At the 2008 International Achievement Summit in Kailua-Kona, Hawaii, Dr. Yamanaka participated in a panel discussion of genetics in medicine. An excerpt from his remarks on that occasion precedes the text of this interview. Dr. Yamanaka, you've been exploring a new form of stem cell research. How did you become involved in this work, and what do you see as the promise of stem cell research?
Shinya Yamanaka: It may be surprising, but I was a surgeon, like 20 years ago. And I found I was terrible in the operating room. So I thought, "Well, I won't help people by doing this!" That's why I decided to move to basic science, and I hope it's working. So, for the last -- let me see -- for the last 12 years I have been working on embryonic stem cells, ES cells. And I think probably... so please raise your hand if you know about ES cells. Oh, not all. Okay. Embryonic stem cells are stem cells which scientists generated from fertilized eggs. It was first derived from the mouse embryo in 1981, so 27 years ago. ES cells have two properties, very important properties. The first one: you can increase -- you can culture -- ES cells as much as you want, almost forever. The second, very important point of ES cells is that you can induce, you can make any types of cells from ES cells. Including cardiac cells, neural cells, blood cells, and also germ cells. That means you can prepare any cells, in any quantity, any time. Because of that, mouse embryonic stem cells -- ES cells -- gave rise to a new technology called "knockout mouse" technology. Which is a super technology in understanding the gene function, and as you may know, knockout mouse technology was awarded the Nobel Prize last year. Then in 1998, Dr. James Thomson developed ES cells from human blastocysts. That opened up a completely new way in regenerative medicine.
Because of his success, we have new opportunities to prepare cardiac cells and neural cells to transplant into patients. So when I saw his paper, I thought, "Wow! It's just amazing." But after that, I realized some problems with human ES cells.
You have to use human embryos to prepare human ES cells. And some people do not like that idea, including the president of your country. And also, because ES cells are not the patients' own cells, we have to deal with immune rejections after transplantation. So we decided to start a new project of our laboratory, in which we tried to generate ES-like stem cells, not from embryos, but from patients' own cells. We thought the project would be very, very risky, challenging, and it would take 20 or 30 years. But it turned out it took only five years to achieve that goal in a mouse. So we were able to publish the generation of new stem cells -- which were designated "iPS cells," induced pluripotent stem cells -- from mouse skin cells in 2006. And last year we were able to translate that technology to the human. So we and James Thomson, almost at the same time, were able to report that we can make ES-like stem cells without using embryos. We can convert a patient's skin cells directly to ES-like stem cells.
Could you clarify the significance of ES cells for us?
Shinya Yamanaka: ES cells have two important properties. The first one: we can proliferate -- we can culture ES cells as much as we want. So from a single ES cell we can have a million, billion or more ES cells within a certain period of time. The other important property of ES cells is something called pluripotency. So pluripotency means that we can make any types of cells that exist in our body. We have more than 200 types of cells in our body. So we can make those 200 types of cells from ES cells. So that's the second important property of ES cells.
Let's take a moment to really define what your stem cell breakthrough is, and we'll go from there to the impact it has on the future of medicine. Instead of using embryonic stem cells, you have taken skin cells, and what have you done with them?
Shinya Yamanaka: Because of this technology, iPS technology, now we can prepare many types of human cells. For example, heart cells -- cardiac cells -- or neural cells from patients. So you can easily imagine that without this technology, it's impossible to take cardiac cells from patients who have some kinds of cardiac diseases. If the patient dies, we may be able to get a small amount of cardiac cells from that patient, but those cells do not proliferate, so we cannot increase the number. But with this technology, all we need is a small piece of skin from that patient, and by making iPS cells, we can increase the number of cells as much as we want. And then we can make cardiac cells from those iPS cells. So I think for the first time in the history of medicine, we now have an opportunity to prepare many, many cardiac or neural cells directly from patients, and those cells should be very, very useful, to understand why those patients become sick. And to search for very effective drugs for that patient, and also to study -- to predict -- any side effect for that particular patient. So that is the most beautiful approach -- I mean application -- of this iPS cell technology.
Dr. Yamanaka, many of the scientists we've spoken with say that failure is the biggest teacher. Have you experienced that in your career?
