THE 20TH SYMPOSIUM OF THE FIELD-DRIVEN HEALTHCARE REFORM PROMOTION COUNCILCutting-Edge Clinical Research and DevelopmentIslet Transplantation for the Radical Cure of Diabetes

Shinichi Matsumoto

Visiting Professor, Department of Surgery

Graduate School of Medicine, Kobe University

At the 20th Symposium of the Field-Driven Healthcare Reform Promotion Council, I was given the opportunity to deliver a lecture for the first time in quite some time. I spoke about islet transplantation, a curative treatment for diabetes. I would like to share the content of that lecture through MRIC.

THE ROAD TO TRANSPLANTATION RESEARCH

When I was in the second year of junior high school, I lost my father to cancer. During his long battle with illness, my mother often told me, “Your father has been told that his disease cannot be cured by current medicine. But somewhere in the world, there are doctors conducting research to cure diseases that cannot yet be cured. One day, a treatment may suddenly be discovered.” When my father passed away, I resolved to become a doctor who conducts research to cure diseases that cannot be cured by contemporary medicine.

I entered Kobe University School of Medicine, and during my student years, I learned that “transplant medicine is a medical miracle of the 20th century. It can cure diseases that were once considered incurable.” At that point, I decided to pursue research in transplantation medicine. After becoming a board-certified surgeon, I entered graduate school in surgery and began research on pancreas transplantation. My research theme was pancreas preservation prior to transplantation.

At that time, clinical pancreas transplantation was not performed in Japan. In order to apply the two-layer pancreas preservation method developed at Kobe University to clinical practice, I went abroad to study at the University of Minnesota.

RESEARCH AT THE UNIVERSITY OF MINNESOTA

The University of Minnesota is the institution where pancreas transplantation and islet transplantation were first performed in the world. I was overjoyed to be accepted by Professor Sutherland, but immediately after arriving, I encountered the language barrier. I realized that I could not speak English. While struggling with communication, Professor Sutherland instructed me to join the organ procurement team.

Organ procurement for transplantation usually takes place at night or on weekends. I participated relentlessly, regardless of day or time. As a result, an Indian fellow suggested that we attempt clinical application of the two-layer pancreas preservation method developed at Kobe University. We successfully implemented it and published the world’s first paper on the clinical application of the two-layer pancreas preservation method. Through this experience, I learned that if you work desperately enough, things can somehow work out.

While I was immersed in organ procurement using the two-layer method, Dr. Hering from the University of Giessen in Germany was recruited to the University of Minnesota to establish an islet transplantation program. Dr. Hering, a strict German researcher, found American researchers to be somewhat lax and invited me to establish the islet transplantation laboratory together.

Using my knowledge of pancreas preservation, we developed a method for isolating islets from the pancreas, known as the “Minnesota Islet Isolation Method.” I had never handled cells before, but believing that desperate effort would make it possible, I devoted myself to islet isolation research.

Around that time, Dr. Shapiro at the University of Alberta in Canada reported that seven patients who received islet transplantation no longer required insulin injections. This brought islet transplantation into the spotlight. Subsequently, under the directive of President Clinton, a multicenter clinical trial of islet transplantation was conducted across North America. The University of Minnesota participated and achieved the best results among all participating centers.

As a result, a multicenter Phase III clinical trial using the Minnesota Islet Isolation Method was conducted in North America. Based on these results, the U.S. regulatory authority, the FDA, approved islets as a biological product. Obtaining approval as a pharmaceutical product requires enormous effort, but Professor Oberholzer at the University of Illinois established a pharmaceutical company called CellTrans and obtained approval for human islets. Today, human islets are provided as Lantidra™ at the University of Illinois.

ISLET TRANSPLANTATION IN JAPAN

While I was conducting islet transplantation research in the United States, I was suddenly contacted by Professor Koichi Tanaka, then hospital director of Kyoto University, who asked whether I would like to perform islet transplantation at Kyoto University. I was extremely pleased at the opportunity to conduct islet transplantation under Professor Tanaka, a world authority in living donor liver transplantation at Kyoto University, and decided to return to Japan.

Naturally, Japan had none of the infrastructure for islet transplantation that existed in the United States, and we truly had to start from zero. There were numerous challenges, but believing that desperate effort would lead to solutions, we overcame them one by one. In April 2004, we successfully performed the first islet transplantation in Japan.

Because Kyoto University was globally renowned for living donor liver transplantation, we planned living donor islet transplantation. Islet isolation, which allows no margin for failure, requires extremely high technical skill. However, we believed that the Kyoto University islet team at that time was capable, and in January 2005, we successfully performed the world’s first living donor islet transplantation. This case was reported in The Lancet, and it led to invitations from transplant centers around the world.

