[Feature: The Future of Regenerative Medicine] Roundtable Discussion: The Era of Regenerative Medicine Has Begun

Today, we have gathered several professors to discuss the theme of "Regenerative Medicine."

In February of this year, the clinical research for "Regenerative Medicine using iPS cell-derived neural progenitor cells for subacute spinal cord injury," which Keio University Hospital had submitted, was approved. This will be the world's first clinical research for spinal cord injury treatment using iPS cells (induced pluripotent stem cells).

While there are great expectations for regenerative medicine involving actual transplantation into patients, I would like to discuss what stage we are currently at, what will be possible in the future, and what the challenges are.

First, I would like to ask each of you to introduce your efforts in regenerative medicine from your respective positions. Mr. Yamanaka, could you please start by telling us about the current efforts of the Center for iPS Cell Research and Application (CiRA) regarding iPS cells for regenerative medicine?

We at the Kyoto University Center for iPS Cell Research and Application are manufacturing iPS cells as a national project, so to speak, within the framework of the iPS Cell Research Core Center, which is one of the Regenerative Medicine Realization Base Network Programs of AMED (Japan Agency for Medical Research and Development). Our responsibility is the supply of iPS cells for regenerative medicine. While autologous transplantation (using the patient's own cells) is naturally the best, it currently takes too much time and cost, so we preserve and supply cells from healthy third parties in advance.

To minimize immune rejection as much as possible, we search for donors with HLA (Human Leukocyte Antigen) homozygosity with the cooperation of the Japanese Red Cross Society, and create and store iPS cells. So far, we have established a system to supply four types of HLA-type iPS cells. These four types can cover just under 40% of the Japanese population.

On the other hand, as we move forward, we are left with increasingly rare HLA types. To cover 90% of the Japanese population, more than 100 types of iPS cells would be required, which would necessitate an enormous amount of labor, time, and money.

In the last few years, genome editing technology has advanced rapidly. By using genome editing on the HLA-homozygous iPS cells we have created so far, it has become relatively easy to modify parts of the HLA.

Therefore, by adding genome editing to our previous strategy of searching for HLA-homozygous cells, we are conducting research to supply cells with relatively low rejection reactions to the majority of Japanese people, and even people around the world, with a smaller number of cell lines. We hope to be able to supply clinical-grade strains with genome-edited HLA by around next year.

Thank you. Next, Mr. Okano, please.

I am a professor of physiology in basic medical sciences, but the first Dean of the School of Medicine, Dr. Shibasaburo Kitasato, made the integration of basic and clinical medicine the motto of this university. To conduct research and development together until it can truly be implemented in society, I have been conducting joint research on regenerative medicine for 20 years with Mr. Nakamura's team in Orthopedic Surgery, starting from the time of his predecessor, Dr. Yoshiaki Toyama. The results of our basic research have finally reached the point where they can be applied to humans.

As part of this translational research (bridging research), I am using iPS cell technology or stem cell technology to study intractable neurological diseases in addition to spinal cord regeneration. Regarding ALS (Amyotrophic Lateral Sclerosis) in particular, clinical trials are currently underway and progressing smoothly with a drug discovered through so-called iPS cell drug discovery.

As for my own basic research, from the standpoint of neural development, I want to develop innovative treatments for central nervous system diseases that were previously incurable. To achieve this, rather than going straight to actual clinical practice, I have been working for many years on the underlying neural development and stem cell control mechanisms.

As Mr. Okano just mentioned, we have continued our joint research for nearly 20 years. Basic researchers and clinicians have moved forward step by step toward a common goal while sharing ideas. We have also conducted research on axonal growth inhibitors with Sumitomo Dainippon Pharma. Since the construction of evaluation systems is also important in clinical practice, we have also conducted research using MRI and other methods. I believe that regenerative medicine can only be realized through the culmination of many such research results.

Now, Mr. Nagayama, how about from a corporate perspective?

