego piece is missing about 50 percent are needed to be missing you get the symptoms of Parkinson's disease. Now here it's important to mention that Parkinson's is not exclusively just affecting movement. It's also known that you get the so-called non-dopamine symptoms for example one of the earliest symptoms often is that patients before they even know they have those symptoms on the movement side they lose sense of smell or they often complain about constipation and other issues and that's often kind of one kind of reassuring thing if you have a good sense of smell not only do you not so much need to worry about COVID which is a whole other issue now they lose of smell but actually also in Parkinson's that's often happening early but that is obviously chronic and so if you're very good smell the chances that you develop Parkinson's in the next five years is actually relatively small. Now there is also important to understand that it's basically a better understanding of the genetics of the disease so in most cases we actually don't have a specific gene that's responsible for the disease but in rare populations we have right now identified about 20 different genes that can predispose patients to Parkinson's disease and if you then look at the cell biology side you kind of get some kind of an idea of what might go wrong in these cells for example one part in the cell that's affected is the mitochondria which is like the energy factory that's probably the case because these cells are not only kind of rare I told you it's only 300,000 out of 100 billion but it turns out they are giant so it turns out one cell one dopamine neuron if you add up all the processes is several yards of length so several meters of length and each cell makes about two to ten million connections in all the cell so they're kind of monsters in cells and therefore they need to really have a very high energy metabolism which maybe makes them vulnerable to disease sorry. In addition they also need to clear up all the proteins that generate in such a long cell which is again the cleaning system that might also go wrong so there are all kind of ideas about what could go wrong but the truth of the matter is so far there is no new therapy available for patients since the original idea of replacing just simply the dopamine that the cells produce so kind of this fact that we despite all the scientific knowledge we still have no satisfactory therapy brought kind of the provocative idea which really gets us to this themselves so the idea is if you don't really know how to fix it you don't know exactly how to stop the process why don't you just simply replace what's missing and again you can compare it to like if you use your your iphone and it breaks nearly no one ever tries to kind of bother exactly wide broke or that we just get a new one and so that's kind of the simplistic idea maybe we can just put new nerve cells in a couple of hundred thousand doing the job now before we got to the the stem cells they're obviously already currently a useful therapies and i mentioned one of them that was a revolution but six years ago that did a Nobel prize for that finding which is basically just simply giving the patient a dopamine that's produced by those cells so this is actually a highly effective approach at the beginning of the disease it feels like like like a cure for a couple of years but then what actually happens is as the cells continue to die off not only 50 percent more and more and more eventually that that drug you give which is actually the precursor of the dopamine still needs to be converted into dopamine in the brain you lose the cells becomes less and less effective and becomes a real problem so one approved treatment for that is that you can put a stimulator in the brain called dbs and for some patients that has quite dramatic improvements after the dbs so when you install this electric stimulator you switch it on for example the shaking that i showed in this movie before sometimes just simply stops within seconds so it's very dramatic however that approach also doesn't really work for many of the other symptoms very well and it has complications and for example patients often complain of certain side effects that they have more problems in speaking in a very precise manner so you can speak these are three it's called and there are other problems associated with that that makes it not an idea of therapy for all the people so that brings us then again closer to where the whole lecture is about which is the newest experimental therapy either gene therapy which again people try to basically make kind of a fake dopamine cell the dopamine cell but maybe you can force another cell with a bunch of genes to behave like a dopamine cell or finally you put actually dopamine neurons back and so that's the question so can you do that can you put in a brain now a brain is such a complicated structure can you integrate new nerve cells so this actually has been tried and has been tried already for a couple of decades which is kind of the past as contrast to what you want to do currently or in the future so it's basically the work using fetal cells i'm going to spend a bit more time on that in a few minutes but there are studies that show that you can just simply isolate from a human fetus from elective abortions typically six to 10 weeks of age you can dissect out the region of the midbrain shown here in this cartoon you dissociate the cell and inject them into the brain and if you inject them in the right place what actually happens is you can stave off the continuous loss of dopamine which is shown here by this imaging procedure that labels dopamine function or dopamine release you see on that one side the patient starts losing dopamine but then actually looks like in this case this can be staved off the continuous loss and actually you get even increased dopamine levels so that was kind of exciting and it's also exciting that at least a subset of the patients and we have to say it's a small subset that we know about seem to have a remarkable effect so these are patients that are now 15 years after they got that procedure and they are off this al dopa medication that's very very unusual because you have a progressive disease that gets worse and worse and in this case they seem to be not needing the medication at all but obviously fetal tissue despite again having started those studies in the late eighties has never really completely taken off due to some of the ethical and logistical issues again that's something going to go back to in a minute but just as a contrast what i'm going to focus on today obviously primarily is using stem cells and there we have to be very careful what i mean by stem cells because stem cells is a kind of a catch-all word for all kind of stem cells so what you think is particularly promising and at the verge of translation are so-called pluripotent stem cells that are either embryonic stem cells so these are cells that are harvested from IVF type embryos so when a couple that wants to have a pregnancy via IVF and they have their child they're happy they don't have additional children usually they have left or embryos and those are used for isolating embryonic stem cells and that's again a very very early stage of development shown here by the tip of the needle this very very small structure is called a blastocyst about five to six days of human development very different from fetal tissue very early embryonic stage now the other equally promising source are adult-derived IPS cells that's again another Nobel prize-winning technology but you can now take any pretty much any cell type of your body most it's taken blood or skin but actually you can for example even take urine you can isolate episodes that are from urine put these genes in convert them and you get stem cells that seem to be largely indistinguishable from the cells you can derive from those embryonic cells and then those cells because it's such an early stage of development we want to guide them down to make for example dopamine neurons and that's again an area that i'm going to go into obviously in a minute in much more detail. Lorenz I have a few questions so the the graphic on the left represents the past work using fetal cells and I know most of that work was done in Sweden many many years ago um now when you make your own dopamine cells from stem cell lines do you feel and did you have to do a lot of testing to make sure that they were equivalent to the fetal source tissue so does your work require an aerosol to do with fetal cells? That's a very good question our personal work actually does not but as a community in the field these experiments have been done side by side so for example you can do is you can inject those cells into an animal model of Parkinson's disease and see how many cells do you need to rescue the animals we have to potency per cell and so there will be comparison studies were done where you make the same presumably or a very similar cell from the stem cells you put them in and you do a comparability and that actually for us was very important those studies to guide our own dosing because it's not perfectly one-to-one it's very similar but it's not exactly the same but obviously here in the US it's actually relatively tricky now to get the fetal tissue for doing those studies because at least early we had a lot of NIH funding for developing this work and so forth so we're in a way fortunate again that we had our colleagues in Sweden particularly who did those comparisons and obviously had a lot of experience with fetal tissue even though my own experience uh I felt quite a bit of experience from myself and a fetal tissue back in Europe but in the US we never really engaged in that too much. Great, thank you. Let me just move to the next slide here. Oh you know I would like to just talk through some of these points here on this slide because you raised a really good point about the US situation as we know fetal tissue from elective abortions is necessary for at least you know some aspects of this work and we're talking about six to ten weeks plus conception here. Typically in the case of fetal tissue procurement the standard best practices both ethically and medically would be to gather the discard the tissue before discarding as medical waste and what you normally want to do is get permission from the woman who's getting the elective abortion prior to her or separate from her decision to have an abortion her decision to donate the materials for research purposes so really the third point is crucial the decision for the elective abortion has to be independent of the permission to use that tissue for medical research. You want to keep those two consents completely separate and to follow up once the decision has to be made to terminate a pregnancy then you would go in and ask for the tissue instead of discarding the tissue. There shouldn't be any changes to the abortion procedure there should be no financial gain or access to abortion that's linked to that decision to provide for research. Now the no changes to abortion procedure is a little bit tricky as we'll see later on today but just in summary we have three broad sets of challenges we have the political and the religious challenges obviously about right the debate about abortion this is really a hot topic right now with the confirmation hearings happening on the Supreme Court and other NIH funding policies that have just arrived for fetal