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What is necessary for industrialization of regenerative medicine? (2) -All 2 episodes-

Dr. Ken-ichiro Hata

Cells are living things

Photo:An aseptic technique (provided by J-TEC)

An aseptic technique (provided by J-TEC)

Interviewer :
I hear that cells are living things and can live only two days.

Hata :
That is right. It is a matter of transportation or stability of storage. You may think that you can store and transport cells in its culture medium, but this is not recommended because cells will grow rapidly in the medium during storage and transportation, and may change their properties. So, before shipment, we have to remove the culture medium, rinse the cells and add a non-nutrient solution such as physiological saline. The cells, transferred from a nutrient culture medium into non-nutrient physiological saline, will live for several tens of hours at the longest. If we assume that they can live only as long as 50 hours, we will have practically only 30 hours left because it takes about 20 hours for sampling inspection after packaging. Therefore, it will be long before industrialization.

Pharmaceutical industries are clothing stores, while cell industries are laundries.

Interviewer :
For industrialization of cells, we need to have a different vision, you say.

Hata :
I say often that it is like a difference between clothing stores and laundries. Mass cloth retailers can sell clothes mass-produced in any place where costs are low, while laundries should be situated close to customers.
Pharmaceutical products can be mass-produced, while cells should be produced close to each hospital. Professors seem not to understand well the situation.
They often say that they need a venture business, but do not understand well that technologies necessary for industrialization do not lie in science.

Identity and standardization are essential

Interviewer :
You said that establishing specifications for iPS cells will be much more difficult than for cultured skin.

Hata :
For industrialization, it is necessary that identity and specifications of the finished products be established. It seems that we have not only to develop scientific evaluation methods, but also to set rules different from those for examination of pharmaceutical products.
It is needless to say that the finished products should not contain a dangerous level of impurities, but it is necessary to establish rules by which the mass of mixtures containing impurities at a not dangerous level is accepted. It is of course important to respect release specifications of the finished products, and it is realistic to have a concept of process management.

Dr. Ken-ichiro Hata

Interviewer :
What are you planning to do in the "joint research for realization of retinal regeneration using iPS cells" with Dr. Takahashi Masayo of RIKEN?

Hata :
We are to study how to regenerate retina with pigment epithelial cells degenerating and coming off with age, using iPS cells.
We want to evaluate the outcomes of this iPS research, in terms of pre-industrial clinical application. To do this, RIKEN will be in charge of scientific aspects, and we will be in charge of other aspects of evaluation.
Cells cultured with different culture techniques will be different. We are just on the starting line, and have to study where to set the endpoints.

Interviewer :
The last interviwee Dr. Okano said that it is possible to produce cornea from cultured oral mucosal cells. Is it difficult to culture pigment epithelial cells?

Hata :
There are some reports on successful cultures of pigment epithelial cells, but it is very difficult to do it. On the other hand, these cells are not heterogeneous and relatively simple, and in this sense they are cells that we will be able to produce relatively easily from iPS cells. And it is easy to distinguish these pigmented cells from other cells.

This is where iPS cells are needed

Interviewer :
Then, this is where iPS cells are needed.

Hata :
That is right. iPS cells will be used for producing cells for repairing a damaged tissue where a small amount of cells are needed but it is difficult to obtain cell cultures from the original tissue. Different from the case of ES cells, we are able to grow iPS cells derived from the patient and it seems that we will be able to develop interesting treatments using iPS cells if we choose suitable target tissues.
It seems that iPS cells may serve for other purposes. So far it is easy to build a two-dimensional structure, and is difficult to build a three-dimensional structure. How can we arrange heterogeneous cell populations into a simple three-dimensional structure? We will be able to do it if we will select similar cells from iPS cell derived cells. To realize it, it is important to have innovative engineering techniques.
In the future, regenerative medicine using iPS cells will significantly change the paradigm of medicine itself. For the moment, still we have many problems to solve, even if we have got non-tumorigenic iPS cells.
For example, it is difficult to build a large portion of tissue from cultured cells. After transplanted, cells inside will not receive nutrient supply and cells will die easily. It is not the case in the human body that has a vascular network, but is the case also for iPS cells.
When, for instance, we try to build an organ composed of heterogeneous cells A, B and C in a ratio A : B : C = 1 : 2 : 3, if A has high nutritional requirements and die soon after transplantation, we are not allowed to obtain an organ composed of the cell populations in this ratio. If I compare iPS cells to cars, we are at a stage where we have just iron and other useful materials. How to assemble a car from these materials is a question of science in the future.
Anyway, it is important that these materials are ready.

