stem cell institute of america

welcome to tyt interviews, and we’ve gota fascinating one for you guys. this is actually three different doctors who are gonna talkto you about stem cell research. we’re here in youtube space new york. let me introduceyou to the doctors first – first actor, todd evans, and doctor jim cheung, and doctoralbano meli. that’s right. ok, as good as i could get it. ok. so, thisis a fascinating story. it involves a couple of different countries, and one person’sheart, and how we’ve…. so these doctors have tracked the mutations, and hopefullyfix some of the issues that are at hand and involve stem cell research. it’s enormouslyfascinating. the more i talk to them off air,

the more i get a sense of how much i lovescience. ok, so in my mind, these are the good guys.and so let’s have an interesting conversation about how it all works and how we all cameto be in the same room. so doctor cheung, let me start with you. we have someone onstaff, praveen singh, she is head of business development for the young turks, and she hadan issue with her heart, and she came to you. so, what was her issue? actually what happened was that praveen – severalyears before seeing me – had actually had an event when she just completely blackedout while at her office on the phone. and she… it was actually quite a significantevent and she ended up getting hospitalized,

she found she’s having arrhythmia, had severalprocedures done, and actually done well on treatment but as it turned out she had foundout that her mother actually had the same condition. then fast forward few years later – that’swhen she met me in my office. she had explained to me and she was actually an advocate forherself, because she really… you know she was actually pregnant at the time and said:look, you know, i really think i have a genetic problem here. at that time her diagnosis wascalled short couple torsades de pointes - quite a mouthful but what it really is is a formof arrhythmia that tends to affect patients who have otherwise normal hearts. you know,she was young, otherwise healthy, no other

medical problems, but she passed out fromarrhythmia. so it turns out that her mother had the sameexact condition, so two very rare occurrences, so she was thinking this could be genetic,so what can we do to maybe find out if there is an actual mutation that we can identify,with very direct implications for herself – she was pregnant at the time with a childand she was worried – is it possible that i might pass this along to my child and futuregeneration. so that’s really how it all started. so let me understand this. it’s pretty scaryfor a lot of people. you might not realize you have this condition?

and you might simply have… is it a cardiacarrest you’re going into? yes, pretty much. do we know if it’s the same thing, or notnecessarily same, but similar to conditions we see on tv from time to time – if youare a sports fan, you know reggie lewis died suddenly while playing basketball… and dowe know how many people it affects, is it similar, and how much overall does it affectthe country. thankfully, it is very unusual. a lot of patientswho have cardiac arrest tend to have prior heart problems. like, patients who have myocardialinfarction, meaning they had a blockage to a part of their heart, a part of their heartdied as a result. or a patient has a very

weakened heart, what we call a cardiomyopathy.so that’s just to put it in perspective. it is still the vast majority what causescardiac arrest. however there is a distinct subset of patients who have otherwise totallynormal hearts – young and otherwise healthy – who may have some unbeknown conditionthat predisposes them to have cardiac arrest. exactly like the examples you’ve mentioned– reggie lewis had something called hypertrophic cardiomyopathy where he had a thickening ofhis heart. obviously, it led him to have electrical abnormalitiesof the heart but he was an nba basketball player, so obviously it was not affectinghim so much that it would prevent him from competing at the high level. every so often,absolutely, we would hear stories of marathon

runners or other athletes, who are otherwisevery much high performing – people who pass out suddenly or even have a life-threateningarrhythmia. so again, in perspective it is relatively infrequent. so for example, themost common form of this kind of disorder, it’s called long qt syndrome - it affects,you know, one in a thousand, one in two thousand let’s say, it’s not super rare, it’sdefinitely out there but it’s not super common, but it’s definitely something weneed to know about. about 280 thousand people die in a year fromheart attacks. but it’s a smaller subset that is affected by this. i mean, what scaresa lot of people, is that it seems to come out of the blue and there is no other indication.we all know we need our cholesterol checked,

