Feature

ILLUSTRATION: RICARDO SANTOS; PHOTOGRAPHS: BEN WELLER FOR NATURE; WOODBLOCK PRINT: UTAGAWA HIROSHIGE (1831)
JAPAN’S BIG BET
J
apan is brimming with signs of an
approaching medical revolution.
Shiny white robots are tending dishes

ON STEM-CELL
of cells, rows of incubators hum in new
facilities, and a deluxe, plush-carpeted
hospital is getting ready to welcome its
first patients.
Building on the Nobel-prizewinning

THERAPIES MIGHT
work of stem-cell scientist Shinya Yamanaka,
researchers across the country are crafting
cells into strips of retina, sheets of cardiac
muscle or blobs of neurons, in the hope of

SOON PAY OFF

treating blindness, mending hearts and
reversing neurodegeneration. Results from
early-stage clinical trials — some announced
just in the past few weeks — suggest that the
cells might actually be working to treat con-
ditions as varied as Parkinson’s disease and
spinal-cord injury.
Induced pluripotent stem cells are being tested Now, after nearly two decades of hard work
and setbacks, many say that Japan is on the
to treat blindness, paralysis, Parkinson’s disease cusp of bringing these therapies to market.
and more. Approvals might be around the Yamanaka, who runs a lab at Kyoto University,
discovered in 2006 that adult cells could be
corner. By Smriti Mallapaty reprogrammed into an embryonic-like state,

584 | Nature | Vol 640 | 17 April 2025

 capable of becoming practically any kind of
tissue1. These induced pluripotent stem cells —
or iPS cells — won Yamanaka the Nobel Prize in
Physiology or Medicine in 2012, and propelled
him to superstar status. They have become
a symbol of the country’s global scientific
aspirations.
The Japanese government has poured more
than ¥110 billion (US$760 million today) into
research and development on regenerative
medicine, on top of billions more from private
funders, organizations and companies. “Peo-
ple thought, ‘Now we can treat any incurable
disease’,” says Shigeto Shimmura, director of
Fujita Health University Haneda Clinic. “There
was so much hype.”
BEN WELLER FOR NATURE

Scientists launched clinical trials and

start-up firms. Large biotech companies
swooped in, investing even more in manu-
facturing hubs. Now, medical facilities are
preparing to welcome a rush of patients from
Japan and abroad. “Regenerative medicine Masayo Takahashi ran the first clinical trials for iPS cells.
in Japan is moving very dramatically,” says
Masayo Takahashi, an ophthalmologist at three individuals who received the treatment,
Kobe City Eye Hospital and president of the the cells have survived and are safe one year
biotechnology company, Vision Care. In 2014, after surgery2. But the signs of benefit are

REGENERATIVE
she became the first to treat someone with mixed. One of the three individuals said she
cells derived from iPS cells. could see her husband’s face clearly for the