Shinya Yamanaka: I was an orthopedic surgeon, and my first failure was that I was not good at doing surgery, and that failure gave me an opportunity to move to basic science. Then my first major was pharmacology, and in pharmacology we only use many inhibitors and stimulators, all just drugs. And any drug cannot be 100 percent specific and 100 percent effective. So although I did many, many experiments, I did not obtain the answer, because the drugs I used weren't specific enough. So that was kind of my second failure in my career. But that second failure got me interested in knockout mice, mouse technology. So I think failure is important in my career.
In science, because it's based on experimentation, it seems that scientists rely on failure, not only to tell them what not to do, but what to do first. Shinya Yamanaka: I agree, yes. Did you start working with stem cells in graduate school?
Shinya Yamanaka: In my Ph.D. school, I didn't work on stem cells. I just worked on basic pharmacology. But by doing pharmacology, I got very interested in so-called "knockout mouse" technology. Knockout mouse is a way to study the function of genes. You know, both human and mouse have approximately 20,000 genes. With knockout mouse technology, we can select one gene out of those 20,000 genes, and completely destroy that one particular gene so that we can understand the function of that particular gene. I got very interested in that technology. It was 1992 or 1993 when I graduated from my Ph.D. school. So I decided to study -- I decided to learn about knockout mice technology. But at that time in Japan, only a few scientists were working on knockout mice technology. That's why I decided to move to the States, San Francisco.
Did you already have a position lined up in San Francisco? Shinya Yamanaka: Yes, I became a postdoctoral fellow at the University of California in San Francisco. What brought you to that particular university?
Shinya Yamanaka: Usually to find a job in the States -- from Japan -- usually you have to ask your professor in Japan to recommend some place. But unfortunately, at that time, my professor -- my mentor in Japan -- did not know any labs working on knockout mice. So I did not get any good recommendations. So I had to apply for many positions, which I learned from scientific journals such as Nature and Science. I applied to -- I forget -- like 20 or 30 different universities and laboratories in the States. And UCSF -- University of California at San Francisco -- was the first to give me an opportunity. That was why I ended up coming to San Francisco.
What was your next move after San Francisco?
Shinya Yamanaka: After finishing my post-doc training in San Francisco, I went back to Osaka in 1996, and I was lucky to get an assistant professor position in the same laboratory where I got my Ph.D. But compared to my scientific career in the States, in San Francisco, I had a hard time after going back to Japan, because the funding was not good enough back in Osaka. And at that time I only had a few scientists around me who I can discuss with. So I had a hard time in the first two or three years after I went back to Japan, Osaka.
How did you cope with these difficulties after you went back to Japan?
Shinya Yamanaka: I really had hard times, so I was about to quit doing science. I was about to go back to clinics, but again, I was lucky to find another position, in Nara. Nara is very close to Osaka. It's only one hour by car. There's another university in Nara, and I was lucky enough to find a position as an associate professor over there. The funding was much better, and the scientific atmosphere was much better over there. That means there are many, many good scientists in that university in Nara. So without that promotion, probably I [would have] quit my scientific career.
You've mentioned luck, more than once. Shinya Yamanaka: Yeah. I have been very lucky. Did you ever see being a doctor as a fallback plan, if other things didn't work out? Shinya Yamanaka: Yes, because I had a medical license. Although I'm not so good at seeing patients, because I only did two-year residency in orthopedic surgeon. I think having a medical license is kind of a backup. I can always go back to clinics and do a training again. That did help me to do some very risky projects in science. Where did you take these risks? Were they in the lab? How was risk important in what you were doing in the lab?
Shinya Yamanaka: In order to achieve something, it's very important that it should be very risky, because if it's not risky, that means it's very easy, many people can achieve that. But if you really want to solve very tough questions, or very difficult goals, you really have to take risks.
In your field, what is a risk? Could you give us an example?
Shinya Yamanaka: For the last ten years or so I have been working on stem cells, especially embryonic stem cells, ES cells. When I started working on ES cells, most people were trying to generate some kind of cells such as cardiac cells or neurocells from ES cells. So that kind of project was not so risky, because many people are trying to do that. To me, at that time, the most risky project was the reverse. Instead of making some special cells from ES cells, I wanted to make ES cells from, like, skin cells. So it's the opposite direction, and I knew it would be very risky. The chance is very small.
Did you find more collaboration in the lab at Nara than at Osaka? Shinya Yamanaka: Yes. In Osaka I almost worked by myself. I used many, many mice. I had almost 1,000 mice for my own project, and I had to take care of all of them by myself. So it was a lot of work. After I moved to Nara, I had many, many technicians and students who helped me. So I was not alone, that's very important for me. Did the direction of your work change when you came to the second lab?