we all do our check-ups, so you have a senseof how to make your heart healthier, but if you have this – boom! you’re either – inreggie lewis’ case you’re exercising, and all of a sudden you get…. or in praveen’scase you’re at rest, and it’s even scarier in some way. you didn’t even know that that was possible.so now in her particular case, they know what it is, you guys know what it is, and you knowthat it’s a mutation, right? so we think it might be genetic but we don’t know. so now how do we find out more about it, howdo we then transition to doctor evans? with praveen’s urging actually, we decidedto send off genetic testing. actually, to

be honest with you, i was quite skepticalin the beginning, because i felt that her story did not fit. the list of disorders thatcan cause sudden cardiac arrest in an otherwise healthy heart – so there is a list. andher condition did not fall under the known list which has been known to be associatedwith specific mutations. so obviously, there are genetic anomalies that are out there,we just don’t know what genes they are because we haven’t explored every possible geneout there. so at that time i was a bit skeptic aboutdoing a genetic testing because i felt, you know, what’s the likelihood of us findingsomething? this could be low. there are actually downsides of finding something, because ifyou find something, that mutation, the alteration

of genetic code may or may not be what’sactually causing the condition. so what happens is that the downside duringgenetic testing when you don’t know what you are testing is that you may find someabnormality which is actually totally benign, you know it’s just as benign as the differencein hair color, but then you link it to some potentially you think fatal condition, withoutthe full scientific knowledge of what’s going on. in any case, just a backtrack. so in praveen’scase we did the genetic testing, and we found a mutation in a gene, which is really quitesurprising, because that mutation is associated with arrhythmia generally with exercise, andin her condition, it occurred purely at rest.

so at the time i was, well, that’s interesting,and we tested the mother, and the mother had the exact same mutation. now that does not prove anything. so that’sthe thing. now we have two patients with relative uncommon presentation, with relatively raremutation, and then now, however, the hard work begins, which is making sure we can provethat we have the science to make the association between the actual mutation and the actualmedical condition we’re trying to make the diagnosis for. and that’s where doctor meliand doctor evans step in. where they can actually give us the scientific evidence to supportthat hypothesis. so already this is really interesting anda little scary for people if they have this.

so they’re rooting for you, i think, toget this right. but i think what is more interesting is to see what doctor evans and doctor melihave done. so you sent praveen’s blood to doctor evans. doctor evans, what did you dowith the blood? what our group did with the blood was… weare actually turning them into stem cells. what we like to do – to be able to studypraveen’s cardiomyocytes or other cellular components of her heart, but of course we can’tdo that. a physician can study various clinical aspects of her condition but we actually liketo understand the molecular basis for what’s going on, to actually be able to understandthe biochemistry in terms of how the proteins are functioning in her heart.

and there are certain things we can do nowthat even five or six years ago we could not do. a lot of times, for example, you could studysomebody’s blood cells and try to make an assumption about how a gene being dysfunctionalthere relates to the cardiomyocyte but that’s a big stretch. we’d actually like to beable to do is generate a cardiomyocyte, replicate what we call the “disease in a dish”.actually create functioning cardiac tissue in a dish which has the exact same geneticmakeup of the patient. and we can do that now. so what we do is we can take blood cells and introduce four genes that are called “pluripotency genes”, they are genes that are importantform of parting phenotype of a stem cell,

similar to an embryonic stem cell – thatallows these cells now to become reprogrammed. so they forget basically that they are a bloodcell. actually one of the beauties of this processis that blood is easy to obtain just from the periphery. everybody goes to the clinicand gives blood. we need very little blood. we use the blood cells that would normallymake red blood cells, which is the most abundant cell in your body. so we can expand it ina petri dish these what i call a erythroblast. and we introduce a virus, an engineered virus. that virus is such that it will go in thesered blood cell precursors and express these pluripotency genes. essentially, erasing thememory of that cell as a red cell. and the

culture conditions are such that we can capturecells as they transition and reprogram to become a stem cell. the reason that’s importantis that one of the great features of a pluripotent cells is that we can grow them in a dish,and make as many of them as we want. we can grow them up, grow them up, grow them up. so that’s occurring actually right now atthe weill cornell medical school in the incubators. now the beauty is that over the last fiveor ten years – something that my own group is very much involved in but many other laboratoriesare working on actually using these embryonic… these are actually called “induced pluripotentstem cells”, ips cells. that does not do that much good, just to grow lots and lotsof them. we have to do something with them.