My position is both from my own company and from the perspective of the Bio-Strategy Expert Committee (established under the Cabinet's Integrated Innovation Strategy Promotion Council), which was launched in February of this year and for which I serve as the chairperson.

Regarding the company, Sumitomo Dainippon is working on new regenerative medicine on a very large scale. While we have developed many biotech products, we have not yet done anything major in the field of so-called regenerative medicine.

Basically, pharmaceutical companies in the 20th century created drugs using low-molecular-weight compounds, and the market for pharmaceuticals for lifestyle-related diseases, mainly in the area of metabolic disorders, formed a large market. Since the end of the 20th century and after 2000, as the decoding of genome sequences progressed and we entered the era of biotechnology, antibody drugs and the like have grown in the market. In addition to low-molecular and high-molecular weight drugs, modalities (treatment methods) such as medium-molecular weight drugs or nucleic acids are now attracting attention.

What comes next is treatment using regenerative medicine. Our company has not yet entered very deeply, but we are currently partnering with a venture in Hiroshima. Since they have the technology to culture MSCs (Human Mesenchymal Stem Cells, a type of stem cell) in a serum-free environment, we have a project in Phase 3 to culture cells collected from the synovial cells of healthy individuals in the form of gMSC1 (Note: development number for a knee cartilage regeneration cell therapy product) to create allogeneic cartilage preparations.

Then, Mr. Kimura, please.

During the bubble era of the late 1980s, when we had ample research funds, our company started a program with the theme of "Central Nervous System Regeneration" to tackle the most important challenges in neurological drug discovery from a long-term perspective.

While exploring various methods, we worked on axon (neurite) regeneration using low-molecular compounds and found a compound that seemed likely to actually extend axons. Therefore, I asked Mr. Okano, who was conducting very advanced research in that field, for his cooperation, saying, "I want to confirm whether this actually works for spinal cord injury," and we have been conducting joint research since 2000. Then, Mr. Nakamura also joined us in working on axon regeneration using low-molecular compounds for spinal cord injury.

In the midst of this, human ES (embryonic stem cell) technology and then Mr. Yamanaka's iPS cells emerged, and we thought that using cells might make it easier to perform regenerative medicine.

In fiscal 2012, when I was involved in formulating the medium-term management plan as the General Manager of the Business Strategy Department, while low-molecular drug discovery was in a sense at a standstill, I launched a strategy to work on regenerative medicine using cells as a new business aiming for sales of 200 billion yen in ten-plus years. It was around that time that Mr. Yamanaka won the Nobel Prize, the Regenerative Medicine Promotion Act was enacted, and the momentum for promoting regenerative medicine grew. Currently, in addition to Mr. Okano and Mr. Nakamura, we are working together on many of the ongoing national network core programs, such as those of Dr. Masayo Takahashi of RIKEN (Institute of Physical and Chemical Research) and Dr. Jun Takahashi of Mr. Yamanaka's Kyoto University CiRA.

We initially focused on the central nervous system, but recently we have gained some confidence and decided to expand into peripheral nerves, as we announced in a press release just the other day, and we have also begun working on regenerative medicine for the kidney.

Each of you has just spoken about your efforts in regenerative medicine from your respective positions. Based on that, I would like to discuss the current challenges of regenerative medicine in Japan.

I believe there are three main categories: challenges related to basic research, clinical application and industrialization, and ethical issues. First, Mr. Yamanaka, what is your view from the perspective of basic research?

As exemplified by genome editing, science is changing rapidly, so I feel that a very big challenge is how to connect the results of cutting-edge basic research in real-time to efforts like ours that aim for application.

Since it involves clinical cell manufacturing, we are constantly required to standardize and solidify methods through GMP (Good Manufacturing Practice), but at the same time, we are proceeding while feeling a dilemma as the technology itself is changing day by day.

Also, in the case of previous low-molecular compounds, if you had a good low-molecular compound, the job was finished once it was administered. However, in the case of regenerative medicine, no matter how good the cells you create are, it will definitely fail if the surgery is not mature.

