Scientist Uchiyama Masateru: Of Mice, Music, and Heart Transplant Operations

Mice on Stage

In September 2013, Uchiyama Masateru stood beaming in a mouse costume on stage at Harvard University. He was there as part of a research team that won the 2013 Ig Nobel Prize for medicine for the discovery that listening to opera suppressed rejection of heart transplants in mice, allowing them to live longer.

The mouse costumes were Uchiyama’s idea. “I wanted it to be as much fun as possible,” he says. Watching comedy duo Bakushō Mondai performing as mouse characters on television inspired him to buy the outfits at a 100-yen shop and take them to the award ceremony. He and another team member, Jin Xiangyuan, wore the costumes, flanking the team leader Associate Professor Niimi Masanori of Teikyō University, and belting out La traviata to roars of laughter from those watching.

“I think the audience liked us most among that year’s award winners. We were the most popular at the photo shoot after the ceremony,” he recalls with a proud expression.

A special magazine published by Annals of Improbable Research, which organizes the Ig Nobel Prizes, after the awards ceremony. Uchiyama appears on the cover, at right. (Courtesy Uchiyama Masateru)

A leaflet advertising Ig Nobel lectures at the Massachusetts Institute of Technology, the day after the ceremony. (Courtesy Uchiyama Masateru)

He was playful on stage, but Uchiyama’s research into transplant immunology is highly serious. Among the co-authors of the mice-and-opera paper was Professor Amano Atsushi, known for performing heart bypass surgery on Emperor Akihito in 2012.

Operatic Treatment

Typically, replacing a mouse’s heart with a new one leads to the animal’s death through heart failure after an average of 8 days, as the organ is rejected by the immune system. However, mice that were played music from the opera La traviata lived for 40 days on average, with one holding on for 90 days. By comparison, the test mice that listened to Mozart lived for an average of 20 days, and those that listened to Irish singer Enya for 11.

To further test the efficacy of opera, mice with ruptured eardrums were played La traviata, and their hearts stopped after around a week. The experiment shows that music may help to boost immunity.

Test mice observed by Uchiyama and his team. (Courtesy Uchiyama Masateru)

The research was inspired by a chance observation made by Niimi in his younger days while studying at Oxford University in Britain. While administering various kinds of medicine to mice after heart transplants, he noticed a difference in the results for mice on shelves where many people passed by and those on quiet shelves.

He wondered if their environment after the transplant might affect immunity. When he returned to Japan, he instructed an assistant in his research lab to try playing music to the mice. At that time, he was unable to find data that substantiated any effects, and the research went no further.

A New Start

A decade or so later, the research started up again when Uchiyama, who was studying cardiovascular surgery as a graduate student at Juntendō University, came to Teikyō University to learn about organ transplantation under Niimi. Uchiyama heard the story about playing opera to mice from another assistant, and thought that, “If we continued the experiment, it might lead to interesting results.”

La traviata, Mozart, and an Enya album Uchiyama was fond of were played continuously to different mice, along with noises from a construction site, English listening exercises, and single frequency sounds.

Incidentally, opera aficionado Niimi recommended La traviata, which had such a positive effect on the mice’s survival time. Uchiyama, who knew nothing of opera, tried listening to the work himself at all hours. “To be honest, it was just painful,” he recalls.

Hurdles to Publication

While Uchiyama now had the data for a paper, the next stage was a challenge. His superior at the time at Juntendō University was Professor Amano, who praised the experiment as interesting, but predicted it would be difficult to publish. Indeed, the paper was rejected by a number of academic journals without even being reviewed. Finally, the paper was published in the British Journal of Cardiothoracic Surgery in March 2012, a year and a half after it was submitted.

“It’s because it was an experiment with extremely strong environmental factors,” Uchiyama summarized the issues involved. The impossibility of providing scientific, objective evidence on the differences between the various forms of music and the construction noise created greater hurdles to being reviewed.

Uchiyama gives a presentation at the Japanese College of Angiology in October 2013, one month after the awards ceremony. (Courtesy Uchiyama Masateru)

However, the year after the paper appeared in the journal, a message came from the organizers of the Ig Nobel Prize. Niimi and Uchiyama initially both thought it was a prank, but were overjoyed when it turned out to be real.

“I was truly happy that a third party, who didn’t know me, appreciated my particular way of thinking,” says Uchiyama. He adds that, “I can feel confident about the results of the research that I believed in,” based on the recognition of the award.

What can one say about applying the results to clinical practice with people? In an interview after receiving the prize, Niimi said, “It’s in line with the importance of hope, motivation, and family support.” He had seen patients expected to live just a few months go on to thrive for several years, and conversely those who seemed like they would be fine for a number of years suddenly deteriorate and pass away. Niimi said that the research convinced him that there was a factor affecting the immune system via the brain that could not be explained by Western medicine.

Some patients, hearing of the prize, ask, “What should I listen to for a rapid recovery?” Uchiyama first recommends approaches based on Western medicine, saying, “Listen to whatever music you enjoy.”

Three Research Topics

Uchiyama says that when he was young, “I was withdrawn and used to blush constantly. I didn’t like standing up in front of other people.” However, when he was in high school, he realized he would not get by in the world like that. As a university student, he taught at a cram school and overcame his issues. By the time he stood on stage at Harvard University in a mouse costume, he could hardly be said to be shy.

Meanwhile, he also developed the strength of his convictions. At the recommendation of his parents, who were teachers, he attended a junior high school attached to Ritsumeikan University, but chose not to take the natural route to the university, setting his sights on getting into medical school instead. At a high school where more than 90% of students continued to Ritsumeikan University, it was not easy to study for an entrance examination. He persuaded teachers to give him extra lessons in biology and English after school, while cutting classes he considered to be unnecessary. “People around me told me I was a weirdo,” he says.

Uchiyama gives a presentation at the Japanese College of Angiology in October 2013, one month after the awards ceremony. (Courtesy Uchiyama Masateru)

Uchiyama tells the graduate students he supervises, “Always have three research topics.” One should be a conventional topic that is easy to do. Another should be one expected to continue for a lifetime. And the third is “eccentric research that nobody else is doing,” like the opera mice.

Uchiyama uses a mountain climbing metaphor. “The first is like climbing a reasonably tall mountain on a fine day. The second is like Mount Everest in that although it’s tall and the journey is long, the summit is in sight. With the third, you don’t know how tall the mountain is or the climbing routes, so you have to be inventive with your equipment and play it by ear. You keep thinking, ‘What? You must be joking!’ waiting for the final thrill, when you say, ‘This is fun!’”

Those who train their research “legs” on the conventional paths, he explains, are most able to discover new routes and the undiscovered scenery they lead to.

Uchiyama says: “It’s important training for researchers to respond flexibly with free thinking to the obstacles they inevitably face, and to reach their goals with a theoretical and constructive attitude. This allows their abilities to blossom.” One hopes that as many as possible will find fresh scenery on their journeys.

(Originally published in Japanese on May 17, 2023. Interview and text by Hamada Nami and Power News. Banner photo: Uchiyama at Teikyō University Hospital in Itabashi, Tokyo, in March 2023. Courtesy Uchiyama Masateru.)