tissue research so we're not going to get into the issues of when life starts and the moral status of the fetus but we do know obviously that the religious and political dimensions are very large here but two other equally important issues are scientific challenges as Lawrence will talk a little bit further we need several embryos or fetal tissue samples to cobble together to treat a single patient which means you have to coordinate the timing of these abortions or the collections at least relatively close together to get that sample for transplantation this is all in the case of using fetal tissue of course. So you know again there is a need for intact tissue you might have to have ultrasound guided abortion and you know there's a looming fact that there is an increase in drug induced abortions at home chemical abortions at home which again you know is outside the clinical setting and so that's an additional challenge scientifically to gather that material and then finally you have challenges to the patient in the trans-hero study that maybe Lawrence will touch upon many patients actually had to stand by they had to wait to get enough tissue in the sufficient amount for the transplantation so yet another challenge not just scientifically but also from the patient's perspective and with that I'm going to just turn it right back to Lawrence thank you. Great thanks so again what I focus on is just a little bit kind of from a stem cell perspective know what did we really learn from those studies and so that's clearly important from the studies that were done including so-called placebo control studies again an interesting topic we're going to discuss further is that this therapy doesn't work routinely very well now it's very challenging to get it to work with fetal tissue because as Inzu mentioned we need a lot of tissue we need to know exactly how to inject it and this was actually done the very early stage actually interesting to know that some of those controlled studies that were done placebo control studies had also needed to do with the political debate at the time that was when Clinton came to power and the idea was fetal tissue would now become available after Bush and Reagan before and would now cure many diseases and they very quickly rushed out money that would allow to do control placebo control clinical trials and maybe prematurely so and actually caused again some issues that set the field back to some extent but we still learn quite a lot from this whole experience and again what we particularly learned from when we look at the many patients that got these grafts is we know kind of which patients might respond better that is one important point and we have certain criteria for example they still have certain what's called L-dopa responsiveness and so forth and that they don't have certain side effects of the drug already it's called dyskinesia because that's something that has been seen in some of the patients that got fetal cells that actually got those side effects. The other important thing we learned is that the design of the trial is very important very different than what you would do for a drug because this is a living drug and it actually matures so it takes not only one year which we saw at the time but probably two to three years before they become fully functional and that seems to actually play out if you go back and look at the patient's progression. It also kind of made important points about immunosuppression because in some cases immunosuppression was used you notice it was not used but it's still not fully resolved within the brain what really needs to be done and that's something again we'll come back to a little bit and then the other thing we learned is that the grafting doesn't really affect other aspects of the disease which I refer to it as LB which means Louis brought the disease so Parkinson's disease makes also this this alpha-synuclein aggregates which again can be seen and actually a part of the disease and they can spread to other parts of the brain very late stages for them because cognitive problems need a little bit like in Alzheimer's disease even so they have different aggregates but unfortunately in some of those patients even the patient that did really well that didn't need any drug treatment some of them that part of the disease continued and so that again suggests that if you maybe can clinically or from the genetics predict that the patient is more prone to get this Louis body component of the disease but less the movement disease that might be not the ideal patient so again we learn quite a bit from those fetal studies on how to do that but we also learned it's not really terribly practically feasible we have today now something between a million patient in the US for at least 10 million patients worldwide and so that's not going to be ever a therapy that can be used broadly so we need enough to show of source and here just what I wanted to point to before I forget is that again another interesting part from the studies because they were done some of them in the 80s 90s we had really long-term data so we know now that such cells can survive literally for 24 years and still make this brown dopaminergic marker pigment after such such a long time and so that's again evidence that might be really a one-time treatment if you do it right so what can stem cells then do in this context so the idea is very similar you want to replace lost function but in a reproducible and scalable manner now not just having to cobble together enough tissue patients having to wait and set back until we have enough but we want to be ready and have it like a drug product ready to go we hope that the stem cells can actually hook up in the brain and we have good evidence for that so they will probably do more than dopamine and actually integrate into the circuit and maybe save off some of the progressive loss of circuit function we think they will provide long-term benefit with a one-time surgery and also interestingly obviously that's more a commercial issue now but they could be cost-effective because if you can make a lot of cells and we can already now make a lot of cells at the reasonable cost actual cost of the product is really not the cost of the goods it's the cost of the treatment itself but at least we are not really having this very expensive situation that already the cost of the goods is very very high just very very quickly and i'm not going to spend too much time of that but for me that was really kind of a whole personal journey also how to get to that stem cell source so again i was involved in some of those fetal trial studies and you can see how long that is because i have embarrassing haircuts and sweaters here but so so we did actually clinical trial also in switzerland again and got me a lot of experience how to go from an ID all the way to a clinical trial and i searched for many years now what would be the right cell source pre embryonic stem cells we tried to isolate stem cells from the brain and tell them how to proliferate and become dopamine cells which by the way i also met my wife at the same time and that's somewhat interesting because it's actually also going to be the search and performing now to study hopefully is this in the next coming months and finally again moving to new york because i got converted from neuro stem cells to embryonic stem cells we tried everything we tried to call nuclear transfer stem cells think of dolly the sheep but in the mouse we did partner genetic stem cells and then various version of embryonic stem cells ips also it worked remarkably well at the beginning of my career we had very nice papers mouse cells were working beautifully but the story was not so easy turns out because yes we published some similar work with human cells initially so these are just some markers that show us the cells are functional they seem to have dopamine markers but the big surprise was when we put the human cells into mouse brain they actually didn't survive very well in some cases they caused overgrowth so at this early stage there was kind of a lot of work that needed to be done and eventually we figured out how to do it better but it took us again at least by the decade to get there we came up with protocols that can now make these two reportant stem cells ips very precisely to neuro tissue it's just two precise molecules they all become neural cells then from there you can specify which neural cell type you make until you end up for example with the dopamine nerve cell so it became much more predictable not just trial and error but real basing it on developmental cues and understanding those cues this allows us today now to make actually most cells of the human body so you can actually think this what i'm talking to you about parkens disease you can easily plop it and copy it for other diseases but you need to replace cell types whether it's in the heart whether it's in the peripheral nervous system it's a very very similar situation so really the breakthrough paper for us was in 2011 so again about the decade ago already but where we could show that we can make those dopamine nerve cells we can inject them into parkens and small in the mouse in the rat or in a monkey in all cases the cells seem to survive very well and they restore some of those classic behavioral deficits but i'm sure it is just one of those rats and if i start the movie you will see that the rat is not really moving properly the left paw he basically moves it along the the table he cannot really properly what's called initiate movement after the treatment you see it starts initiating movement so it's a little bit more sophisticated and just say it doesn't move at all it's not paralyzed it's similar to a parkensan's patient that stands at the red light the light turns green what you can see is actually cannot properly initiate movement this step and then suddenly they make a bunch of steps together and so this is the equivalent in in the rat model that we can nicely recover we also showed that we really know how these cells work it's not just we put them in and then we pray it works but we actually know mechanistically how it works because we can put them in genetically engineered so that we can now take a light source shine them into the brain and it's called the technique called optogenetics and you can now literally switch on switch off just the cells you're graphed so the animal recovers i showed you the movie on the left but if you then switch off the cells the animal is again fully sick if you then switch off the light the animal works again so what that shows you it's not just the complicated way maybe affecting the host or regeneration it's actual function of the cell and they are properly hooking up and that could spend many many minutes or hours talking about that this is i'm very excited about in this case that we really have a good understanding of how it works but again understanding is one thing can we actually eventually translate it and that comes to the next question how you do that that's an academic lab and where can you find the resources to do that and what's the best model to actually move that forward and three of our fortunate at the time that the word is state initiatives such as in new york there was so-called nice them initiative that allowed like three or four projects to move from the bench to the bedside and so you see some of the steps know that we had from planning how do you take now this