Therefore, in the series of processes that constitute regenerative medicine, I believe that what we basic researchers and pharmaceutical companies can do is actually limited. Thus, it becomes important to form teams with clinicians, centered on surgeons, from an early stage of research and development.

I think Mr. Okano and Mr. Nakamura are an ideal team, and Dr. Masayo Takahashi and Dr. Jun Takahashi, who are already in clinical practice, are also surgeons as well as researchers, so their team formation has gone well from the beginning.

I feel that how to form a team with good collaboration is an important aspect of regenerative medicine that did not exist in previous drug development.

I truly believe that collaboration is important. In the case of our Parkinson's disease program, it has been designated under the Sakigake Designation System, and we are proceeding while consulting with the PMDA (Pharmaceuticals and Medical Devices Agency) about 10 times a year. I believe that having Dr. Jun Takahashi, who is a physician, and our pharmaceutical company discuss things together with the authorities is a very big factor in the promotion of regenerative medicine.

Another thing is collaboration between companies. Pharmaceutical companies usually conduct research only within their own company or with peers, but we are now conducting research in the same lab as Hitachi or Western machinery ventures. I daily feel the importance of collaboration with other industries or people in different positions.

Collaboration is truly important. Regenerative medicine is like the ultimate interdisciplinary research aimed at social implementation, and to evolve this further, I believe we should proceed by fusing it with methods such as gene therapy and genome editing. In fact, the FDA (U.S. Food and Drug Administration) reviews under the category of Cellular & Gene Therapy, and the Health Science Council in Japan is actually already reviewing cell therapy and gene therapy together, so I think they will proceed as inseparable technologies.

On the other hand, I believe it will be necessary in the future to generalize products created by the combined efforts of highly capable teams to the point where they can be administered even at municipal hospitals involved in community medicine. That is still a high hurdle. Since it extends to changing social and distribution structures, I believe we must talk with various people.

As Mr. Okano mentioned at the beginning, the integration of basic and clinical medicine is the starting point at Keio School of Medicine, so in that sense, I think the team building between basic and clinical medicine has proceeded in a very good way from the start of the project.

The challenge of regenerative medicine is that because it uses live, raw cells, it requires collaboration different from previous systems, and as a result, I think a very large number of processes are required. For example, with allogeneic cells, when creating a regenerative medicine product, where do the raw materials come from? How are they transported, and where are they manufactured and processed? Where are they evaluated? A series of processes like these follow.

In this context, Japan took the lead in the world in legal development with the Regenerative Medicine Promotion Act and has led in research seeds, but when social implementation is imminent, what will be necessary for it to spread as medical care for the public? I am concerned that unless we adopt a collaborative system like never before, it will not become a truly widespread regenerative medicine.

For example, even taking MSCs as an example, where and how to obtain the raw materials is currently a very unstable situation in Japan. I heard that companies that have already started clinical applications are importing cells from overseas. However, because the system is different from overseas, paying volunteers to receive cells is a no-go in Japan.

While CiRA is firmly creating public iPS cells, such a system has not yet been established for other cells. To make regenerative medicine something that can lower prices and spread widely to the public in the future, the creation of mechanisms for cell raw materials, processing, and transport, as well as collaboration between multiple companies, will become increasingly important.

That is exactly why you are discussing what is lacking in Japan and how to solve it at the Bio-Strategy Committee and other forums where Mr. Nagayama serves as chairperson, right?

The Bio-Strategy Committee is set to hammer out Japan's bio-strategy by June, but what needs to be addressed at the national level in the field of regenerative medicine is, after all, the commonality of international standards. Regarding the approval system, in Japan, the Act on the Safety of Regenerative Medicine, which is one of the regenerative medicine-related bills, will mark five years since its enforcement this November, and revisions are being discussed. If we do not move forward with such standardization, there is a possibility that the path to using regenerative medicine technology socially will be closed. Since approval standards differ slightly between the U.S. and Europe, I believe international standardization is necessary.

