Lasker Lecture: Dr. Shinya Yamanaka, 2 of 3

now I'd like to proceed with the introduction of our Lasker laureate speaker professor Yamanaka he began his professional life in medical school at Kobe University in 1981 where he trained to become an orthopedic surgeon he kindly last night at dinner permitted me to share the personal detail that his interest Northup edicts apparently came from experiences growing up as he did in Osaka making frequent visits to the doctor for bone fractures suffered while playing rugby and practicing judo he indeed continued his training as a resident at the National Osaka Hospital in 1987 but ultimately elected to choose a research career over medical practice and to that end in 1989 he began pursuing a doctorate in pharmacology at Osaka City University his interest in genetics apparently came upon a paper about genetically engineered mice with the concept of knockout and transgenic which fascinated him and prompted him to seek training in the u.s. sending some 30 letters to various American universities and I haven't checked the archives by the way to see whether Einstein was among them but presciently and brilliantly the University of California San Francisco offered him a postdoctoral position in 1993 and he pursued his training they're returning to Osaka City University in 96 as an assistant professor in the pharmacology department in 1999 he assumed positions at other universities ultimately becoming a full professor at Kyoto University in 2004 and in 2010 assuming the directorship of the Center for induced pluripotent stem cell research and application at Kyoto University I think it's fair to say that the start out as an orthopedic surgeon is a little counterintuitive I'm reflecting on a couple of my medical school classmates one was the starting center of the UVA basket football team that is going into orthopaedics and I don't think that he embarked or considered embarking on a stem research career but perhaps given the fact that as we know some amphibian species can regenerate an entire limb once it is amputated and that problem and that D differentiation that occurs has some echoes in the work of dr. Yamanaka and indeed in reflecting on the context of that work John Gurdon in Cambridge decades ago created entire frogs from somatic cell nuclei a reprogramming event no one got particularly excited it's a frog after all not a prince that would that would have been a trick Ian will MIT's famous creation of Dolly the sheep did arouse a good bit of interest again somatic cell nuclear transfer but sort of a one-off that led to the whole controversy of therapeutic versus reproductive cloning but then professor Yamaha cos breakthrough work on induced pluripotent stem cells came upon the scene and this has truly revolutionized the field in a variety of ways that I'm sure he will share with us this breakthrough work has been recognized by the receipt of numerous prestigious award the Shaw Prize in 2008 the Gairdner award in 2009 and in the same year the Lasker Award for basic science research for which he is celebrated today and will give his lecture on induced pluripotent stem cells professor Yamanaka [Applause] good morning dr. Allen's speaker thank you very much for your kind introduction and thank you very much for for inviting me to this great campus and also or I'd like to thank the Lasker foundation again dr. Maria prayer and dr. James Otis for awarding me the Lasker Award in 2009 and also give me this great opportunity to be here so today I'd like to discuss about these cells induced pluripotent stem cells which we generated in 2006 but before talking about IPS cells I'd like to give you a brief history all my scientific career because there are summe many medical students and graduate students as well as postdocs in this audience so I did my postdoctoral training in San Francisco between 93 and 97 this is the director of Gladstone Institute he is now director invertors dr. Robert robot Mehdi and this is what I learned PW so Oh dr. Mary he told us all stock you have to do you have to remember VW to succeed as a scientist well at that time I had well even still now I have Toyota so I thought I can I'm in in trouble but he said BW in this case is not Volkswagen but instead be that will means vision and Waka heart so this simple but very important to us it's still something I always remember I always keep in mind probably this is the most important thing which I learned during my postdoc training and this is my real boss Tom in linearity next to me is myself the main purpose of this slide is to show you that I used to have more more hairs so this is what I did with Tom this is Tom's hypothesis we were working on one enzyme a popeck one which is RNA editing enzyme you don't have to remember the details of this gene but Tom thought that by overexpressing this editing enzyme a public one endeavor that will lower plasma cholesterol level so we should be able to prevent atherosclerosis so we may be able to use this a public one gene in as gene therapy in order to test his hypothesis this is what I I did I generated transgenic mice or by expressing this gene a public one in deeper specific manner so I worked very hard and I was able to generate transgenic mice within six months but one day in the morning a technician working with me helping me with this mice very early in the morning she came to me and said something strange she said senior senior you're mice are strange you're mice are pregnant however they are male so I I was confused so I went to do the I'm of facility and I did see many mice looked like