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Researchers for the future

His aim is to develop a treatment for muscular dystrophy with iPS cells (2)
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Dr. Hidetoshi Sakurai

Interviewer :
In 2008, you moved to the Center for iPS Cell Research and Application, iCeMs, Kyoto University, the predecessor organization of the present CiRA. What was your motivation to do it?

Dr. Hidetoshi Sakurai

Sakurai :
I was back to Nagoya University as a post-doctoral fellow after submitting my doctoral thesis. As a member of the immunology lab, I was studying ES cells, and at that time I had no colleague and had to do everything by myself. In the meantime, I knew that a researcher published a study using the marker that I had found, in the field of skeletal muscle regeneration, and I felt I was behind. I wondered whether I could compete with such a researcher in this field if I stayed in the position, and I thought at that time that I would quit my research activity to work as a clinician again.
On the other hand, Dr. Yamanaka generated human iPS cells in 2007, and it seemed to me that it was the beginning of a new age. Then, Dr. Nishikawa told me that Dr. Yamanaka was perhaps looking for researchers, and I sent an e-mail to Dr. Yamanaka, saying that I would like to work in his lab.

Interviewer :
At that time, you sent an e-mail, and not a phone call?

Sakurai :
Yes, I sent an e-mail. It seemed to me that there were high hurdles to clear, but what was important was to tell him my will, and I was employed for one year as a postdoctoral fellow. I had my family in Nagoya (about 150 km distant from Kyoto), and I commuted by the Shinkansen (super-express train) every day from Nagoya to Kyoto. I was like a triathelete who took a bicycle at the Kyoto Station to run along the Kamogawa river to the University. It was in 2010 that I got a post of lecturer for a term of 5 years and called my family to stay with me in Kyoto.

Interviewer :
How is it possible that iPS cells will serve a treatment of muscular dystrophy?

Sakurai :
For skeletal muscle, there are stem cells called satellite cells also in adults, which are combining with destroyed muscle fibres and repairing them. In DMD, destruction of muscle fibres is always going on and repairing satellite cells become exhausted. We inject here skeletal muscle precursor cells induced from the patient-derived iPS cells. The precursor cells develop into satellite cells that grow and differentiate into myoblasts. Then the myoblasts grow and combine with the patient's skeletal muscle cells, to produce dystrophin. Or the myoblasts combine with each other to form muscle fibres expressing dystrophin. We treat beforehand the patient-derived iPS cells with gene manipulation, so that the cells derived from the iPS cells will produce dystrophin. We can expect a treatment using such a process for complete cure of the disease.
The present situation is that the exon skipping is taking shape as a gene therapy, and there are some countries that are skeptical about cell transplantation therapies, while some other countries have good results from studies using fetal periaortic cells. My dream is to show that we will be able to regenerate skeletal muscle cells from iPS cells, a Japan-made technology, by using a given method of induction, and develop a technology that allows us to prepare skeletal muscle precursor cells for clinical use wherever we want them.

Interviewer :
At what stage is you research at present, and what is the problem to solve? It is considered that cell transplantation therapies will be realized only after a long period of development. What will be necessary for accelerating the development?

Sakurai :
For transplantation of mouse iPS cells into mice, we have specified the precursor cells to be used and developed a technique using these cells. We have demonstrated that satellite cells are induced from these cells by this technique and dystrophin is expressed in skeletal muscle cells induced. At present, we observe this dystrophin expression only locally in the injection sites, and are studying what is necessary for having the injected cells distributed systemically and engrafted throughout the animal's skeletal muscle. We find several articles reporting that skeletal muscle precursor cells are induced from human ES or iPS cells, where any highly reproducible technique is not yet available. So far, we have no established technique for inducing the precursor cells. I want to find it as soon as I can.
There are different techniques available for inducing skeletal muscle cells. If we will develop a new technique using transcription factors for inducing the precursor cells from iPS cells more efficiently, it will shorten our way to clinical applications. There are also different techniques for generating iPS cells, for example, one using Sendai virus, plasmids, or mRNA, and it will be important for us to adopt such a technique where necessary, to accelerate the development. I hope we will be able to demonstrate in 2 or 3 years that human iPS cells serve to treat the disease in a mouse model.