Furthermore, creating high-quality iPS cells, as mentioned by Mr. Yamanaka, is also a challenge. Regenerative medicine mainly involves treatment using cells, but cells change their state, including genes, during the process of division and differentiation. Creating such cells and tissues differentiated from them is another aspect that differs from drug discovery centered on conventional organic chemical synthesis. In the future, I see a need for the formation of companies and CMOs (Contract Manufacturing Organizations) that can properly create cells, as well as ventures, not just the conventional pharmaceutical industry.

Specifically, what kind of things will be necessary?

When new technology and science emerge, Japan has not been able to properly depict an "ecosystem" compared to the U.S. and other countries.

For example, in the automobile industry, powerful companies emerged in Japan and demonstrated competitiveness globally. This was because the automobile industry flourished as the government built roads with tax money, allowing cars to run comfortably, but this road part cannot be done by private effort alone. Similarly, in regenerative medicine, I believe that unless the government develops systems for licensing and the like, it will not lead to international competitiveness.

In the U.S., the Department of Commerce spends about 70 million dollars a year investing in manufacturing and culture technologies that can be commonized across a consortium of about 120 companies, universities, and research institutes. Therefore, by depicting the "roads" in Japan as well, I want to clarify the points that the government should handle on this occasion.

Also, I want to standardize the licensing part as much as possible. For drugs, we have long had an international conference body called ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use), but regenerative medicine is not included in this. Therefore, we need to create a regulatory harmonization conference for regenerative medicine and ultimately create something common globally. It is difficult if regulations and standards differ by country each time.

That's exactly right.

Furthermore, within open innovation, Japan still overwhelmingly lacks the number of biology and life science ventures and investment in them. In the IT industry, a culture seems to be forming where talented young people join IT startups, but that is not easily the case in the life sciences. I think we must create the money to support that and a culture that can challenge new things.

Sumitomo Dainippon is very active in the regenerative medicine field, but it is difficult to enter this field unless the company has biotechnology such as cell culture. Also, since the capital that must be invested becomes large, it is necessary to incubate ventures and realize a division of labor and collaboration system between academia and ventures, and between ventures and companies.

Ecosystems are now being attempted in various places, such as around CiRA in Kyoto, Kobe (RIKEN), or in Kanto at Kawasaki Tonomachi (Keio Tonomachi Town Campus) and Nihonbashi (Forum for Innovative Regenerative Medicine: FIRM). Rather than just mimicking Boston or Silicon Valley, the creation of an ecosystem in a form suited to Japan's climate is beginning, so I hope you will look upon it warmly.

FIRM, a federation of companies related to regenerative medicine, is chaired by Mr. Yuzo Toda, formerly of Fujifilm. Recently, we had a discussion with the Japanese Society for Regenerative Medicine about how to work on this as a nation. It seems the challenge is how to distinguish between the most important know-how that each company can share and what they cannot. Everyone agrees on the general principles, so I want to continue the discussions and put them into a good shape.

Speaking of Keio, when I was the Dean, I surprised everyone by saying, "Let's create 100 Keio ventures," but it has already reached 13, and a federation-like organization of ventures from Keio School of Medicine or founded by its graduates has begun to form. It is still weak, but since we faculty members alone can never achieve social implementation, I believe we must create organizations that support inventions and medical care coming from researchers and somehow put them into a form that can be used in the world.

I think ventures dealing with regenerative medicine have quite difficult aspects. For example, if you want to give shape to a regenerative medicine product, you need a CPC (Cell Processing Center), and considerable resources are required for obtaining raw materials and quality control of the product.

When I think about future social implementation in regenerative medicine, I believe it is important that a platform for incubating the seeds held by young researchers is created, and that they are given a chance if they come there without having to make such a large capital investment.

In that way, forming a consortium that can create an ecosystem where industry, government, and academia collaborate in the future, and nurturing young people while inviting them there, will be one important key to transmitting Japanese regenerative medicine to the world in the future.

