Nakamura: When I was studying at the School of Medicine, I played on the university’s basketball team. In the winter of my second year, the team went on a ski trip to Happo, Nagano, and one of the younger students sustained a neck injury on the slopes. At the time, I didn't understand what it meant to injure your spinal cord, and even after the three-and-a-half-hour trip back to Keio Hospital with the emergency response team, I really thought that surgery would be able to make everything better.

Sometime later, when I visited my teammate at his parents' house, he came into the room in a powered wheelchair using only his chin. It's hard to explain how I felt at the time. This friend of mine, who had been playing basketball with me just days earlier, was now paralyzed below the shoulders and couldn't move his elbows, hands, or feet. How could this have happened? And why couldn’t it be fixed? A bolt of rage struck me like lightning.

He ended up transferring from the School of Medicine to the Faculty of Letters and then went on to work as a librarian. I could understand his frustration at not being able to recover from his spinal cord injury, and at the same time, I was genuinely inspired by how he accepted what happened and tried his best to live with the reality of the situation. At the time, I didn’t speak much about wanting to find a way to treat spinal cord injury, but here we are, 40 years later, and my feelings haven't changed. There’s no doubt that his presence in my life started me on the path to where I am today.

Okano: I originally entered the School of Medicine to do research. As a student, I spent most of my time doing molecular research on cancer genes, but I wasn’t sure where to go from there since institutions like MIT were already leaders in the field. So I took a chance and visited the National Cancer Center Japan to see Dr. Takashi Sugimura, the director at the time. Since I didn't have an appointment, I naturally assumed I would be turned away by his secretary, but when Dr. Sugimura came out of his office to see what I wanted, we talked for close to 30 minutes.

You might think that Dr. Sugimura would have told me to continue my cancer research, but he didn't. He told me, “You need to do things that others won’t. That's how I've lived my life." As this pioneer of cancer research shared with me how he had carved out a unique path for himself, the scales fell from my eyes.

I started thinking about an unexplored area where I could make a difference and arrived at the idea of using molecular biology research to elucidate neural structures. In the early 1980s, very few methods were used to study nerves other than morphology and electrophysiology. At the suggestion of Dr. Katsuhiko Mikoshiba, a respected neuroscientist, I entered Keio’s Department of Physiology to study the development of the nervous system. Actually, before starting university, an acquaintance of my father who had a spinal cord injury said to me, “I hope they’ll find a cure for this kind of injury in the future.” And now here we are, on our way to making that dream come true.

Prof. Okano, you spent the next 15 years pursuing basic research on neurogenesis.

Okano: I graduated from university in 1983 and went to Johns Hopkins University in 1989 to study neurogenesis in small fruit flies, which led to my discovery of Musashi, a molecule expressed in neural stem cells, in 1991. After returning to Japan, I continued my research and, in 1998, published a paper that showed, for the first time, that Musashi is also expressed in the adult human brain—in other words, that the adult human brain contains neural stem cells.

These neural stem cells are the ones that differentiate into a variety of cells, including neurons, astrocytes, and oligodendrocytes. The presence of neural stem cells in the adult human brain means that regeneration of the nervous system may be possible after all. The paper was well-received upon publishing. We began to receive letters from patients with spinal cord injuries and intractable neurological diseases, asking if we could do anything to help them.

I also went to work at Osaka University in 1997, where I was greatly influenced by the work of immunology researcher Dr. Chuzo Kishimoto, who was Dean of the Faculty of Medicine at the time. Dr. Kishimoto discovered a cytokine called IL-6, and IL-6 receptor blocking antibodies have been used to treat diseases including rheumatoid arthritis and Castleman disease, and more recently, novel coronavirus pneumonia (NCP). Dr. Kishimoto embodied the concept that outstanding basic research can be used in clinical practice to treat intractable diseases. Watching his work inspired me to begin full-scale basic research on regenerative medicine to find practical applications for our findings.

I understand that you decided to work together after meeting in Washington, D.C., where Prof. Nakamura was working at the time.

Nakamura: I joined the Department of Orthopedic Surgery to conduct research on spinal cord regeneration, but at that time, it was considered something of a pipe dream. I felt there were limitations to the research I could do in Japan, so I traveled to the US on my own, against the wishes of those close to me. But even then, due to various circumstances at the lab where I began my joint research, I wasn't able to do as much as I would have liked.