and so a lot of people had been working onthe protocols to then differentiate them into different cell types. you could start witha blood cell, reprogram it back to the stem cell, make a lot of it, and now induce itto turn into whatever cell type you like. and one of those, which we now have a verygood protocols for are cardiomyocytes, the cells that make the beating heart. we arealso very interested in making other cells of the heart, like the cells of the conductionsystem that’s involved in controlling rhythmic beating, and very actively involved in thatas well. so we can make those cells in a dish. andas doctor cheung was saying, it’s just absolutely true – even if you took a cell and for example,put in that mutation, even a cardiomyocyte,

it’s not really where we want to study.because the genetic background will be different. and genes interact with each other. so whatwe really need to do is have the exact genetic background to understand how that affectscardiomyocyte function. ok, so let me try to break this down, andi love this because a lot of times i deal with politics. and you guys are so much smarterthan the politicians, that it’s exhilarating to talk to you guys. and i’m trying to learnas best as i can. now you can turn the red blood cells into stem cells, and so alreadythat’s amazing. it is amazing. as we were chatting earlier,this is one the pioneering events, it did lead to the nobel prize in 2012 by shinyayamanaka and his colleagues.

so when you got the stem cells, can you … ifi’m understanding this right, and that’s why i need help here, you can make them intoheart cells of that particular person, right? can you do other cells – liver, kidney?you can do all that? and so then you can begin the study how that person’s heart cellsreact when you introduce a disease to be able to track it. is that roughly right? yes, that’s roughly right. now there aremany caveats because of course even though you can make, for example, heart cells, cardiomyocytes,that really are from the patient essentially, i mean, secondarily derived, but they arenot a heart. and so they are not affiliated with the whole physiological response thatoccurs in a living human being, so it is very

much of a surrogate assay. that’s why wecall it “disease in a dish”. but they do function, they beat, they have,hopefully, the same physical characteristics as they did in the person. you can now asmany of them as you want. and so you can look for what other proteins or genes might bealtered in those cells. they are very easy now to add drugs to, to test the screen forwhether or not drugs give certain responses. it’s a way of boot strap from a patient into essentiallya clinical trial in a dish to think about pharmacological approaches to working on adisease. so, i’m gonna make it personal for me, ihave a fairly rare skin disease. it’s called pemphigus vulgaris, i don’t know if youguys are familiar with it, you wouldn’t

be, it’s not in your fields. so could wethen take my kids’ red blood cells and test them? is that a different course of action?or to see if they would have it also because it is genetic, and then how we can treat itafterwards? my point being – forget about me, forget about praveen, can this be appliedacross the board with other genetic diseases? very widely. there are many scientists nowactively engaged in that type of research, whether it is for example, neuro-degenerativedisorders, diabetes, complex genetic diseases. cystic fibrosis is a very well understooddisease but one of the things we have been working on recently is generating, for example,pancreatic ductal cells that are the target of this disease. there are many mutationsthat can cause cystic fibrosis.

but now you have a screening platform to actuallylook for drugs for not only “cystic fibrosis” but for the cystic fibrosis that person hasbecause not only the mutation in the known disease gene but all other genes in the genomewill interact with that. this is what now is called “precision medicine”, the medicinethat is really designed for the patient, not for a disease. ok. no, we’re not done yet. it’s aboutto get more interesting. now we take the heart cells that doctor evans has made and we shipthem over to france to doctor meli. and what do you do with that? so basically based on the clinical featuresthat doctor cheung can reveal, we focus on

some mutation occurring in some particularprotein, what we call a “calcium receptor”. we focus on all the calcium that needs release.calcium is a major component to allow the contraction actually, precede the contraction.and what we do back in france, we focus on all the properties that are related to thecalcium into the cells. and for that we basically we use different techniques. and also basedon what we did with doctor cheung so far, we know which part of the cells and whichprotein in particular we should really focus, and eventually do model the disease. so basicallyfrom the initial patient through the ips via doctor evans we get cardiomyocytes, and wetry to model some features of the disease, still in the dish.