Interviewer :
Another field in which iPS cells will be useful will be drug development in vitro. How is your research in this field?

Sakurai :
It is important to develop a medicine that delays the progression of the disease, as well as to develop a treatment by cell transplantation. Data from animal experiments suggest that destruction of muscles without prolonged severe inflammation does not lead to severe muscular atrophy, and I am trying to develop a drug that targets molecules responsible for prolongation of inflammation up to a chronic stage. For this study, it is necessary to establish an easy screening system. A possible system is of skeletal muscle cells induced from iPS cells with a fluorescent labelling specific for the responsible molecules. We prepare such a system from a DMD-patient-derived iPS cells, with a control from a healthy person-derived iPS cells. We stimulate the muscle cells so that they expand and contract in a manner similar to that in vivo. Then only the patient-derived muscle cells with muscular dystrophy give inflammation and this inflammation visualized by fluorescence. Such a system using mouse iPS cell-derived muscle cells is already established. If we have a similar system of human iPS cell-derived muscle cells, it will be useful for screening drugs. We add a candidate drug to such a system in which cells with muscular dystrophy are emitting fluorescence. If the fluorescence disappears following the addition of the drug, the drug is effective against inflammation. I have an idea that this kind of screening systems will be useful for finding a drug specifically effective for DMD. And, to realize the idea, it is also important to develop a system for mass culture of human skeletal muscle cells.

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

Interviewer :
The Center for iPS Cell Research and Application (CiRA), Kyoto University, where you are working, is a new establishment with an open-concept design where the space of each floor is not partitioned into small rooms and all members of the floor are sharing the space. Do you think this system is good for young researchers? Is it comfortable for you?

Sakurai :
I find my research speeded up by this system. When I need someone's advice, I am allowed to ask any colleagues working on the same floor without reserve. When I ask them "I have such and such idea, and what do you think about it?" some of them give me immediately their idea or advice. When I want to do something new, many colleagues who have experiences in the field or technology may help me if I have poor knowledge or experience in the new work. We have common objectives, and perhaps this makes it possible for us to work in this way. CiRA's purpose is to develop clinical applications of iPS cells, and it is favourable to me. I find it the best research environment in the world for me, where researchers who have common objectives and specialize in different fields are working together on the same floor. This system was established with the leadership of Prof. Yamanaka, and I thank him. I want to work here longer, if the situation allows it.

Interviewer :
In 10 years, how will be the situation of research in this field, and what will you be doing? Can you tell us what you imagine?

Sakurai :
For my research, I will have already found what type of cells will be most suitable for the cell transplantation treatment, started joint pre-clinical studies using dogs, and will be discussing what to do in clinical trials. In the most successful case that I can imagine, the first patient who has received the treatment in our clinical trial gets his/her muscles recovered and walks. If it will happen, I will be very happy, though this will be the case in which everything goes well to give the best possible results at all stages of research. For the treatment of muscular dystrophy in general, we will be in an age where less expensive and more efficient nucleic acid analogs will be available for exon skipping treatment, and patients will receive monthly injections to recover to a stage of mobility with wheelchairs. For drug development, one or two candidate drugs will be screened at my lab, tested in animal experiments and demonstrated to be effective, I hope.
If we will have successful cases of cell transplantation treatment in dog DMD models, at a first stage, there will be more researchers coming to this field. To invite more researchers, I have to continue my way as a pioneer. When there will be many researchers working in this field, the research will advance rapidly. I wait young researchers who want to work for clinical applications. We are looking for graduate students who will study in my lab. If you are interested in this offer, please contact us. We are waiting for you.


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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