The Future of Medicine: Japan Forges Ahead in iPS Cell Research

Promising Research

In 2006 Professor Yamanaka Shin’ya of Kyoto University published a paper reporting his success in producing induced pluripotent stem (iPS) cells. This marked a major breakthrough in stem cell research that brought huge therapeutic potential. What is unique about iPS cells is their ability to transform into any other kind of cell, much as when a fertilized egg divides to form the various organs in a multicellular organism’s body—a process called differentiation.

Yamanaka Shin’ya. (Courtesy Kyoto University’s Center for iPS Cell Research and Application)

During differentiation, immature cells express specific genes for different specialized function, like heart or liver cells, shutting off all other potential gene expressions. “Once a cell’s role is determined, it rarely changes to another type,” explains Etō Kōji, deputy director of Kyoto University’s Center for iPS Cell Research and Application. “With iPS cell technology, though, it is possible to return ordinary, specialized cells to a state where they can become any other type of cell.” By adding a few specific genes, for instance, a scientist can essentially reprogram skin or blood cells, enabling them to differentiate into heart, nerve, or other cells, what is called pluripotency.

Along with their ability to be reprogrammed, iPS cells also have the unique ability to proliferate almost indefinitely. Yamanaka highlighted the potential of iPS cells in treatments to heal wounds as well as in regenerative medicine. In 2012, he was awarded the Nobel Prize in Physiology or Medicine for his discovery.

Researchers in the field of regenerative medicine have long studied the potential of embryonic stem (ES) cells. Scientists succeeded in producing ES cells from the embryos of mice in 1981, replicating the feat with human ES cells in 1998. However, Etō points out that while fertilized human eggs can proliferate and differentiate, their use raises ethical questions not associated with iPS cells, which can be made from a patient’s own body tissue. He stresses that there are practical advantages to this as well. “With transplants,” he explains, “there is a reduced risk of the body rejecting a new organ, something that researchers around the globe are keen to exploit.”

A Track Record for Regenerative Medicine

Etō credits the strong support of the Japanese government for making Japan the world leader in regenerative medicine. “There are eight chief programs underway using iPS cells to differentiate into things like retinal, cardiac, platelet, and immune cells,” he says. “Research continues to progress and is several years ahead compared to other medically advanced countries around the world.”

Among the leaders in their fields is Takahashi Masayo, an expert in retinal regeneration. Takahashi, who is the president of medical startup Vision Care, headed a team at the Riken scientific research institute in Kobe that successfully cultured iPS cells to create sheets of retinal cells for potential use in treatment of such eye diseases as age-related macular degeneration and genetic disorders like retinitis pigmentosa.

“Doctor Takahashi is a global frontrunner,” exclaims Etō. Potential treatments must pass through several phases of clinical trials before being approved, a process that can take years if not a decade or more. But Takahashi is applying for approval through Japan’s Advanced Medical Care Program in a bid to bring her therapy to market more quickly. “The initiative facilitates patient access to promising healthcare technologies.”

Takahashi’s husband, CiRA director Takahashi Jun, is likewise achieving groundbreaking results in treating Parkinson’s disease. He has completed physician-initiated clinical trials with seven patients and is working to make his therapies generally available.

In the field of cardiology, University of Osaka Professor Sawa Yoshiki created the world’s first myocardial sheets using iPS cells, which he transplanted into the hearts of patients suffering from a type of severe heart disease. Meanwhile, Professor Fukuda Keiichi of Keiō University is running a project to assess the safety and effectiveness of a revolutionary treatment using so-called myocardial spheres made from iPS cells to help patients with heart failure.

Etō’s team, too, is leading the way in developing new medical treatments. ”We’re researching ways to produce large quantities of platelets, which play an important role in stopping bleeding.” In 2021, he led a clinical study involving the transfusion of iPS cell-derived platelets into patients with rare blood types. “The iPS cells were made using the patients’ own tissue. The results were encouraging, and we are now aiming to start the next phase of clinical trials in the development of functional platelets from human iPS cells sometime in 2027.”