BACK TO THE UNITED STATES

Following the publication of the living donor islet transplantation paper, I received an offer from Baylor University in Texas to serve as Director of the Islet Transplantation Research Institute. Knowing that Texas, due to gun violence, had a large number of brain-dead donors, I decided to once again pursue islet transplantation in the United States.

Building on the islet isolation techniques developed at Kyoto University, we refined them further and developed the “Baylor Islet Isolation Method.” At that time, human islet isolation was technically very difficult, and success rates at most institutions were below 50%. The Baylor method, however, achieved success rates exceeding 90%, far surpassing others.

At Baylor University, Professor Jacques Banchereau, a world authority in human immunology, was developing treatments for autoimmune diseases using anti-inflammatory therapies. After discussions with Professor Banchereau, we decided to use the IL-1 inhibitor anakinra in islet transplantation. Compared to the Edmonton Protocol, which required two transplantations, islet transplantation using anakinra enabled insulin independence with a single transplantation. This Baylor method was highly evaluated by the NIH and received grant funding.

TOWARD XENOTRANSPLANTATION

For the vast number of patients with diabetes, allogeneic islet transplantation requiring human donors has clear limitations. As an alternative donor source, we focused on pigs. Xenogeneic islet transplantation using pigs was performed in the 1990s by a Swedish group in patients who had undergone kidney transplantation, demonstrating that porcine islets could engraft in humans.

Subsequently, porcine islet xenotransplantation was performed in New Zealand, Russia, Argentina, Mexico, and China. In particular, in Argentina, patients who underwent porcine islet transplantation using immunoisolation capsules were surveyed more than ten years after transplantation. The results showed that HbA1c levels remained lower than before transplantation, and episodes of severe hypoglycemia and hospitalization-requiring hyperglycemia were reduced.

Because immunoisolation capsules eliminate the need for immunosuppressive drugs, there were no cases of cancer and very few serious complications. Additionally, none of the patients reported the psychological burden often associated with transplantation medicine. Immunosuppression-free islet transplantation resulted in extremely high patient satisfaction, as it required no medications and simply replenished islets.

In Japan, we are planning to implement xenogeneic islet transplantation to address donor shortages. The key challenge is obtaining medical-grade pigs. Although companies exist that produce pigs with high sanitary standards, using them for medical purposes posed enormous hurdles.

To address this, we established the Medical-Grade Pig Development Organization, a general incorporated association, within the Department of Hepatobiliary and Pancreatic Surgery at Kobe University.（https://medicalporcine.com/） This organization connects pig producers with clinical teams aiming to perform xenotransplantation. With the establishment of this organization, we have secured prospects for donor pigs necessary for xenogeneic islet transplantation in Japan.

Once donor pigs are secured, the path opens to islet isolation and transplantation, my area of expertise. Islet isolation requires craftsmanship. Specifically, the pancreas is mixed with digestive enzymes and placed in a special container called a Ricordi chamber. Samples are taken every one to two minutes, and while observing the digestion status under a microscope, the chamber is manually shaken up and down.

Over-digestion damages isolated islets, while insufficient digestion prevents islet separation. To transform this delicate artisanal technique into a standardized method, we are currently developing an AI-powered islet isolation robot. Because AI development requires substantial funding, we are raising funds through Japan IDDM Network via the hometown tax donation system.

Details of the project and its return gifts can be found at the following website:

https://japan-iddm.net/

Please consider using the hometown tax donation program, which closes in December.

THE “DO-M” GROUP

Although I performed the first islet transplantation in Japan and achieved the world’s first successful living donor islet transplantation, pioneers are inevitably criticized. About twenty years ago, I shared this experience with Professor Yukio Osawa of the University of Tokyo. At that time, Professor Osawa founded the entirely new field of Chance Discovery Science and achieved numerous accomplishments, including earthquake prediction. Establishing such an unprecedented academic discipline subjected him to intense criticism.

What Professor Osawa and I share is that we used criticism as fuel to grow, preparing ourselves so that we would not be criticized again, and continuously evolving. Eventually, we realized that criticism itself fosters personal growth and project maturation. We resonated with the phrase “Do-Ms save the world” and established the “Do-M Group.” To grow from criticism, we formed a LINE group to exchange ideas, and one member even created a mascot for the group.

IN CONCLUSION

I decided to pursue research as a middle school student, began pancreas preservation research in 1992, and for over thirty years have continued research to make diabetes a curable disease. During this time, there were many hardships, but I also gained many colleagues. At the 20th Symposium of the Field-Driven Healthcare Reform Promotion Council, I was delighted to reunite with long-standing colleagues and to gain new ones through this forum.

Do-Ms may save the world, but what truly matters is creating as many comrades as possible. Using my medical license, I also opened a wine and dining restaurant called CODA in Sannomiya, Kobe. Yes, in Japan, it is possible to open a restaurant using a medical license. Anyone who would like to become a colleague is welcome to visit.