In the world of drugs, it is said that there are thousands of ventures in the U.S. alone, and about 5,000 in the world as a whole. Drugs that get approval from the FDA are considered innovative in the world, and the 62 approved last year was the record so far. But the fact that only that many come out from among the pharmaceutical companies and thousands of ventures means, conversely, that new drugs will not come out unless the population is quite large.

It is true that many ventures have emerged in Japan recently. However, as a platform, it is still weak. In the U.S., the NIH (National Institutes of Health) funnels about 1 billion dollars in funding to startup companies every year. Within that, the government promotes it with a mentor system that includes not just money but also management guidance, accounting, and legal knowledge. For things like CROs (Contract Research Organizations), there are those directly connected to the government that ventures can use. I think such an ecosystem is indeed important.

Regarding clinical application, the topics of industry-academia collaboration and ventures came up. While Japan is ahead of the world with various seeds running toward clinical use, I think Japan must transmit the standardization of regenerative medicine products and product evaluation criteria to the world and create world standards. Mr. Yamanaka, what are your thoughts on this?

Japan established the Conditional Early Approval System for pharmaceuticals in 2017. Although it has been criticized by the U.S. and others, I think this is a very big opportunity.

In the era of low-molecular drugs, Japanese pharmaceutical companies were also at the top of the world, but since the era of biotechnology in the late 90s, innovative drugs have stopped coming out easily. Since the way money is gathered in the U.S. is extraordinary, various drugs are created, but development based on U.S.-style investment inevitably becomes very expensive, and drug prices are in a state close to the asking price of the companies there. CAR-T cell therapy is about 50 million yen.

Therefore, as is exactly the case with Actemra (the first domestic biological preparation developed in Japan), if it is first released in Japan, a drug price that is not outrageously high can be set. I think it is amazing that a drug price was first set in Japan. Once a drug price is set in the U.S., Japan is dragged along by that price.

That's why I am persistent about iPS cells: I want to get approval in Japan first by all means and get a drug price in Japan. If we take it to the U.S. that way, for example, if Japan is providing it for 1 million yen, I don't think they can possibly make it 10 million yen no matter what.

I go to the U.S. every month, and U.S.-style development is taken for granted, with a feeling of "50 million yen is natural, it will gradually get cheaper," but in the meantime, I see many people dying because they cannot pay 50 million yen.

In Japan's case, I think many patients can have access through insurance and the high-cost medical expense system, but national finances will definitely not hold up, so I definitely want to think about that.

This is an important theme. Since regenerative medicine products are expected to have quite high drug prices, discussions on cost-effectiveness will likely become active within the Ministry of Health, Labour and Welfare.

This will naturally differ between the standpoint of academia and the corporate side, but as a clinician, I believe that in the near future, regenerative medicine must not be a special medical treatment that only a few people can receive. I want it to be a treatment that everyone who becomes ill or injured can receive. To spread it as such medical care, various breakthroughs are necessary.

No one disagrees with the ideal that good things should be made cheap so that regenerative medicine can be performed at ordinary hospitals and used by many patients, but to actually finish the technology to that point, a cycle where investment is recovered and can be reinvested must function as an ecosystem.

Money is moving as the fuel to drive that. Setting aside the profit or loss of individual companies, I am concerned that the perspective of "how to move money to spread regenerative medicine to society" is missing from the discussion. What is necessary in the process of becoming able to provide cheap things far and wide? We are approaching a time when several products will soon be approved, and discussions on drug prices are beginning to occur, but if, for example, a very low price is set, no pharmaceutical company will conduct research and development anymore.

Our company is investing on the basis that as long as there is a social need, a viable drug price should be set, but many companies cannot make the decision to invest because they have no prospect of recovering their funds.

To widely spread regenerative medicine products, technical or systemic challenges are still piled high, and solving each of them requires time, people, things, and money. A discussion from the perspective of how to create a system to supply those is definitely necessary.

My concern in the drug price discussion is that high-cost medical care and high-unit-price drugs are being confused in the discussion.