protocol we published into something that's highly standardized that we could submit than a protocol to the fda that they think this is a proper way to make those cells no zero manual product and so forth can we make them in the right numbers because we want to treat many patients in the future not just the goal the proof of concept is one patient and start all over from the beginning we wanted to have an off-the-shelf approach then the other way can you do that reproducibly what do you do if it's again think of a drug drug formulation can you make it with similar precision and so forth and then how do you actually design a clinical trial as you can see we were pretty optimistic with the timeline at the time because by now we should have already two or three years of clinical experience unfortunately that's not the case but as i talk to my colleagues we are not completely alone in that that things you should take a little bit longer and we're learning what really is truly needed so the first step really was the question what is the right cell to move forward and this was a decision we had to make quite early we had this funding we had to make a decision in hindsight i'm not sure but it's absolutely the best decision six years later but that's the decision we made we chose to take an embryonic stem cell if you remember we have embryonic IVF derived we have IPS derived cells and basically we used that because again there was manufacturing was already kind of known how to do that we partnered with a Y cell which is the company started with the organization started with Jamie Thompson who first isolated those cells and we could relatively easily make large numbers of those cells and do all the testing for example pathogens that is needed to make sure that the cell line should be safe but i was particularly excited because we need to make sure that the cells are genetically stable we don't want to have a risk of tumors and so forth that we had already data from the provider that they took the exact same cells literally the same vials and they grew them for another 50 passages and showing that they were genomically normal so they had seemingly a pretty good starting point and so we had made this decision but again here we can maybe go a bit slower and again so what is really the pros and cons now of doing that so on the one hand what for us was important or we had the grant we needed to go ready to go was important we knew these cells can differentiate and that's probably also good for the patient we don't want to have surprises in the differentiation potential but what it came as a drawback is these cells were never designed to be used clinically they were derived by Jamie Thompson many many years ago i think it's 1998 and actually he's personally told me he specifically had a certain time when he derived the cells but he didn't perfectly keep track so that they will never be used in human patients that was his idea now obviously that didn't work perfectly and they were also on mouse feeders and so forth but actually what was done including by its own effort then later on is that they were re kind of specified so all the vital pathogens you might be worried of all the genetic testing all of that was tested and they were re-qualified as potentially clinically suitable there are also interesting things we can discuss that in more detail in the discussion there are specific FDA rules that are actually quite tricky if not impossible to fulfill with embryonic stem cells one of them is called donor eligibility status or criteria which was a rule put into place in 2005 that basically wants to protect the patient from again pathogens so the ideas if you get certain tissues that are soon after injected in individual you really want to know that the donor was healthy had no HIV no HD no hepatitis and so forth a whole set of testing that needs to be done very close to the time the tissues donated so that works pretty well I think it's a very reasonable rule for that case however if you think how embryonic stem cells made embryonic stem cells made nearly all of those lines were made from IVF embryo that were left over so contemporous consent and testing is really not possible because they didn't really know at the time that many a state when they don't want to have additional children they donate those left over they didn't know that they would do that in the future and so again actually embryonic stem cells it's very difficult to achieve that because you don't really want to already derive your stem cell line when it's donated because there's priority first to get the couple to child that they so decide so that's clearly one one issue there but also for the scientists it's it's it's actually quite tricky so what currently the situation is that it was decided up for the cells derived before this rule this rules just don't really apply so they kind of are grandfathered in but not grandfathered in for the actual product so it looks like like for us we can move forward to nervous stage clinical trials seems to be fine but we have this uncertainty hanging over our head if you really want to have this treatment for thousands of people routinely it's not clear that the FDA will actually approve that and so that gives a lot of uncertainty that's still not completely resolved then again there is obviously the the ethical political debate Inso already mentioned that in the context of fetal tissue a little bit and people often get confused or patients get confused what the cells exactly are no is this again fetal tissue I showed you previously like a fetal stage but actually it's IVF no it's just left over embryos what are the differences and so forth we mentioned a little bit no the concerns particularly with the current government there's always a looming scare that actually they might even ban embryonic stem cell work outright at least for funding but there's also again some patients just simply might not want to have that for their own for their own ethical or religious reasons we also had this issue quite concretely know that actually certain companies so I'm going too much into this but particularly in Europe now they have issues with embryonic stem cells because in Germany in other countries it's much more obvious that embryonic stem cells seem to be more difficult to be used in that case they have different patenting laws because they consider it more like human life to be patented in this case with an embryonic stem cell that's a whole lot of debate but so in this case it's also just simply for a company to corporate image there are actually some companies we talked about in the US they really don't want to do that not necessarily because they personally have a big problem but they think that maybe the customers somewhere in the in a very religious state that buys at the same time their washing machine when they see that they do these embryonic stem cell work and then they're gonna no longer buy their washing machine so it's a complicated decision what's really the best product but maybe with IPS cells which are derived by reprogrammed from adult cells that's much preferable for some of them on the other hand there's also the scientific concerns that we have there is the risk associated with IPS3 programming so if you get the cells from an embryo they are the perfect environment they have been obviously going to the first days of development nothing trickier to make IPS as you put all these transcription factors to get kind of reshuffled the genome epigenome gets reshuffled there's a certain risk associated with that and the safety also it's not clear that the stability is exactly the same on the other hand this issue of the immune response this IPS cells you can literally make them from your own cells I mentioned your own blood your own urine cells you could have matched cells but then you can make the counter argument if it's your own cells and your Parkinson's is that really a good idea because those cells might get Parkinson's right over again so again there are many pros and cons and I don't think there's an absolute winner and there are IPS and ESL programs moving forward to date so I'm just going to go now back a little bit quicker again through some of the more technical things which is actually how we then go from actually how we develop a real product and so one part again that's really technical is kind of how do you make the protocol work and we saw it again Vienna the master took us 10 years to make human ear cells behave we had a nature pay but everything is great we can just do that now with slightly better reactions so they're cleaner but when we actually did that it didn't work anymore protocol so took us another three four years to kind of re-optimize that and again for the aficionados at least here's some of the points we had to do doing the bottom know that we had to switch certain media and so forth but eventually we figured out again that we can do that even at higher efficiency highly reproducible and so forth so another issue we had to do is we want to have an off-the-shelf product off-the-shelf means can in our nature pay but we always made the cells fresh injecting the animal we're happy it recovers but in this case actually we want to have a frozen product so can you take nerve cells freeze them down and saw them and they still function so first you want to just simply see now is that possible can we freeze them and what you can see this is a viability plots that they we can do that pretty good at the beginning which is here to zero hour time where we see pretty good vial viability after a frozen product and even if you then leave that product for many many hours dies still stable now why is that important that's important again from a regulatory perspective you need to tell regulatory what's the shelf life time once you make once you prepare your sample how quickly does the surgeon needs to inject it so it's very important that you know that it's also very important that you know the shelf lifetime of the frozen product so what you do is you make some cells that are made a little bit before the final clinical product like the cannery in the the coal mine you have them going ahead and make sure that they still test well after one year two years three years by now we are something like up to four to five years where we have data showing the shelf lifetime of the frozen cells is also still very very good then obviously it's it's one thing to say they look good via viability assay but can they still function in an animal model so we then take those cells inject them in this case into a Parkinsonian rat and show that they make this very nice brown fibers that renaissance the brain and what you can see on the right side you see this plot which is a so-called rotation assay that you can use Parkinson one side of the animal's brain the animal is asymmetric it rotates and it becomes symmetric if you then put cells back where the cells were lost it goes back to zero and indeed the frozen cells can do that beautifully so i gave us again many of the pieces now to say okay we have all the pieces of the puzzle together so can we now do that truly clinical can we make the clinical batches of the shelf product to use and so we actually did that and we did that already in 2016 so what that means we made about 10 billion cells in this very fancy facility it's called a gmp facility very basically had a number of rooms just dedicated for our product and they made the