MEDICINE IN JAPAN
There are more than 60 iPS-cell clinical tri- first time in ten years, but only through a small
als in progress worldwide, nearly one-third of section of her eye, where the cells had been
them in Japan. The treatments have proved to
be safe and shown signs of benefit. Moreover, IS MOVING VERY transplanted.
The difficulties might come down to the
the technology has been improving apace, says
Shimmura. And thanks to a fast-track approvals
process for regenerative medicine, Japan could
DRAMATICALLY. retina’s natural resistance to regeneration.
But other parts of the eye might benefit more
from cell therapies: the cornea, the clear cov-
become the first country to approve iPS-cell- grown into thin sheets of retinal cells and ering that lets light in, is maintained by a pool
based treatments. This could happen within a transplanted into the woman’s eye, where they of stem cells and constantly being rebuilt.
year for Parkinson’s disease. have survived for ten years and prevented fur- In November, Kohji Nishida, an ophthalmol-
But those approvals are not yet in hand, ther vision loss, Takahashi says. ogist at Osaka University, and his colleagues
treatment costs are high, large trials showing It was a procedure with practical limita- published the results of donor iPS-cell-derived
clear clinical benefit have yet to materialize, tions, however. Self-derived, or ‘autologous’, transplants into four individuals for whom
and concerns about safety could still sap the cell therapies are time-consuming and expen- those natural cornea-building stem cells had
public’s willingness to try this treatment. sive to make, and the large cell-sheets that been depleted — a condition that results in cor-
“We’re down to realizing what the potential researchers crafted for implantation required neal scarring and vision impairment. Three of
of these cells are, and what the limits are,” intrusive surgery. Takahashi says she chose them saw sustained gains in vision3.
Shimmura says. this approach to ensure the highest chance Nishida has since set up a start-up company,
of clinical benefit — to demonstrate to the Raymei, which plans to launch a larger trial and
Eye see world what was possible. It was designed to aims to gain formal approval in three years.
Yamanaka’s iPS cells promised to bypass a be “scientifically, the best treatment”. “The next clinical trial is pivotal,” he says.
bioethical stand-off that had threatened the But Takahashi wanted to create a
potential of embryonic stem cells for a decade. commercially viable treatment. This meant a Brain and back
Because production of iPS cells doesn’t require change in approach, using cells from donors The regeneration of nerve tissue has been
the destruction of human embryos, they were that could be mass-produced, and finding less one of the great hopes for iPS cells, but it has
considered ethically less fraught. Further- invasive ways of getting them into the eye. been fraught with challenges. Jun Takahashi,
more, because they could be made from the She and her team initially tried injecting husband to Masayo, has an office lined with
cells of the person in need of treatment, they a pool of donor-derived cells just under the statues of elephants and an imposing, life-
promised to offer transplantable tissues with- retina, where they might form sheets on their sized set of navy-blue samurai armour, “just
out the need for immune-suppressing drugs. own. But the researchers had limited control to encourage my lab”, he says.
In 2014, Takahashi put this idea to the test. over where the cells grew. They next tried Takahashi is a neurosurgeon and the
She took skin cells from a 70-year-old woman growing strips of cells, 2 centimetres long director of Kyoto University’s Center for iPS
with a progressive eye condition known as and 200 micrometres thick. They used a tube Cell Research and Application (CiRA), an
macular degeneration and guided them into to slide several of these strips onto the retina institute established by Yamanaka as a hub
a younger, more pliable state using a recipe through a tiny incision in the eye, in the hope for iPS-cell research.
similar to the one Yamanaka had devised that they would expand into sheets. In 2018, Takahashi led a trial that used
and refined. The resulting iPS cells were then Results published in March suggest that for donor-derived iPS cells to treat Parkinson’s

Nature | Vol 640 | 17 April 2025 | 585

Feature

BEN WELLER FOR NATURE

This robot in Kobe is preparing cells for transplant to treat people with macular degeneration.