then what we can do once we have those featuresof the phenotype, we basically can try different drugs that are under clinical trial, so fdapproved and see which drug would basically prevent or treat any of these features thatwe can reveal. so again, let me try and see if i got thisright, correct me where i’m wrong. red blood cells, then stem cells, then heart cells?ok. and then once you’ve got that person’s particular heart cell, you then introducethe disease to it, and then you test it against a control to see what the difference is. basically, the idea of patient specific cardiomyocytesis that the mutation is there already. and thanks to doctor evans’ expertise, we actuallycan correct some of the stem cells to the

a perfect control. so the only differencebetween two cell types is just one mutation. ok, so let me pause there because the audiencemight not quite understand that, cause i had trouble understanding that in the beginning.so normally you would find a person who is about the same age, who is also female aroundpraveen’s age. and that would be your control group to see how that reacts differently asopposed to the one with the mutation in it, which were praveen’s cells. but you guysdon’t do that anymore. doctor evans actually fixes the mutation, so that it’s praveen’sheart cells but that are fixed, and that’s your control. and then you test it versusthe one that has mutations. absolutely.

phenomenal! all the rest of the genetics is the same. so then you introduce the disease… i’msorry, you have the one that’s mutated, and then you… what do you do? you experimentwhat happens and how to fix it? i mean, in layman’s terms. we try to exhibit some of the features ofthe disease in the dish, and only with the cardiomyocytes. try to reveal some of thefeatures either by applying some sort of pharmacological compounds that will activate some proteins,or we try also to improve the matter of the cells by some physiological or patho-physiologicalstimuli just to reveal the disease. once we

have those features, once we characterizethe cells and we can reveal the features, we then go to the second step which is basicallytesting different drugs and see which one would be the best for the patient – in thedish – and maybe eventually at the clinical level. so doctor cheung, would that then come backto you and say, ok, doctor meli says this is the one that’s most likely to work forpraveen, so do we eventually try it and see how it works for praveen? is that roughlyright? right, i think that…. thankfully, praveenis doing well right now, so there is no… she’s doing ok with the current therapybased on the previous procedures she’s had,

so she’s doing quite well. but it has obviousimplications for other patients like her. so again, with doctor meli’s work – thatwill first at least establish that the mutation is indeed disease-causing. that’s the firstthing. that’s what we need to do. we need to prove that it really is, this mutationreally is causing a problem here. and if he can recreate the disease in a dish, then itups the evidence level for the fact that, ok, this mutation is causing a problem. andif on top of it, as doctor meli says, if he can find the best compound to treat it, thenthat will be again, even greater significance. then it comes back to me, and we can thinkabout things. we can think of a more big picture. how many people are out there with this diseasethat we don’t know about? they may have

the same mutation. then you may talk aboutemploying ideas about screening all patients. now it’s a relatively rare disease. thisis something where we require multiple… you know, across the nation, and internationaleffort to identify patients with her condition. and then we are doing more wide-spread screening. and if we find that hey, certain percentageof patients – usually never 100% but let’s say a good substantial percentage of patientswith her similar condition have this mutation, then that would – or at least of the samegene, the same gene is affected – then you can think about using that same drug thattested so well in the petri dish in a say clinical trial.