equivalent what we think is about thousand human doses now we know it's never going to use thousand doses from that product but you actually use most of the cells not for the patients but for doing all the safety testing all over again miss the same product that you want to use in the patient so again the cells are cryopreserved again i have here three years by now even five years we have to are close to five years with the precursor of the product and again we have certain criteria you need to specify to say okay do i have the right cells in the in the tube that's very very important again the way you do that is you have to kind of pre-specify how your cells need to look how pure how pure do they need to be for example here i have an example of one marker it's called foxy2 which is a marker quite specifically expressed in the midbrain cells and midbrain dopamine cells otherwise usually expressing the liver in all the regions but in the brain it's quite specific to just those cells and you can see we have nearly every single cell being positive for that marker conversely for safety you need to make sure that none of the stem cells are left you might know that if you inject undifferentiated stem cells into your brain you get a tumor called a teratoma so obviously that's something we absolutely want to avoid you want to be sure we have no single cell left promise is not so easy to prove that because it depends on the sensitivity of your assay but so we developed three different assays here just shown one which is a gene expression assay where it's very small maybe you cannot read it but you can see here at the end it's actually the expression in a fibroblast and this is a negative curve so the higher you are the less expression you have so fibroblasts which are skin cells they should have none of those pretty potent cells you can see that our product is basically as low as for example fibroblasts so we cannot detect any any cells there in that are left over and so the way you can think about it more again all of you are familiar with the pharmacy now you get a drug label with information and so you kind of very similarly you want to have information so how many of your foxy two cells are there how many of maybe the wrong cells paxis cells could be there what could be then try to understand know kind of how to formulate that we cannot do it as precise as a pharmaceutical drug it's more a work in progress but that's kind of the goal know that you have the same precision of formulating what you need in your in your vial to actually hopefully help the patient so now we have the cells we have all this pretty clinical data early on so what do we need now all over again and how do you interact with the regulatory agencies so there are usually multiple steps to interact one is called this pre-pri-ind meeting which is now renamed as the interact meeting where you can ask very general questions for example for us it was really the question is it okay to use this cell line or what needs to be done to use this cell line what kind of testing and so forth and so we had that already in 2014 and then 2016 another meeting which really then focused more on the way we make the cells what kind of media what kind of factors are the cells exposed what kind of animal models are we going to propose to test the cells again and so forth and that went pretty well and then the feedback we get is that they were particularly obviously a little bit more information we knew on the final what's called definitive testing so we have now a product now we have billions of cells so let's take those cells and do all the safety and efficacy again so we know product that's going into the patient's brain was fully fully tested they wanted to have also some more device testing meaning the actual device we put into the patient is obviously not a device you can test in a mouse or in a rat and so that required actually some limited monkey studies again again these are some of the studies you have to do so called GLP studies so you can not just do them routinely in your lab you need to do this a specialized contract research organization a zero the classic ones are too much in a city by distribution toxicology many of them obviously kind of make sense even though some of them are really more designed for a drug for example again you could argue is it really as essential to look for liver toxicology now if you put your cells into the brain and if they don't get away and so forth but again you need to go through all the different rigmarole that you would go also for any other product and then we also had to do a whole complete efficacy study and if you can see the numbers obviously this is a very very extensive effort that you have to do very expensive studies that you don't really hopefully have to do too many times again to just give you a little bit of a flavor again we don't need to go into details but what you could show is for example again that the cells really don't really move around much so where we inject them that's where they stay and you can do that with very sensitive assays where you look for human genome copies and you can see that in most regions you can absolutely detect nothing that's just noise and that the very early stage maybe some cells travel through the ventricular area or not but afterward you basically find nothing in different brain regions or so forth and so therefore bi-distribution is really restricted to where you inject the cells equally important is a tumour analysis study and there's again a lot of interesting debates now how you best do that and what's the goal of that study kind of classically it was the idea of the remaining stem cells even so as I just told you we think we are noticing a stem cell left you kind of have to prove that functionally and one way you can prove it is by on one hand injecting obviously completely tumourogenic cells and show that they form a tumour which they did in our study or that you put your cell product that obviously doesn't make tumours but what they also wanted us to do is to actually spike in some of the stem cells so either at this case 0.1 percent 0.01 percent to show that even if you had some that they still seem to not really form a tumour and again there's a lot of controversy but this is still really a good assay because with modern techniques I think we get much more sensitive than this in vivo assay ever can do and furthermore there's the issue note that you can kind of change the condition you can just put inject human stem cells but the way they were maintained maybe makes them survive poorly for example there were studies from a company called Cheron first company to make human embryonic stem cell based transplantation spinal cord they claimed that they could inject up to 5 percent pluripotent stem cells never getting a tumour so if we do that we get massive theratomas because we treat the stem cells differently so it's then really not a reliable assay that can be used for everyone so that's how that looks if you have a tumour it looks like here on the left if you're a nice graft it looks like here on the right if you look for efficacy we found that we can replace this lost dopamine in this unilateral model you see this is the graft that doesn't they complete the restore dopaminergic innervation in the animal they complete the restore this behavioural asymmetry both in male and in female animals and we get this very beautiful looking very mature dopamine cells that look exactly like they would look in your midbrain when you are a normal health individual and we can get them actually in pretty large numbers so in a rat these are very large numbers if you remember the numbers in humans you have about three to four hundred thousand the rat is much much smaller than just three or four times so so we could get really load up the rat with a lot of dopamine neurons and again the viability helps us then to understand what's the potential dose in humans that leads us now to the real discussion of the clinical trials so how do we go about that how do you design the clinical trial for something that's really kind of radically new and not a standard drug something stays there forever so you i'm sure you know about the different phases of trial phase one phase two phase three and so in this case obviously I have to start with the phase one it's the first in human study but you can call it phase two a if you want because we already have some pre-specified parameters that we look for some signs of efficacy there's no way you can really get statistically meaningful data with such a small court but you can see obviously signs maybe in the treatment group versus basically just a control court so what we plan to do here is to use basically 10 patients and we have certain inclusion criteria and exclusion criteria some of them go back to what I told you about fetal tissue where we learned where this therapy might be more suitable we had to think about those levels and we have now a lot of experience where we know how well these cells survive coming back to in this point about comparing the fetal tissue we know how many fetal cells survived in the patients that did well and so that's it looks like about 100 000 cells are needed to get a reasonable at least a measurable effect and so that's for us actually the guidance for our low dose now we also want to have a higher dose which would be more to a complete replacement if you assume there's a one-to-one function the other issue is can you actually do that in a bilateral fashion because usually the patients have problems on either disease but if you do surgery into the brain then obviously you might cause have a certain risk for each injection that you do we're going to make basically three tracks into the brain on each side of the brain to target the what's called the putamen and what you can see on the right side is actually an interoperative MRI system where you can not only inject very precisely into the brain but you can do that under image guidance so you can see exactly where the cells are in this case it's a dragnet of the cells but it's the same region and you can more importantly show that you don't cause any bleeding so you can be pretty confident there's no major bleeding and therefore you can move through the other side and this is what again very important discussions we have with regulatory agencies because traditionally are very hesitant to allow you to do a bilateral procedure for a new for a new study because for obvious reasons if something goes wrong but in this case that was at least seems to be that they allow us to move forward with a bilateral procedure another important point is now how can you in such an early study already have some evidence now to have the right patients and how do you select those patients if you don't have the approval for the study you cannot really recruit patients for the study on the other hand you really would like to have a good understanding of the progression of the disease because in some cases Parkinson's disease can progress quite quickly some cases it's much more slowly and that might impact how you know how to select the patients how to compare them so something we did by me i mean Claire Henschcliffe was our neurologist in the study developed the study that's independent patients consent to an observational study without any promises to be part of any new experimental therapy but they basically have an observation study where they get a lot of