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Leading regenerative medicine research in Japan (1) -All 3 episodes-

Dr. Teruo Okano

Photo:Dr. Teruo Okano

Dr. Teruo Okano

Professor Teruo Okano's group at Tokyo Women's Medical University has been working to develop advanced regenerative technologies fusing medicine and engineering since before the advent of induced pluripotent stem (iPS) cells, leading to the international recognition to his discoveries as "living treasures." We spoke with him about his firsthand perspectives on Japan's leading regenerative medical research activities.

Interviewer :
As you may know, JST has established a public outreach website called "iPS Trend" to bring the latest from the frontlines of iPS cell research to the public in an easily understandable fashion. We'd like to ask you a few questions on your own experiences from working in the world of medicine, and with iPS cells.

The 21st century healthcare will treat diseases, not symptoms, through regenerative medicine

Dr. Teruo Okano(Sketch by Sato Katsuaki)

Dr. Teruo Okano
(Sketch by Sato Katsuaki)

Okano :
My approach to regenerative medicine is actually very different from that of iPS cells, so let me introduce that first.
In the last century, we saw tremendous advances in chemical engineering, leading to a golden age of drug development. Then, in the 70s and 80s, the advent of new cell and genetic engineering technologies made it possible to mass produce peptides and hormones by the ton, marking the shift from small molecule-based to biological medicine, and making it possible to treat patients with, for example, enzyme deficiencies using peptide hormone therapies.
But I think when thinking about therapies in the 21st century, we need to start looking for ways to develop true cures. At present, medicine generally treats symptoms. There are about 5,000 hemophilia patients in Japan with defects in clotting factor VIII, but it costs 20 billion yen a year to treat them using a recombinant version of that protein. Similarly, diabetes can be treated using synthetic insulin, but this is also extremely costly. For young children, we should be able to offer them something better than a life of ongoing treatments.
In the new century, we need to move away from treating symptoms and toward curing the underlying diseases by using cells and tissues in new kinds of regenerative therapies.

The power of cell sheets

Interviewer :
That is exactly what you are hoping to achieve with the cell sheet technologies you have been developing, isn't it?

Okano :

For years, there have been attempts to use injections of myoblasts in suspension to treat heart conditions, but the improvements have been modest at best, at only a few percent, as the transplanted cells don't make it to the target tissue, or die in vivo.
To address such problems, our lab devised a method for generating sheets of autologous cells taken from the patient. Such cells express cell-to-cell adhesion proteins and interact with each other in culture. The problem was that when we detach the cell sheets from the substrate using DISPASE (a protease), the enzyme destroys also the adhesion proteins and consequently the structural and functional connections between cells.
So, we developed a technique that uses a cell culture surface modified with poly (N-isopropylacrylamide), or PNIPAAm, and not with a protease.
This surface with PNIPAAm has an affinity with water turning at 32℃.If we coat the culture surface with a nanometer order thin layer of this polymer, the coated surface is hydrophobic at 37℃, the normal incubation temperature, where cells adhere to the surface and grow.
After an incubation at 37℃, when the temperature is lowered to 32℃, the surface turns to be hydrophilic, and cultured cell sheets can be detached without destroyed. We patented this technology around 1990.
However, it is necessary to have a nanometer-order thin uniform coating of this temperature-responsive polymer fixed on the culture surface, in order that we are able to culture cells on the coated surface. How thin is the coating? We found that, when the coating was as thin as 20nm, cells adhered onto the surface or detached from it in response to temperature changes.
When we detach cells in this way, cells do not lose their own adhesion protein, fibronectin, and keep a form of sheet. It is just like a cellular Scotch tape.

Interviewer :
I remember that, when I asked you in 1990, you said the PNIPAAm coating was thicker, wasn't it?

Okano :

That's true. We were really able to determine the thickness at 20 nm only when we had a highly sensitive surface analysis technique in sometime after 2000. We developed a technique using TOF-SIMS (time-of-flight secondary ion mass spectrometer), which enabled us to translate a so far empirically estimated "thinness" into accurate figures.

Interviewer :
It appears you have been able to obtain funding for your work from a number of sources.

Okano :

For a five-year period around 1995, I received 150 million yen per year through the Mirai Kaitaku program. Since then, I've received funding under a number of programs, including High Tech Research, COE, and CREST. At present, I have a grant to promote "Advanced Fusion," which provides 700 million yen per year for a 7-year project. Thanks to this sustained support, we have been able to develop quite a well-equipped research environment.

Interviewer :
Given your background in chemistry, what inspired you to seek to make this sort of contribution to medicine?

Okano :

Until I was around 40 years old, my main research goal seemed to be publishing in major journals like Science and Nature. Then, after I returned to Japan from the University of Utah and took a position at Tokyo Women's Medical University, I started thinking about ways of combining medicine and chemistry in a graduate program in advanced biomedicine. At the time, physicians expected engineers would make something that contributes to medicine and engineers hoped that physicians would think how to use their good techniques and products and use them.
I myself graduated from the faculty of engineering and served as an assistant professor at the faculty of medicine. At that time, the importance of combining the different domains was not understood, and I struggled through my 30s. I realized that I needed to get direct insight into how to wed medicine and engineering and went to USA for some time before returning to Japan. It was after that that I began working on cell sheet engineering as a means to meeting patient needs.


Interviewed by Miwako Honma (supervisor of iPS Trend website), Katsuaki Sato (Japan Science Technology Agency)
Published on 19 October, 2009

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Dr. Teruo Okano

Professor, Tokyo Women's University,
Director, Institute of Advanced Biomedical Engineering and Science,
Professor, University of Utah,
Member, Science Council of Japan

After receiving his Ph. D. in polymer chemistry from Waseda University in 1979, Dr. Okano served as an assistant and lecturer at Tokyo Women's Medical University (TWMU) before taking an assistant professorship at the University of Utah. He returned to TWMU as an assistant professor, and was appointed to professorship at both universities in 1994. He was appointed director of the TWMU medical engineering facility in 1999, and has served as the head of the Institute of Advanced Biomedical Engineering and Science at the same university since 2001.
His research interests include biomaterials, artificial organs, drug delivery systems, and regenerative medical engineering. He is particularly focused on how regenerative functions can be achieved by fine-tuning polymer structure. He developed the concept of cell sheet engineering, which first entered the clinic with bioengineered corneal epithelium. He hopes to extend to regenerative applications in the cardiovascular system, liver, and bladder as well. He is the director of the Japanese Society for Biomaterials, and a member of the board of the Japan Society of Drug Delivery System, the Japanese Society for Tissue Engineering, and the Japanese Society of Inflammation and Regeneration.

Awards and Honors
1990, 1995, 1996 Outstanding Paper Award from the American Controlled Release Society
1992 Japanese Society for Biomaterials Prize
1997 Clemson Award for Basic Research
1998 Society of Polymer Science Japan Prize
2000 Founders Award, Controlled Release Society
2000 Fellow, Biomaterials Science and Engineering
2005 Leona Esaki Prize
2006 Nagai Innovation Award, Controlled Release Society
2009 Medal with Purple Ribbon for scholarly or artistic achievement

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