Shinya Yamanaka: When I went to my second lab, in Nara, it was my first time to be the so-called "principal investigator." So I became independent for the first time in my scientific career. That means I will have to have many students and many post-docs, so I thought I really have to have some wonderful research project in my own lab to attract as many people as possible. So I thought what the goal should be, and I thought making stem cells from patients' own cells should be my goal. That was the beginning of my full research.
Did it attract students as you'd hoped? Shinya Yamanaka: Actually it worked, yes. I got more then 20 or 30 applicants that year. I could only afford three students, so I was able to select the three best students out of those 30 applicants, and they did very well.
Shinya Yamanaka: Well no, actually. I thought that kind of idea should attract many young scientists. In these induced pluripotent stem cells, iPS cells, how do you maintain pluripotency, and why is it important? Shinya Yamanaka: iPS cells and ES cells are indistinguishable in many aspects. We have good conditions for mouse and human ES cells to maintain pluripotency. We can use exactly the same conditions to maintain mouse and human iPS cells. So it is not so difficult. Pluripotency is the most important property of ES and iPS cells, because with the pluripotency, we can make many types of cells from stem cells. Can you describe the process of reprogramming adult cells to revert to an embryonic state? Shinya Yamanaka: It's very simple. All we have to do is to put three genes -- namely Oct-3/4, SOX2 and Klf4 -- into adult skin cells, and those three genes can convert skin cells into stem cells. When we read about your work a few months ago, you were using four genes, weren't you? How did you get it down to three?
A couple of months ago, wasn't it thought that two of the genes were perhaps cancer-causing? Is it only the one gene? Shinya Yamanaka: Yes, actually. One of the three genes, Klf4, had some relationship with cancer, but compared to c-Myc, the risk is much, much smaller. Now that it's only three genes, has it reduced this risk? Shinya Yamanaka: Yes. So it's gone from a 50/50 ratio to one out of three? Shinya Yamanaka: Yeah. Dr. Yamanaka, we'd like to ask a few questions about your childhood. Where were you born and what was your childhood like? Shinya Yamanaka: I was born in Osaka, Japan. It was 45 years ago. My father has a small factory in Osaka, and we lived next to his factory, so I was surrounded by many types of machines. Even as a child, my hobby was using those machines. I was a kind of technical person from the very beginning. Did you have any brothers and sisters? Shinya Yamanaka: Yes, I have a sister. She is an English teacher in Japan. Is she older or younger? Shinya Yamanaka: She's seven years older than I am. When you were growing up, did you get a lot of encouragement from your parents and your family?
Growing up in Osaka, did you like school or did you struggle with academics? Shinya Yamanaka: I liked school pretty much. I liked to study, and I also liked to play some sports. I played judo. It's a traditional Japanese sport. So yeah, I liked my school pretty much. Did you gravitate towards math and science at an early age? Did you enjoy reading? Shinya Yamanaka: I remember I liked math and science much better than reading. Were there any books in particular that you really liked as a young person? Shinya Yamanaka: I remember I read many books about physicians. Not a novel, but a real story. I was very interested in how physicians were trying to help patients. When did you decide to study medicine? Was it something you decided in university?
Shinya Yamanaka: Even when I was a high school student I wanted to be a physician. That was because, as I mentioned, I played judo. And I got injured so many times -- I fractured myself more than ten times -- so I saw an orthopedic surgeon so many times. It was very natural for me to become a doctor.
Were your parents supportive of your ambitions? Shinya Yamanaka: Yes, they were very supportive. My father had a small company, and I was the only boy in the family. It's kind of surprising he didn't want me to take over his job. Instead, he encouraged me to be a doctor. Was that typical in Japan at the time? Shinya Yamanaka: No, I don't think so. Many fathers want at least one of their boys to take over his own company. It's very typical in Japan. But he knew how difficult it is to run a small company. He thought I would not be good at running a company, so instead he encouraged me to be a doctor. Besides your parents, were there others who supported you when you were growing up? In the university, or perhaps a judo coach? Shinya Yamanaka: Yeah. I remember especially my judo coach. He was very supportive.