the tests that later on we would like to use in the patients and therefore we get a very good baseline and the idea was that you can recruit from those patients in the future you have obviously to get consent for the action procedure in our case the procedure to inject those and really extensive right dopamine neurons but it's also nice because then the other patients that are kind of matched you can try to have matched cohorts and see if they get another or if they get no other intervention you have kind of a no intervention group with enough follow-up. Lorenz when people enroll in this trial do they not get other standard treatments for intervention? They get busy the best available clinical care again i didn't go much into into that in the issue with regard to when when is this therapy most efficacious and again there's even some interesting discussion there but usually it's when the standard care doesn't work very well anymore so they take the levodopa for the first five years it works pretty well but then it doesn't work very well it starts to wear off they start getting symptoms of different parts of the face and they kind of need something else they could go to DBS they could go to something else and so so that's kind of the the fact that we try to keep the patients in the best possible group now obviously in our study for now at least if they then go to DBS then they could no longer serve us as a competitor they can serve as a competitor but they can no longer enroll in our study in the future that's a whole lot of discussion it's actually not a contraindication you could have potentially both treatments because they don't really treat exactly the same thing but initially it just makes it too complicated and therefore that would be a different approach but they get basically the best available care at that stage and it's actually a good point because one thing that happened in such designs is that sometimes when then the patients need something else so they could need our team they could need something else then if our therapy is not ready and we go a little bit too late they go get something else then the patient you still have they didn't get to that stage and maybe they actually are selected for the patient to have a slower course of the disease so you might actually potentially skew a little bit overall population so that interesting discussions know how good that model really works but that's what they decided to do and it also will allow us to move more quickly to actually have patients ready assuming that some of those patients seem interested in this approach they would have already some of the imaging some of the testing done so we don't have to start from the beginning now if you think about clinical trial design there are also some interesting points that come up there with regard to conflict of interest in regulations and so one issue that we came up with is now the issue who should really be the PI on some of those trials and i come back i should have had my conflict of interest slide one earlier but i mean we started a company called Blue Rock Surabutics and got bought by Bayer and so forth and my wife is also co-founder of this effort as a neurosurgeon and has developed all the animal data obviously very qualified knows exactly how to do it and has all the expertise but she cannot really be a PI on this project because she would have a conflict of interest but then you have to train someone else who basically doesn't have the same skills in doing it they have to be completely coming from new and they don't understand the cells very well and so there's interesting conflicts that happen and the question is can it then maybe not be the PI but still do some surgery and so these are very interesting discussions that we had with some of the oversight boards another point is that the regulations know if you design such trials or even the cell product itself are actually not consistent across different regulatory agencies so the whole place know you in the future in a couple of years know you're going to have regular BLA FD approval you have a product but the question is is it going to be approvable in all the other agencies if they have different rules about that the cells can have seen certain creations or not whether there is a placebo controlled trial that needs to be done and so forth and these are again issues which are interesting to discuss and we can discuss further but I don't have a good answer but if definitely came across that talking to different regulatory agencies you get actually quite different responses. Lawrence real quickly do you think that will lead to patients traveling to other locales where it is approved? Sure I mean that is one thing and we get obviously there another issue that there's the whole issue of stem cell tourism now there are other cell stem cell products that are basically down in places that are out of certain regulation regulatory landscapes where people go to get certain treatments that are different than this but even for this kind of treatment it's possible that some people actually I get contact and other people all over the world that would want to have our treatment if it's not ready another place I know some companies that basically then transfer their trial to different countries because they think they have a more beneficial regulatory landscape and so it's definitely an issue that you can kind of try to play the game a little bit to your benefit. So again one point that also came up in Parkinson's here we definitely can discuss in much more detail if there's interest it's the issue of surgical placebo so everyone knows of a placebo in drug trial but what about surgery where you inject cells into the brain how do you do a placebo and so that actually was done in those some of those trials the way it was done is that the patients actually went they got randomized they got busy a burr hole in the brain they went into anesthesia and if I understand correctly I didn't do the trials but they even got immunosuppression which I think again you can argue is that ethically an acceptable approach the pros is saying if you don't do that you never know what it works and I have that example of people did before even fetal tissue grafts they did something called adrenal graft you take your adrenal gland which has hormone producing cells that when injected in the brain they make dopamine like cells it actually never really worked the cells never really survived but because it was never really properly controlled surgeons started doing it patient out of side effects and only got stopped after many many years because there was no clear clear control and again in some countries it might be required for regulatory approval and it's true that in Parkinson's disease depending on the study you look some studies had a huge placebo effect in placebo control there was a study of his porcine grafts done by diacrine a company actually in Boston that had about 20 improvement in the placebo and around 20 improvement in the porcine grafts and so obviously it was not significant and so so you can say it's really important it also was important maybe to detect the side effect which are this graft induced dyskinesia which were never really reported in the open-labeled studies so maybe it needed that control and you really know that it's more than just what you see in a normal Parkinson's patient I mentioned already some of the cons clearly we can discuss more now is it ethical if the patient has no chance of benefit but the significant I think it's in my opinion more than a minimal risk in this case is that acceptable to do then again it also prevents them open from participating in trials that that might actually gift them a new therapeutic window maybe gene therapy trials dbs and so forth and the other argument that's made of my Roger Parker who runs the Tron Zero trial now if you really need that placebo trial maybe it's not even worth it because you really want to see a massive effect you want to see that they don't need levodopa 10 years later and that's not a good endpoint for the clinical trial but there's no doubt no that it worked in those specific individuals and also if it's used prematurely it can actually set the field back let's just put here this one I dug out the New York Times front page it was actually at the time when the placebo control trial placebo control trials came out Gina Collada wrote this piece on the front page of New York Times saying that really it was was a real setback and there were even all the quotes that are much much harsher than that from from a cure to disaster or something like that and what really happened is now that these trials were poorly designed yet weird endpoints and so forth but because they were placebo controlled they really set back the field for many many years because it was not proven it doesn't work but so again so there are some of the pros and cons of thinking about that I think they might have a place but they would have to be done in a reasonable way and they would have to be done with with truly minimal risk and it would have to be at the stage when we really already have very good evidence now that this works and with the minimal number of patients needed but again that's something we can discuss further and there are alternative approaches as well now just quickly now the way we try to approach that for all these various issues we started a consortium a global consortium that's not only my group in the US there are other groups in the US that are part of it Europe Japan and they come regularly to get at least once a year but we decide some of those points regulatory landscape we for example put out the PSN cell stem cell on clinical trial design where it put out how maybe to make a better clinical trial design and really try to be even though we are you could call us competitors many of them actually have now started their own companies we still try to have the academic spirit of also be collaborates because we think we are all in the same boat to make that really hopefully eventually a new treatment that really can change the situation in Parkinson's disease and so and so just maybe a few comments on that there is the issue that actually kind of things have started now there are at least two groups that are part of our consortium now one is Chuntakashi has been part of that for a long time they actually have started one patient to be grafted now with IPS derived dopamine neurons and so they want to have seven trials seven patients in this initial group its government and company fund is an interesting tidbit there now they actually started company too but then Shinem and Akano this got worried and they tried to actually have to try a government funded so there's less pressure of commercial interest for this because it's again obviously the the big thing in Japan that is early key IPS trials go well and have no conflict of interest to the extent possible but there was this very interesting study actually being on train of medicine just this year from a patient an end of one that also got its own IPS derived dopamine neurons and in this case actually it was patient funded it was a wealthy patient who had certain symptoms seemed to be not particularly severe but he basically funded research and actually then funded his own treatment in this case he got the exception from the FDA that this is not like a regular trial it can be used on compassionate use and it moved