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Researchers for the future

Toward innovation based on biology-technology fusion

Dr. Kiyoshi Ohnuma

In 2010, Dr. Kiyoshi Ohnuma took up his new post at Nagaoka University of Technology that was founded for the purpose of building up "GIGAKU", the science of technology, where he is working on developing a cell culture environment in which one will be able to study ES, iPS and other stem cells at the single cell level. It is a study in a new field based on biology-technology fusion.

Interviewer :
I have heard that when you were a graduate student, you were majoring physics at the Graduate School of Science, Nagoya University. How did you start your career as researcher?

Photo:Dr. Kiyoshi Ohnuma

Dr. Kiyoshi Ohnuma

Ohnuma :
My research theme was to study plasticity of brain synapses and translate it into mathematical expressions. I used the nervous systems of Japanese spiny lobsters (Panulirus japonicus) for experiments. I gave electric stimuli at different frequencies, and monitored changes in calcium ion levels in correlation with the quantity of electric stimuli. I was working in the lab of biophysics and was trying to understand the dynamics of the calcium ion in cells in terms of physics, and its relations with biological functions including memory. At that time, there was an atmosphere in the lab that we would understand living organisms from the viewpoint of physics.

Interviewer :
After that, you went to study at the department of molecular biology, University of California, Berkeley.

Ohnuma :
Yes. There, I used a sea hare (Aplysia) species, and studied the relations between calcium ion levels and released neurotransmitter levels at the level of synapses. I found in experiments using different neurons that there were differences in the mechanisms of transmission between synapses with rapid transmission and those with slow transmission.
I saw what was a "world-leading level" when I was at UC Berkeley. There, authors of famous articles came to give lectures one after another every week in an omnibus style class, and I realized that there was a large stock of scientists.

Interviewer :
In 2000 when you came back to Japan, you found embryonic stem (ES) cells already generated. How did you get involved in ES cell research?

Ohnuma :
After coming back to Japan, I started working on nerve networks in culture as a complex system in the framework of the COE project "Complex systems biology analysis"(Research Center for Complex Systems Biology from 2004) at the Graduate School of Arts and Sciences, The University of Tokyo.
In this study, we had to handle cells in a same state and placed in line, and were looking for cells most suitable for this kind of experiments among many candidates including cells induced from ES cells. At that time, I thought that any type of cells would be OK if these would be easy to handle as a tool.
Then, I chose rat neurons for my study. However, it did not work well, as I did not have technique for handling two or more cells and, if I placed five cells in line, four cells among them died, or two cells among them fused.
It was only I who was studying neurons in that project. In such circumstances, Dr. Makoto Asashima, Professor at the Graduate School of Arts and Sciences, said to me, "Come to work with us, if you like?" Dr. Asashima had discovered the ability of activin to induce the mesoderm and successfully induced different organs from undifferentiated cells of frogs by adding activin to the cells. And he just began to study how to apply this technique to inducing differentiation of ES cells.

Interviewer :
What did you do in his lab?

Ohnuma :
Besides my main research themes, I was involved in studying serum-free culture of ES cells. Conventionally we use a culture medium supplemented with a serum for culture of ES cells. In serum-free culture, we use a medium supplemented with proteins such as insulin and transferrin in place of serum to grow cells. Serum may contain unknown factors, and there are differences by lot. In serum-free culture, we can reconstitute exactly the same medium from known factors, and we do not have to care about any risk of contamination with pathogenic substances. In this way, through development of serum-free culture techniques, I was involved in studying ES cell culture. It was indeed difficult to culture ES cells, however, if we managed culture conditions appropriately, we were able to culture these cells efficiently. I found it was interesting to develop a technique.

Interviewer :
Then you came up with iPS cells. How did you find them?

Ohnuma :
In August 2006, Dr. Yamanaka published an article on generation of mouse iPS cells in the Journal Cell. One of my students told me about the article, and at that time I did not found it so exciting. I had an impression that the new iPS cells were something similar to the existing ES cells Later, when I heard that "iPS cells rewind the cellular clock", I realized that it was really exciting.

Interviewer :
You and your colleagues began to deal with iPS cells in the Asashima lab. What were you studying?

