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SEIZE THE WORLD / Yamanaka: Prioritize patients above papers

Tetsuo Nagai/The Yomiuri Shimbun

Prof. Shinya Yamanaka answers during the interview at his office at CiRA in Kyoto.

The Japan NewsRegenerative medicine is expected to be one of the ultimate treatments to help patients who suffer from intractable diseases and chronic conditions arising in a progressively aging society. With that in mind, The Japan News conducted an interview with Nobel laureate and Kyoto University Prof. Shinya Yamanaka, a pioneer in iPS cell research, which is a key technology for the development of regenerative medicine in the future.

Q: What do you expect of the future and possibilities of regenerative medicine using stem cells, including iPS cells?

Yamanaka: There are many possibilities in terms of using iPS cells in our medicine. Many patients could be helped by these new strategies. We are now trying to bring iPS cells to patients suffering disease, for example, Parkinson’s disease, Type I diabetes, cancers. I believe that in the next 10 or 20 years, we can come up with many new treatments and therapies by using iPS cells and other related technologies.

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  • Tetsuo Nagai/The Yomiuri Shimbun

    Shinya Yamanaka speaks to The Japan News.

Q: Recently, more Japanese researchers have been awarded the Nobel Prize in science. Do you think it is a good sign for the development of Japan’s science and technology?

A: Yes. I am very proud of our country because, at the moment, Japan is No. 2 in terms of the number of Nobel recipients [in the 21st century] in the fields of medicine, chemistry and physics, after the United States. All the Japanese people should be proud of that.

However, at the same time, I need to worry about our future because in most cases the Nobel Prize is awarded for past research results, which were conducted 20 years ago, 30 years ago, even 50 years ago. Many Japanese scientists are actually receiving Nobel Prizes, but that doesn’t necessarily mean we are doing great in science in the present time.

When I was young, in my 30s, I was in the U.S. to do my postgraduate training. I met many young Japanese scientists, doctors and physicians then. But nowadays, I see more and more Asian scientists from China, Thailand, [South] Korea, Singapore, Malaysia, the Philippines, but not many from Japan.

I really hope Japan will continue to keep a leading position in science for a long time. But I’m afraid it may not be the case after five years. We may see more Nobel laureates from countries like China and [South] Korea.

Experience, patient focus drives research

Q: When you were awarded the Nobel Prize in 2012, it was impressive that you said in an interview that failure and discouragement as a surgeon made you stronger as a scientist.

A: That was one factor, that’s for sure. I saw many patients who we couldn’t help at all when I worked as a clinician. Through those experiences, I thought I really wanted to do something to help these patients. The answer was to become a medical scientist. I decided to contribute to medicine and patients in a different way, not as a clinician but as a scientist. I always keep my original vision to perform, to do “science.” It does not mean writing or publishing papers, but helping patients by making new therapies. I think that experience in my early days is very important in my science.

Q: You also said in the interview that you had not been able to get up early due to discouragement after returning from the U.S. How did you overcome such depression?

A: I got depressed to some degree because of differences in the scientific environment and atmosphere between the two countries.

I was already working on mouse embryonic stem cells then. Nobody around us could understand the importance of them.

However, in late 1998, human embryonic stem cells were reported for the first time. That was a big hit to me because we could help thousands of patients by using ES cell-derived brain cells or heart cells. That really activated me again. This is one reason how I overcame scientific depression.

Another reason was that I was lucky enough to be promoted to an associate professor at Nara Institute of Science and Technology in 1999. I got my own laboratory for the first time. The research environment of the institute was very good, like in the U.S. That was the second reason.

Struggle with time, cost

Q: RIKEN’s Masayo Takahashi’s team successfully conducted the world’s first iPS cell (see below) transplantation into retinal tissue. How do you evaluate this trial as a developer of the cells?

A: We helped Dr. Takahashi in evaluating their iPS cells and retinal pigment epithelium cells derived from the iPS cells. We used next-generation sequencing machines to perform whole-genome sequencing of their cells.

Takahashi’s team used iPS cells generated from patients’ own skin cells. That is, it was autologous transplantation.

From that experience, we learned that autologous transplantation is very expensive and also it takes a very long time, at least six months.

I think that, for the next five or 10 years, instead of autologous transplantation, utilizing iPS cells from healthy volunteers is the way to go. Such tissues generated from others are called allografts. By utilizing allografts, the cost can be much lower. We can also prepare cells [for transplantation] in advance.

While there are many advantages of using allografts, the downside of using iPS cells from non-patients is immune rejection.

We need to suppress immune rejection in order to succeed in this method.

The biggest effort to control this problem in this institute [the Center for iPS Cell Research and Application (CiRA), Kyoto University] is to establish a so-called “Stock of iPS Cells” for regenerative medicine. The question is how to overcome immune rejection. We found that, if we make iPS cells from some specific donors — more precisely, donors who have HLA homozygous alleles — we can minimize immune rejection after transplantation.

On the basis of a database of all Japanese HLA types, we have calculated that all we need is 140 lines (donors) in order to cover more than 90 percent of all the Japanese population.