Shinya Yamanaka: Yes, just a very simple reason. Didn't you play rugby, too? Shinya Yamanaka: Rugby, I played only three years. I played judo almost 15 years. I have a black belt. Was this a particular type of judo? Shinya Yamanaka: Well, I don't know how much you know about judo, but it's like wrestling. There's only one type of judo. Did you think that from a very early age you were always destined to be in science? Shinya Yamanaka: When I was a junior high school student, I was very interested in science. At that time, I wanted to become a scientist as well. After I went to senior high school, being a doctor was my dream, so I didn't imagine I would be a scientist. And now you're one of the most famous scientists in the world. Did you go to university in Osaka? Shinya Yamanaka: No. Actually, I did not graduate from Osaka University. I graduated from Kobe University. It's like two hours by car from Osaka to Kobe. Now you're working in San Francisco again. Was there an incentive for you to leave Japan? Was it simply the opportunity to work in the lab in San Francisco? Shinya Yamanaka: I did my post-doc training in San Francisco, and I'm very grateful to the city of San Francisco and the institute where I did my post-doc training. So it was kind of a dream to come back to San Francisco, to that institute. That's the main reason. Were there any added benefits in moving to San Francisco? Was there something that was missing from the labs in Japan? Shinya Yamanaka: Because of my family, it's very difficult to completely move from Japan to San Francisco, so now I have two laboratories, one in Japan and one in San Francisco. The one in Japan, in Kyoto, is much, much bigger, so right now I can only stay in San Francisco a few days every month. I have to commute every month. Has your life in the lab changed significantly since you made your major discoveries?
Have the restrictions on ES cell research caused scientists to leave the United States? Shinya Yamanaka: Well, that's what I heard. Some people moved to the UK and some people moved to Singapore because of the difficulties of working on ES cells. But now we have iPS cells, I think that problem has been overcome. Hopefully many scientists will come back to the States. In San Francisco you're working at the University of California and the Gladstone Institute of Cardiac Disease. What are your goals in attaching yourself to these institutions? Shinya Yamanaka: The Gladstone Institute has a strong, strong research project in the three major diseases in the States and in the world. That is, cardiovascular disease, neural disease and HIV. I believe that our technology, iPS cell technology, can be used in all three of those areas of human disease. I already have a strong collaboration with many, many scientists at Gladstone. Where do you think these developments will take science in the short-term, maybe the next five years or so at UCSF? Shinya Yamanaka: In the next five years, I think scientists will make iPS cells from many patients so that they can study the cause of diseases more extensively, and so that they can search for more effective drugs. I think that will happen in the next three, four, five years. We'd like to ask you about Ian Wilmut, who's also an Academy member, best known for his achievement cloning a sheep, Dolly, from a single adult sheep cell. Because of your breakthrough, he's changing the direction of his work. Would you like to comment on this?
Was it difficult to gain access to eggs for research? They were in limited supply. Shinya Yamanaka: Yes. If I had to use eggs, it would have been more difficult, but another scientist in Japan saw that not only eggs, but also ES cells themselves can be programmed skin cells. So from his success, I learned that I didn't have to use eggs. Instead I can use ES cells, and ES cells are much easier to handle. Did you have a lot of collaboration with Dr. Wilmut before your breakthrough? Shinya Yamanaka: Actually no. We have been talking about future collaboration and it's been great fun. What do you hope to achieve, working with Dr. Wilmut? Shinya Yamanaka: By collaborating with him, we can make iPS cells from various patients who are not so common in Japan or in San Francisco. So we can enlarge our project by collaborating with many scientists including Dr. Ian Wilmut. Wasn't it significant that Dr. Wilmut decided not to renew the permission he'd been granted for working with embryonic stem cells? Shinya Yamanaka: I didn't expect such a rapid decision, because he kind of gave up doing cloning anymore. But I think this technology is still very young. There are many problems which we have to overcome. So I think we still have to study nuclear cloning, nuclear transfer. So I was very surprised to hear that he decided to stop doing any cloning experiments. Have you talked with him about why he decided that, and why it was so quick?
Shinya Yamanaka: I did talk to him about that, but I forgot the real reason. Maybe he didn't tell me the real reason, but I can imagine it would be very difficult for a scientist like him, who studied for a new project, to say that, "I'm going to stop this." So I think he's, in a sense, very brave, and I admire him so much. And that's a good lesson for me too. Since this technology is still very young, iPS cell technology is very young, I may have to do the same thing in the future. If some other method comes up, and which, if it's much better then iPS cell technology, I think I should be brave enough to say that we should not continue iPS cell technology. Instead we should do this new technology. I hope I will be brave enough like Dr. Wilmut.
