By Tim Hornyak
Guiding a recent tour of a Kyoto University lab, a staff member holds up a transparent container. Inside are tiny pale spheres, no bigger than peas, floating in a clear liquid. “This is cartilage,” explains the guide, Hiroyuki Wadahama. “It was made here from human iPS cells.”
A monitor attached to a nearby microscope shows a mass of pink and purple dots. This is the stuff from which the cartilage was grown: induced pluripotent stem cells, often called iPS cells. Scientists can create these seemingly magical cells from any cell in the body by introducing four genes, in essence turning back the cellular clock to an immature, nonspecialized state. The term “pluripotent” refers to the fact iPS cells can be “reprogrammed” to become any type of cell, from skin to liver to nerve cells. In this way they act like embryonic stem cells and share their revolutionary therapeutic potential—and as such, they could eliminate the need for using and then destroying human embryos. Also, iPS cells can proliferate infinitely.
They can also give rise, however, to potentially dangerous mutations, possibly including ones that lead to cancerous tumors. Thus, iPS cells are a double-edged sword—their great promise is tempered by risk. Another problem is the high cost of treating a patient with his or her own newly reprogrammed cells. But now Japanese researchers are trying a different approach.
When Kyoto University researcher Shinya Yamanaka announced in 2006 that his lab had created iPS cells from mouse skin cells for the first time, biologists were stunned. In 2007, along with James Thomson of the University of Wisconsin–Madison, Yamanaka repeated the feat with human skin cells. Many hailed the opening of an entirely new field of personalized regenerative medicine. Need new liver cells? No problem. Patients could benefit from having their own cells reprogrammed into ones that could help treat disease, potentially eliminating the prospect of immune rejection. In 2012 Yamanaka shared the Nobel Prize in Physiology or Medicine with John Gurdon for discovering that mature cells can be converted to stem cells. “By reprogramming human cells, scientists have created new opportunities to study diseases and develop methods for diagnosis and therapy,” the Nobel judges wrote. To capitalize on the discovery, Kyoto University set up the $40-million Center for iPS Cell Research and Application (CiRA), which Yamanaka directs.
A decade after the Yamanaka team’s groundbreaking discoveries, however, iPS cells have retreated from the headlines; to the layperson, progress seems scant. There has only been one clinical trial involving iPS cells, and it was halted after a transplant operation on just one patient—a Japanese woman in her 70s with macular degeneration, a condition that can lead to blurry vision or partial blindness. Doctors at Kobe City Medical Center General Hospital used her skin cells to grow iPS cells, which were reprogrammed into retinal cells and implanted in her eye. The treatment stopped the degeneration but the trial was halted in 2015 because genetic mutations were detected in another batch of iPS cells intended for another patient. Regulatory changes, under which the Japanese government allowed the distribution of iPS cells for clinical use, also prompted researchers to switch the study to a more efficient process of using cells from third-party donors instead of using a patient’s own cells. “The Japanese government has a lot of incentives to consider—we’re developing a new science, a new technology and also a new economic market,” says CiRA spokesperson Peter Karagiannis. “So there’s the ethical issues, but there’s also money to be made. How do we balance the two?”
The Kobe clinical trial had a lot riding on it. And the setback followed a major stem cell scandal in which biologist Haruko Obokata of the Riken Center for Developmental Biology was found to have falsified data in studies, published in 2014, that claimed a new method of achieving pluripotency. Then, earlier this year, Yamanaka had to apologize at a news conference after it was discovered that a reagent used to create iPS cells at CiRA was mislabeled, which could mean the wrong reagent was used. Although the mix-up is being examined, the center has halted supplies of some of its iPS cells to researchers across Japan; the error also set back by a few years a CiRA project to produce clinical-grade platelets from iPS cells.
But Yamanaka says he remains focused on the bigger picture of iPS cells and is still optimistic they can not only help researchers but may be key to transformative clinical therapies. CiRA still has a bank of tens of millions of iPS cells that have already been reset and checked for safety, so they can be used in patient applications. “In terms of regenerative medicine, things have gone quicker than I expected,” Yamanaka says, adding, “iPS cells have exceeded expectations because of their potential for disease modeling, which allows us to elucidate unknown disease mechanisms, and drug discovery.”
Those hoping for quick clinical success should remember it takes time for revolutionary treatments to go from lab bench to bedside, says Andras Nagy, a stem cell researcher at Mount Sinai Hospital’s Lunenfeld–Tanenbaum Research Institute in Toronto, who has not been directly involved in Yamanaka’s work. “If you fully appreciate the paradigm-shifting nature of iPS cells, tremendous progress has in fact been made over the past 10 years,” says Nagy, who in 2009 established a method of creating stem cells without using viruses (which had initially been used to deliver reprogramming genes into targeted cells). “By comparison, penicillin was discovered as an antibiotic in 1928, but it was not available in the clinic until the early 1940s.”
Researchers in Japan are meanwhile using iPS cell technology to pave the way to better drugs. For instance, CiRA’s Kohei Yamamizu recently reported developing a cellular model of the blood–brain barrier made entirely from human iPS cells. It could become a useful tool for testing drugs for brain diseases.
All eyes, however, are back on Kobe City Medical Center General Hospital, which is resuming its retina trial—this time with iPS cells from donors instead of cells from patients themselves. Using CiRA’s bank of iPS cells, there are significant time and cost savings—it could be one fifth the cost of cell preparation and patient transplant or less. The initial study, with its personalized approach, reportedly cost about $875,000 for just one patient. “We plan to evaluate the efficacy of transplanting the [donor] cells and consider the feasibility of using this method as a routine treatment in the future, accessible to the wider society,” study co-leader Masayo Takahashi of the RIKEN Center for Developmental Biology said at a February press conference in Kobe. Her husband Jun Takahashi, a researcher at CiRA, is also planning to use donor-derived iPS cells for a clinical application—to help treat patients with Parkinson’s disease.
Nagy admits the promise of personalized cell regeneration is probably too costly for mainstream use, and he believes genomic editing—in which DNA is inserted or deleted—is key to safe iPS cell implants. For his part, Yamanaka is cautiously optimistic about iPS cells as a therapeutic tool.
“Regenerative medicine and drug discovery are the two key applications for iPS cells,” Yamanaka says. “With the use of iPS cell stock, we are now able to work quicker and cheaper, so that’s the challenge going forward.”