pregnant although they were male so I decided to sacrifice some of them and instead of finding babies I found these agree rivers so it turned out that April week one causes liver tumors hepatocellular carcinoma so this is it turned out that a public one is an active on coaching we can never use this gene in gene therapy so from this experiment I learned three important rules in science number one science is surprising its roll group surprise that's why I'm still doing science the second rule is that use you should not test any new procedures or any new medicine directly on patients you should do animal tests the third rule which is probably most important rule is that you should never believe in your bosses hypotheses so Tom my boss got very disappointed depressed by this result of course but I got very very excited I got very interested in in the molecular mechanism how this one ends I'm a public one can cause this kind of ugly tumors so I continued working on these mice trying to understand the cause of this at origin st and and i identified one gene which is a barren tree which is heavily edited remember this a public one is an RNA RNA editing enzyme it changing change changes the sequence of mRNA and I found that this new gene which I designated not one novel a public one target number one is a variant three edited by this OVA expressed a public one in transgenic animal livers as a result it generated many many premature stop codons and as a result in transgenic mice sleeper not one protein almost disappears so I thought this loss of function of not one may be the cause of hepatocellular carcinoma bio by expressed a public one to test that hypothesis I decided to make knockout mice of a public one I'm sorry and knockout mice of not one so I learned how to make knockout mice from my one of my best friends wolf Eris at Gladstone Institute and I again worked very hard I made targeting constructs in like three weeks and I got targeted es embryonic stem cells in two months and I got climatic mice in six months so our experiments went very well however thank we got kinetic mice my wife who is here with me did something very brave or very terrible she and and two of my daughters were all with me in San Francisco but after three years she decided to go back to Japan with my daughter's leaving me behind so I I became alone we call so my because of the education of my daughters we decided that way so I became wrong but my boss Tom became very happy because I can be my in his lab for like 20 hours a day so I worked much harder and but after six months by trying to give up I felt very lonely and I decided to go back to Japan but tom was very very kind he allowed me to bring those chimeric mice back into Japan so that I was able to continue my research about not one in Japan and it turned out that not one is essential for re Mouse development not one now mice cannot survive they died soon after implantation because those not one knockout embryos are very small I cannot study these mice furthermore so I decided to knock out not one in ES cells in embryonic stem selves because I knew that not one is also expressed in embryonic stem cells II in ES cells so I generated not one knockout es cells and I found that when ES cells were undifferentiated on feeder cells not one now not one look at es cells looked just fine however when I try to induce differentiation I observed market difference as you can see here we found that not one knockout es cells were not able to differentiate at all so from this experiment I got very very interested in the biology of embryonic stem cells as all you know embryonic stem cells ES cells are derived from early embryos they were first generated from mouse embryos in 1981 and they are essential for generating knockout mice they have two important properties the first one is the rapid proliferation and the second one is their pluripotency and I found that not one is not essential for this fast proliferation first property but not one is essential for pure potency of embryonic stem cells so with that without not one ES cells cannot differentiate so again from this finding I got very very interesting in ES cells themselves up to this point ES cells were just the tool to generate knockout mice for me but thanks to not one I got very interested in ES cells es cells become the targets of my so again I was able to publish this paper in EMBO journal in 2000 year 2000 however it took more than three years to publish just this one paper when I was a postdoc I published at least one paper every when from my third year of my graduate student and throughout my postdoc training I make it a rule to publish at least one paper every year but after going back to Japan it took more than three years to publish just one paper that was because I got sick I got suffered from PID well this is a medical school so there are many doctors but I don't think you know about PID because this is what I named PID stands for post America depression so I suffered from this mental disease it slowed me down so that's why it took more than three years to publish just one paper there were there were many reasons when I was a postdoc I have at least two or three people who helped me keeping and taking help mice but in Japan I didn't have any help I brought two mice comic mice from u.s. to Japan I named one mouse Tom there's a mouse Connie Connie is Tom's wife and I would time to very good care of them it was only two in the beginning but after three months I got 20 and after six months I got 100 and after year I got more than 200 mice and I had to take