and if you already had a parent that has thesekind of conditions, you are far more likely to know that you should test. and so whatit might do is for the people who had been dealing with this, and it’s a mystery andthey don’t know why, they have to live in panic for the rest of their lives, that i’mliterally gonna fall down one day and not get up, have a heart attack in a way thatcould not be predicted – well, now we can test for it. so one more part of this that i have to understand.you guys build this whole system for understanding it, for mapping it, etc. then when a personcomes, is the medicine personalized for them? is there a process you build, or you takethe blood and it becomes easier? you guys

are building the beginning of it, but it’sgotta be easier to go through all three of you for each patient, right? how do we makethis process a little more efficient? the hope is that down the road this will becomemore of a wide-spread approach but right now this is just one case. we just fighting thebattle on one particular patient who said, hey, test me. there are tons of people outthere that we don’t have this… or they don’t have the resources, we don’t havethe technology, we don’t know which gene. so the thing is we need to take a step back,we don’t wanna whole scale start screening everyone who has a genetic condition for something.because then you’re gonna pick up random things that we don’t know whether they havesignificance or not.

but yes, down the road, as we sort of startcataloguing more of the genes that are associated with these genetic disorders, then we cansort of do more of this approach. but you know, it’s still in its infant stages, butobviously, it’s hopefully something that, as doctor evans has pointed out, this ideaof personalized medicine which president obama had raised in the state union address, it’skind of that idea. so doctor evans, once you’ve mapped allthis, you still take somebody’s blood from them, and then you bring it through this processfor medicine to most likely to work given the research we’ve done in the past, isthis? is that how?.. i would say that of course there are two aspects.one is that the screening we are doing now

is physiological screening in a dish to tryreplicate the disease. you’re not gonna want to screen people like that generally.but if for example this mutation is identified for really being responsible for the patient’sdisease, then it’s easy to screen for that genetically. you would just add it on as apart of standard genetic testing ultimately. if it was a really strong indication of thedisease. so genetic screening… you know, there arestandard genetic screenings right now for far more common diseases. we all imagine thatat some point it would become standard protocol to have your genomes sequence. it’s controversialbecause there may be… first of all, there is a lot of issues about protecting patientprivacy, and that information is patient’s

own, and newborn’s own – genetic information.but ultimately i think we all believe that at some level that would become standard ofcare. but it’s still very complicated because of the fact that – as we brought up severaltimes – even the identification of this allele – i can pretty much guarantee, andprobably that was the part of the reason why there was skepticism, and we’re still very,not skeptical… you know, we’re gonna test a hypothesis and we don’t know if it’scorrect. but that same allele – let’s call it amutation, a difference, a gene difference in a different person might not have any consequenceat all because of other protective genes for example.

doctor meli, you are trying to find out whatdifferent medicines could work to help if you already have this condition but you were saying earlier to doctor evans fix the mutation in order for you to have the control teston it, right. so can we fix the mutation in the body without treating it with the medicine? that’s a really good question. there isa lot of fantasy around such a possibility. i am sure in the future it might be possible.currently this is not the case for many reasons. but like you just said, indeed what we tryto do is that we try to get perfect control. perfect control over just a single mutationis the only difference between the two samples. because if you pick one patient, you alwayshave a genetic background that differs, some

genes might be more expressing one side tothe other side and so on. the question in the future, can we just fixthe mutation like this in the whole patient, in the whole body. technically it might bepossible in the future. and doctor evans might be more of an expert than i am to answer thisbut i think currently this is not possible. so right now it’s enormously complicatedbecause of what you were saying. there could be different things that can be reacting withineach person. so even if you figure out that one mutation and you try to fix that, it mightaffect other things in your body. is that right? well, there is two issues. one there's that but i think more importantly right now, technically it's feasible to do.

it certainly has been done in animal models, in mice, single mutations have been corrected and “cured the mouse”. currently the recommendation coming through the nih for federal funding is that we shouldn’t be even doing this experiments in humans because it’s just too early, we need to take thetime to think it through. because if you can correct mutations, you can do any kind ofediting that you want in the genome. and that has serious ethical consequences. so currently,at least in the us we are not doing any types of experiments like that in people. otherthan for use in a dish to actually study the biology behind the specific changes in a genome. but somebody could?