Ohnuma :
We first discussed about possible studies using iPS cells. Somebody proposed to work on "direct reprogramming" that is to generate necessary cells without the intermediary of iPS cells. Finally we came to a conclusion that it would be with serum-free culture that we would be able to work in an original manner, and decided to work on generation of iPS cells under serum-free conditions.
It was possible to generate ES cells in serum-free culture, and I thought that it would be possible to do the same thing with iPS cells. However, it did not work when we used infant cells grown in serum-free culture. Then we tried to use adult cells grown in a serum-supplemented culture medium and in this case we could generate iPS cells. "Serum-free" means all the constituents of the culture medium are known. If we know precisely the culture conditions, we will be able to generate iPS cells in a safer manner, and will be able to discuss what we will have to do further in a more precise manner.

Interviewer :
You moved to Nagaoka University of Technology in 2010. Can you tell us what distinctive features of the university are, and what you are working on there?

Ohnuma :
Nagaoka University of Technology is a university that focuses on "GIGAKU", the science of technology. I am trying to generate different types of cells with different functions from pluripotent stem cells including iPS cells, and to construct a micro-machine with these cells as its parts.
On the other hand, like the other side of a coin, I am planning to control and observe iPS or ES cells in a single-cell state, using the same techniques, to understand how the cells maintain their undifferentiated state and control their differentiation. It will be necessary to review the conditions used by researchers for inducing differentiation of iPS/ES cells into a certain type of cells, to see if these conditions were really those which induced differentiation. It is possible that the researchers selected cells that were highly susceptible of becoming the target cells. In order to do this kind of analysis, we need to control precisely the conditions of cell culture and maintain cells in a single-cell state. For providing precisely controlled conditions, we use serum-free culture, and a protein called E-Cad-Fc to separate ES cells from each other to disperse in a single-cell state. E-Cad-Fc is a chimeric protein constituted of the extra-cellular domain of E-Cadherin, ES cell adhesion protein, and Fc Region of IgG. It is Dr. Toshihiro Akaike at Tokyo University of Technology who developed this chimeric protein.
The only objective of my research is to show under controlled conditions at the single-cell level how cells are developing. This study will either bring about purely scientific results that will shed light on the origin of the cell, or lead to development of techniques for drug screening.

Interviewer :
Building a micro-machine with cells is an innovation brought about by a fusion of biology and technology. This kind of multi-disciplinary fusion is regarded as a new field that is important for providing safe cells and realizing regenerative medicine using stem cells. How do you see the present situation of such studies based on biology-technology fusion?

Dr. Kiyoshi Ohnuma

Ohnuma :
It seems that the technology side is more active, that is, they are looking for cells suitable for various devices that they want to construct.
In contrast, it seems that the biology side is somewhat reluctant to take a step forward. Meanwhile, there are research groups or institutions that are devoted to encourage life science-technology fusion, such as the research group headed by Dr. Mitsuo Okano at Tokyo Women's Medical University for regenerative medical engineering, and iCeMS (Institute for Integrated Cell-Material Sciences), Kyoto University. If there is an environment in which researchers in life science and those in technology are allowed to discuss closely, it will be nice.
At our university, research exchange meetings are organized to invite researchers from different fields including material engineering, machine engineering, and life science to work together in certain research projects. I attend these meetings and feel that experiences on such occasions to exchange ideas from different standpoints and find common solutions are a good training for me.
Researchers in life science and those in technology have different "common senses" in some way. It may be important in some situations not to stick to your own research, and respect your counterpart, to let them start their research first, and then you follow it.
Fusion of biology and technology will lead not only to practical applications such as drug development and diagnosis, but also to a great scientific innovation such as artificial cells. I hope this kind of joint works will be further going on.


Interviewer :
Jiro Urushibara
Interview date : June 24, 2011

Dr. Kiyoshi Ohnuma

Associate Professor, Department of Biotechnology, Top Runner Incubation Center for Academia-Industry Fusion, Nagaoka University of Technology

In 1967 he was born in Shizuoka Prefecture. In 1998 he finished the doctoral course in physics at the Graduate School of Science, Nagoya University. In the same year he was enrolled as doctoral research fellow in the Department of Molecular & Cell Biology, University of California, Berkeley. In 1999 he was granted a doctorate in science. From 2000, he was a technical assistant to the Department, JSPS research fellow and COE research fellow at the Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo. From 2006 he was Assistant Professor at the same department. From 2010 he is Associate Professor at Nagaoka Univeristy of Technology.

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