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iPS cell research and the drive for cures(2) -All 4 episodes-

Prof. Shinya Yamanaka

image:Prof. Shinya Yamanaka

Standardization of iPS cells

Interviewer :
What do you think about the future of basic iPS cell research over the next 10 to 15 years?

Yamanaka :
I think the field will mature within the next 5 years or so. Standardization should be possible in that timeframe as well. Our group is receiving 5 billion yen over 5 years from the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST) initiative for this, so we have to achieve that within the remaining four years. But I think that the goal is well within reach.
Dr. Konrad Hochedlinger, a researcher in the U.S., determined the extent of reprogramming in iPS cells, by using as a marker the genes responsible for DNA methylation whose pattern changes when cells are reprogrammed, and found that only about 1 or 2 in 50 of their mouse iPS cells were fully reprogrammed. At that time, we did similar work in our lab, and found that more than 50% of iPS cells generated by our method were in an ES cell-like state. So it is clear that there are still differences in the quality of iPS cells that depends on methodology and culture conditions. We have yet to find a protocol that enables any labs to generate iPS cells of the same quality.

Interviewer :
So it's clear that standardization is needed, and Prof. Yamanaka, you will take the initiative, won't you?

Yamanaka :
Yes, I think so, and hope I will do it.
But that doesn't necessarily mean that we should generate just a single type of iPS cell. It would be just as good if we are able to generate the right cell for a specific purpose. Take PCR (polymerase chain reaction). It is now an essential technique for amplifying DNA that has diverse uses in many different labs and fields of study. By varying conditions such as enzymes, reagents, temperatures, and thermal cycling protocols, it is possible to adjust the technique to a desired use. I think the same may be true for iPS cells one day. We may be able to tailor them as needed to suit uses in regenerative medicine or disease modeling. Once we overcome these technical hurdles, the way will lie open to begin developing clinical applications. I think we should be able to start demonstrating safety and efficacy in the first applications in the next 5 to 10 years.

Canceration is not an insurmountable problem

Interviewer :
When thinking about uses in regenerative medicine, I suppose you can't avoid confronting the problem of canceration.

Prof. Shinya Yamanaka

Yamanaka :
Like ES cells, iPS cell colonies contain undifferentiated cells, and the cells will form teratomas if injected into a mouse. In fact, that is considered a defining feature of these cells. So what we need to be able to do is to filter colonies so that they don't contain these undifferentiated cells. Very stringent techniques for differentiation have been developed, and although the colonies may not be 100% differentiated, through a process called "purification" it's possible to remove all the undifferentiated ones.
There is another safety issue for iPS cells, however, as they are prone to forming a different sort of tumors as well. But I think that solving this will also prove to be no more than a technical issue as well, and in a few years we should reach the same levels of safety that ES cells are at today.

Interviewer :
If you generate blood cells, wouldn't it be difficult to completely filter out all of the undifferentiated cells due to the large quantities needed?

Yamanaka :
Differentiated platelets and red blood cells have no nuclei, so it actually should not be so difficult. However, if the idea was to generate hematopoietic (blood-forming) stem cells for use as an alternative to bone marrow transplants, great care would need to be taken as such cells can proliferate indefinitely, which could be a real problem.
But there are around 2,000 patients per year in Japan who need bone marrow transplants, and only about 1,000 transplants are performed. If we develop a safe and effective method for generating hematopoietic stem cells from iPS cells, it might help to fill that gap. But we know that if undifferentiated cells remain in a transplant, it could lead to other forms of leukemia, so we need not only to find techniques for inducing the differentiation of cells but also for purifying away any that remain in the undifferentiated state.


Interview by Miwako Homma, supervisor of iPS Trend website, and Katsuaki Sato and Bisei Watanabe from the Japan Science and Technology Agency.

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Shinya Yamanaka, M.D., Ph.D.

Director, Center for iPS cell Research and Application (CiRA), Kyoto University Senior Investigator, Gladstone Institute of Cardiovascular Disease

After graduating from the Kobe University School of Medicine in 1987, and doing his residency at National Osaka Hospital, Yamanaka received his Ph.D. in medical science from Osaka City University Graduate School of Medicine in 1993. He moved to the Gladstone Institute of Cardiovascular Disease in San Francisco that same year as a postdoctoral fellow. He became a Japan Society for the Promotion of Science special postdoctoral fellow in 1996, and an assistant professor in the department of pharmacology at Osaka City University the same year. He moved to the Nara Institute of Science and Technology as associate professor in 1999 and was appointed professor in 2003. He took a professorship at the Institute for Frontier Medical Sciences, Kyoto University in 2004, moving to the Institute for Integrated Cell-Material Sciences (iCeMS) at the same university in 2007, and named director of CiRA,iCeMS Kyoto University in 2008. He is the director of CiRA, Kyoto University since April 2010.

Major Awards

2004 Tokyo Techno Forum 21 Gold Medal (Japan)
2008 Robert-Koch Prize (Germany)
2008 Shaw Prize in Life Science and Medicine (Hong Kong)
2008 Medal of Honor with Purple Ribbon 2008 (Japan)
2009 Canada Gairdner Foundation International Award (Canada)
2009 Albert Lasker Basic Medical Research Award (U.S.)
2010 Imperial Prize of the Japan Academy (Japan)
2012 The Nobel Prize in Physiology or Medicine
etc.

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