Regenerative medicine is now at a stage where music composers are making gramophones

Interviewer :
Is it still a long way off?

Hata :
Regenerative medicine is now at a stage where music composers are making gramophones.
Composers longed for a gramophone because they wanted many people to listen to their music. They might understand the principle of gramophone, just as I could understand the principle of phonograph records.
Then, the gramophone system was to be replaced by CD, MD and finally iPod systems following technological innovations. It was possible only with innovations made by many researchers who were not composers and industries. Without such innovations, gramophones would still be in use.
Similarly, for controlling three-dimensional arrangements of cells, we will probably see innovations if researchers from other fields and industries get involved.

Interviewer :
Development in semiconductor technologies brought new systems replacing the gramophone system. It seems to me that there has not been any significant development in cell technologies, isn't it?

Hata :
Newsweek dealt in 1997 with regenerative medicine under the title of "The New Era of Medicine". The situation has little changed during the last 12 years since then.
One sheet of cultured cells costs three hundred thousand yen, and a maximum of 20 sheets can be covered by insurance. If 30% of the body skin is burned, only 10% can be covered. This means that it is only rich people who are allowed to receive sufficient medical care
How are we going to provide such medical care at a low cost?
For instance, a television set of 30 years ago had a quality much lower than that of the present day but was very expensive. Now there are good quality and low price television sets available to many people .
For business, it is necessary to provide users with products prepared at low costs with versatile technologies. When we will be able to do it for iPS cells, they will probably provide us with dream tools.

Policy suggestions towards the future

Interviewer :
iPS cells can be said to play a role like semiconductors that changed the world of gramophones. Do you have any policy suggestion towards the future?

Dr. Ken-ichiro Hata

Hata :
We need to change our way of thinking vis-a-vis the risk. So far we require that a product has benefits much larger than risks, but this way of thinking may also need to be changed.
We have to understand that greater benefits involve higher risks. Investments that seek higher returns involve higher risks. In this sense, how do we deal with high-risk pharmaceutical products and medical devices? We have to discuss whether we will keep our option open on special "high-risk pharmaceutical products and medical devices".
Another thing is to have an idea of "ex-vivo medicine". There is a clinical example of treatment for bone cancer. This treatment is to "remove the bone and destroy its cancer cells under high pressure, and put the remaining matrix back to the body". This idea of treating the target organ or tissue out of the patient's body will be a key to future studies for regenerative medicine.
If the target organ or tissue is treated ex-vivo, other organs would not be affected. This will be an ultimate form of autologous transplantation. In this case, iPS cells may serve as parts of treatment.
How to deal with cells as materials to be used in such new paradigm of medicine, and not as pharmaceutical products or medical devices, will be a subject of discussion.
The most advantageous point of blue light-emitting diode (LED) is not to embellish Christmas decorations with blue color but is to make white when used mixed with other color LEDs. It will be possible that iPS cells also bring such a new added value.
Japanese people are dexterous in manufacturing products and workers are very skillful. In Japan, we have foundations on which reliable products are manufactured uniformly. If we take advantage of this, Japan will be a leading and reliable country ahead of other countries in the field of medical care. I think it will be possible in the future that cell industries for regenerative medicine be new industries closely linked to hospitals, like convenience stores and supermarkets.

Interviewer :
The Ministry of Education, Culture, Sports, Science and Technology published a roadmap for iPS cell research, and according to this map iPS cells will be put into clinical studies in five years.

Hata :
We want to launch these studies earlier, at the latest in five years. Otherwise, the enormous efforts of many researchers and the vast amounts of money invested will come to nothing. Besides, we are in competition with other countries.


Interviewed by Sato Katsuaki, Watanabe Mio(Japan Science Technology Agency)
Published on 12 January, 2010

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Dr. Ken-ichiro Hata

Dr. Hata Ken-ichiro is Doctor of Medicine, dentist, and Managing Director, R&D Department, Japan Tissue Engineering Co., Ltd. (J-TEC).

He graduated from the Dental department at Hiroshima University in 1991, and received his Ph.D. from the Graduate School of Medicine, Nagoya University. After positions of physician working for the Department of Dental and Oral Surgery at Meijo Hospital (Nagoya City), research associate at the Graduate School of Medicine, Nagoya University, associate professor for endowed courses of tissue engineering in the Faculty of Medicine, Nagoya University, and associate professor in the Center for Genetic and Regenerative Medicine, Nagoya University Hospital, he has been holding the present post since 2004.

The research theme is regenerative medicine in general (e.g., skin, cartilage, cornea, peripheral nerves, cardiac valves and bones).

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