Bringing Sight To The Blind

Professor Masayo Takahashi, who performed the world’s first induced pluripotent stem cell-derived transplant into humans, has a vision for stem cells in the clinic.

AsianScientist (Feb. 11, 2016) – With its promise of eternal youth, stem cell biology has captured the imagination of the public in a way that few other fields of science have. Two landmark events stand out as turning points in the history of this relatively young field: the cloning of Dolly the sheep in 1996 and Professor Shinya Yamanaka’s demonstration in 2007 that adult human cells could be reprogrammed into a pluripotent state, commonly known as induced pluripotent stem (iPS) cells.

Seven short years after the discovery of iPS cells, yet another landmark has been reached: the transplant of iPS-derived cells into the first human patient. This achievement has won Professor Masayo Takahashi the attention of Nature magazine, which named her as one of five “Scientists to Watch in 2014,” a choice that was vindicated by her further nomination as one of ten “People Who Mattered in 2014,” also by Nature magazine.

Despite the accolades, Takahashi remains cautiously optimistic. Understanding that a negative outcome in her small clinical study of six patients could scuttle the efforts of other researchers hoping to bring iPS cells to the clinic, Takahashi’s responses were measured and she was careful to highlight the limitations of her findings thus far.

Nonetheless, there was a clear sense of purpose in her work, with the urgency of finding treatments for patients driving the research.

Takahashi’s success no doubt comes as a relief to her home institution, RIKEN, which was recently rocked by high-profile publication controversies. In the institutional crisis that followed, RIKEN’s Center for Developmental Biology (CDB) saw the halving of its staff and a major overhaul of its organizational structure.

Will Takahashi’s work help to restore the reputation of RIKEN and Japan’s standing in iPS research? Perhaps only time can tell. In the meantime, we catch up with Takahashi to hear about the latest developments in her research and her plans for the future.

What is your background and how did you get into iPS research from ophthalmology?

I graduated from Kyoto University in 1986 and since then I worked in ophthalmology, especially retinal diseases. In my roughly 20 years of experience, I have been active in both research and clinical work. During that time, I went to the Salk Institute in San Diego and I encountered the new concept of neural stem cells. Since then, I started research on retinal regeneration.

Would you say that your time at Salk was a turning point for your research?

Yes, it certainly was. When I was at Salk institute in 1996, I encountered the very new concept of neural stem cells while working in a brain research laboratory. In fact, I was the first ophthalmologist to encounter the concept of neural stem cells. This early exposure gave me the idea that I should be the one to develop regenerative medicine for the retina.

What were your feelings leading up to the clinical trial?

First and foremost, I was very relieved. At the same time, I felt that this was just the start and that I would go on to do many things from then on. I wouldn’t say that I felt particularly excited; the excitement first came seven years ago when I talked to Professor Shinya Yamanaka about using iPS cells in the clinic. That was the most exciting period for me.

What was the hardest part about doing this clinical study?

I had extensive support from our institute, RIKEN. The most difficult part was clearing the ethical committees and paperwork, and forming a team that spanned the various institutes that participated.

How was the patient selected?

The patient is a lady in her seventies suffering from wet-type age-related macular degeneration (AMD). The current treatment for this condition is anti-VEGF drug injection directly into the eyeballs, a treatment she had already undergone 18 times in both eyes. Nonetheless, her visual acuity gradually deteriorated.

Wanting to stop the eyeball injections and hoping to help the next generation of AMD patients, she volunteered for the study with the understanding that the aim was only to examine the safety of iPS cells and that she cannot expect high recovery of visual function.

I understand the study was approved for six patients. What is their current status?

It’s a little bit complicated because law has been changed recently. The changes specify that clinical studies should only be done at medical institutes, which means that I will have to re-apply as RIKEN is a research institute and does not have any associated hospital.

What are your future plans for your research?

The first patient received an autologous transplantation, which means that the cells were derived from her own cells rather than a donor. We are preparing to conduct allogenic transplantations, whereby patients receive transplants from donors.

While autologous transplants are too expensive and difficult to do for many patients, we believe that allogenic transplants can become a standard treatment. Along the way, we may also start a company providing allogenic transplants.

Are the retinal pigment epithelium (RPE) cells you have used safe?

We chose RPE cells for the first treatment because they divide very slowly. In my entire career, I have only seen two to three patients with tumors of the eye; there is something in the environment of the eyeball that supresses tumor formation.

Another advantage of treating retinal diseases is that we only need a small number of cells, allowing us to thoroughly check each transplant. Furthermore, we can purify the RPE by color and get very high purity cells. For example, for the first patient we got 100 percent purity.

Besides, we can precisely evaluate the status of the grafted cells with ophthalmologic examination. I doubt that tumors will form, but if they do, we can detect them immediately and treat them by laser. All these characteristics make RPE derived from iPS cells safe.

What are some of the breakthroughs you hope to see in iPS research?

The next target will be Parkinson’s disease; I’m sure it will begin to bear fruit within the next five years. Other than that, we are preparing for photoreceptor transplantation along with iPS-derived cells within five years which should not only slow AMD but could possibly even restore some vision. Only iPS or embryonic stem cells can make RPE, and only RPE can treat certain diseases. There may be several iPS-derived treatments for such specific cases, but not so many treatments in other types of disease.

Do you mean to say that iPS treatments aren’t that versatile?

What I mean is that you don’t need to try to treat everything with iPS cells. For one thing, iPS cells are difficult to handle, and if you need high cell numbers in the heart or pancreatic tissue for example, it would be very difficult to confirm the safety of the cells used.

In those fields, the numbers (of cells required) can be thousands to tens of thousands more than in retinal diseases. Cost can also be quite prohibitive. Other types of cells, such as bone marrow cells, might well be able to perform better. In other words, we need to cleverly choose which cell type or disease needs iPS cells.

How can Japan remain a leader in iPS research?

It is a good strategy for us to focus on iPS cells as it is our strength and we have accumulated good data on it. iPS cells will be a good source of cells in certain fields of regenerative medicine, so we should keep that area in our hands.

Last year was a very challenging one for RIKEN. What do you think is the way forward?

I hope the confusion will cease soon; at the moment we still have a mess. I have many meetings every day over the direction of CBD, which take me away from my research. I hope that things settle down soon and we can move on.

What is your personal research philosophy?

Our laboratory focuses on doing research that contributes to the welfare of patients, not the publication of papers or pursuit of money and fame. Our goal is patient happiness. I only care about the treatment; I don’t care about papers at all. Sometimes people say that I should publish more papers, but I’m interested in creating the shortest path to treatments for patients.

Finally, do you have any advice for young scientists in Asia?

I know that there are many ambitious young researchers in Asia; I’m really looking forward to seeing them grow. Please look into very new fields, and not current trendy research. Always seek brand new research fields to make your dreams come true.

This article was first published in the print version of Asian Scientist Magazine, April 2015.


Photo: Masayo Takahashi/RIKEN.

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Rebecca did her PhD at the National University of Singapore where she studied how macrophages integrate multiple signals from the toll-like receptor system. She was formerly the editor-in-chief of Asian Scientist Magazine.

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