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Researchers for the future

To prepare hepatocytes useful for toxicity evaluations from iPS cells

Dr. Akihide Kamiya

The liver is a unique organ that has high ability of regeneration and whose cell functions change in the course of development. The wonders of this organ have interested Dr. Akihide Kamiya at The Institute of Medical Science, The University of Tokyo, in studying natural science of the organ. His aim is to develop cell transplantation therapies and drug screening systems using iPS cells, based on his accumulated findings and skills and in collaboration with researchers working in different fields including medicine, engineering and pharmacy. He says, "If one has a multi-disciplinary perspective, one will make a discovery", and he is actually heading the keen competitions in research in this field.

Interviewer :
Why are you interested in the liver, in the first place?

Kamiya :
The liver is a metabolic organ that has functions of absorbing food or drugs that we ingest and detoxifying harmful substances. However, it serves as a heamatopoetic organ when it is in the fetal stage. In this stage, the maternal metabolism covers the fetal one. In late stages of gestation, the liver of the fetus changes its functions from those of a heamatopeotic organ to those of a metabolic organ. I am very interested in such a drastic functional change that takes place in this organ during the course of development.
I am also interested in the regenerative ability of the liver. It is not common in higher animals, although there is an example of the tail of the newt. Even if 70% of the liver has been lost, this organ is able to regenerate its size and functions to the original dimensions. It is why liver transplantation from a living donor is possible, where a half of the donor's liver is excised and transplanted to the patient.

Interviewer :
What visions do you have in your research?

Kamiya :
For liver transplantation from a living donor, we have to perform a surgical operation on the healthy donor, and there is a shortage of donors. In such a situation, development of new therapies by regenerative medicine is expected. For patients who are waiting liver transplants, I want to prepare livers in vitro. This is my goal. Is it possible to reach the goal? I am always thinking over what will be necessary to do it in my research. My objective at present is to produce a large number of functional hepatocytes. Hepatocytes grow in vivo, but not in vitro and cannot keep their functions. I am working on developing a technique for inducing differentiation of ES or iPS cells into liver stem cells or liver precursor cells, growing them in vitro, and inducing differentiation of these cells into functional hepatocytes.

I am also working on developing a technique for inducing differentiation of liver stem cells collected from adult or fetal liver into mature hepatocytes, and on direct reprogramming of somatic cells into hepatocytes without intermediary of iPS cells.

Interviewer :
That is to say, you produce livers from hepatocytes derived from iPS cells?

Kamiya :
As a first step, I am aiming at using such livers for toxicity evaluations in the field of drug development. The liver is the most important organ responsible for metabolizing chemicals, and, in drug development, human hepatocytes can be used for studying efficacy and toxicity of candidate compounds. However, as I said, hepatocytes do not grow in vitro and lose their functions. There is another problem that it is difficult to obtain human hepatocytes. Under such circumstances, there are expectations for iPS cells. iPS cells will enable us to solve these problems. In fact, there is a JST project called "S-INNOVATION" for building up toxicity evaluation systems using iPS cells.

Interviewer :
iPS cells can be used in the field of drug development. What are the present situation and the problems to be solved in your research in this field?

Kamiya :
We know from recent studies that it is possible to induce human fetal hepatocyte-like cells from liver stem cells derived from human iPS cells. And we need one more step to have these fetal hepatocyte-like cells transformed into mature hepatocytes. Another problem is how to grow the hepatocytes obtained. In the process of liver development in vivo, there must be some mechanism that will give us hints for inducing functional hepatocytes from iPS cells. I am also studying molecular mechanisms by which the fetal liver transforms into the mature liver.

Interviewer :
To make a liver as a whole organ from iPS cells. Will it be more difficult and take more time to realize than preparing a large quantity of functional hepatocytes?

Kamiya :
To generate an organ, we may need a completely new approach. If somebody will have a completely new idea, it will open a door to generating an organ relatively easily. It is always that a large breakthrough is made when science or medicine sees a great advance. One typical example is iPS cells. ES cells were generally used in this field when iPS cells appeared several years ago, and after the appearance of iPS cells the field has seen a rapid progress.

Interviewer :
There is a keen competition in research, and do you have any strategy for being a leader there?