disease, a degenerative brain condition that spinal-cord injury. The researchers presented The first was rejected for formal approval
affects movement. The team injected between preliminary results — not yet peer reviewed — after nearly a decade on the market because it
five million and ten million cells, which had at a press conference in March, showing that failed to show clinical benefit. The second was
been coaxed into acting like neural progeni- one individual with paralysis can now stand withdrawn about five years after being condi-
tors, into the right and left brain hemispheres independently and is learning to walk. Another tionally approved, because surveillance data
of seven individuals with the disorder. can move some of their arm and leg muscles did not reproduce results observed in earlier
Two years after the treatment, according but cannot stand. Two others did not show trials.
to results published this week, at least four substantial improvements. Hiroshi Kawaguchi, an orthopaedic surgeon
individuals saw noticeable improvements in Similar trials are under way outside Japan, at Nadogaya Hospital in Kashiwa, says he is
symptoms, such as fewer tremors and rigid some of which involve many more partici- concerned that the fast-track process shifts
movements4. One went from requiring assis- pants than the Japanese trials. But unlike other the cost burden from pharmaceutical compa-
tance to being able to live independently regions, Japan has made the path to approval nies, which would otherwise have to conduct
when not taking their regular medications. relatively easy, says Clive Svendsen, a stem- large-scale trials, to the public insurers, which
Another trial involving 12 individuals using cell researcher at Cedars-Sinai Medical Center then pay for expensive, unproven treatments.
neural progenitors derived from embryonic in Los Angeles, California. In 2013, Japan Last year, Japan’s Ministry of Health, Labour
stem cells also showed, on average, moderate introduced a system through which regenera- and Welfare issued guidance documents that
improvements in movement 18 months after tive-medicine products could be conditionally clarified that conditional approval should not
the transplant5. Knowing that the treatment approved if they are shown to have no major be the ultimate goal for companies.
could work has brought Takahashi great relief. safety issues and are likely to be efficacious. Others are less concerned about Japan’s fast-
But, unlike his wife, he has not set up a Companies can offer the treatments, with track process for conditions that are rare or
company to develop the technology for costs mostly covered by the national health have few other treatment options. “In order to
manufacturing the cells and conducting the system. But they must continue to collect move this field forward quickly, you’re going to
surgery. Instead, he has instead transferred data on safety and efficacy to earn full clinical have to have an element of risk,” says Svendsen.
that knowledge to Sumitomo Pharma, based approval. “What I’ve seen in Japan has been pretty sen-
in Osaka. “As a scientist, I am kind of satisfied,” Some researchers have raised concerns sible; they are putting regulations in place.”
he says. He has now diverted his attention to about this fast-track process and related
developing cell therapies for treating stroke. programmes in Japan. Last year, two of the iPS cells for all
Hideyuki Okano, a stem-cell scientist at four products that had received conditional Even without approvals in hand, the industry
Keio University in Tokyo, has demonstrated approval under this mechanism — one involv- is building capacity in the expectation that
another potential trick for iPS cells. Between ing thigh-muscle cell transplants for the heart, demand for these treatments will be high.
2019 and 2023, he and his colleagues used the other a gene therapy to treat ulcers in nar- In 2018, Sumitomo Pharma completed con-
donor-derived cells to treat four people with rowed arteries in the limbs — were withdrawn. struction of what it describes as the world’s first

586 | Nature | Vol 640 | 17 April 2025

 manufacturing facility for donor-derived iPS- ¥1-million target for creating autologous cells a transplant to replace cells that line the inner
cell products. The building, in Osaka, looks like by this June, but differentiating the cells into surface of the cornea, derived from donor iPS
a giant, floating silver box. In 2020, it delivered a desired cell type costs many millions more. cells, to treat a form of swelling in the eye. The
its first cells for transplant — for the fourth par- The next goal is to shave that combined figure treatment proved safe and the individual’s
ticipant in Takahashi’s Parkinson’s trial. The down to ¥5 million. vision became less blurry, but Shimmura had
company is also supporting two early-stage to end the study abruptly.
Parkinson’s trials in the United States. Safety first The iPS cells came from the CiRA Founda-
Masayo Takahashi has chosen a more So far, stem-cell therapies have proved safe, tion and were certified at the time to have no
portable manufacturing model for her say researchers. Although there have been mutations known to cause cancer. Genomic
macular-degeneration treatments: a white, concerns that the process of creating iPS cells sequencing after the cells had been coaxed
muscular-looking, two-armed robot. Pow- could make them prone to forming cancers, into corneal endothelial cells was also clear.
ered by machine learning, it checks in on safeguards have been established in the matur- But sequencing just before the transplant
cells’ progress as they are prepared for trans- ing process to ensure that no pluripotent cells revealed a deletion in the EP300 gene, which is
plant through a microscope. In 4 months, it remain in a transplant, and that cells for trans- considered a tumorigenic change6. Investiga-
can produce enough cells for more than 800 plant have been screened for cancer-causing tion by Shimmura’s team revealed no adverse
individual treatments. gene mutations, says Shimmura. events related to the mutation, and lab stud-
Developed together with Koichi Takahashi “Remarkably, of all the patients that have ies showed that cells containing the mutation
(no relation to Jun or Masayo), a compu- been implanted, there were no serious events weren’t more likely to form tumours.
tational biologist at the RIKEN Center for that were related to the product that we could It’s possible that regulatory agencies will
Biosystems Dynamics Research in Kobe, the find,” says Carpenter, referring to results from now require all trials to conduct whole-genome
robot ensures that cell-culture techniques clinical trials approved by regulatory author- sequencing of the cells just before transplan-
developed in a laboratory can be reproduced ities globally. Still, the fear persists. And any tation. “It’s good to be safe,” says Shimmura.
anywhere, thus avoiding the logistical uncer- abnormalities in the cells are double- and But, he adds, researchers and regulators need
tainties that delivering the cells would entail. triple-checked. to get together “to figure out how we’re going
“It is easy to transfer our treatment to the One recent scare involved a trial, led by to cope with these minor mutations”.
world,” says Masayo Takahashi, who hopes Shimmura, in which a 73-year-old man received
to partner with groups across Japan and Asia. Medical travel
But for many, the ultimate goal of iPS-cell The stakes are high, as are the costs. Masayo
therapies is to return to the idealized version Takahashi’s company plans to seek regulatory
of autologous transplants. Such transplants approval for its macular-degeneration treat-

