Juichiro Ito (staff writer of the Sankei Shimbun)
January 9, 2018

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Professor Shinya Yamanaka of Kyoto University, 55, became more widely known after he was awarded the Nobel Prize in Physiology or Medicine in 2012. Five years before that, however, in November 2007, he announced that he had generated human-induced pluripotent stem cells (iPS cells).

His research on treating illnesses has seen impressive progress, but, according to him, “this is just the beginning.”

Yamanaka, 55, was born in 1962 in Osaka. He graduated from Kobe University School of Medicine and completed his PhD at Osaka University Graduate School. He became a professor at Kyoto University in 2004 and the director of Center for iPS Cell Research and Application in 2010.

He recently spoke with journalist Juichiro Ito of Sankei Shimbun’s Science Department about the future of medical treatment through iPS cell generation.

It’s the 10th anniversary of human iPS cell generation.

It sounds like a long time, but it feels like yesterday. I can’t believe it has been that long. Maybe time flies faster for me because I’m old now, but this is only the beginning.

Research on regenerative medicine and clinical trials of new drugs have begun.

iPS cells have been a catalyst to research that use embryonic stem cells (ES cells). I cannot take all the credit because I wouldn’t have made it this far without the efforts of everyone involved. I always remind myself how grateful I should be. Clinical research on age-related macular degeneration (AMD) led by Masayo Takahashi of Riken research institute impressed me the most. By skipping the preclinical development stage consisting of animal testing, she managed to make significant accomplishments in a very short period.

What was the challenge?

The challenge was to build an iPS cell stock which ensures that iPS cells will always be available for regenerative medicine and drug discovery. The process involves providing cells to a specialized company for mass production, which then supplies the cells to medical institutes and pharmaceutical companies. It was a very difficult process because university researchers are a type of people who want to challenge themselves with the unprecedented. Conversely, the production of cells requires the dull repetition of prescribed steps in order to maintain quality. Dealing with this contrast was very difficult.

At first, people pointed out the risks of the cells becoming cancerous.

The early-stage iPS cells couldn’t be used for clinical research because of these concerns. However, the production method has evolved and the situation has changed. The risk has not been completely eliminated but is significantly lower, so the cells can now be used for clinical research.

You were awarded the Nobel Prize in Physiology or Medicine in 2012.

It was a great honor. The moment I successfully generated iPS cells, I had the huge responsibility of getting things off the ground, starting with the clinical research. But receiving the prize increased awareness within the general public and those in the industry, and this became a tailwind for my research in many ways. I’m very grateful for that, as it also helped Kyoto University collect funds for the Center for iPS Cell Research Application (CiRA).

If you were to compare the current iPS research to a marathon, how many kilometers do you still have to run?

It might be an exaggeration to say that we’re only at the start line, but I would say we’ve run no more than 10 kilometers. The real challenge—the crucial stages—starts now, including clinical research and trials of new drugs. Our goal is truly ambitious, as we are taking unprecedented steps while prioritizing the safety of the patients. I’m assuming that the challenges that lie ahead will be incomparable to anything I’ve faced in the past.

What is the goal of the research?

I estimate that several treatments using regenerative medicine and new drugs will be developed, authorized, and covered by insurance around 2030. However, some treatments may take longer to develop, and unforeseeable challenges may come up. We cannot simply visualize our goal. It’s more important to take slow but sure steps towards it.

What are the problems regarding cost and time?

In regenerative medicine, it takes a lot of money and time to custom-make iPS cells from the patient’s cells. Instead, we create iPS cells from dozens of people with an immunological type that has a lower risk of rejection in Japanese people. However, the great hurdle is how to maintain ample stock of these cells.

What percentage of the population do the cells cover?

Currently, we provide iPS cells of three immunological types. They will not trigger a rejection response in 30% of the Japanese population. It shouldn’t be long until we reach 50%. However, we are concerned that increasing the types of iPS cells available will inevitably lead to a higher production cost, which means the cells might become difficult to access for medical treatment. The more cell types there are, the more production facilities the manufacturing companies will require, and more money and time will be necessary for safety checks. Alternatively, it might be more efficient to use just one type of cell which covers the greatest percentage of the population, and to provide immunosuppressant drugs to those that have a rejection response.

What is your plan for the future?

