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Researchers for the future

Toward safe applications of human ES cells

Dr. Hidenori Akutsu

Dr. Hidenori Akutsu is a researcher in reproductive biology and is the second Japanese who generated human ES cells. He is working on techniques for generating and growing ES cells for their safe applications at the clinical level at the National Research Institute for Child Health and Development (NRICHD) where one is allowed to work close to clinical medicine. He was working as clinician in obsterics and gynecology, and changed his occupation to researcher when he met many people who encouraged him to do so and had opportunities to do so. Not only he was working on what he is most interested in, but also he had a flexibility of adapting himself to a new environment with new colleagues, and this opened him the door to a next stage of working.

Photo:Dr. Hidenori Akutsu

Dr. Hidenori Akutsu

Interviewer :
You were the second Japanese who generated human ES cells in 2010. What is your research theme at present?

Akutsu :
I am working on techniques for generating and growing human pluripotent cells including ES and iPS cells that will be safe for use in regenerative medicine. For growing these pluripotent cells, we have so far been using many xenogeneous materials such as culture broths containing fetal bovine serum, feeder cells containing mouse fibroblasts, matrices coated with gelatine derived from pigs, and enzymes for separating cultured cells into small aggregates. It is not to say that it is dangerous to use ES cells grown under such conditions in regenerative medicine, however, it will be better if we will be able to grow these cells without xenogeneous materials. In this case we will have much safer cells. Recently we have succeeded in growing human ES and iPS cells without using any xenogeneous materials and replacing them, for example, with human fibroblast derived feeder cells.

Interviewer :
For generating and growing stem cells available for regenerative medicine in the future, you have still some technical difficulties to clear, don't you?

Akutsu :
Mouse ES cells are not very difficult to culture. They grow in culture when separated into single cells. But this is not the case in human ES and iPS cells. These cells die when separated into single cells, and are not easy to culture. Generation of human ES cells was first reported in 1998, and there was no following report for several years after that. This seems to be partly because it was technically difficult to culture the cells. It is not easy even for research purpose.

Interviewer :
What is your aim to study human ES cells at NRICHD that is the very center of pediatrics in Japan?

Akutsu :
NRICHD has a hospital and a research institute. There are many children with intractable diseases who come to the hospital. There are still many diseases for which any diagnosis or treatment is available. NRICH, since its foundation, as a research institute, has set an objective of promoting treatments of children's intractable diseases with stem cells, and I am involved in it. So, my work is not only to establish ES cell lines, but also to develop techniques for using these cells for treatments of intractable diseases. This will be my challenge.
The hospital is in front of our research institute, and it is an environment by which I am immediately motivated. Patients and their families are hoping that research will advance and one day their diseases will be cured. I can imagine. And we have to give some answer to them. I am working jointly with clinicians at the hospital. It is always important to share clinical points of view. At the international level, there are many cases in which stem cell studies are reported from children's hospitals at different locations. Now clinical applications are something realistic, and I hope that our work with clinical members will contribute in a synergistic manner to realizing some of them.

Cover:Three human ES cell lines established at the National Research Institute for Child Health and Development.
Three human ES cell lines established at the National Research Institute for Child Health and Development.(large view(PDF))

Interviewer :
Since last years many people have been speaking of iPS cells, and it seems that ES cell research has become a field that is not so much paid attention to, doesn't it?

Akutsu :
ES cell research projects are subject to examination and approval at the ethics committee under the present regulations, and I can say that it takes more time and effort to launch a project in this field. Meanwhile, the Ministry of Health, Labour and Welfare tends to take more and more flexible measures, and this makes it easier for us to proceed to do ES cell research under certain conditions that are not too strict to respect. I will tackle ES cell research more actively.

Interviewer :
In USA, they started clinical trials in which the first case was treated with ES cell-derived cells in October 2010, followed by three other cases so far. If you will launch a clinical trial in Japan, what will be the most difficult points?

Akutsu :
For starting clinical research, we have to follow complicated procedures that are different from those required for basic research. And, we have to conform ourselves to the requirements in terms of techniques and facilities for generating, growing and maintaining the cells under appropriate conditions. We will go on working, with many trials and errors. In USA, private companies took initiative of the clinical trials for the four cases, and it is not likely that they disclose detailed information. In Japan, most of the research projects are financed by public funds, and it will be better for us to work jointly with institutions from different fields, including private companies, for clinical research.

Interviewer :
You were a clinician in obsterics and gynecology, and what led you to move to the field of ES research?

