Overcome ‘Valley of Death’ for Medicine’s Sake

Fifteen years have passed since the announcement of the production of human induced pluripotent stem (iPS) cells. Over that period, my colleagues and I, supported by the government and many other entities and people, have made continuous efforts to develop medical applications for iPS cells. In the process, I have learned new things day after day in a way different from my earlier years of experience in basic medical research.

Looking back on the past 15 years, I would like to describe the challenges I have found in researching and developing new medical treatments.

In 2007, after my group reported that we had successfully generated human iPS cells, I resumed my earlier research activity in the United States, spending about one week each month as a senior investigator at Gladstone Institutes, where I had been a postdoctoral researcher in the 1990s.

The U.S. research environment I experienced in 2007 was markedly different from what it had been about 10 years earlier. Words that had rarely been heard in the 1990s, such as patents, venture, investment and the like, were flying about. Backed by abundant financial resources, the United States kept accumulating research and development (R&D) capability, with particular concentrations in the San Francisco Bay Area on the West Coast — where Gladstone Institutes is located — and Boston on the East Coast. Each of these U.S. hubs had a combined R&D capability exceeding that of the whole of Japan. I became seriously worried that although iPS cells were a technology developed in Japan, it might be only a matter of time before the United States emerged as a global center for its medical application.

So, every time I met Japanese government officials, I tried to plead with them, saying things like: “Japan will have to keep competing with foreign countries from now on. Even just one area in the United States, such as the Bay Area or Boston, has R&D capability superior to Japan’s overall capability. Japan should set up an all-Japan team to compete with each U.S. team. Otherwise, it will have no chance to prevail.”

In 2013, Research Center Network for Realization of Regenerative Medicine was launched. Kyoto University’s Center for iPS Cell Research and Application (CiRA) became Japan’s hub for iPS cell research, mobilizing all relevant research institutes across the country like one team to advance research.

Researchers set goals in two major areas of the medical application of iPS cell technology: regenerative medicine and drug discovery. Thanks to their efforts, more than 10 projects involving iPS cells for regenerative medicine and four projects for drug development have begun clinical trials.

Nonetheless, the real challenge in new iPS cell-based treatment development is just down the road. To date, the clinical trials have been carried out mostly by academic researchers and doctors, and all of them have been small-scale efforts to verify the safety and effectiveness of their approaches with the cooperation of only several patients, dozens at most. What we need next is to launch large-scale clinical trials, principally undertaken by private-sector enterprises.

However, there exists the so-called “valley of death,” the huge gap between academia and business. The shifting overseas of R&D on some technology from Japan means the reimporting of excessively costly medical treatments. Medical applications of iPS cells are facing this valley of death.

Bridge between business, academia

To overcome the R&D valley of death, the key issues concerning financial resources and human resources must be resolved.

CiRA has been offering itself as a bridge to liaise with enterprises across the valley of death. One of its activities is T-CiRA, a joint research program implemented in fiscal 2016 with Takeda Pharmaceutical Co. This is a 10-year R&D program with CiRA’s faculty and Takeda’s research institute staff forming a joint R&D team with an annual budget of ¥2 billion.

When the team was told of the decade-long budget scale, the academic researchers initially thought that an annual budget of ¥2 billion was an enormous sum while Takeda’s researchers thought the amount would be insufficient when taking clinical applications into account. The difference in their initial reactions to the budget size represents the challenge that has to be resolved in overcoming the valley of death.

For new cell-based treatment, in particular, the amount of funding required increases by orders of magnitude as the stage of R&D progresses. One reason for this is that the generation and culturing of cells to be used for transplantation to human patients need to be done in a highly controlled facility, which requires massive investment. Under the T-CiRA program, both the academic and business sides have provided equipment, human resources and expertise for their joint work as required. So far, the program has functioned as a bridge between academia and industry, with some of its projects transferred to businesses.

CiRA has another important project to stock quality-assured iPS cells for regenerative medicine. The project first involves the collection of somatic cells from healthy donors who have immunotypes that are thought less likely to cause rejection. Those somatic cells are used to manufacture iPS cells for transplantation to humans. Only iPS cells that meet rigorous quality evaluation criteria can be distributed for transplantation.

Even among the same iPS cells, there is a big difference in the strictness of the standards depending on whether they are used for research or regenerative medicine. It takes a researcher about a month to generate iPS cells for research use. In contrast, huge amounts of time and human resources are required to produce iPS cells for regenerative medicine. In the early stage of the project, nearly 100 staff members of CiRA remained involved in rounds of trial and error until August 2015 — two years after the start of the stock project — when we made the first shipment of iPS cells for medical use.

It costs tens of millions of yen to produce a single clinical-grade iPS cell line — a collection of cells originating from one cell. But, as we want to facilitate collaboration between academia and business, we provide such iPS cells to academic institutes for free and to businesses at an exceptional bargain rate of ¥100,000 per cell line. And so far, more than 10 clinical trials have used iPS cells distributed from the iPS cell stock with no severe adverse events reported.

The 100 talented specialists working on the iPS cell stock project are indispensable as bridge builders between academia and business. To make so many non-regular employees into regular employees under the national university corporation system, however, we had to overcome multiple regulatory walls embedded in the system. Further, there was an institutional objection to the manufacturing of iPS cells for commercial use at a place of academic research such as a national university corporation. To resolve such issues, the CiRA Foundation started operating in 2020 as a public interest incorporated foundation.

Kyoto University and the CiRA Foundation are separate entities. As such, it has become possible to hire researchers as regular employees and remove concerns about the manufacturing of iPS cells for commercial use. About 100 people, many of whom had been involved in the iPS stock project while working for CiRA, which is part of Kyoto University, were transferred to the CiRA Foundation, which is independent from the university.

The mission of the foundation is to serve as a bridge for conveying iPS cell technology from academia to business. To make cells with a lower risk of immune rejection available for as many patients as possible, the foundation has been working on the production of genome-edited iPS cells, using the iPS cell stock. It aims to begin their delivery as early as June this year.

The CiRA Foundation’s key mission also includes the realization of transplantation treatment using iPS cells manufactured from a patient’s own cells. Currently, the production of such cells costs tens of millions of yen for each patient and takes several months. The foundation is currently developing new technology in collaboration with many enterprises to reduce the required cost to about ¥1 million and the time to less than one month.

Research Center Network for Realization of Regenerative Medicine came to an end at the end of March this year. The program was instrumental in enabling relevant researchers in Japan to work as a team, with their efforts having made the world more aware of Japan’s presence in the area of iPS cell-based regenerative medicine.

Our endeavor for the medical application of iPS cells is set to enter the second half of the race when the real competition begins. We would like Japan to be at the vanguard of the world in realizing iPS cell-based medicine to help many patients awaiting new treatments.

Shinya Yamanaka

Shinya Yamanaka, winner of the 2012 Nobel Prize in Physiology or Medicine for generating induced pluripotent stem (iPS) cells, is a professor at Kyoto University’s Center for iPS Cell Research and Application (CiRA) and representative director of the CiRA Foundation. He was the director of the center until March 2022.

The original article in Japanese appeared in the April 2 issue of The Yomiuri Shimbun.