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Researchers for the future

His aim is to develop a treatment for muscular dystrophy with iPS cells (1)
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Dr. Hidetoshi Sakurai

Dr. Hidetoshi Sakurai, in his late 30s, is an up-and-coming researcher working at the Center for iPS Cell Research and Application (CiRA), Kyoto University. After graduating from Nagoya University School of Medicine, he was working as a physician in the department of nephrology in a private hospital, and it was 10 years ago, when he found an article on vascular regeneration from mouse embryonic stem (ES) cells, that he decided to leave his position as a clinician to concentrate his activity on research. His goal is always to cure diseases, and he is doing his utmost in his research to find a way to treat muscular dystrophy with induced pluripotent stem (iPS) cells. In his private life, he has four children, the eldest being a schoolchild. He says, "it is a challenging work", and also, "I try to do all that I will be able to do, and I take what is more difficult when it is difficult to choose among many things." He seems to be a very dependable person.

Interviewer :
Dr. Sakurai, you were a physician at the start of your career, and why did you decide to change your path and work as a researcher in the field of regenerative medicine?

Photo:Dr. Hidetoshi Sakurai

Dr. Hidetoshi Sakurai

Sakurai :
In the first place, I wanted to be a physician who would be able to treat any kind of disease. After graduating from school of medicine, I chose the department of nephrology to work. There were many dialyzed patients in the department of nephrology, and I thought it was good for these patients to extend their lives with the aid of dialyzers. However, I heard some patients say that it was hard for them to live in such a way, or that they did not want to receive such a treatment any more. I realized then that it was only a doctor's imagination that it would be enough to extend the patients' lives.
When I was in the third year of my experience as a clinician, I read an article published in Nature by Dr. Jun Yamashita (currently Professor at CiRA) working in the laboratory of Prof. Nishikawa at Kyoto University at that time. It was about a three-dimensional regeneration of blood vessels from mouse ES cells. Then an idea came to my mind that it would be possible to do the same thing for the kidney. On the other hand, several professors gave me an advice that it would be better for me to be a researcher. In the clinical works of internal medicine, we test, diagnose, and treat patients according to given schemes. Out of these schemes, I often asked questions about why a person was affected with such and such disease, or why such and such medicine was effective against a disease. Seeing this, the professors might think that I was suitable for research. If I would be a researcher, I would do something new and useful in clinical medicine, I thought.

Interviewer :
You started your research activity in the lab of Prof. Shin-ichi Nishikawa, specialist of regenerative medicine. You made a quick decision and took a quick action, didn't you?

Sakurai :
I called Prof. Nishikawa without any letter of introduction. I said, "I would like to work in your lab from next year". He said, "Come to my office to talk with me". Then I came to his office and said, "I want to make kidneys to cure diseases". He said, " It would not be possible before the end of your life". I said, "It will be so if you say so".I did not know anything about research in this field. I had not studied embryology and had not seen ES cells. He said, "You may come to work in my lab if you understand well that things will not go as you expect". Then I moved from the graduate school of Nagoya University to RIKEN Kobe Institute to study there.

Interviewer :
I guess Prof. Nishikawa was surprised that a graduate student called you without any letter of introduction and came to your office, wasn't he?

Sakurai :
At that time, there were four other graduate students of the same year who came to his lab. They were medical doctors who were inspired by the article of Dr. Yamashita. It was Dr. Takumi Era (currently Professor at the Institute of Molecular Embryology and Genetics, Kumamoto University) who taught us. Dr. Era was looking for graduate students to organize a group of research, and it was a good timing. We were all beginners in this field and did not know what to do when we started working in his lab. And I could continue my work with these good colleagues.

Interviewer :
You found that it was not easy to regenerate the kidney and changed your research subject to muscular dystrophy. How did you decide to change the subject?

