"The Paper Even Nature Rejected"... Shimon Sakaguchi Wins Nobel Prize After 30 Years of Research [Japan Insight]

Professor Shimon Sakaguchi Reveals the Existence of "Regulatory T Cells"
Rejected by Journals as a Fringe Researcher... 30 Years of Perseverance
Raising Hopes for Conquering Autoimmune Diseases and Cancer

In Japan, there have been two Nobel Prize winners this year. It is said to be the first time in ten years that two Nobel laureates have emerged in a single year. The most talked-about figure is Professor Emeritus Shimon Sakaguchi of Osaka University, who received the Nobel Prize in Physiology or Medicine. He was awarded the Nobel Prize as the culmination of 30 years of research to prove a hypothesis that no one cared about or believed in. The process of persisting with his research despite the world's skepticism has drawn significant attention. This week, we share the story of Professor Shimon Sakaguchi.

Professor Sakaguchi was born in Shiga Prefecture in 1951 and graduated from the Faculty of Medicine at Kyoto University in 1976. He received this year’s Nobel Prize for his research on “regulatory T cells,” which are related to the body’s immune system. Our immune system identifies bacteria and viruses that enter the body as invaders and attacks them. T cells within white blood cells are responsible for this. However, if the immune system makes a mistake, it can attack our own organs and tissues. This is how autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, and lupus occur. These are side effects caused by excessive immune responses.

Professor Shimon Sakaguchi, Professor Emeritus at Osaka University, is receiving a bouquet congratulating him on winning the Nobel Prize. NHK.

Regulatory T cells play a leading role in orchestrating immune cells. They are crucial in establishing “immune tolerance,” which prevents normal cells from being mistaken as invaders. If these regulatory T cells can be controlled, it is believed that conditions ranging from allergies to autoimmune diseases and even cancer could be conquered.

How did this line of research begin? Professor Sakaguchi recalls having many thoughts as he approached graduation from the Faculty of Medicine at Kyoto University. While it was customary to become a university hospital physician, he decided to explore research in graduate school rather than clinical practice. He chose pathology research at Kyoto University, resolving that if he lacked talent as a researcher, he would become a physician in the countryside.

In 1977, while conducting research, he happened to come across a paper. The paper reported that when the thymus was removed from a three-day-old mouse, inflammation occurred throughout the body, even though there had not been a significant infection. The thymus is where T cells that attack invaders are produced. So why did the removal of the thymus suddenly cause T cells to attack the body’s own tissues? Professor Sakaguchi hypothesized that “cells that serve as a brake to suppress attacks are also produced in the thymus.” He thus assumed the existence of regulatory T cells. To prove this, he left graduate school at Kyoto University and moved to Aichi Cancer Center to devote himself to research.

In 1985, he published a paper pointing this out, but the response was cold, as he had not definitively identified “regulatory T cells.” There was criticism that it was just a hypothesis. He continued his research in the United States to achieve results, but because it was considered an unprovable and fringe study, he did not receive much support. For ten years, his research was not published in major scientific journals. As a result, he did not have enough research funding to hire assistants, so his wife took on the role of research assistant. She even raised the laboratory mice. Despite people around him saying, “Are you still researching that?” he continued his experiments, believing, “Even if the world denies it, what I am seeing is correct.”

Professor Sakaguchi expressing gratitude to his wife at the press conference. NHK.

While conducting research in California, he finally succeeded in revealing the existence of regulatory T cells. T cells are classified by the types of proteins on their surface. Among the T cells that urge other immune cells to attack, 10% had a molecule called “CD25” on their surface. He theorized that this molecule played a braking role and conducted experiments with mice. When the molecule responsible for braking was removed, autoimmune diseases and inflammation reoccurred. This was the moment when the existence of regulatory T cells began to be revealed.

However, even this discovery did not receive much attention at first. In 1995, he published a paper, but prestigious journals such as Nature rejected it. Eventually, after submitting it to several places, it was published in another scientific journal. The research that won the Nobel Prize did not initially attract much attention when it was first announced.

The situation changed when a renowned American research team confirmed the existence of regulatory T cells through additional experiments based on Professor Sakaguchi’s paper. What had previously been considered only a hypothesis was now shown to exist. Since then, this field has become a cutting-edge area of research. Professor Sakaguchi continued to focus on this area, even proving in 2003 the gene involved in the development of regulatory T cells. It took nearly 30 years for his work to be properly recognized, eventually leading to the Nobel Prize.

At the press conference, Professor Sakaguchi cited “Soshin,” meaning “pure heart,” as his personal motto. It refers to maintaining one’s original, unadorned sincerity. He explained that he devoted time to research with an honest and unpretentious heart.

For this reason, an interview in which he once gave advice to aspiring medical students has also attracted attention. At the time, he said, “You study to convince yourself. The same goes for research and for schoolwork.” His determination to persist on his own path, even without recognition from others and despite being considered an outsider, is truly remarkable.