Kamiya :
I majored in biophysics and biochemistry at the school of science when I was a student, and now at this Institute of Medical Science, I have colleagues of different specialties including clinical medicine. There are also colleagues specialized in engineering or pharmacy, and I am allowed to have close discussion with these specialists of different fields. This may be a good point of a cross-disciplinary institute like ours. If you persist in working in the same field and accumulating knowledge and experiences there, it is good. However, if you will have multiple viewpoints beyond your specialty, it will enable you to have a new idea and make a discovery. One of the characteristics of this institute is that it has both research division and health care division, and I want to develop original activities in this unique organization.

Photo:Dr. Akihide Kamiya

Dr. Akihide Kamiya

Interviewer :
When you passed from master's course to doctoral course, you moved to a different lab, didn't you?

Kamiya :
When I was a student, I wanted to see different worlds. When I was an undergraduate student of the 4th year and a graduate student of master's course, I was working on biochemical analysis of proteins responsible for inter-cellular signal transmission. During these 3 years, I got some knowledge of the world of proteins, and as a next step I wanted to do research at the cellular level. That is why I moved to a different lab. That was a lab where blood was mainly studied, and I became interested in the fetal liver.

Interviewer :
Since then, you have been working on the liver. Were there any decisive events that led you to do so?

Kamiya :
When I was a doctoral student, I identified Oncostatin M, a cytokine that serves to transform the fetal liver into a mature state. This constitutes a basis for my research today. In fact, we are studying how to generate functional hepatocytes from iPS cells or ES cells, using this cytokine. There are some other groups who are doing the same thing.
And I learned much from Dr. Taisei Kinoshita (currently working as a researcher in the company Rigel ) who was my teacher when I was a doctoral student. He taught me the "basics" of doing research, such as how to design an experiment and how to write a scientific paper.

Interviewer :
When do you find it interesting in your doing research?

Kamiya :
I have two cases. In one case, it is when I come to verify a hypothesis, and in another it is when something that I have not expected happen. If it is something that we do not know well, it may be a reflection of some important biological phenomenon. It may be something that will give me a new idea. It is exciting to me.

Interviewer :
Sometimes you may lose in research competition, or your work may not go well and you have a hard time, I suppose.

Kamiya :
Yes, it is inevitable that I lose sometimes in competition, and in most cases things do not go well. We repeat this. If we see it from the other side, we can say that we have to continue our efforts until things go well. There are always keen competitions in every branch of the field of regenerative medicine. So, it will be important to change your mind toward another direction if you lose in the present study.

Interviewer :
To conclude, would you give advice to your younger colleagues?

Kamiya :
Recently in Japan, people tend to be oriented inward. There are many students who prefer to be employed in industries rather than to work as a researcher because it is not a stable job. There are a smaller number of students than before who go to study or work in other countries. In place of such an inward way of thinking, I think what is necessary is to have a positive idea that it is yourself who chose your way to go. A doctoral degree is something like a car license, and we are permitted to pass the road of research with this license. If you have a doctoral degree, you will have chance to work where you choose, in Japan or in another country. I want young people not to confine themselves to an immediate profit and try to work in different fields, to find finally what they want to do.


Interview date : February21, 2011

Dr. Akihide Kamiya

Assistant Professor, Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo

In 1972, he was born in Nagasaki. In 1994, he graduated from the Department of Biophysics and Biochemistry, School of Science, The University of Tokyo. From 1994 to 1999, he was a graduate student at the Department of Biophysics and Biochemistry, Graduate School of Science of the same university. In 1999, he was granted a doctor's degree. He was working as a Research associate, Stem Cell Regulation Project, Kanagawa Academy of Science and Technology, and as a research fellow at the National Cancer Institute, USA. In 2004, he began to work at the Center for Experimental Medicine, The Institute of Medical Science, The University of Tokyo, and in 2008, he was appointed an assistant professor at the same institute. In June, 2007, he was granted the Chairman's Award in the 14th annual meeting of The Japanese Society of the Research of Hepatic Cells, and in 2009, the Young Investigator's Award in the 8th annual meeting of The Japanese Society for Regenerative Medicine.

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