During that time, in the spring of 1999, Prof. Okano, then at Osaka University, was invited to NASA for a peer review and came to Washington, D.C. I picked him up at Dulles Airport, and we caught up with each other as we took in the cherry blossoms along the Potomac River. When I explained my situation to Prof. Okano, he told me that I should come to Osaka University and study the technical side of things. After that, I went back to Japan for about a month and received intensive training at Osaka University on how to culture neural stem cells. This allowed me to return to Georgetown University in D.C. with a new skill set and continue my research. If it had not been for that meeting with Prof. Okano, I might have completely given up in the middle of my research.

Okano: At the time, I was also trying to figure out how we could treat spinal cord injuries using neural stem cells. While teaching Prof. Nakamura techniques such as cell culture methods at Osaka University, I also came up with various ideas about treating scoliosis.

Nakamura: I still remember what Prof. Okano said to me on the car ride home from his laboratory at Osaka University. He said, "Masaya, the field of regenerative medicine is still the wild west. There are no leaders yet. All we can do is keep going, and together, we can take on the world." I had dreams of my own but had yet to realize any of them at the time, so I was very inspired by what he said. I thought that we could make something happen if we worked together.

Okano: After that, we both returned to Keio around the same time. In April 2001, Keio established the Center for Integrated Medical Research, and with Prof. Nakamura and other talented researchers, I began research on spinal cord regeneration using human neural stem cells. That meeting with Prof. Nakamura in D.C. in 1999 was, in many ways, the starting point of our research.

Can you tell us about the mechanism behind your regenerative spinal cord treatment that uses iPS cell-derived neural stem/progenitor cells (iPSC-NS/PCs)?

Okano: When we talk about “regeneration,” we are talking about making something “occur again.” By transplanting neural stem cells into the spinal cord, developmental events involving neurons, astrocytes, and oligodendrocytes can be repeated. In this way, we can do many things. We can reestablish interrupted neuronal circuits or supplement axons with glial cells and reestablish myelin sheaths. We can take once damaged skin, repair its structure, and restore its functionality.

In fact, by early 2000, we knew that we could cure spinal cord injuries by transplanting neural stem cells. We transplanted fetal-derived neural stem cells into mouse and monkey models of spinal cord injury and observed dramatic recovery of motor function.

Even before the discovery of iPS cells, you had successfully regenerated spinal cords in animal models.

Okano: That’s right. I thought we would finally be able to attempt transplantation in human patients, but that was not the case because, in 2006, it was determined that the clinical application of fetal-derived neural stem cells was premature. Ethical restrictions prevented us from starting clinical trials in Japan, which was quite frustrating.

But then, in 2007, Dr. Shinya Yamanaka at Kyoto University discovered iPS cells. I had heard about iPS cells even before his paper was published, and I was convinced that they could be a solution. And subsequently, I was successful in generating neural stem cells from iPS cells provided by Dr. Yamanaka. Then, in 2012, we successfully transplanted human-derived iPS cells into mouse and monkey models of spinal cord injury.

So there were many more hurdles to be cleared before being able to conduct transplantation in a human patient.

Okano: It took us close to ten years to perfect the development of cells that we could administer to humans. This is because neural stem cells divide and proliferate to produce neurons and glial cells, and if they are not stopped from dividing at the right time, they can become tumors. It took us a long time to consider how many cells should be transplanted and under what conditions they should be cultured to produce cells that would grow well and repair tissue but not become tumors.

Nakamura: iPS cell technology is also, of course, a brand-new technology, so it is still developing and will continue to be improved over the coming years. We are thrilled to be able to produce better iPS cells, but if the iPS cells change, the differentiation and induction methods will also change, which could add months to development. We will also need to administer these newly created cells in animal models and confirm that tumorigenesis does not occur several months after transplantation. We can work on something for years at a time, which can be challenging.

Okano: There were multiple times when I had my head in my hands thinking, “Where has the last year gone? Have we not made any progress?” [laughs] Strict shipping criteria also had to be met—making sure there was no viral contamination or cancer-related gene mutation—before we could conduct a clinical trial. We cleared one hurdle after another before the final evaluation was completed on August 31, 2020. After that, there were many twists and turns, including a temporary suspension of patient recruitment due to the COVID-19 pandemic. Still, in December 2021, we were finally able to transplant cells into the first human patient of our clinical study.

Nakamura: We encountered so many obstacles, both scientific and non-scientific, but it was all worthwhile. Our policy is always to provide the best possible treatments for our patients, so even if we stumble, we don't just get back up—we always learn from our mistakes. I think that’s how we’ve made it to where we are today.

Okano: That’s right. It took years of effort, but the experiences and knowledge we’ve gained have filled us with confidence. I am incredibly grateful for the support in and outside of Keio that made this first-in-human surgery possible, including everyone at Keio University Hospital, our partners at the Murayama Medical Center, and the Center for iPS Cell Research and Application (CiRA) at Kyoto University.