care all of them so I thought am I very scientist while my just mouse keeper and also oh I was in a medical school and there are many good reasons but only a few colleagues could understand what I was walking on so I was often told by my colleagues this way Shinya I was working on mouse embryonic stem cells so they told me that Shinya working on those strange mouse cells may be interesting to you but probably you should do something more related to medicine so it was very tough you know I was working very hard but nobody else could understand what I was working on so because of those many reasons I got depressed and I was about to quit from science but very likely to events happened who rescued me from PID the first event was the generation of human ES cells in 1998 by dr. Jamie Thomson human years cells have the two same properties as Mouse ear cells they can wrap it infinitely and they can differentiate into many types of somatic cells so by using human year cells we may be help many patients by making many kinds of human cells like dopaminergic neurons neural stem cells cardiac cells from human ear cells and then by transplanting these somatic cells into patients we may be able to help many many patients suffering from various diseases and injuries such as Parkinson disease spinal cord injury and cardiac failure so it turned out that ES cells themselves are very very related to medicine so I thought wow I don't have to change my research just continuing ESL's may help may may be very very related to medicine so that was the first event which rescued me from PID however at the same time human year cells have many many challenges we have to use human embryos to generate human years cells so or they are not two patient's own cells so we have to worry about immune rejection after transplantation and also more importantly many people are against the usage of human embryos and human years cells at the time in Japan we were not able to use human ES cells at all in in Japan the second event which rescues Me from PID was my promotion to this new Institute in Nara Nara Institute of Science and Technology so this Institute has a very very good scientific environment good campus they have many good scientists they have good scientific fundings and more importantly they have good graduate students and I got my own laboratory for the first time in this nada Institute of Science and Technology because of this promotion and because of the generation of human year cells I my PhD had gone and I was able to continue science but soon after I moved to Nara I realized one big issue I have to recruit graduate students every April in in Japan school starts in April so every April we have approximately 120 graduate students and there are approximately 20 laboratories so every spring there is a competition among 20 laboratories for 120 students and a choice is in students they can select laboratories so I was the youngest P I I was not a full professor I would just associate professor so my lab space is only half and I was not famous at all I didn't I didn't have nature papers I didn't have science sell papers I didn't have enough money so I was not sure whether I can recruit any attract any project students well not if I cannot recruit any graduate student I will be in trouble so I thought what I can do and I thought well what I can do is BW vision and work hard so if I have some very clear attractive vision I thought that may attract young students so after some thinking I made this as a long-term goal or vision of my own laboratory reprogramming making es like stem cells directly from somatic cells not from human embryos by doing this we can overcome many challenges which human ES cells face this is after the success for generation of Dori so we knew that this should be possible but at the same time of course I knew this is very very difficult it will take 20 years 30 years or more but in April I have this kind of opportunity in front of 120 students I had a chance to present to introduce my own laboratory so I used almost the same slide to show them my vision of course again I knew how difficult this disease but I don't tell them at all how difficult this is I just tell them how wonderful if we can make it and very fortunately it worked I was able to recruit three students in my own laboratory Castle Aiko and you see me this is two years greater when he when they got when they finished their master degree but because of these three first students I had I got a clear vision and they worked very hard haha it was a nice combination so this is my strategy or hypothesis I thought you know es cells maintain proportion see for a long time so they have so called real potency maintenance factors so I thought by identifying identifying those reporting C maintenance factors and by introducing those factors into somatic cells we maybe what we should be able to induce pre potency in somatic cells so we try to identify as many through the potency maintenance factors as as possible I'm sorry this is what we knew about how reported through the potency is maintained in Mouse ES cells in year 2000 when we started this project we knew if cytokine death is important and we also knew that star 3 is essential as a downstream target of RIF in most ES cells in addition to transcription factors of 3 4 and Sox 2 are very important in the maintenance of pre potency but these factors are very very popular so many laboratories were already working on these very famous payers so instead of working these famous players we try to identify new factors which are not listed in this slide