Great progress is also being made in the field of cancer treatment. CiRA’s Kaneko Shin is working to exploit the special characteristic of iPS cells in immunotherapy by reprogramming types of white blood cells called T-lymphocytes to target cancer cells. By introducing something called chimeric antigen receptor (CAR) genes into iPS cells, his team succeeded in producing large amounts of powerful CAR-T cells altered to specifically recognize types of cancer. By reducing the reliance on customized therapies, the technology opens the way for standardized treatments that will be available to a broader range of patients.

Clinical-Grade Cells Drive Innovation

Along with advances in treatments, CiRA is facilitating regenerative medicine research more broadly through its iPS Cell Stock Project, an initiative that provides iPS cells for clinical use. Producing iPS cells from a patient’s own tissue—called autologous cells—requires several months. But the project uses cells made from healthy donors, providing researchers and medical institutions in Japan and overseas ready access to a stable supply of high-quality iPS cells.

Etō emphasizes the importance of the program, saying, “Access to a shared stock enables research to progress more quickly and efficiently.” In 2020, the cell stock project was transferred from CiRA to Kyoto University’s CiRA Foundation, a public interest incorporated foundation chaired by Yamanaka Shin’ya. “The organization serves a vital role as a driving force to strengthen and advance the regenerative medicine industry.”

The CiRA Foundation is dedicated to providing research- and clinical-grade iPS cells at affordable prices. (© CiRA Foundation)

A Rapidly Advancing Field

While Japan has emerged as a global leader in iPS cell research, Etō warns that it will be a challenge to hold that status as other countries race to close the gap. “Researchers in Europe, the United States, and China are making strides,” he says. “The US biopharmaceutical firm Fate Therapeutics, for instance, is conducting clinical trials of iPS cell-derived immunotherapies it has developed.” He notes that in the expansive US venture capital market, companies can attract investors willing to put up mass sums of money to bring new technologies to market, while in China, large-scale research is backed by the government. “In 2023, Chinese researchers reported success in using iPS cells to regenerate cardiac muscle. As other countries make advances, Japan could see its hard-won advantage slip away.”

Holding the top spot is made more difficult by the heavy reliance of domestic iPS cell research on government funding. In fiscal 2024, legislators allocated only around ¥20 billion for research into regenerative medicine using stem cells and gene therapy, a scant amount compared to what many countries are investing in these technologies. Japan also lags behind Europe and the United States when it comes to researcher mobility and facilitating industry-academic collaborations. To stay ahead, Japan must fundamentally revamp its current approach, including taking advantage of private funding, promoting joint research with institutions overseas, and reassessing its patent strategies.

Joint Effort Needed

Etō says that for Japan to stay ahead, it needs more than just top-notch researchers and adequate funding for projects. “Research can only come to fruition with the coordinated efforts of a team that includes experts in intellectual property, public relations staff, skilled technicians who maintain equipment, and fundraising managers.” He stresses, though, that Japanese universities typically lack the budgets to hire such a team of professionals full time and so must rely on donations from alumni and others to afford their services.

“Turning iPS cell-related research into a full-fledged medical industry that can export its technologies around the world requires the understanding and active support of the public,” Etō declares. “As researchers, we have a duty to explain our work in a clear and open manner in order to pave a path forward together.”

Yamanaka Shin’ya (center) finishes the Osaka Marathon in 2018. Since 2012, he has regularly participated in different charity events to raise money for CiRA’s iPS Cell Research Fund and to increase public awareness of iPS cell research. (© Kyōdō)

The potential of iPS cell research to contribute to human health is immense. However, for Japan to retain its lead in the field, more funding needs to be made available for projects and there must be greater buy-in and support from society as a whole. Fostering interest and encouraging individuals to take actions to support the field will be crucial for iPS cell research to progress to the next stage.

(Originally published in Japanese. Reporting and text by Ōkoshi Yutaka of Team Pascal, with editing by Power News. Banner photo: Etō Kōji at his office at Kyoto University’s Center for iPS Cell Research and Application. Courtesy of CiRA.)