At Tufts University, they extracted 106 new drugs that received approval from the FDA and other global agencies between 2000 and 2010 and calculated how much research and development expenses the companies involved in creating them used during that period, and the figure of an average of 2.558 billion dollars per drug came out.

The reason it is so high is that it includes the costs of failed drugs. It would be good if failures could be reduced, but there is an aspect of research where you don't know until you try. Of this 2.558 billion dollars, about 1.1 billion is for pre-clinical development, and the remaining approximately 1.5 billion dollars is for clinical development costs.

Therefore, from now on, it will indeed be important to use AI and other tools to rationally conduct clinical development and reduce costs. I think ingenuity to make pre-clinical research a little cheaper is also necessary.

In the current drug price discussion, high-unit-price areas are easy to attack, but this is a very simple story: if a company cannot cover the money it spent, no one will do it anymore. Therefore, I think high unit prices and high-cost medical care are slightly different, but it is a fact that it is better to make them as cheap as possible.

Regarding regenerative medicine, since no one has set a price yet since the current legal system was applied, it ends up being a question of what should be done.

That's right. Dr. Masayo Takahashi's first clinical research case for retinal regeneration—that was autologous—but she mentioned a figure of 100 to 200 million yen.

Then there is Terumo's skeletal muscle cell sheet (HeartSheet: 14.76 million yen), which received conditional and time-limited approval. There are even some bold opinions suggesting that we should align with this.

Mesenchymal stem cells already have prices attached to them. For example, Nipro's "Stemirac."

That's true. However, the most important thing is how effective the product was. And from the perspective of national medical finances, I think it depends on the specificity of the disease—in other words, how many patients there are and how severe the disease is.

For example, in the orthopedic field, regenerative medicine for lower back pain faces high hurdles. There are over 20 million patients, and if people say, "Aren't there other drugs available?" it becomes difficult to make progress.

Therefore, it's not just a matter of simply lowering the cost of each regenerative medicine product. Unless we bring in a medical financial perspective—such as how effective the treatment is and how many people will benefit from it—I think medical finances, which are already on the verge of collapse, will become even more strained.

I would like to consider Japan's future global strategy for regenerative medicine. I hope we can move the discussion toward the expansion of the value chain—such as the construction of cell stocks (the raw materials for regenerative medicine products), manufacturing and processing, quality evaluation, transport, and storage—as well as what the ideal form of regenerative medicine should be in the near future.

I would like to ask Dr. Yamanaka: while it might be desirable to have manufacturing facilities and cell banks in each region, from the standpoint of uniformity, I feel it might be better to manufacture them collectively in one large location. What are your thoughts on this point?

In the case of stocks, since there are very few types, I think it is better to produce them in a few locations rather than all over the place. Within Japan, transport within 24 hours is possible anywhere. Since iPS cells are merely raw materials, the important thing is what to do with the final differentiated cells.

Currently, retinal cells can already be cryopreserved. This allows for transport in a frozen state. They can then be thawed and transplanted on-site. For stocks, I believe we can handle it that way.

However, allogeneic transplantation is not the ideal form; in the near future, I want to aim for autologous transplantation, where the necessary cells are created from the individual themselves. In that case, it would indeed involve production at each location.

Not just in regenerative medicine, but in medical sciences as a whole, we have traditionally mass-produced a single type of drug and administered it to hundreds of thousands or millions of patients. From now on, however, individual responses will be required, such as "this drug for this person, this treatment for that person," even for those with the same disease.

Until now, those who mass-produced a small number of drugs and supplied them efficiently have won. But from now on, I believe it will be about small-scale production of a wide variety of things on-site when needed. This applies not just to regenerative medicine, but to everything. I think the old blockbuster success stories, where a single drug could build a whole building, will likely be difficult to achieve now.

Even for the same Alzheimer's disease, I think we are entering an era where we will use dozens of different drugs depending on the case.

That is exactly what precision medicine and personalized medicine are about.

However, when that happens, from a business perspective, there will likely be various challenges, especially regarding costs. Therefore, to get there, we will still need breakthroughs in basic medical sciences.