and after four or five years of hard work we were able to identify [Music] another important transcription factor nanog and also a que el que el que el f4 which we identified as the stream target of stat3 and also we identified many other factors in addition other laboratories also identified some other factors like Simic so or I moved to Kyoto University in 2004 but by that time we have these many candidate factors which may be able to induce prepotency in somatic cells so Oh in Kyoto we tested those candidate factors whether they can actually induce pure potency however we found that any single factors can induce pre potency in Mouse skin cells or mouse fibroblasts however to make a long story very short it turned out that by combining these four factors out of those many candidate factors to our surprise we can actually induce pretty potent C in Mouse skin cells Mouse King fibroblasts so these four factors are optical socks to Simek and kalynn for all transcription factors so in 2006 we were able to report this in Mouse we designated these es like cells iPS cells induced pluripotent stem cells and we were able to recapitulate the same thing in human in 2007 so I often introduce IPS cells to in this kind of occasion but I did not make IPS cells it was this mainly these three young scientists who generated IPs sells Yoshimi and kazoo kazoo Toshi well till my very first students Tomoko was my first technician so without these three young scientists I could we could never have generated IPS cells at least in my laboratory so I'm very very grateful to these young scientists well I have two daughters slightly younger than these three a person but these scientists are as important as my daughters well again I have my wife here today that's good of course is more important than this so Oh starting last year Kyoto University has opened this new center center for IPS cell research and application this whole building is working on IPS cells we have more than 300 people in this building I also have a small laboratory in San Francisco at Gladstone Institute of cardiovascular diseases so in these places we have been making IPS cells from many patients and also from healthy volunteers all we need is a skin biopsy by punch biopsy we take tiny skin fragment and from that tiny skin fragment we can have a dish of fibroblasts skin fibroblasts and by introducing those four factors we can convert skin fibroblasts into IPS cells once they become like IPS cells we can expand these cells as much as we want and after expansion we can make many types of different cells from IPS cells including this kind of beating cardiac myocytes so when I saw these cardiac myocytes for the first time I my own heart synchronized I still remember that moment so oh this is what we can personally do by using IPS cells we can make many types of somatic cells from patients on cells so we could transplant those cells back into patients we have a strong collaboration with keio university in japan dr. Hideki okano we would like to treat patients suffering from spinal cord injuries by transplanting neural stem cells derived from IPS cells we are now testing we I mean dr. O'Connell has been testing this strategy in mice and in also or monkey marmoset so this is a result of of a mouse model without treatment this formals cannot move his lower legs it's a incomplete injury so he can slightly move but not completely but by transplanting neural stem cells derived from IPS cells we can the mouse is much much better so we're hoping and we obtained a similar result in marmoset so we are hoping that in the near future in like five years we can start clinical trial using the same strategy so by using patient specific IPS cells we put a void like ESCO issues and immune rejection however at the same time making IPS cells from each patient would cost a lot and it takes very long making fibroblasts it takes a few weeks converting fibroblasts into IPS cells it takes at least one months and expanding iPS cells takes one or two months and differentiate differentiating like yourselves into neural stem cells it takes 2 or 3 months so in total it takes 5 6 months however in treating spinal cord injuries many scientists have shown that we have to transplant neural stem cells within 10 days or one month after the onset of injury so if we make IPS cells from patients we can never make it so to overcome that timing issue in addition to making patient all IPS cells we are proposing to prepare IPS cell Bank this is just like a blood bank so or instead of making instead of patients we will make IPS cells from healthy volunteers we are now on the process to determine the best origin for making IPS cells and the best method and also best quality control method to prepare this kind of clinical grade IPS cell Bank how about HLA we cannot use patients on IPS cells so we have to worry about actually matching as you know its array is very complicated we receive different HLA from father and mother so I have actually a pro types in a very simple presentation of 10 individuals none of these 10 individuals have the same color combination so the same HLA prototypes so if we make IPS a bank for these ten patients we have to make IPS cells from all of them so it's a huge effort however if we identify this kind of ETA homozygous donors who happen to have the same color in this case red by making IPS cells from this just one individual we can transplant these four individuals it's a one-way reaction so ETA homozygous donors may be very very useful in Japan according to our calculation if we can identify 75 unique HLA