OUR ULTIMATE GOAL

would reduce the risk of rejection and avoid ment following larger clinical trials. But before
the need for immune-suppressing drugs over that, she plans to collaborate with physicians

IS AUTOLOGOUS
extended periods. They could also address to start therapies through a government pro-
some ethical worries that have been raised, gramme that would require that individuals,

TRANSPLANTATION.”
such as the idea that transplanting another and not the national health system, pay for
person’s neurons into the brain is like changing most of the therapy. The price tag for such
someone’s identity, says Jun Takahashi. “Our therapies, which some have pegged at ¥10 mil-
ultimate goal is autologous transplantation,” lion, makes it likely that this would be an option
he says. only for wealthy Japanese people and medical
Of more than 680 individuals who have tourists. Takahashi is also looking at whether
received iPS-cell-derived products in trials the procedure could be covered by private
globally, only 11 have had autologous trans- health insurance.
plants, according to an analysis by Melissa The first site that could start offering these
Carpenter, president of the stem-cell-focused advanced therapies is Fujita Health University
Carpenter Consulting in Seattle, Washington. Haneda Clinic, where Shimmura is based. A lux-
It’s possible that there have been more recip- ury facility, it is just one train stop from Tokyo’s
ients than this, because many firms have not Haneda International Airport.
disclosed figures, says Carpenter. Yoko Ozawa, an ophthalmologist at the
But often, companies do not prioritize the clinic, is collaborating with Takahashi and
autologous route, because production of these identifying potential patients. She’s confident
treatments is just too costly. One project by that the substantial investments in iPS cells will
the CiRA Foundation is trying to change that. pay off. People might hesitate to accept the
Tucked away in a high-rise building in Osaka, treatment at first, she says. “But after several
the myiPS project aims to create autologous successful cases, more will come.”
iPS cells at a cost of ¥1 million per patient,
much cheaper than comparable efforts so far. Smriti Mallapaty writes for Nature from
On one floor of the new facility — set up Sydney, Australia.
in 2024 — four cell-culturing machines sit
BEN WELLER FOR NATURE

behind glass walls. Each can transform adult 1. Takahashi, K. & Yamanaka, S. Cell 126, 663–676 (2006).
cells from a patient into enough iPS cells for 2. Sakai, D. et al. Ophthalmol. Sci. https://doi.org/10.1016/j.
xops.2025.100770 (2025).
a personalized treatment in about a month. 3. Soma, T. et al. Lancet 404, 1929–1939 (2024).
The room is designed to hold 48 machines, 4. Sawamoto, N. et al. Nature https://doi.org/10.1038/s41586-
with space for another 150 next door. 025-08700-0 (2025).
5. Tabar, V. et al. Nature https://doi.org/10.1038/s41586-025-
Masayoshi Tsukuhara, who heads the project, Jun Takahashi is trying to treat Parkinson’s. 08845-y (2025).
is confident that the foundation will meet the 6. Hirayama, M. et al. Cell Rep. Med. 6, 101847 (2025).

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