forward and again that's again something we maybe can discuss further what are some of the issues associated with that they also had colleagues of mine know that really did that also quite early on they had basically crowdfunding they had patients that are not completely know what they were really promised by funding to get their own treatment from that group but at least it gets very close to the area where you really think carefully how that's best done and again there are all these different models that I mentioned here a little bit how this gets funded in some cases there is a what's called the ISCO trial that's not really dopamine neuron from yes or IPS as they come from a so-called partner genetic cell they actually put up very early progenitors not specified don't have time to go into details but this is like a very shaky company and they really try to raise the the profile by a lot of publicity and try to push very hard and have patients travel there so there's all kind of models that really companies that try to make the clinical trial to even survive to then big players like what we try to do with Bayer or in Sweden with Novo Nordisk that are part of it do then government paid like Syrah to really move forward with that not interesting feature that really comes up in those trial designs is that actually you have kind of a policy that you need to say how you're going to communicate about that now you don't want to if undue hope you don't want to have kind of a messy communication but again talking to Roger Parker which I know very well the Transurotry was a huge problem and also in other trials and in the age of social media that just doesn't work anymore for the patient just say hey I had this nice treatment and I feel so much better and send it to I don't know how many people and even so you discourage them it's extremely difficult to control to have proper and appropriate communication what we really try to do we work with patient groups you have patient advocates that are very well trained about the pros and cons of the treatment they go out to the community tell the patients what they do expect but again it's something very difficult actually to control just again so in our effort and kind of where are we now in the overall timeline about 10 years again to get to the nature paper and now pretty much another 10 years to basically starting our clinical trial and so it's a very very long road and again here also my disclosures so in 2016 we start the blue rock therapeutics because again the NYSTEM started to run out the state sponsor and we knew we needed significant funding to make that the real clinical product and so the question is kind of why did it take longer than expected so some of the things are still getting feedback from regulatory agencies and I think it's a tricky thing because it's really kind of a different paradigm in this case it's because we try to have an off-the-shelf product not just the one-off thing we want to have something that really can move forward and it's a kind of a permanent implantation of a nerve cell product so how is that going to be regulated we know very well know our cell product but can you be sure that there's really every single cell exactly the nerve cell you want to have in vivo we think we can at least characterize like 98 or 99% of those neurons but there might be few cells that are not they're probably perfectly healthy normal glial cells and so forth but there's a lot of thought that goes into how do you specify that that's really safe it's really a lot of additional work to really convince everyone that this is safe and then also the patient group what's the best risk benefit is again something maybe we should discuss further in the discussion and again typically death is very conservative if they want you to go to the most severe patients for a person human study but those patients have also the least chance to benefit from it and they might have other features in late stage that makes them much more prone to have side effects from the treatment as well surgical and so forth so it's a very tricky thing and again something we are going through very quickly and we are indeed literally at the verge of actually getting hopefully the final word so that we hope we can start either by December or January of this year to actually start with our first patients so it's a very timely presentation because we think we finally had the stage to actually implement all of that now just maybe two three minutes about the future because again one thing is to make that early product it's already off the shelf but if you actually want to make a commercial grade product that can be used for very large number of patients you need to again go several logs up in the production capacity and you need to have something which is called in vitro potency you cannot always go back to a mouse and do a nine-month study and see that it works you need to be able to predict from the cells themselves are they potent or not and that's actually a difficult job then the other thing is that we think we still give the patients immunosuppression at this stage for at least one year and I told you there's a bit of a controversy about to what extent that's needed but we had several panel of immunologists, esthesists, clinicians and so forth and the consensus was to give the the initial graph to get the most information and the relatively limited risk for short-term immunosuppression so the best way to go for 12 months is immunosuppression but that has certain certain risks for the patient and the future for the complete off-the-shelf product could be a cell that's no longer immunogenic at all they can be engineered such and we've already done that at least scientifically and so that leads us again to the point so what would you do beyond phase one and so one interesting regulatory issue there is that for these medicines that has been kind of a situation where you can get what's called armad designation which is the regenerative medicine advanced therapy designation early on after a phase one study so phase one study has some evidence not exactly defined what it means the idea of the breakthrough is actually defining what the breakthrough exactly means you can get this armad designation allows you more quickly to go a phase two study phase two two b study in this case which may be 60 70 80 patients and that study could be enough to get your biological license application approval for actual broader commercial use so you would not have to go to full-blown phase three study before you could sell it as a product that's its armad designation that's exciting it might make things go fast but obviously it has also risks in certain ways which again we can discuss further but it also brings the point that you have then to be ready for such that and you have to be ready for a commercial grade type product and again we get then to the question for this kind of studies what control groups are needed what do you compare it against some people get dbs a study good control group how do you perform a complex multi-center study with research patients what's the number of patients can you implement new designs instead of placebo so something it's called adaptive trial design which has been mostly used in cancer therapies for testing multiple drugs multiple doses very quickly within one trial you basically pre-specify a scheme where you don't just conduct the trial but during the conducting you have pre-specified points where you do through you and then you are allowed to adapt it if you have pre-specified the possible adaptation so it makes it statistically much more complex but has been very successful in certain areas to really get the therapy much more quickly because if you think here if you need to wait i had the data there one year is not enough you might need two to three years before you know it works you cannot do three four trials one after the other before you get there so we need to be creative in the trial design and again i'm not going to spend much time about that but again our vision again that's my personal vision but also the vision of of blue rock is that we actually would like to develop universal cell technology as a true of the shelf as a true of the shelf product again this is just a final future-looking slide the point that i'm trying to make here is my lab hasn't really stopped working on the basic side on dopamine neurons the protocol the gmp protocol was established set in stone made an SOP in 2015 but five years later we know actually more we probably can make a better product so why do we need to give the patient a worse product than the better product and so how how can you bring that back in or do you need to go all the way back and then do all the trials again so that's the idea can you do basically comparability studies that are acceptable if they meet all the release criteria we defined is it okay to go with those lines and again i'm happy to discuss some of those points later later as well so just as a summary i think what i tried to tell you is kind of the story how we got there to show that cell transportation could present the novel therapeutic option for PD that it can now definitely technically make those cells at high efficiency we can rescue various animal models we can make them off the shelf we have clinical trial design and again the trial now is literally imminent and we have many ideas for the future there and we think again that what we've learned here we have access to many other cell types i'm happy to chat about that another time now we have many other diseases that we think could be addressed and each of them with its own benefits and challenges and just last here i have some of the key people from the lab i'm not going to go through it but just mentioning here the consortia the nice and consortium that was really critical here and obviously now working with blow rock to really getting that to the clinic and here in highlight some of the postdocs and students that maybe contributed the most to our dopamine project i'm going to stop here and hope again we can have an interesting discussion thank you so much laurence while we're getting the questions sorted out for the discussion i just have two quick questions for you one is your approach does not address the non dopamine symptoms Parkinson's disease do you think that's a big limitation to your approach i think so i mean i had actually that listed here i rushed through it a little bit so there's the non dopamine symptoms there are various non dopamine symptoms and the problem in a way is that it's a cell-based approach you it's kind of the legal piece now you can make multiple legals for example we have very good techniques to make enteric nervous system so these patients can have very severe constipation that can dramatically basically reduce the quality of life for a completely different application we develop enteric nervous system transplantation paradigms and you could imagine once that's ready in those severe diseases it's very safe you could add that on top and so there are a few cases where you could imagine doing that and but for example the louis body disease no i don't think that can be easily done in the cortex but even there there are cell-based approaches interesting too now you can combine cells with genes you can change inflammation within the brain by introducing for microglia cells so that interesting ideas there very in a piece by piece manner you