homozygous donors and making IPS cells that would cover more than 80 percent of Japanese corporations at [Music] major 3hn loci with four digit specification so I I don't know all the number in the states probably it's more diverse so you may need more numbers but still I think it's still feasible to have this kind of HLA olmos I was her prototyped IPS cell bank so in our Institute Institute in Kyoto we have already set up this kind of GMP facility to generate clinical grade IPS cells another useful application of IPS cells is making disease models and performing drug screening let me give you just one example it's a me Oh terrific lateral sclerosis ALS known as Google disease in this country of course bill gaelic was a great butter but he suffered from this disease so he had to retire when he was only thirty five and two years later he passed away when he was only 37 so this happened more than seventy years ago but we still don't have a good cure of this disease so yoga guru gaelic disease is also known as motor neuron disease this is caused by not by muscle itself but caused by abnormal motor neurons for unknown reason their motor neurons became degenerated and eventually died so again we don't have good effective treatment primarily because we don't have good disease models to understand disease mechanisms and to develop effective drugs well we do have mouse and rat models of areas and some effective drugs were developed on mice however those drugs were were only effective on mice but not on human patients but now that we have this technology many scientists in the world are generating IPS cells from areas patients and after expansion of IPS cells they are converting IPS cells into motor neurons so these motor neurons have the same genetic information with areas patients so all many scientists are now using these motor neurons to understand disease mechanisms and also to perform drug screening so we have set up this kind of robotic system in Institute and we have collected more than 50,000 chemical compounds so we're hoping that in the future we can identify some effective chemicals so again these are the applications but there are many challenges as well for example we still don't know whether IPS cells can really replace human years cells we still don't know whether they are really equivalent or not and we still don't know whether IPS cells are very safe after transplantation and we still need a lot more researches about how to differentiate IPS cells and how to recapitulate diseases in by using IPS cells I want to focus on this very important question ES cells are ES cells and iPS cells equivalent one they are similar that's for sure but are they really prevalent or not this has been a very hot topic in this year and in blastia many papers have been published in prestigious journals like Nature so I think the situation is something like this we do see more variations in IPS cell clones many of them are indeed indistinguishable or equivalent to human cells but we do have some but IPS cell clones so all the real or issue is how to avoid and how to detect such but IPS cell phones for future applications so again I have laboratories both in Kyoto and in San Francisco in kilt I have many many students and Pharaohs I do have some strange student like this geisha this is a boy student I'm sorry and in San Francisco I have a much smaller group all all good so I am very very grateful to all of them and also I'd like to use this opportunity to thank many helps and friendship from the states regarding the March disaster we are still struggling with the nuke problem we got many many helps from your troops as Operation Tomodachi and also many missions us visions immediately after the disaster so I really really appreciate your friendship and support thank you very much [Applause] Thank You professor Yamanaka for an outstanding talk and certainly exemplary for students and fellows in terms of tracing a remarkable career so far many more I hope to come and also showing us that humor and creativity go together in a very important way so outstanding I wanted to ask about this question of rejection I think within the last year there's a paper in nature from a Chinese group using mouse derived IPS cells claiming evidence of rejection upon transplantation and I've asked colleagues about it the opinions were varied you're probably familiar with this work raising the notion that even IPS cells from the donor given back to a genetically identical recipient could potentially cause rejection because of some aspect of reprogramming do you have any comments about that well that's a very very important study so because these cells are very artificial they may express some some proteins which normally he won't be expressed in normal cells so we really have to keep that in mind when performing clinical trial but compared to allograft I believe if we see any rejection should be very very minor so by using small doses of immunosuppressants I think we should be able to overcome but we really have to keep keep that in mind before we let you go we have a small token of our appreciation it's a great pleasure to thank you for a wonderful lecture for your outstanding work and to wish you great continued success in the future [Applause]

Channel: Albert Einstein College of Medicine

Views: 41,999

Rating: 4.9478259 out of 5

Keywords: stem, cell, research, cells, iPS, Shinya, Yamanaka, Lasker, Lecture, The, Foundation, Albert, Einstein, College, of, Medicine, Allen, Spiegel, M., Stem Cell

Id: DQNoyDwCPzM

Length: 49min 0sec (2940 seconds)

Published: Tue Dec 06 2011