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New technologies towards the promotion of "Integrative Celerity Research (ICR)" ~ Human resources are essential in studies ~(1) -All 2 episodes-

Prof. Hiroo Imura

Photo:Prof. Hiroo Imura

Prof. Hiroo Imura

This time we interviewed Mr. Imura Hiroo, the advocate of Integrative Celerity Research (ICR), who is the board chairman of the Foundation for Biomedical Research and Innovation and was the former President of Kyoto University.
In this interview, Mr. Imura talked about Japan-originated iPS studies from various viewpoints, such as "developments in the clinical medicine field" by elucidating the disease mechanisms, "improvements in the quality of medical care" for those who receive the care, and "measures" to implement them. (Interpretation : Integrative Celerity Research [ICR])

Interviewer :
JST (the Japan Science and Technology Agency) is launching the website named iPS Trend intended for the general public, and today we would like to ask you mainly about the recent research trends surrounding iPS cells and to hear your message for young researchers and the general public.
According to the first interview with Mr. Goro Eguchi, fundamental studies to investigate why somatic cells are reprogrammed as well as the viewpoint of the clinical application are important.

Imura :
I am going to talk in terms of the clinical work.
Because many of the human organs do not regenerate if they are lost, it has been the most crucial issue to discover how to regenerate important cells (e.g., nerve cells, myocardial cells, and pancreatic beta cells), which will lead to the application for medical care.
Thus, regenerative medicine has rapidly become a focus of attention during the last approximately 10 years.

It was in 1981 that an attempt to regenerate organs with ES cells (embryonic stem cells with pluripotency) was first made after Professor Evans, of Cambridge University, succeeded to cultivate murine ES cells in vitro.
In 1998, Professor Thomson, of the University of Wisconsin, established human ES cell lines. It was expected, for regenerative medicine, that these cells will be able to develop into any tissue cell that composes an individual.
As you know, however, there were ethical problems for ES cells in that a fertilized oocytes, an embryo, which can essentially develop into a human, is used, and the Pope and President Bush of the US expressed objection to it.

In addition, there were immunological problems regarding ES cells. Since cells derived from another individual's embryo are used, rejection is supposed to occur at the time of transplantation.
Thus, the clinical application of ES cells for treatment was substantially delayed due to the major limitation, but it was not until recently that conducting clinical studies on spinal cord injury was approved.
Various experimental attempts were made to prevent rejection.
One typical example was studies of "nuclear-transplant embryo", in which a somatic cell nucleus of the patient is transplanted into an enucleated oocyte. Such studies were conducted all over the world, but all ended in failure, one example of which was the fabricated data by Professor Hwang Woo-suk of Korea.

The historic discovery of iPS cells

Imura :
On the other hand, Professor Shinya Yamanaka, of Kyoto University, aggressively challenged with the idea that it may be possible to return differentiated cells to those with an undifferentiated status (reprogramming), which nobody thought of at that time. In 2006, Mr. Yamanaka succeeded in producing iPS (induced pluripotent stem) cells, similar to ES cells, from murine somatic cells, and it was sensationally reported worldwide.
In 2007, Mr. Yamanaka, Mr. Thomson, and the Bayer Yakuhin Ltd., Kobe Research Center concurrently succeeded in producing human iPS cells. Due to the difficulties for nucleus transplantation in terms of experimentation and ethics, expectations for iPS cells highly increased.
However, there was a problem in this method. Retroviruses are used as a vector that introduces four types of genes, but there is a risk for "carcinogenesis" because these viruses are integrated into the genome.
First, Mr. Yamanaka excluded c-Myc, an oncogene, from the four factors, which resulted in a decrease in the carcinogenicity. However, the safety in humans is not guaranteed as long as retroviruses are used, because it is integrated into chromosomes. For instance, a research group of France succeeded in treating patients with adenosine deaminase deficiency with retroviral vectors, but this procedure was reported to occasionally cause leukemia.
Next, Mr. Yamanaka used plasmid to introduce genes safely, but, in fact, the possibility that plasmid is integrated into the genome can not be excluded, although the frequency is very low.
Recently, however, a report was published in which protein itself could be successfully introduced into somatic cells, although efficiency was low.