can try to treat that but on the other hand i mean i'm so excited we're using stem cells a lot now you understand what the disease is all about my iphone analogy we're still interested why the iphone breaks no and so so we actually use them so it's very intensive for that and so ideally what you would have is you would find something that really mechanistically slows down the disease at the stage where you can replace the cells that are already lost and that would be probably the ideal situation yeah real quickly what why don't the transferred cells also become lost through the disease process i mean originally the patient lost their dopamine neurons and so why wouldn't the replacement also be lost yeah it's an interesting point and it's indeed the case that they largely do not get lost i show you the 24-year-old graph it's it's 90 true so it turns out that you get some in some case actually some signs of disease in the cells after 10 to 15 years you can actually get some of those Lewy bodies in the graph which is again very interesting mechanistically because it suggests that this disease can spread it's very unlikely that those cell lines have Parkinson's disease so the disease probably spreads and leads us to the prior and hypothesis of Parkinson's disease but the bigger picture to what you bring about this the interesting point that when you make embryonic stem cells or your reprogram IPS cells those cells go all the way back to this five to six day old embryonic stage and we graft the cells they're probably the six to eight week old feet like dopamine neuron and as you know there's no Parkinson's patient that i know of that gets the disease and they are five years old or ten years old so for the five ten years old they seem to go chronologically at that stage and there's really cool data you can actually look at that you can you get a pigment in dopamine neurons when they get old so when you're very young it's like the trees in the rings in a tree you get more and more pigment to all that they get and you've actually find if a patient dies car accident whatever had a fetal graft after one year has no pigment if the patient dies five years later has a little bit of pigment dies 20 has more pigment so they seem to age somewhat chronologically according to the age of the cell and not the age of the person actually receives the graft that's very interesting so i want to turn it over to our moderators and they can lead us through some of the questions that have come in and we're happy to have Lorenz address as many of those as possible so why don't you hit us with the first few questions great thank you so much for the presentation the work that you're doing sounds super intriguing and very promising but as you have articulated it raises lots of practical and ethical issues and our audience have many questions they're eager to hear your thoughts so one of the first questions that we have is which potential side effects are you most concerned about as we move into human trials yeah that's a good point i mean the most obvious one that came again from our experience of fetal studies is really the side effect of getting graft induced dyskinesia so what happened there in the fetal graft is that patients got kind of certain uncontrolled movements that is similar to what can happen if patients take too much of this levodopa and so that's something which we think we hope will not happen in our case so questions obviously why did it happen in the fetal graft and the answer seems to be that it was likely not just the dopamine cells but some other cell types within the grafted cells which are called serotonin neurons that can take up the same drug the levodopa but they don't release it properly reason in an unsynchronized manner and so it was kind of recreated in some of those animal fetal tissues nearly as many serotonin than dopamine in our case we have nearly zero so if that's the reason then we should be fine but is it really the reason the trial is going to tell us so clearly i think that's something we need to look about is graft induced dyskinesia and then otherwise it's difficult to say i don't really have another very obvious concern obviously we want to make sure that it's safe with any first in human study you know this this remaining cells not out there are they exactly the same as the fetal cells i personally think there's no additional risk from what i see but you can always make the argument now with cell snapping growing in the dish they're not plucked out of her fetus what about 10 15 20 years later and this that maybe it's not a problem because advanced partner's patients that that we want to treat in average sadly the life expectancy of those patients about 11 years so maybe the super late problems are not going to be as much of an issue but i think nobody can guarantee or know that there's not a single genomic change in your cell that maybe many years later could cause the problem now our cells are 99 percent neurons which is pretty good but there's maybe a few other cells that are not neurons and maybe those would proliferate or would do something again i think it's very unlikely but it's still something we have to worry about definitely and we have another question that's actually pretty similar in terms of clinical trials so this actually comes from Christine Mitchell she's wondering i see you do not do large animal studies is this because of ethical concerns related to research on primates and if so can you say what if anything would be lost by not testing injection on these cells by a primate brain and conversely if what would be gained by pre-clinical testing on primates so i'm wondering more so about the safety as well as clinical effectiveness no i think this is a very valid point and that's something we actually we did do some primate studies and we did merely on the initial publication but focusing mostly on kind of the scaling because the primate brain is obviously much bigger than the mice of the rat so can it translate can they still reach the whole structure so for that it was very helpful for us to really see the anatomical integration of the cells and the other area where we did use some primates primates is in the context of the device so we actually did test our final product in six six monkeys together with the CRO and we inject them with the exact same MRI guided injection device we had actually the surgeon going to the CRO doing the doing the injection exactly there to make sure that it works mostly the cells survive so i think for that primates are still indispensable because they're the closest to what we can do to compare to the human brain and even the frames that we use the surgical frames can be actually generated can can be modeled exactly the same way so that's very good the reason why we didn't really do kind of an efficacy or a large-scale or long-term study in the primates which our colleagues in japan did junta gashi focused on that approach so different countries different approaches is on the one hand it was not required by the regulatory agencies and the u.s is actually somewhere in between in europe they they nearly abhor i mean they do very little of primate studies at all so they actually they're pretty much zero in in their effort to move forward within our consortium in the u.s we did something in between we did some for those criteria i mentioned in japan they did most of their kind of final studies in the primates the problem we don't like to do much has not so much to do with ethical reasons even so i think one has to be very mindful of that if you if you watch monkeys and the behavior know it it's it's ealy know how close they can be without human behavior and i think we have a special responsibility but there is also the issue that exactly because of that you cannot do the numbers that you would want to do so if you talk about safety you can do maybe five six monkeys and you get approval and do that but in the rat and mouse we did four hundred of them so if something happens that's really rare something that happens kind of in a freakish way you can capture it easier in some of those models and similar to behavior the park and the model in the monkey it's a bit more shaky you can make this what's called mpdp monkeys but it goes over a long time you inject this drugs and sometimes the monkey spontaneously recovers so it gives you more noise in the basal readout and therefore with that noise you need even larger numbers to show good efficacy and so these are some of the reasons why we didn't really push towards an efficacy study in the monkey but only used them for like anatomical integration injection device and something like that we have a question about immunosuppression and using immunosuppression how intense would the regime be and how risky might that be for a patient yeah so we have a regimen that he kind of tuned down a little bit so it's primarily takrolimus that's the the main reaction against these responses and then we have a short a short treatment with steroids but if you high dose and then very low dose steroid maintenance up to a year initially we had some other drugs as well and so we basically reduce those because they seem to not make a big difference in the models we checked but even that treatment can have clearly a risk and there was again a big discussion about that it's it's only happening for one year so there's some of the common risk now if you have a kidney graft or liver graft often these are long-term effects where you get toxicity in your kidney or in other cases that i think is a is a relatively low risk because again it's short-term treatment but still some patients will get complications and there are statistics out that say first some of these immunosuppressive treatments is about the one year one percent sorry a one percent risk of some malignancy that you have if you do one year of treatment with such immunosuppressive treatment so if you get 10 years of treatment maybe you have a chance that 10 percent chance of getting some leukemia or something like that down the road and so one definitely needs to be mindful of that it also requests a lot from the patient because you need to constantly check the drug level so that it's safe and so forth so it makes it much more difficult for the patient's life some of those patients are not terribly mobile and so that's one of the reasons why we hope that eventually we have this universal technology where you don't even need to use that on the other hand there's again the interesting discussion there's Kurt Fried was again one of those p.i.s who did a fetal grafting trial he did add he added no immunosuppression to any of the fetal grafts he still had many years later surviving dopamine neurons now if you look at the numbers it seems to be at three times lower so it's again a little bit tricky it's not like that so i seem to get rejected but they probably survive worse if you don't give this one year of immunosuppression that's why we chose it but again with the risk that have to be balanced that i just mentioned it so that's also another question kind of looking into the ethical considerations regarding fetal tissue and embryonic stem cells aside from religion and politics so secular bioethics has not produced an ethical consensus regarding nascent human life the ethical debate centers around the tension between ciliterium and outcome-based ethical frameworks and a framework that favors can't pedagogical imperative that human life