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CREST Research Supervisor Dr. Toshio Suda talks about iPS cell research and what will come next (1) -All 4 episodes-

Dr. Toshio Suda

Photo:Dr. Toshio Suda

Dr. Toshio Suda

Dr. Toshio Suda, who is a specialist of stem cells, assumes the Research Supervisor of CREST(Core Research for Evolutional Science and Technology), a project of JST (The Japan Science and Technology Agency), and is playing a leading role in basic research on iPS cells. In this interview, he will give us his ideas about how basic research leads to applied research for regenerative medicine using iPS cells.

There are large differences between somatic stem cells and induced pluripotent stem cells

Suda :
iPS cells are basically pluripotent (able to develop into any other cell).
Studies of stem cells began with hematopoietic stem cells in the 1960s. Later, when embryonic stem cells (ES cells) were first generated, stem cells of the type of hematopoietic stem cells were called somatic stem cells.
Hematopoetic stem cells are destined to always become blood cells, and neural stem cells to always become nerve cells. On the other hand, embryonic stem cells have a "pluripotency" that enable them to become blood, nerve or any other type of cells.

Embryonic stem cells are produced in vitro from an early-stage embryo, and iPS cells are also produced in vitro.
When Dr. Yamanaka used small "i" for iPS cells, he wanted to emphasize that these cells are induced in vitro from human or mouse differentiated cells.

There are large differences between somatic stem cells and induced stem cells, and these differences are important subjects of discussion. iPS cells had a large impact in that they were generated by gene manipulation, and that is why it is difficult to handle. Do they behave in the body as they are expected? Do they not develop into cancers or tumors? Is it really possible for them to be controlled in the body?
In this respect, some researchers are somewhat pessimistic and cautious, saying that "iPS and ES cells are both induced cells and it is not so easy to put them into practical applications", while others are optimistic, saying that "these stem cells are capable of growing indefinitely in culture and will find applications".

Whether we will be able to use iPS cells in practical applications, we will see in two to three years

Interviewer :
You do not know yet whether you are already able to use iPS cells in certain fields of application and not in other fields, do you?

Suda :
No, we do not yet even see "whether we will be able to use iPS cells in a certain field or not". Even for ES cells, we do not. I think the next two to three years will be important to see the possibility.

Interviewer :
Does it also depend on whether iPS cells can be standardized?

Dr. Toshio Suda(Sketch by Katsuaki Sato)

Dr. Toshio Suda
(Sketch by Katsuaki Sato)

Suda :
The term "standardization" seems to be used often in an industrial context. Before standardization, what is more problematic I think is that we do not yet see whether we have "ideal iPS cells" available or not.
We have yet no safe iPS cells that "will not develop tumors".

Interviewer :
I hear that stem cells can grow indefinitely.

Suda :
When we maintain cultures of somatic stem cells, including hematopoietic and neuronal stem cells, they do not stay permanently in their stem cell state and differentiate into other types of cells after some period of time. In normal human somatic cells, the chromosomal structure called "telomere" that plays an important role in chromosome replication tends to shorten gradually with age, and this impairs cell division in older individuals after 60 of age. Cancer cells continue to secrete "telomerase" that extends the telomere length, and they continue to grow indefinitely.
ES and iPS cells are capable of growing indefinitely, with their pluripotency maintained.
If iPS cells get into the body as undifferentiated cells, it may be possible that they continue to grow like cancer cells.

Interviewer :
Do iPS cells show any other risk or inconvenience in the body when transplanted?

Dr. Toshio Suda

Suda :
In usual allogeneic transplantation, transplanted cells are derived from another person and if there is something inconvenient it is eliminated by the patient's immune system in the body. In contrast, in transplantation of iPS cell derived cells, transplanted cells are derived from the patient and therefore his/her immune system does not work against these cells.
This is said to be an advantage of using iPS cells for regenerative medicine, but, in fact, this may be a problem.

