Cell therapy “promising” for cancer, Parkinson’s and more

Seventeen years ago, the world woke up to an astonishing scientific breakthrough: a team of Japanese scientists, led by Shinya Yamanaka, had reprogrammed skin cells to resemble an embryonic state.

The news quickly reverberated around the world headlines on the front pagewhen people understood the significance of this achievement: for the first time, scientists had turned back the clock of a cell’s development by adding four genes, now called ‘Yamanaka factors’, to return a mature skin cell to pluripotency, the condition can give rise to almost all cell types in the body. No embryo was needed in the process.

I remember how fascinated I was when I first heard the news. At first glance it sounded like science fiction to me, and I certainly didn’t fully realize at the time its potential to treat and possibly cure disease.

I never thought at the time that I would have the honor of speaking to Prof. Yamanaka himself about his discovery, for which he won the Nobel Prize in Physiology or Medicine in 2012. In a recent interview from his office at the Gladstone Institutes in San Francisco, he shared fascinating insights into the backstory of his work and the doors it is beginning to open for patients today.

History and ethics

Yamanaka first got his own laboratory in 1999 at the Nara Institute of Science and Technology in Japan. His colleagues worked on differentiating embryonic stem cells into different specialized states, such as neurons or heart cells. It was difficult to be competitive in that area, so he decided to take the opposite approach: “Instead of doing differentiation, I thought we should do de-differentiation,” he explained. “So instead of making skin cells from embryonic stem cells, I thought we should make embryonic stem cells from skin cells.”

It was already theoretically possible to do this, using the same technology that cloned Dolly the Sheep, called nuclear stem cell transfer – but this was a challenging process. Yamanaka wanted to make personalized embryonic stem cells easier and faster because he knew it could pave the way for a new paradigm in medical treatments.

Yamanaka initially thought it would take twenty to thirty years for his experiment to be successful, as his team used trial and error to test combinations of different factors to convert a cell to pluripotency. But after six years, they found 24 factors that worked repeatedly. Later experiments showed that the team was able to reduce the required factors to just four, and these worked even more efficiently to reprogram the cell into the desired state: “A real wow moment,” Yamanaka recalls.

“My main motivation when we started this project was to find an alternative to using human embryos. I believe that human embryonic stem cells are beautiful and have enormous potential. And if there is no better way, we should definitely use these cells to help patients. But if we can find another way, we should try.”

Yamanaka acknowledged that while induced pluripotent stem cells avoid the use of embryos, they raise other thorny ethical issues, such as the ability to construct sperm and egg cells from skin cells – a process known as IVG that has already enabled mice to reproduce to plant.

Yamanaka is a strong supporter of regulation and public discussion of bioethics to ensure that scientists’ work is consistent with societal values. “The rate of technical progress is getting faster and faster, so we need to discuss not only among scientists but also with the general public about how much scientists can do or should do? That discussion is very important now.”

Clinical trials

Aside from the potentially complicated future use of induced pluripotent stem cells (iPSCs), Yamanaka and I talked about the current landscape of investigational treatments for today’s patients.

Although there are no approved therapies yet, at least 50 clinical trials are underway in the US, Japan, China and other countries. One of the most promising is the use of iPSCs to reverse type 1 diabetes – a world-first breakthrough just reported last month in Nature.

Another promising use is for corneal diseases, which he suspects will be the first approved use “very soon.”

It is now possible to “make a transparent sheet of cornea from iPS cells,” says Yamanaka. “So by replacing the damaged cornea with an iPSC-derived cornea, the effect is remarkable. Patients can restore their vision.”

He added: “The question is: how long can those sheets maintain their transparency? That’s what we don’t know. We hope this will be the case for many years to come. But even if they go dark, we can easily add another one, because that’s the beauty of iPS cells. We can make tons of iPS cells and we can make tons of corneal sheets from iPS cells.”

Parkinson’s disease is another “promising” area, as is iPSC-derived cancer immunotherapy. The latter would be an “off-the-shelf” temporary solution while patients wait for their own cells to be converted into CAR-T cells. The problem is that the process can currently take four to six weeks, and some patients die in the meantime. Yamanaka is optimistic that iPSCs can be turned into a short-term immunotherapy to save their lives until they get their own CAR T cells.

Such cell lines would be genetically modified to be matched to patients, to avoid a strong need for immunosuppressive drugs. The use of CRISPR theoretically streamlines the process significantly. Without CRISPR, Yamanaka estimates we would need about 300 different cell lines to match different immune profiles. In doing so, he says that just 10 lines should be sufficient as source material for ready-made immunotherapies.

Two of these cell lines are already available for research or clinical use, and the CiRA Foundation, of which Yamanaka is president, began shipping them last year to academia and companies promoting regenerative medicine. Other applications on the horizon include, but are not limited to, spinal cord injuries, heart failure and blood transfusions.

“Yamanaka’s discovery of reprogramming was nothing short of a revolution in biomedical research,” says Dr. Stefan Irion, Chief Scientific Officer at BlueRock Therapeutics, a biotech company co-founded by Leaps and now owned by Bayer. It aims to develop therapies using pluripotent stem cells. “For the first time, any human disease could be modeled in a dish, and scientists in the field realized the infinite possibilities of using this platform to treat diseases previously thought to be untreatable. The progress has been astonishing.”

Last month, BlueRock received FDA approval to use iPSCs in a clinical trial to treat primary photoreceptor diseases, a subset of inherited retinal diseases that cause irreversible vision loss in both children and adults.

Also last month, famed synthetic biology pioneer George Church announced a new start-up which raised $75 million for a cell therapy platform that aims to deliver ready-to-use iPSC medicines up to 100 times faster than conventional methods, using a four-day process. It’s called GC Therapeutics, and it’s aptly named because Church himself donated his own skin cells to be reprogrammed into the stem cells used by the platform.

That’s just one of several exciting companies working to make iPSC drugs more quickly available to patients for a variety of diseases, including aging itself. Altos Labs, funded to the tune of $3 billion by Jeff Bezos and other investors, has extended the lifespan of mice by 25% by activating “Yamanaka genes” later in life. (Shinya Yamanaka is a scientific advisor for Altos Labs.) Like recently reported Through BBC Science Focus magazine“If this result holds up when the results are published in full, that will be exciting news. And if Altos Labs succeeds in creating a human treatment based on this work, Yamanaka could become the first person in history to earn a second Nobel Prize for the same discovery.”

Whether that research is successful or not, what we know for sure is that Yamanaka has already changed medicine as we know it. And cell therapy is just getting started.

Thanks to Kira Peikoff for additional research and reporting on this article.