In 2015, we were able to ship the very first iPS cells stock line from this institute. We have distributed that line into institutions. That one line alone can cover up to 20 percent of all the Japanese population. It will be enough to perform clinical studies by using just that one line.

For the future, we would like to go back to autologous cell transplantation. In order to achieve that target, we still need to find a way to generate iPS cells much faster at much lower prices.

That kind of research has been on going in this institute and in other research institutes. As we have seen much progress in that area, hopefully in five or 10 years we can go back to autologous transplantation.

Q: In the U.S., some people including scientists are trying to realize immortality or super-longevity. Do you think these challenges can come true?

A: Cells in a body divide, but there is a limited number of cell divisions. Finally, unless we replace all of our brain cells and all of our heart cells, I don’t think we can live forever. We may perform heart transplantation. However, if we change the brain, I’m not myself anymore. So I don’t think that it will come true.

On the other hand, we are trying to expand our “healthy life expectancy.”

At the moment in Japan, we have the best record of life expectancy. Average women can live up to 86 and men can live up to 80. But healthy life expectancy, which is calculated by the Health Ministry as a measure of the lifetime span in which people can live without trouble, is around 70 in men, and in women must be around 74 or 75. Thus, there is a significant gap between life expectancy and healthy life expectancy.

During the 10 years of that gap, we will be in trouble. So the goal of our research is to shorten that gap.

I really want to live in a healthy way [up to] the time I die. That’s the best scenario of how we die.

Q: Recently, “scientific misconduct” problems have occurred in your field, such as the STAP cell scandal. Why have these scientific misconduct cases never ceased?

A: I believe our area, the stem cell field, is very competitive. As many of our research results can lead to medical applications, many people like venture capitalists, venture companies are paying attention to us. That’s maybe one major reason how this kind of problem happens multiple times in our field.

Traditionally speaking, many results in stem cell fields have been published in leading journals, such as Nature, Science, or Cell. I shouldn’t say “many,” but some of them are very difficult or almost impossible to reproduce.

That kind of history may make it much easier for some bad scientists to fabricate [false results]. Some such scientists may think it will be OK, even if their finding won’t be reproduced by others, because there are many precedent examples in this field. I think that may be another reason.

But after the STAP scandal in 2014, more and more scientists in our field have become very careful. The No. 1 keyword for us is “reproducibility.” Before publishing any important papers, we need to do a double check that other scientists can reproduce our results. It is an important lesson in this field.

Father’s blood

Q: How did your father affect you?

A: In many ways. I thank my father.

Actually, he was one of the patients who I could not help. He suffered from liver failure.

Nevertheless, he was very proud of me for becoming a medical doctor.

When I gave him some small medical procedures, such as infusions, despite pain caused by his illness, he seemed to be smiling at receiving some small medical procedures from his own son.

Soon after, he passed away.

After that, I became a scientist.

I often think my father may be upset with my career change.

My father was an engineer, who managed a town parts factory in Higashi-Osaka, Osaka Prefecture. I grew up, in many years, in the house next to his factory. As I watched his work in his factory, I sometimes feel like an engineer myself. It is very important for our work because being an engineer is very application-oriented, not paper-oriented.

Q: How about marathons? Reportedly, you successfully finished running the Osaka Marathon this year.

A: I run three or four times per week. I’m now preparing for the next marathon held in Kyoto in February 2016. Running the marathon means a lot to me.

First of all, I’m running to perform fund-raising. Though we are getting a lot of research support from the government, it is not enough to hire people for a long time. In order to offer them better and more stable employment, I perform fund-raising. Finally, I’m running in order to raise the idea of charity in the minds of Japanese people.

It is also very good for my mental and physical health condition.

Without running, I don’t think I can maintain my mental and physical health because my father and grandfather suffered from Type II diabetes. If I don’t run, I will become very big and suffer from diabetes.

This interview was conducted in English by Japan News Deputy Editor Kyoichi Sasazawa on Dec. 28, 2015.

■ Profile: Shinya Yamanaka

Professor and Director of the Center for iPS Cell Research and Application (CiRA), Kyoto University

Yamanaka was born on Sept. 4, 1962, in Osaka Prefecture. He was educated at the Tennoji Junior High [Middle] School/High School attached to Osaka Kyoiku University. In middle school, he joined the judo team at his father’s recommendation. In 1981 he entered Kobe University School of Medicine. After receiving a medical doctorate from Kobe University in 1987, he earned a PhD from Osaka City University in 1993.

After serving as a professor at Nara Institute of Science and Technology, he was appointed as a professor at Kyoto University in 2004. Yamanaka’s team reported the world’s first generation of mouse iPS cells in 2006 and the generation of human iPS cells in 2007.

Yamanaka shared the Nobel Prize in Physiology or Medicine 2012 with John Gurdon of the United Kingdom. He has also received many prominent awards, including the Albert Lasker Basic Medical Research Award and the Wolf Prize in Medicine.

■ induced pluripotent stem (iPS) cells

These cells have the ability to differentiate into various types of somatic cells. This feature is very similar to embryonic stem (ES) cells, which are controversial because the process of making them involves destroying an embryo. But iPS cells can avoid such a controversial process because the cells are derived from adult somatic cells, including skin cells.

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