should not be used as a means to an end so how do you and your colleagues balance these views? Laura maybe i can take this one to get away yeah sure so so these are valid concerns about secular bioethics and whether secular bioethics can really wrestle with deep questions about the meaning of early human life and the use of human life for scientific progress i think in the case that Dr. Studer just presented to us a lot of those issues are sort of not quite triggered or engaged because he's talking about cells that are prepared from adult cells that are transformed into stem cells and then differentiated down into dopamine neurons so the line of work he's involved in and the cell product that he's testing and developing it doesn't come from a fetal source and it doesn't come from an embryonic source although the studies are informed of course by that kind of work but this this this type of work i think could easily be supported by people who come from many different spectrums of beliefs about early human life and the morality of MRI, some sort of research on abortion so that's point number one but i also think that it's also important for everybody to consider in secular bioethics that there is whether you are as a person referred to a utilitarian or a content that there is a deep commitment to wanting to reduce human suffering and to do the best you can for patience and great need no matter what your religious or philosophical orientation is so in light of those two comments i think that you know we can we can safely say that there is a place for those concerns generally but in the kind of research that Dr. Suter is doing you know i think that we need to really focus on the good that it can do for people in the future i don't know if Lawrence you want to add anything more to this theological or philosophical issue that's come up i mean obviously as you mentioned it has been an issue for a long time and i think again the fact that he can derive IPS cells has alleviated some of those concerns and again one could have a long discussion now with regard to embryonic systems of fetal cells what's what's the pros and cons and case and how we had some of those in the slides now with regard to but it's a good thing to have tissues used for medical use versus again versus versus basically having to go to medical waste and so forth and for me it's an interesting thing because i'm actually a race Catholic my my mother was teaching religion at school so we had a lot of interesting discussions throughout my life now what's really acceptable and what's not acceptable but i think again the fact that we can now make such cells pretty much completely independent of any having to isolate any tissue i think that really kind of changed the game it's really now more like a renewable source where we don't need ever any fresh tissue anymore now that's kind of the the main point that that really changed the game but it's definitely a very interesting discussion and a valuable discussion again i think enzu which the point i didn't make before now with regard to the importance of fetal tissue was important for us for the comparison for the dosing but it still also remains very important one important way not necessarily as a therapy like i mentioned i don't think that's currently anyone wants to propose that but as a comparator so actually when you get these cells we have such fancy techniques molecular techniques and so forth what's the gold standard how do you know what you made in this dish with all these factors how do you know you have the right cell you always can go back scientifically see what they turn into but you can actually compare it side by side is it the same that nature makes tell me how close do we get i think that's extremely valuable for me that's actually most important use of remaining use of fetal tissue currently in my own work we have another question and i'm cognizant of the time so i want to quickly get at least one or two more questions in you mentioned a little bit about the placebo control group and conducting what would effectively be a sham surgery and the ethical questions that come with that would you consider it more ethical if those patients were promised treatment with the curing effects if they were shown to be curative down the road yeah no exactly that is something that was done in some of those studies and again to make it a more palatable for those patients and the problem is that is a little bit that the disease again is a progressive disease and they might still miss kind of the best window where it works the best and so so i think that's for me still the issue and we don't know exactly how long they have to wait i can pass for a drug trial it's very easy you know you do six months this and then you flip the groups and you see where it works but here it's a it's a treatment that continues to grow i just mentioned the point this is you know i put this in the brain after one year they look different after two years and after six years so when do they have exactly the best benefit and and so it gets a little bit tricky when you actually would do the crossover and give the patients that didn't have it give it later but but it's it's a valuable sort and i think that's something we definitely would consider if we are required to do placebo and you would just have to define now the hopefully a good end point and but you would definitely lose the long-term control if you do that now that's the for for later time but which kind of also scientifically a little bit unfortunately how are we for time yeah maybe i have one one more question and just looking towards how you can maybe use what you're studying now and apply it towards other things so we had one attendee asked if you're looking to apply your studies into something like ALS or if you're solely focused on Parkinson's no we actually try to develop a number of different cell-based therapies ALS is very difficult because again it's it's a disease of a very specific population where at least the nerve cells i think cannot be easily replaced because it's such a complex way they have to grow back and it happens throughout the body axis not just the lego piece not a big hundreds of lego pieces we have to put back so it's very tough but there are groups that are doing that with other cells that not really replace the cells but they have like a chaperone a protective effect that are injected from work by clive svensson and others try to develop cells or a B but i personally think ALS is maybe not the easiest one for this approach but there are clearly other examples where this could be the case from hunt against diseases a classic example that might benefit from that which is not a motor disorder that could work in a potentially similar manner or we have again certain childhood related diseases i mentioned in the enteric nervous system which is in your gut children with hisprung disease that's actually something we try to develop in actual trial currently but we had also got a nature paper showing that this can work in a mouse and we are trying to put that forward to the clinic in children which is a whole other regulatory landscape how you do something first time in a child which usually have a different regulatory landscape so i think this approach will come about in many ways and i think it will also change a little bit from this simple maybe not so simple replacement idea but actually combine it with gene therapy so there's now quite a bit of success or promise that is in gene therapy and at least we think that the combination could be even more powerful that he would put the cell back to replace but he would also hopefully stay for further disease or you can use the cells as a mule to deliver the therapy all over the body so i think there are a lot of exciting areas where i think cell therapy will come about and there's kind of an explosion now thinking about that and Parkinson's was an early example but i think it's definitely not going to stop there well with that we are out of time i would love to thank our audience members for joining us here today this event was sponsored by the center for bioethics of harvard medical school and i'd like to thank in particular ashley troutman angela alberti and christina larson for for their help in this session today join us on november 20th for organoids and covet i would like to then thank our speaker lorenz suitor for joining us and thank you so much for your simulating discussion and your presentation we really appreciate your time thank you everybody for joining us we'll see you next month thanks so much


Let me thank everyone who has participated in today's launch of the IOM institutional framework for addressing gender-based violence GBV in crises. I would like to express my appreciation to the distinguished panelists for their important contributions and the time they have committed to this event. Your support for this initiative and your leadership on tackling GBV is invaluable, not only to this organization, but to the humanitarian community as a whole. I'm very pleased with the progress that IOM has made in its institutional and global commitments to address GBV in crises, and I'm proud to say that this framework will be part of my legacy. As IOM's first such framework, it represents IOM's contribution in an extremely important step toward transforming the way GBV is addressed in crises. I trust that through the strategic interventions set out in the framework, GBV programming, in particular risk mitigation, will become an integral part of the organization's core crisis operations. I count on all staff within IOM to continue to participate actively in collective efforts at the global, reasonable, and local levels to take action against GBV so that we meet our essential commitments to uphold the fundamental rights, safety, and dignity of the people we serve. I strongly encourage and hope and expect that all of you present here today continue your tremendous efforts in addressing GBV together. Specifically, I call on IOM Regional Directors and Chiefs of Mission to demonstrate leadership by keeping GBV in the spotlight and advocating for and prioritizing interventions that mitigate GBV risks and alleviate the harm and suffering of GBV survivors. We must ensure that our staff and partners have the skills and the knowledge they need to address GBV in crises and foster collaborative relationships with all relevant stakeholders in order to achieve our common goal. I call on IOM staff, particularly those on the front line of crisis operations and those working in fragile contexts, to sustain your efforts to integrate GBV risk mitigation, response, and prevention in your daily work and to support and empower crisis-affected individuals and communities to strengthen their resilience and recover from crises. I call on civil society and global partners to build inclusive collaborative partnerships in order to translate high-level commitments into concrete action, own the ground, and further advocate for ending this violence. And finally, I call on states and donors not only to prioritize funding at all levels aimed at eradicating GBV worldwide, but also to leverage your unique position to galvanize action, raise awareness, and promote accountability.  We count on your partnership to scale up good practices and build the evidence base for quality interventions that save lives, mitigate risks, and promote the dignity and well-being of the people we serve. Thank you.