Dr. Shinya Yamanaka’s Keynote Address - 2013 Annual Conference

The following is a transcript of Dr. Shinya Yamanaka’s address to the 2013 U.S.-Japan Council Annual Conference on October 4, 2013.

Good afternoon. Hiro Ogawa, thank you so much for your kind introduction. Hiro and his wife Betty have been my mentors for me and my family for the last several years, and Hiro has been my golf coach.

Approximately a year ago, I got a call from Stockholm. It was the chairman of the Nobel Selection Committee, and he told me, “We have decided to award you this year.” And then he said, “Would you accept?” so I said “Yes, why not!” Then he said, “Shinya, I am happy to hear that, but this will be confidential for the next two hours.” But as soon as I finished that phone call, I broke the embargo and I called Hiro.

Today, I would like to talk about VW. I will not talk about German automobiles. I will talk about my own motto.

I started my career as a surgeon, as a doctor, not as a scientist. It was my father who talked me into medicine. This is my father who passed away 26 years ago. I respected him a lot. I liked him a lot. I like his hair. I am actually envious. My father was a businessman. He had a small factory in a small city called Higashi-Osaka in the Osaka area. I am his only son. When I was born, my father must have been happy to have a successor to his business. However, when I became a junior high school student, he started saying, “Shinya, you should not take over my business. You should become a doctor to help patients.” I don’t know why he said that. Maybe my father thought his son was not smart enough, or brave enough to be a businessman. Or maybe he thought his son was too honest to be a businessman, I don’t know. Just joking, I’m sorry. So I listened to his opinion and became a doctor, I became a surgeon. When I was doing my residency, he passed away, when I still needed him a lot. He must have been in pain before he died. But, he did seem happy receiving some medical procedures from his own son. He must have been proud that his son became a doctor.

When I was doing my residency, I saw many patients who we couldn’t help at all, like patients suffering from spinal cord injuries, patients suffering from Lou Gehrig’s disease. I started thinking that it would be basic medical research that could help these patients. At the same time, during my residency, I found myself not talented at all in surgery. Actually, I was terrible, so I thought I wouldn’t be able to help any patients by doing surgery. It was dangerous, actually. So, I decided to change my career. I escaped from hospital and I entered graduate school.

I got my Ph.D. in pharmacology in 1993, and after that I decided to continue my training as a scientist. I went to San Francisco, I became a post-doc at Gladstone Institute. You know, I sometimes feel, I am afraid that my father is very angry, saying, “Shinya, stop shaking test tubes! Come back to clinics!” but I decided to continue my research.

This picture was taken when I was in San Francisco with my boss, Tom Innerarity. The purpose of this slide is to show you that I used to have more hair.
So, here comes “VW.” This is the then president of Gladstone Institute Dr. Robert Mahley. He had, and he still has, VW. But, one day, he taught us young scientists at Gladstone how to succeed as a scientist, and he said, “it’s simple, we have to follow VW.” Well, I had a Toyota, so I thought, you know…but he said in this case, “VW” does not mean his Volkswagen. In this case, it means Vision and Work hard. It is a very simple message. However, it is a very strong message to me. I was, and I am, working hard and confident. However, when I was asked what my vision was, I could not answer immediately. Is it to publish papers? Is it to get funding from NIH? Is it to receive awards? No! I recall my initial motivation to be a scientist. My vision is to help patients, to develop new cures for patients suffering from intractable diseases and injuries. So from that moment, I always kept this simple message, “VW,“ in my mind.

Also at Gladstone, I met some very important cells: embryonic stem cells, or ES cells. ES cells were first generated by scientists in the States and the U.K. from mouse embryos in 1981.

Mouse ES cells have two important properties. We can expand mouse ES cells as much as we want. Then, we can make many types of cells, from mouse ES cells, in a large amount like brain cells, heart cells, blood cells and so on. So mouse ES cells have been very useful in biology. Because of this importance, Dr. Martin Evans, who first generated mouse ES cells, received the Nobel Prize in 2007.

After spending three years at Gladstone, in 1997 I and my family went back to Japan. I continued my research on mouse embryonic stem cells. But, after a year or two, I became sick. The name of my disease is PAD. PAD stands for Post-America Depression. When I was at Gladstone, I was surrounded by many top-class scientists. I was surrounded by many supporting staff. The scientific funding was very good. But after going back to Japan, I lost that stimulating environment. So that’s why I became depressed. I was not sure whether I could really realize my vision by doing science. 
I was often told by my colleagues, “Shinya, you should stop working on mouse cells.” “You should do something more related to human patients.” “Do you want to be a mouse doctor?”  So, I was about to quit from science and go back to clinics. But, very luckily, two events happened that rescued me from PAD.

The first event happened in 1998, when Dr. James Thompson, in Wisconsin, generated human embryonic stem cells from human embryos for the first time. Human ES cells have the same two important properties as mouse ES cells, in that we can expand human ES cells as much as we want, then we can make various types of human cells in large quantities, such as dopaminergic neurons, neural stem cells, heart cells and so on. Then, we could transplant these human cells into patients suffering from various diseases and injuries, such as Parkinson disease, spinal cord injuries and heart failure. So it turned out that ES cell research, my research on mouse ES cells could contribute to human health, so I was very excited.