If a huge amount of national expenditure is invested into creating more types of cells but the cells end up being unusable, it would be a considerable waste. Until now, we have been aiming to reach 80% of the population by 2022, but we are now reevaluating our goal. This is a problem we cannot solve by ourselves. We want the government to consider implementing a system that ensures safety checks while containing the costs.

Clinical research and trials have started to make the cells useful for patients. 

We have only just reached the start line. For the next 10 or 20 years, it will be more like the patients contributing to the research at their own risk, rather than us contributing to them. I need to start making true contributions to the patients as soon as possible. People enduring incurable diseases have written numerous letters to us about their wish to be cured using iPS cells. I am fully aware of their desperate situation and working hard towards making their wish come true.

Ikumi Yamamoto, 19, from Akashi in Hyogo Prefecture, who suffered from fibrodysplasia ossificans progressiva (FOP), underwent the first ever treatment for incurable diseases using iPS cells in October.

She came to see me when she was a sixth grade elementary student, and told me that she wanted me to generate iPS cells using her cells to further my research. Such encounters have become a driving force in my research. I think of iPS cells as the patients themselves. When I conduct experiments, the face of the patients who provided the original cells always come to my mind, which makes me more determined to find a cure for them.

Hideo Shinozawa, an honorary professor of Gakushuin University, died in October after a long battle with amyotrophic lateral sclerosis (ALS).

The professor sent me a letter to tell me how much he wanted me to develop a treatment. The letter is displayed in my laboratory so that I am always reminded of his strong desire while I go about my work. ALS is one of the diseases I want to defeat the most. I want to find a cure as soon as possible, but I’m unfortunately not at that stage yet.

What kind of attitude should medical researchers have?

As a researcher, you must first conduct good research and write research papers. While doing this, the researcher must have a strong determination to help the patients no matter how long it takes. Being a researcher is difficult, but thinking about the patients keeps us going.

Do you still run marathons as a hobby?

During my lunch breaks on weekdays, I run for 30 minutes along Kamo River and near Nanzen-ji Temple, which are located near the research institute. On weekends, I run around Osaka Castle near my house and around the Tokyo Imperial Palace when I’m in Tokyo for work. Running helps me refresh my tired brain, just like the initialization process involved in iPS cell generation.

I managed to run a personal best of 3 hours 27 minutes and 42 seconds at the Kyoto Marathon in February. I will run the Osaka Marathon in November. The Beppu-Ōita Marathon, which I will be running next February, will be used to select representatives for the 2020 Tokyo Olympics, so I might have a chance. Perhaps we’ll see a miracle (laughs).

The Rapid Progress of Clinical Research and the Challenge of Efficient Cell Generation

iPS cell research has garnered attention as people put their hopes on regenerative medicine to transplant new cells and tissue to injured or ill patients. Research institute Riken succeeded in the first ever transplant in 2014 using iPS cells, setting a major landmark in this field.

The transplant involved creating retinal cells using iPS cells generated from a patient with age-related macular degeneration, a serious eye condition. In March 2017, the transplant of retinal cells from a donor using stock iPS cells succeeded, totalling five successful transplants.

For 2018, clinical research on spinal cord injury and heart failure are being scheduled by Keio University and Osaka University, respectively. Yokohama City University also plans to conduct clinical research on liver failure in 2019 onwards, making Japan the trail blazer in this area. However, most of this research is on cell transplantation; the possibility of transplanting complex organs is still not within reach.

iPS cells are also used to research the pathogenesis of diseases and drug discovery. This is because the mechanisms of diseases can be revealed by creating iPS cells from patients with incurable diseases and replicating the disease outside of the body. Recently, the mechanisms of diseases that affect the motor system, such as Parkinson’s disease and ALS, have become better understood.

The mass production of the patient’s cells for testing makes the development of new drugs more efficient. Potential treatment for FOP, a disease that turns muscle into bone, has been discovered through this method. The method is also being used for ALS and Alzheimer’s disease. However, this method has not met early expectations that it would be available for clinical application sooner than regenerative medicine.

The big challenge is efficient cell generation. It takes several months to create iPS cells and cells of the affected area. Research on implementing artificial intelligence for efficiency and improvement of cell generation methods is intensifying.

Juichiro Ito is a staff writer of the Sankei Shimbun Science news department.