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New technologies towards the promotion of "Integrative Celerity Research (ICR)" ~ Human resources are essential in studies ~(2) -All 2 episodes-

Prof. Hiroo Imura

Photo:Prof. Hiroo Imura

Prof. Hiroo Imura

Interviewer :
In terms of the intellectual property, the Patent Office of Japan approved Mr. Yamanaka's originalities, including human iPS cells. How about in foreign countries?

Imura :
It is of course recognized throughout the world that Mr. Yamanaka is given the priority for studies as science, but problems may arise in terms of the intellectual property.

Interviewer :
By the way, how did Mr. Yamanaka come up with the idea about reprogramming?

Imura :
He was pursuing studies with an interest in ES cells.
Undifferentiated cells, capable of maintaining the undifferentiated state, grow permanently, but they can be directed to differentiate under certain conditions.
He was pursuing studies on genes that are "involved in maintaining the undifferentiated state of ES cells", during which he hypothesized that genes that "maintain the undifferentiated state" are the same as those needed to "induce the reprogramming from differentiated cells to undifferentiated cells". It seemed, in this respect, that Mr. Yamanaka had foresight.
From the perspective of the ability to induce undifferentiation, he narrowed down the candidate genes to 24 using the database of EST (Expression Sequence Tag) of RIKEN (the Institute of Physical and Chemical Research), and, as a result of conducting aggressive studies, he found that four of these genes play a crucial role in the reprogramming.
At that time, he was an associate professor at Nara Institute of Science and Technology, where he was leading a small group, and made an ambitious suggestion to offer a dream to young people. In Nara, he was primarily involved in studies on genes that are expressed in ES cells and was receiving a focus of public attention, but, after moving to Kyoto, he was engaged in studies on reprogramming with genes.

Interviewer :
In other words, his patience and belief led to the accomplishment.

The way support is provided to actualize ideas

Imura :
Mr. Yamanaka said that he was grateful for the support from JST-CREST. Because of the lack of research fund in Nara, he was applying for various research funds, and Mr. Kishimoto Tadamitsu, the supervisor of CREST, approved his application, saying that "It is not an immunological area itself, but it is good to pursue such an interesting research". Of course, Mr. Yamanaka has long been famous among those concerned as an excellent researcher who conducts unique studies. Subsequently, Mr. Yamanaka moved to the Institute for Frontier Medical Science, Kyoto University. I started the Institute during my term as the President, with which I am satisfied because it produced not only Mr. Yamanaka but Professor Sakaguchi Shimon, who is famous for regulatory T cells. As for the name of the Institute, Mr. Nishikawa Shin-ichi of Kobe RIKEN, who was a professor at School of Medicine, Kyoto University at that time, proposed the word "regeneration", and because there was a small feature article on "regenerative medicine" in Science, the director of Graduate School of Medicine visited the Ministry of Education, Culture, Sports, Science and Technology with the article, and explained the world's foremost studies.

Interviewer :
Was there a concept of "regenerative medicine" at that time?

Imura :
No, there was little concept of regenerative medicine because even human ES cells did not exist.
Tissue stem cells are known now, but, at that time, oligopotent progenitors were barely known, which are currently in actual use for regenerating skins, cartilages and so on.
In fact, there is a hierarchy among stem cells, the top of which is totipotent like fertilized ova and can develop into any organ that composes the body.
ES cells, on the other hand, are pluripotent and are thought to be able to develop into almost any other cell but placenta cells.
Further down the hierarchy is tissue stem cells, which are oligopotent and able to develop into certain tissues.

Interviewer :
Mr. Yamanaka discovered that "there are genes by which cells are reprogrammed". Does it mean that cells possess the mechanisms by which they can be returned into the original state?

Imura :
Yes, it does, as is the case with the experiment with Dolly. Although sperms and ova are both differentiated cells, they get reprogrammed a few days to one week after the fertilization and become totipotent stem cells, which could conclude that reprogramming occurs naturally. However, uncontrolled reprogramming would present problems.

Interviewer :
Among the lower animals, lizards, for example, can regenerate their legs.

Imura :
Lizards have stem cells at the base of their legs.
There is an organism called planarian. If it is cut into two, each of them regenerates into an individual that has a small brain.
Mr. Agata Kiyokazu and his study group reported that if the functions of a certain gene are inhibited in planarian, regenerative abnormalities of the brain are caused, in other words, brains are formed throughout the body. They named this gene "nou-darake", which means "brain-filled".
This phenomenon can be seen mainly in the lower animals, and such regenerative ability is gradually lost as the evolution proceeds towards the higher animals.
On the other hands, the phenomena of regeneration and carcinogenesis are similar in that cells are at an undifferentiated state, and hence, individuals with a long lifespan that possess regenerative abilities also possess "cancerous" abilities.
Lizards would probably die before cancer develops.