somebody could. even if we’re not doing it here, somewherein outer mongolia… there has been a report that a chinese grouphave modified the human genome. of course doing it in a manner where there would beno opportunity for the embryos to survive or emerge, to actually grow. at the very veryearly stage of embryogenesis. and there is a bit of outrage about that. i think generallyscientists worldwide believe that this is very powerful technology. it’s ok, we haveso much to do, so much we don’t understand, there are so many great experiments that canbe done – we can do those for a while. we work through these ethical issues and what,where and how human genome should be modified.

now we’re gonna get a tiny bit into fantasyworld here. the work you guys are doing is super real, it’s very important and hasreal consequences for people in the real world. but now that we’ve opened up this interesting – i don’t wanna say pandora’s box – i do wanna blow people’s minds a little bit. if you “fix” a genome within a person – if they have kids later , they would actually pass on the new genome that you corrected. correct? it depends on how you corrected it. you have to correct it… you can correct it in every cell in the body. if you didn’t correct it in the germ line, so the cells will give rise to either the sperm or the oocytes, then you’re not gonna pass it on. so it’s very possible you could imagine – in science fiction world – coming up with strategy that fix a gene in every cell in your body or in some cells in your body. what we would call “tissue-specific” correction.

if fixing genes in all the cells of the heart, because that’s in fact that’s the only place where this gene is being mutated is important. other genes may be important in all cells. but if it’s done with strategy where you would not modify the germ line, then it wouldn’t be passed on. could you – if you were so disposed – change a genome in a way where the person would be taller? that should not be probably difficult. stronger? stronger. oh-oh! absolutely. these are so-called “designer genes”. there are certain physical characteristics that are fairly straightforward to alter. knowing what people know about growth and development, hormones systems, etc. one last piece of fantasy, and then we get back to the real world. when would they do that? let’s say you wanna do it. it’s 38 years after, it’s not here, it’s in outer mongolia, somebody says

“i wanna make a super fast, tall, strong person, and i wanna do it for whatever reason”. would you do it when it’s a fetus, when the baby is born, can you do it to an adult? we’re in super fantasy land here. it’s always going to be easier to fix something with current technology the earlier you do it. because there is just less cells to fix. so if you could fix – genetically edit – from one cell stage, or what’s called the zygote, the fertilized egg, that would be by far the easiest place to do the editing. then it would fix every cell in the body. that would only work if you start from one cell. if you start from a grown adult, then it’s much more challenging. for example, it should be very feasible right now if you had a… there is a way that you can mix stem cell biology with gene therapy.

there are trials ongoing right now that are basically adding genes for example to your hematopoietic stem cells that make all the blood cells of your body. you can take those out of the person’s body, genetically alter by adding a gene, and those stem cells will be put back in, go back to the bone marrow, repopulate your entire body. you can cure diseases that way. there are clinical trials to cure blood diseases like thalessemia for example. it should not be difficult, today it would be feasible to use the same approach, instead of adding a gene, go in and fix the mutation in that sense. and then all the blood cells would be fixed, and it would not be passed on. so those kinds of therapies, probably in the next 10-15 years, may be moving all the way to clinical use. so that’s the perfect way to come back to today and the work you guys are doing. it has both very

specific purpose. for example, doctor cheung, if it turns out, knock on wood, one of praveen’s daughters has the same mutation as she does, all this work can hopefully find medicine to be able to more effectively treat her if she needs it. correct? yes. and that’ll be feasible very soon. five year window or so? roughly speaking. that’s great. we might be saving people’s lives. your work saves people’s lives today. so that’s phenomenal. and then secondly, there are broader implications. that’s just one example. and then you can take this and multiply it out, as doctor evans was talking about, to other diseases, and and see the cases in which you can specifically design medicine or perhaps even fix it within the body. is that right? i think so, yes. that’s phenomenal! i have to say it throughout the interview. i kept thinking

my head, because i am a goofy guy. science! i speak for the entire young turks community and our audience in saying thank you, we really appreciate the work that you do. on behalfof not just people that we know but humanity. so thank you doctor evans, doctor cheung,doctor meli. it’s been a great pleasure talking to you.