Can you talk about some of the problems of iPS? Because it is so young, there is so much that's not understood.
Shinya Yamanaka: The biggest problem is a safety issue. ES cells are derived from embryos, and embryos are pluripotent from the beginning. By contrast, iPS cells are derived from skin cells or other types of somatic cells and those cells are not really potent anymore. We have to put three or four genes into skin cells in order to convert or in order to induce pluripotency. It's kind of a de-differentiation, and de-differentiation is a common feature between deprogramming and cancer. So what I'm really afraid of is that the technology we're doing now is not only making iPS cells, but also making tumor cells. So we really have to double-check the safety, safeness of iPS cells we generated by our method. Because in the future, we want to use these iPS cells in regenerative medicine, that means we would like to transplant iPS cells -- derived cardiac cells or neural cells -- into patients. So that kind of safety issue is crucial.
When you began your work with human cells, how likely did it seem to you that the same three or four genes that reprogrammed skin cells in mice could do the same thing in humans?
Shinya Yamanaka: Well, we have mouse ES cells and human ES cells. They are common, in that they are pluripotent. But they are different, so different in many aspects. They look different. The morphology of mouse ES cells and human ES cells are totally different, and the culture condition of mouse and human ES cells are also different. So from those substantial differences, I thought that the same three or four factors may not work on human cells. But it turned out the same factors can generate human iPS cells, so it was rather surprising to us.
It seems like you were taking a very large risk. Shinya Yamanaka: The real risk was to start this project in mice, because we knew that chance is very, very small, and we thought it might take 20 -- or maybe 30 -- years. So moving from mouse to human was not so big a step. The first step was the highest step for us. What were some of the challenges in working with the mice? Is it true that the mice had to be interbred, and then the cells had to be infected with a virus carrying the gene?
Shinya Yamanaka: It must be infected by viruses having those four factors -- three or four factors. So viruses function as a so-called vector to deliver genes into cells. It's just like a gene therapy. In gene therapy, you use retrovirus to transfer one gene into patients. So we use the same retroviral system in order to transfer -- deliver -- three genes into skin cells. As you may recall, gene therapy to immune-deficient children was very effective in the beginning. But unfortunately, more than 50 percent of those patients who got gene therapy developed tumors, leukemia, after the treatment. That was because of the retroviral integration into a host genome.
So we have to worry about the same type of tumor, leukemia, in iPS cell technology. What kind of setbacks have you had to deal with along the way, and what have you learned from them?
Shinya Yamanaka: Failure is very important. Failure is kind of a beginning of success. Even in my own scientific experiments, I had many, many failures. But in many cases, those negative results gave me many insights into new directions, as you go. You know, in Japan we have a short sentence which -- in Japanese it's stem batoh. That means if you fell down seven times, you have to wake up [get up] eight times, then you can succeed. So I think that's very true in science.
In this country, a lot of funding for scientific research is controlled by the federal government. Have you seen any negative results or obstruction because of the current administration's views on funding for this field of science? Shinya Yamanaka: Funding is essential. Without funding you cannot continue a long project.
Since this project was risky, everybody can tell that it won't work, so I had a hard time to get enough funding. But back in Japan, I was very lucky to have a five-year period of relatively big funding by the Japanese government. But that program was -- how to say? One very famous Japanese scientist was handling that funding program. I presented our data and our project to him and he told me that, "I knew this wouldn't work." But he said he thought this was a good challenge to be funded. So I was very lucky to get some good funding. So I think I really need that kind of person who can predict which risky project would be funded. It's a very difficult job, but I think that kind of person would be essential.
Your work is at the frontier of cell research right now. Where do you think the frontier will be 25 years from now?
What would you like to leave as your legacy? What mark would you like to leave? Shinya Yamanaka: As a scientist who developed this iPS technology, I hope to see that technology used in clinics. That's my hope. At the same time, if this technology is not good, I'd like to say no to this technology myself. Right now I have to be very neutral. Again, this technology is still very young. We have very good hopes, but there are many, many hurdles as well. So I really have to say yes or no to this technology myself, that's my hope. What encouragement would you give to students and future scientists? Shinya Yamanaka: There are many diseases which we cannot cure with the current medical technologies, and it is basic science which can cure those diseases and those patients. So I hope many, many talented, young students will be scientists. Thank you Dr. Yamanaka. Shinya Yamanaka: Thank you very much.
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