Interviewer :
The application of iPS cells for regenerative medicine is highly expected

Imura :
That is right. It is also expected that iPS cells can be applied to determine disease pathogenesis. Monogenic disorders are particularly difficult to elucidate in the absence of animal models, but studies are possible by establishing model cell lines from iPS cells that express the responsible genes.
However, such approach may be difficult for multifactorial genetic disorders (e.g., such as diabetes) because there are multiple responsible genes and interaction of environmental factors. Thus, this approach is useful for elucidating rare diseases for which model animals are difficult to create.
Another expectation for iPS cells is screening of drugs. iPS cells are also thought to be useful for predicting not only the efficacy of drugs but adverse effects, which rarely occur and are difficult to find in actual clinical trials.

How to improve and enrich the research environment in the future

Interviewer :
I hear that research funds are insufficient in Japan as compared with the US or Europe, but how do you think is it possible to encourage support for research, particularly from the government?

Imura :
When I assumed the position of the president of Kyoto University in 1992, the total amount of scientific research fund was only one third of the present fund. The fund for bottom-up research currently accounts for 200 billion yen, which was impossible at that time, but it is still much lower than that in the US. When supporting research, it is important to balance bottom-up research that encourages researchers' free ideas, and top-down research conducted with a certain focus.
Recently, there is a tendency for those without research experience to conduct "project-type" based on the idea that good results can be obtained if how to utilize the study results is predetermined. Besides balancing the both types of research, we also should not forget the importance of broadening the research range.
In this respect, sharing responsibilities is important, where JSPS (Japan Society for the Promotion of Science) supports bottom-up research, whereas JST (the Japan Science and Technology Agency) supports the obtained valuable research on a top-down basis. However, I hope that such top-down research is supported with a full understanding of its characteristics.

Interviewer :
In addition to the application of iPS cells for regenerative medicine, is it also important to raise the standards of the whole fundamental research?

Imura :
I hope that some clues will be found by providing a variety of support for the surrounding fields.
The clinical research has a totally different aspect from that of animal experiments. Since I am a clinician, I think it is important to recognize how to utilize the study results. If this is recognized, human resources can be better developed.
For the clinical research, for instance, not only physicians but biostatisticians with an epidemiological viewpoint are essential. Some courses were finally created in Japan, but the number is still much lower as compared with the US.
There is also a need for developing many other human resources including clinical pharmacists, research nurses and data managers and so on.

One of the current problems in Japan is that the number of physicians enthusiastic about research (namely physician scientists) and of doctoral students in related areas (e.g., science) is decreasing.
This is a serious problem because human resources are essential in studies. I think that there is a need for an increase in fellowship for clinical researchers and graduate students. As I have already mentioned in part, various human resources who support studies are of course necessary.
In Japan, where natural resources are insufficient and the population ages, human resources are the only assets, and therefore, enhancing their abilities to the maximum is an urgent issue.


Interview by Miwako Homma, supervisor of iPS Trend website, and Katsuaki Sato and Shigeo Morimoto from the Japan Science and Technology Agency.
Published on 17 September, 2009

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Hiroo Imura, Ph.D.

1954 : Graduated from Kyoto University School of Medicine
1962 : Received his Ph.D. from Kyoto University Graduate School of Medicine
Since 1962 : Assistant, Kyoto University Hospital
Since 1965 : Lecturer, School of Medicine, Kyoto University
Since 1971 : Professor, School of Medicine, Kobe University
Since 1977 : Professor, School of Medicine, Kyoto University
Since 1989 : Dean of School of Medicine, Kyoto University
From 1991 to 1997 : President, Kyoto University
Since 1997 : Professor Emeritus of Kyoto University
Since 1998 : Head of Kobe City General Hospital, and Excecutive Member of the Council for Science and Technology
Since 2001 : Member of the Council for Science and Technology Policy
Since 2004 : Board chairman of the Foundation for Biomedical Research and Innovation

Mr. Imura is also Chairperson of Inamori Foundation, Consultant of the Japan Science and technology Agency (JST), Principal Fellow at Center for Research and Development Strategy of JST, member of The Japan Academy, and Foreign Honorary Member of American Academy of Arts and Sciences (AAAS). He specializes in endocrinology.

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