Akutsu :
I just wanted to be a medical doctor of any specialty and entered the school of medicine. There I found it interesting to see how a single cell or fertilized egg develops into an individual, and chose the department of obsterics and gynecology. I realized that at that department of obsterics and gynecology at Fukushima Medical University many cases of infertility were treated, and it was there that the first intracytoplasmic sperm injection was done in Japan. They were very active in basic research. There was a custom in the medical office that one of the young members was regularly sent to the lab of Prof. Ryuzo Yanagimachi at the University of Hawaii, and in several years it was my turn to go to study at Hawaii. It was the turning point of my life, though I did not have any will or perspective at that time that I would be a researcher.
I did not have any knowledge or technique, and it was just like dry sand absorbing water that I learned everything in this field. I enjoyed very much this opportunity. At that time, in the Yanagimachi lab, they had just succeeded in generating clone mice, and I learned techniques for somatic cell nuclear transfer. I then came to work with Dr. R. Jaenisch at the Massachusetts Institute of Technology (MIT), who was studying the mechanisms of reprogramming at the molecular level to understand why the efficiency of clone mouse generation was low. I travelled many times from Hawaii to Boston. In doing this, I found it very exciting to be the first in the world to find some phenomenon so far unknown, and found it interesting to do research.
After that, I had an opportunity to deal with ES cells, and I was interested in these cells. At that time I thought to be back to my work as clinician, and came back to Fukushima after my stay at Hawaii for two years and a half.

Interviewer :
You did not return to a clinician, though?

Akutsu :
I once returned to a clinician, but it was always something about research that was in my mind. "Is there still anything left that nobody else but I will be able to deal with? I want to study ES cells." At the department of obsterics and gynecology, while they were dealing with early embryos for infertility treatment, nobody was interested in ES cells. Then I made up my mind and told Prof. Akira Sato who sent me to Hawaii that I wanted to do research. He accepted my proposal, and said that he would keep my post at the medical office so that I would come back any time I want. I owe him. I went to work at the US National Institute on Ageing (NIH/NIA). It was Dr. Minoru Ko, a co-worker at Hawaii, who invited me. He was working on comprehensive genome mapping. His ways of seeing early embryonic development and stem cells were so original, and I learned much from him. However, at that time I had little idea about genetic or molecular mechanisms of these phenomena. When I thought that I did not fit with research and would go back to Fukushima, one of my friends, Kelvin Eggan, who was a graduate student at MIT moved to Harvard University to have a lab, and he invited me to work together. Kelvin and I wanted to do exactly the same thing, and I knew him well, so I moved to Harvard, and began to work in his lab with a student. The grand boss was Prof. D. A. Melton who had established seventeen ES cell lines.
I felt I found a way. I began to study how to generate ES cells, and in my first experiments, I came to generate ES cells from two cryopreserved embryos. It was so lucky, though I had experiences of dealing with human embryos.

Dr. Hidenori Akutsu

Interviewer :
You met many good chances, and came up with exciting situations.

Akutsu :
Prof. Melton created the Stem Cell Institute. It is a cross-disciplinary virtual research institute, where specialists in different fields including basic medicine, jurisprudence, political science, ethics, and business, were working hard to make Harvard leader in the stem cell research. Dr. L. Summers, President of the University, gave a powerful speech at the opening ceremony that Harvard would be the world leader in ES cell research and application, and I was very impressed.
After that I found the National Institute for Child Health and Development was looking for a researcher who would work on human ES cell generation, and applied for it. "In Japan" was something that was always in my mind.

Interviewer :
Would you give some advice to young researchers?

Akutsu :
It will be important to pursue what you find interesting and devote yourself to that point without caring about other things. And respect colleagues around you. It is important for a researcher to get acquainted with other researchers. It is entirely due to such acquaintances with many colleagues that I am now working as researcher. I owe all of my colleagues.


Interviewer :
Jiro Urushibara
Interview date : February8, 2011

Dr. Hidenori Akutsu

Chief, Department of Reproductive Biology, National Research Institute for Child Health and Development (NRICHD)

In 1968 he was born in Minami-Aizu, Fukushima Prefecture. In 1995 he graduated from Hirosaki University School of Medicine, and was enrolled in the Department of Obsterics and Gynecology, Fukushima Medical University. From 1999 to 2002 he was working as research fellow at the laboratory of Prof. Ryuzo Yanagimachi at the University of Hawaii. In 2002 he was granted a degree of Doctor of Medicine at Fukushima Medical University and had a position of Assistant Professor at the Department of Obsterics and Gynecology. In autumn 2002 he got a post of research fellow at the Laboratory of Genetics, National Institute on Aging, USA. From 2004 he was research fellow at the Department of Molecular and Cellular Biology, Harvard University. From 2005 he is Chief, Department of Reproductive Biology, National Research Institute for Child Health and Development, Japan.

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