From the standpoint of basic research, long-standing questions that we had no way of addressing for many years can now be studied using iPS cell technology and stem cell technology.

For example, based on findings from early human development, evolution, and human genetics, we have begun to understand where in the genomic sequence the differences in drug efficacy between Africans and Japanese originate. That knowledge will lead to determining which drug works for a specific pattern of disease in a particular person. I believe that iPS cells, along with genomic information and the technology to create cells for various organs, will become a revolutionary power. Therefore, I think it is important to consider business strategies based on that.

Furthermore, regarding regenerative medicine actually using iPS cells, allogeneic use is naturally easier for business. However, ethics aside, iPS cells can be created from various people. To address HLA diversity, the iPS cell stock that Dr. Yamanaka is currently working on has been established. As technology advances further, autologous transplantation—the inherent strength of iPS cells—will become possible at a relatively low cost. When that happens, I believe the world will change again.

I believe we need to engage in reprogramming technology and epigenetics research as basic research with that vision in mind.

From the perspective of further improving the quality of iPS cells, the process of establishing many iPS cells, narrowing them down, and then narrowing them down further after induction of differentiation—which currently takes a vast amount of money, time, and effort—will become much simpler.

If high-quality iPS cells can be created by establishing just a few lines, and high-quality products can be made by differentiating them, then naturally, pricing can be kept down, and the products will likely become more widespread.

I believe that leading the world in such research will be an important strategy for Japan to further enhance its international competitiveness.

Based on what we've discussed, what are your thoughts on the ideal future form of regenerative medicine?

In the treatment of fractures, bone is taken from one's own hip during surgery and transplanted. Regenerative medicine aims for the same thing, so to speak. The best approach is to prepare and transplant cells autologously and on-site. You don't have to worry about immunosuppression, and you don't have to worry about infectious diseases from third parties. I think we will eventually arrive at autologous transplantation.

Autologous transplantation was actually performed on a patient by Masayo Takahashi in 2014, so it can be done even now if we want to. It just takes money and time.

Reducing the money and time for things that can be done now is what Japanese companies are best at, so I think it is definitely possible if we try. Therefore, I believe we must not send a message that acts as a brake, suggesting that autologous is no longer needed because we have cell stocks.

Furthermore, beyond that lies the inherent regenerative power that humans have as biological beings. If a human loses a finger, it won't grow back, but some other animals can regrow limbs. Why don't mammals, including humans, have that power? Apparently, the U.S. Department of Defense is seriously researching this using geckos and other animals. If someone who was injured on the battlefield and had a leg amputated could regrow it like a gecko, nothing could be better.

Unfortunately, humans do not have such regenerative abilities. In my opinion, such high regenerative capacity was likely lost as a trade-off to prevent cancer, as it might lead to cancer as lifespan increases. But I dream that through some breakthrough, such an era might come in about 100 years (laughs).

Around 2000, at the kickoff party when the CDB (RIKEN Center for Developmental Biology) was established in Kobe, the Director, Masatoshi Takeichi, said, "The goal of the CDB is for my hand to grow back immediately if I were to cut it now."

Through research on planarians and newts, we have come to understand quite a bit about why such organisms can regenerate. This might not be a pipe dream if combined with not only cell therapy but also gene therapy and genome editing.

We've gone quite a bit further than the future I was imagining (laughs). I was waiting for the term "My iPS cells" to come from Dr. Yamanaka.

No, no, the story about human fingers regenerating is just a fantasy. I just meant that research will continue to advance (laughs).

In the near future, I believe "My iPS," created from each individual patient's cells, will be the ultimate form of precision medicine. Last week, we announced that our ultimate goal is to popularize personalized and autologous regenerative medicine, and I believe that can be realized relatively soon.

Another challenge from the perspective of pharmaceutical companies is the issue of cross-border transactions. In regenerative medicine, regulations differ by country. Conventional drugs like small molecules are unified under ICH, so products and test data are valid across borders, but there is no such guarantee for regenerative medicine products. How to unify international regulations is a major challenge.