Let me take an example of leukemia treatment. After bone marrow transplantation, the patient has normal bone marrow cells. It seems a good idea that we collect and store a sample of these normal cells and use them for re-transplantation if the patient will have a recurrence of the disease.
However, it will be possible that the stored cells contain a very small amount of abnormal cells, and in this case, there is a risk of recurrence after re-transplantation because no immunological surveillance works. This may happen when we use iPS cells.

Thus, we have an alternative idea that, when we use iPS cells in regenerative medicine, it will be better to use progenitor cells (for cardiomyocytes, retinal epithelial cells, etc.) differentiated from iPS cells and not the original iPS cells in undifferentiated state.
However, we do not know yet whether we will be able to induce 100% differentiation into the target cells from iPS cells.
In the case of transplantation of retinal pigment epithelial cells, on which Dr. Masayo Takahashi of RIKEN (the Institute of Physical and Chemical Research) is working, the transplanted cell numbers are so small (between 10,000 and 100,000) and we will be able to check whether the cells have been totally differentiated.
In the case of blood cells, on the other hand, the number of transplanted cells is as many as 108, and it is difficult for us for the moment to check whether all the cells have been totally differentiated.

Interviewer :
Then, a very high purity of cells is required, just as in the field of silicon semiconductors where silicon crystals of a purity of 99.99999999% (10N) are used.
Anyway, you are studying the possibility of using differentiated cells derived from iPS cells for transplantation.

Suda :
Using differentiated cells appears to be relatively safe, but the situation varies according to cell types.
Differentiated retinal epithelial cells or myocardial cells function for several years, while differentiated blood cells would die soon after differentiation because the lifetime of blood cells is so short that they are renewed every day. Thus, the lifetime of each cell type is an important point to be considered.

Interviewer :
For corneal transplantation, oral mucosal cells taken from the patient are cultured and used. Instead of this approach, is there any advantage of using iPS cells that involve risks?

Suda :
It will be necessary to make comparative studies, in order to estimate the most effective approach for each target site.


Interviewed by Katsuaki Sato,Mio Watanabe(Japan Science Technology Agency)
Published on 26 February, 2010

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Dr. Toshio Suda

Professor for developmental biology courses, The Sakaguchi Laboratory, School of Medicine, Keio University, visiting professor at the Institute of Molecular Embryology and Genetics, Doctor of Medicine, physician, and, certified physician and educator of the Japanese Society of Hematology.

In 1974 : Graduated from School of Medicine, Yokohama City University
Since 1974 : Resident physician at the Department of Pediatrics, Kanagawa Children's Medical Center
Since 1978 : Assistant at the Department of Hematopoiesis, Institute of Hematology, Jichi Medical University
Since 1982 : Research associate at the Department of Internal Medicine, Medical University of South Carolina
Since 1984 : Instructor at the Department of Hematopoiesis, Institute of Hematology, Jichi Medical University
Since 1991 : Associate professor of hematology at the Department of Hematopoiesis, Institute of Hematology, Jichi Medical University
Since 1992 : Professor at the Division of Developmental Regulation, the Institute of Molecular Embryology and Genetics, School of Medicine, Kumamoto University
Since 2000 : Chief at the Institute of Molecular Embryology and Genetics, School of Medicine, Kumamoto University
Since 2000 : Professor at the Department of Hematopoiesis, the Division of Organogenesis, the Institute of Molecular Embryology and Genetics, School of Medicine, Kumamoto University
Since 2002 : The present post

From 2000 to 2004 : Project leader of "Characterization of Somatic Stem Cells and Tissue Reconstruction", Research for the Future Program, Japan Society for the Promotion of Science.
Since 2008 : Research Supervisor of "Fundamental Technologies for Medicine Concerning the Generation and Regulation of Induced Pluripotent Stem (iPS) Cells", CREST, JST, and committee member of The Japanese Society of Hematology.

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