Interviewer :
It was on Cell Stem Cell and described that nine basic amino acids (arginine) were added to each of the four factors.

Imura :
DNAVEC, a venture business in Japan, proposed the use of Sendai viruses for introducing genes as "a safe procedure in which they are not integrated into the genome", because foreign genes are not integrated into the cell genome if these viruses are used.
As such, there are two important points for the reprogramming of cells : "to guarantee the safety" and "to differentiate reprogrammed cells into target cells". It is relatively easy to differentiate them into nerve cells, while producing liver cells or pancreatic beta cells has not been completely successful yet.
In addition, if the reprogrammed cells that have not differentiated are not removed from the differentiated cell groups, teratoma occurs because these undifferentiated cells are highly proliferative. (This property is taken advantage of in ES cell studies to confirm, by producing teratoma, that the original cells were undifferentiated ES cells.)

Interviewer :
To what extent reprogrammed cells are left as undifferentiated stem cells?

Imura :
It appears to be difficult to determine that accurately because there is no proper marker to prove that they are undifferentiated cells.
In differentiating undifferentiated stem cells into various types of cells such as myocardial cells, a variety of factors that promote differentiation (e.g., VEGF [vascular endothelial growth factor]) are added to medium, and a feeder layer, composed of cells used at the time of cultivation, also plays an important role.

Interviewer :
Is a procedure to induce differentiation also under investigation?

Imura :
Because of the accumulated research regarding ES cells, studies on the induction of differentiation were substantially advanced. It seems that there is not a significant difference in the way to induce differentiation between ES cells and iPS cells.

Interviewer :
On the other hand, the mechanisms by which differentiated somatic cells are reprogrammed have yet to be elucidated, so that fundamental studies seem to be necessary.

Imura :
It is certain that studies on the mechanisms by which iPS cells are reprogrammed are gradually in progress, but it is not understood well.
To what extent differentiated cells are reprogrammed into iPS cells is also unknown in detail. The development of technologies to conduct reprogramming more efficiently is needed, in which both the scientific research and the technology development are involved. If this problem is overcome, the clinical application may be actualized sooner.

Interviewer :
Is there no ethical problem for iPS cells at all?

Imura :
In Japan, inducing differentiation from iPS cells into germ cells (sperms and ova) and artificially fertilizing are prohibited by Cloning Prohibition Act. However, there is no other ethical problem at all.
Thus, Mr. Yamanaka, who overcame the ethical problems by developing the new technology, made a great impression on the Pope and President Bush and was invited to talk with them in person.

Interpretation : "ICR (Integrated Celerity Research)"

The promotion of "clinical research" in humans is essential for the development of new treatment and the creation of an innovation in the clinical field. The clinical research is broadly divided into drug discovery, the development of medical equipment, and the development of high medical technologies (e.g., regenerative medicine), and it is important to foresee the more efficient way to advance the research development towards the industrialization in consideration of the medical care quality as a measure. However, there are currently many obstacles in Japan, which is also called "a developing country for advanced medical care".

In order to break this deadlock, Mr. Imura Hiroo has since 2006 been proposing a radical change, the promotion of "ICR (Integrative Celerity Research)". ICR, unlike conventional TR (translational research), promotes the prompt industrialization and application for medical care by first setting clear goals based on the overview of the research and by consolidating each clinical trial phase together as much as possible, which has previously been performed individually.
There are three main measures that appear to be effective for promoting ICR : to develop new evaluation technologies, to establish a research foundation, and to improve laws and regulations.
The promotion of ICR is also important in "iPS cells" and not only establishes the fundamental research and technologies to elucidate pathogenesis of diseases, but is receiving the world's attention as a revolutionary method to implement new regenerative medicine.


Interview by Miwako Homma, supervisor of iPS Trend website, and Katsuaki Sato and Shigeo Morimoto from the Japan Science and Technology Agency.
Published on 3 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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