One of my ideals is for autologous regenerative medicine to become available in Japan, so that overseas patients can come to Japan with their passports, receive regenerative medicine, and go home. That way, only one regulatory system is needed.

If we think in terms of patients moving, the cross-border challenges disappear at once. Many targets for regenerative medicine are chronic diseases, and patients are able to travel, aren't they?

That's true. As Prime Minister Abe has also mentioned, I am very much in favor of that idea from the perspective of clearly asserting Japan's strengths as medical inbound tourism and bringing foreign currency into Japan. To that end, a platform for creating regenerative medicine products is necessary, and I hope Japan can present the core medical implementation to the world.

In spinal cord regeneration, subacute cases require action within a month, so they involve allogeneic transplantation. However, chronic cases allow for more time and involve a very large number of patients. Therefore, I believe we must first create iPS cell stocks by frequency, and then consider treatments for chronic spinal cord injury as "My iPS."

In that case, the number of target patients for a company would increase dramatically, significantly improving business viability. Investing for a target of 100 million people is completely different from investing for 7 billion people.

To realize that vision, we need to increase success stories and accelerate regenerative medicine over the next few years. It depends on how much the results of future clinical research can appeal to the public and the world. I feel we are approaching the most significant turning point for regenerative medicine in Japan.

Medical inbound tourism was also discussed recently at the Bio-Strategy Expert Panel. Not just in regenerative medicine, Japan's medical standards are high. This medical inbound tourism is very important, and if Japan takes the lead in regenerative medicine in the future, it will become a major highlight.

Regenerative medicine, which was like science fiction until recently, is becoming a reality. Consequently, we need to clear challenges such as social systems, medical insurance, various ethical issues, and the commonization of regulations.

This is the third national bio-strategy meeting, following those in 2002 and 2008. Almost nothing happened after the first and second ones. One reason was that few players emerged on the industrial side. Whether it was food or medical care targeted by biotechnology, existing alternatives existed, and few companies were willing to take the risk. However, China is now likely to emerge in the field of regenerative medicine. Europe is also moving under the slogan of the Bioeconomy. The U.S. has been refining its bio-strategy since the 1980s to seize hegemony.

When Japan draws up a strategy, it tends to focus on setting up the framework, and the implementation part often gets left out. This time, we are planning our tactics quite specifically to avoid that.

Additionally, the use of stem cells in drug discovery is also important. I hope you will proceed with developing drugs using stem cells as a powerful tool for human prediction, toxicity, and efficacy testing.

We call it "Clinical Trials in a Dish" (CTiD), which is a method of predicting things like hepatotoxicity on a plate rather than in humans. This will lead to reducing the enormous costs associated with clinical research.

For example, there is a story like this: a pharmaceutical company was developing a promising new diabetes drug. However, in Phase 3 clinical trials, one or two people out of every few thousand in the U.S. developed liver damage, and development was halted. But that drug was extremely effective for 999 out of 1,000 people, and if the people who would develop liver damage could have been identified in advance, it might have been a breakthrough drug.

A drug that is extremely effective for 100 out of 1,000 people would be a great drug if administered only to those 100 people. But currently, because results are averaged out, development ends at the final stage, and vast investments go to waste. If we can use stem cells to predict who it will be effective for, it would be revolutionary.

That's right. Recently, I read a paper about a family with a complex polygenetic arrhythmia. They created iPS cells from each sibling in that family, evaluated them in vitro (in a test tube), and treated them. This is something that absolutely could not have been done without iPS cell technology.

Instead of for regenerative medicine purposes, each hospital could create iPS cells and prescribe them, saying, "Let's use this drug for you." For conditions like dementia, currently the same drug is given to everyone, so it works for some and not for others. If we can predict individually that "you have a high probability of this drug being effective," it would be a huge help.

Today was truly a lively discussion, and I feel I've caught a glimpse of what the future of regenerative medicine in Japan should look like. Thank you very much.