Dr. Hidetoshi Sakurai

Sakurai :
The research subject given to me in Prof. Nishikawa's lab was to know whether PDGFRα (platelet derived growth factor receptor α), a factor expressed in the mesoderm during embryogenesis that will develop into bone, cartilage and skeletal muscle, is also expressed in ES cells or not. If yes, we would be able to use this factor as a marker for specific cells. I found that ES cells in which PDGFRα was expressed and FLK1(vascular endothelial cell growth factor)was not were highly susceptible of developing into bone, cartilage and skeletal muscle. It was my doctoral thesis.
Prof. Nishikawa said to me when I started working in his lab, "what you should do is to cure diseases". I always keep this word in mind. We still do not know much about the intermediate mesoderm from which the kidney is developed. I imagined that I would have many difficulties at a preliminary stage if I wanted to deal with the kidney. Prof. Nishikawa said also, "once you demonstrate that your research really contributes to curing a disease, you will see your research develop in a wider spectrum in the future". I was also inspired by this word. I guess he wanted to say, "you will limit your research by yourself, if you study always the kidney".
I found some reports on studies for regeneration of bone and cartilage, but not for skeletal muscle. So I decided to concentrate my research on skeletal muscle. I was also interested in knowing whether the ES cells that I had found would be useful in regeneration of skeletal muscle cells. On the other hand, I knew that there are many intractable muscular diseases that nobody had succeeded in treating, and I wanted to contribute to improving the situation.

Interviewer :
Muscular dystrophy is considered as an intractable disease. Why is treatment using cell transplantation expected for this disease?

Sakurai :
Patients with Duchenne muscular dystrophy (DMD), the most severe and intractable type of muscular dystrophy, need wheelchairs at their teenage and mechanical ventilators at their age of 20s, and then die. In 1985, it was found that the patients with DMD have mutations in the dystrophin gene that codes for the protein "dystrophin" that underlines the skeletal muscle cell membrane. Such mutations lead to an abnormal expression of dystrophin and in consequence to a damage of muscles that causes inflammation and atrophy. In this case, we could treat the patients by having dystrophin expressed in their muscles by some means, in theory, but it is not easy to do it.
t present, we give steroids to the patients to control inflammation, or other chemotherapies to control the progression of the disease, but we have no means to cure the disease completely. There is a gene therapy called "exon skipping" that is recently developed and tested in clinical trials. This is a technique using synthetic nucleic acid analogs called "Morpholinos". Many of the DMD patients have a type of mutation called "frameshift mutation"(reading frame shift) caused by deletion of an exon, which blocks dystrophin synthesis. The technique is to inject a Molpholino that binds to a target exon (next to the deleted one) in the dystrophin gene so that this exon is skipped in the process of "splicing" taking place in the gene to produce a protein. This "exon skipping" serves to repair reading frames and enables a synthesis of dystrophin with a smaller molecular weight. In dog DMD models, injection of Morpholinos has been found to be effective. This is not a complete cure, but, for the moment, we will be able to relieve symptoms by different means including this. Meanwhile, I hope to develop ultimately a cell transplantation therapy to cure the disease completely.


Interviewer :
Furugori Etsuko
Interview date : January 12, 2011

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Dr. Hidetoshi Sakurai

Lecturer, Center for iPS Cell Research and Application (CiRA), Kyoto University

Hidetoshi Sakurai was born in Gifu Prefecture in 1973. He graduated from Nagoya University School of Medicine in 1998. He was working as a clinician in the department of nephrology at Nagoya Ekisaikai Hospital from 1998 to 2001. He was a graduate student at Nagoya University Graduate School of Medicine and was doing his studies in Nishikawa lab at RIKEN Center for Developmental Biology from 2001 to 2005. He was granted a doctor's degree in 2005, and doing his studies at Nagoya University Graduate School of Medicine. He has been working at the Center for iPS Cell Research and Application, Kyoto University, as a postdoctoral fellow from June 2008 to October 2009, and a lecturer since November 2009.

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