However, human ES cells face a severe ethical problem, or obstacle. We have to use human embryos. We have to destroy human embryos to generate human ES cells, so many people are still against the usage of human ES cells, including these two important leaders of the world at that time. You know, I don’t think you can read this sentence here, I cannot read it by myself, but I think it says “President Bush and the Pope talking about something bad about human ES cells.” They were totally against the destruction of human embryos. So, I knew the potential of human ES cells were enormous, but at the same time, the hurdle was very high.

The second event that rescued me from PAD was my promotion to this new institute, the Nara Institute of Science and Technology. As you can see here, this institute has a very beautiful campus, they have many good scientists, they have many supporting staff, they have good funding and most importantly, they had many talented and hard-working graduate students. I got my own laboratory for the first time in my life. Because of these two events, I was able to overcome my PAD and I was able to continue my research.

In this new scientific environment, I decided to pursue this goal: I wanted to overcome the ethical hurdle of human ES cells. We wanted to make ES-like stem cells directly from adult skin cells or blood cells. If we can do this, we can avoid the usage of human embryos, so we can overcome the ethical issue of human ES cells. Of course I knew this was very difficult. I thought it would take 10 years, 20 years, or even longer, but I did not tell that difficulty to my students. I just told them how wonderful it would be if we could do this. And I got three very talented graduate students and some staff members. We worked, they worked very hard, and to our surprise, it did not take 20 years.

In 2006, after 6 years, 6 years after we initiated this project, we became able to convert mouse skin cells into stem cells that are very similar to mouse ES cells. The procedure was surprisingly similar: all we have to do is just add four factors, more precisely, four genes, into mouse skin cells. Adding genes is very simple. Even high school students can do that procedure. We designated these new stem cells iPS cells, induced pluripotent stem cells. In the following year, in 2007, we and two or three other groups in the States were able to recapture the same iPS cell generation in humans.

I want to tell you that it was not myself who generated iPS cells. It was many of young students and supporting staff in my laboratory, especially these three scientists. Young scientists were essential. Yoshimi and Kazu were two of my very first graduate students. Tomoko was my first supporting staff member. Without these three young scientists, we could have never generated iPS cells, at least in my own laboratory. Well, I have two daughters who are a bit younger than these three persons, but these three persons are almost as important as my daughters….I forgot to tell you, I have a wife. She is more important.

So, let me show you how we make iPS cells. In the beginning, we generated iPS cells from skin cells, but in order to do that, we have to ask for a skin biopsy from donors. It’s not a difficult procedure, even I can do that, but still, we do need anesthesia, we do need stitches, so it’s not the best way. Another group in San Diego, they have developed a way to generate iPS cells from a single hair. It’s much easier; however, a single hair means a lot, at least to me. So, instead of using skin cells, or instead of using hair, we have developed a way to regenerate iPS cells from blood cells. So, basically, all we need is a simple blood sample, and then all you have to do is add those factors into your blood. Then, the four genes described here will go into the blood cells and initiate the process of iPS cell generation, also known as reprogramming. They start proliferating, and they gradually become iPS cells. This is a microscope image of iPS cell generation, I hope you can see cells proliferating rapidly and form iPS cell colonies.

If we add some drugs to iPS cells, we can make many types of cells, like beating heart cells. This is a microscope image of beating heart cells grown from iPS cells. When I first saw this seven years ago, my own heart synchronized. So we can use these heart cells, or brain cells, liver cells, blood cells, derived from iPS cells in two types of medical and pharmaceutical applications. We could transplant heart cells derived from iPS cells back into patients suffering from heart failure, so instead of organ transplantation, which is still very difficult in Japan, we may be able to save patients suffering from very severe heart failure. By transplanting neural cells into patients suffering from spinal cord injuries, we may be able to treat those patients. Alternatively, we could use these brain cells and heart cells in laboratories. We can make disease models and we can perform drug screening. So there are two types of medical and pharmaceutical applications. We now have more focused vision. We want to make this happen. We want to bring iPS cell technology to patients. It is not my vision; it is the vision of many scientists all over the world.

There are strong scientific activities, both in Japan and also in the States. Actually the States has even stronger activities for iPS research. So in order to achieve this goal, I have been working in two places, in Kyoto and in San Francisco.

In Kyoto, at the Center for iPS Cell Research and Application (CiRA), we have more than 200 people working on iPS cells. In San Francisco, I rejoined the Gladstone Institutes in 2007. They now have this beautiful building in the newly-developed Mission Bay campus, near the baseball stadium in San Francisco. At Gladstone Institute, I have a smaller but excellent group. I brought two Japanese post docs from Japan to San Francisco. So, again, there are very strong activities in the two nations. It is essential to connect the activities in the two nations. Strong collaborations are essential to promote this technology to the public and to critics.

Well, I did receive the Nobel Prize last year, but the truth is we have not yet been able to help any patients by this technology. We still have to work very hard, so I really hope with the help of many scientists in Japan, in the States, and in many countries, we can bring this technology to patients. I hope we can do that before I meet my father again in the near future.

Thank you very much.

 

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