Yamanaka Interview on Clinical Use of Pluripotent Stem Cells

Dr. Shinya Yamanaka

Dr. Shinya Yamanaka.                                           Photo from CiRA, Kyoto University

I invited Nobel Laureate Shinya Yamanaka to do an interview on the future of clinical translation of induced pluripotent stem cells (iPSC).

He provides some intriguing new insights into the iPSC field and the broader stem cell arena.

PK: The Takahashi Team’s active Clinical Study using iPSCs to make RPEs to treat Macular Degeneration has generated a great deal of excitement. Can you please share your perspectives on the importance of this work and the team involved? 

SY: This is the first study to apply iPSC technology to human care. This is a very important study, because if it succeeds it will show that iPSCs can be safely used in humans and also their potential for cell transplantation treatment. We collaborated with Dr. Masayo Takahashi of RIKEN CDB by evaluating the safety of the iPSCs and iPSC-derived cells that were used for the cell transplantation. She is an excellent researcher, and I am not surprised that her team is the first to have succeeded in this transplant.

PK: Any cutting edge investigational clinical work such as this has some risks. Could you please comment on the potential risks in this iPSC trial? Are there some elements here such as preclinical data, the number of cells used, or the target tissue of the eye that lower risks?

SY: One of the major concerns is whether transplanted cells such as the RPE sheets will cause tumors. In our collaboration with Dr. Masayo Takahashi’s team, we evaluated the safety of iPSCs and iPSC-derived cells by genome and epigenome analysis. While we minimized the risk to a level acceptable for clinical trials, we really cannot confirm how the cells will respond until we actually do experiments with humans, which is why this project is so important. One advantage of treating age-related macular degeneration is that it is easy to detect any abnormalities in the eyes, which is why the disease is a good starting model for iPSC-based treatment.

PK: As the inventor of iPSCs did you imagine 7-8 years ago that a patient in a clinical study in 2014 would already have received an iPSC-based treatment? How was this rapid translation from bench to bedside possible?

SY: I was surprised that after the announcement of human iPSCs in 2007, Dr. Takahashi told me that she would bring iPSC to the bedside within five years. I thought it possible technically speaking, but doubted it could be done so soon, since we needed to improve the technology and get government approval. It took 7 years, which is remarkable considering the work required. Both the accomplishment and the speed at which it was achieved are testaments to Dr. Takahashi’s leadership and her strong team.

The rapid transition is because many bright and passionate people are in the iPSC field. The funding and infrastructure provided by the Japanese government is also a major factor, as these have encouraged excellent scientists to enter the field.

PK: We are also starting to hear more about Dr. Jun Takahashi’s Team’s important work towards using iPSCs to treat Parkinson’s Disease. Can you please tell us more about that?

SY: Prof. Jun Takahashi’s team at CiRA is working on cell therapy for Parkinson’s disease, aiming to transplant iPSC-derived dopaminergic neural progenitor cells into PD patients’ brains. Early results suggest this treatment can be effective, and his team has established the protocol for transplantation. They are now focusing on validating its safety using monkey models. We hope his work will soon reach the operating room within the next few years.

PK: What other clinical applications of iPSC technology are in the works and that might begin clinical studies in the next few years?

SY: There are two major clinical applications of iPSCs, namely regenerative medicine and drug discovery. CiRA has a number of researchers working on either or both. For regenerative medicine, Prof. Koji Eto at CiRA is working on generating platelets via iPSCs, and we expect this will also proceed to clinical research in a few years. Besides work at CiRA, a team at Keio University has a plan to conduct clinical research on patients with acute spinal cord injury in four to five years, while Osaka University and Keio University hope to transplant iPSC-derived cardiac myocytes into patients with heart diseases within a few years. CiRA is collaborating with these teams as well.

Regarding drug discovery, you may have heard recently of CiRA’s Prof. Noriyuki Tsumaki’s paper about statins effects on bone growth, which was published online in Nature last month.

PK: Some in the media are taking about a certain tension between clinical iPSC work in Japan and clinical iPSC work in the US. Do you believe such a tension exists and if so, why? What does it mean for the iPSC field overall?

SY: I am not sure what “tension” means. I understand that both competition and collaboration exist between the US and Japan.

PK: How do you view hESCs today? Are there hESC clinical trials or potential applications that are of particular interest? What is your view of the argument by some that hESC are no longer needed?

SY: Human ESC was a great discovery for regenerative medicine and also instrumental to the discovery of iPSC and the type of medical treatments we are aiming to apply iPSC. At the same time, the ethical issues that hESC possess mean that as iPSC technology improves, hESC will be less needed. Still, iPSC is a new technology, and its safety and efficacy still needs to be confirmed. In addition, there may be some therapies for which hESC are better than iPSC. Thus, I think basic and clinical research of hESC is also important and should be done in parallel with iPSC research.

PK: What excites you most about the stem cell/regenerative medicine field right now today?

SY: I am excited about the possible number of people treated with iPSCs. This field has great potential to provide treatments for currently incurable diseases. Hopefully, within 5 years, we will refer to Dr. Masayo Takahashi’s AMD work as just one of many patient studies using iPSCs.

PK: Where do you see the iPSC field and the broader stem cell field in say 5-10 years?

SY: It is pretty amazing how much it has changed in the past years, so predicting the next 5-10 years is very difficult. I certainly hope we will see more diseases being treated with iPSC and related technologies such as direct reprogramming. I also hope that iPSC will be used more widely and routinely in drug development.

PK: What advice would you give to young scientists today who are excited about a career in stem cells/regenerative medicine?

SY: Through biomedical research, you could help thousands of patients in the future. Stem cells provide unprecedented opportunities in stem cell therapy and drug development. Biology of stem cells itself is extremely interesting. I hope many young scientists will enter to this field.

Prostate cancer postcards

In a few days it will be the 5-year anniversary of my diagnosis with a very serious form of prostate cancer. So far since then I’ve been doing pretty well (knock on wood). I am still getting PSA tested and life still has a cancer thread through it for me.cancer park

As much as having cancer is a very personal and in some ways private experience, I have found it helpful to write and talk about it. I hope that my experience has been helpful to other men who are facing this cancer, some of whom I’ve met over the years.  If you are dealing with prostate cancer and want someone to talk to drop me an email ([email protected]).

Every so often I have written a sort of a postcard view of how I was doing and what it felt like to have cancer at that point, often including images. I have linked to some of those postcards at the end of this post and sprinkled the images from those posts throughout here.

Kirk SpockIt’s been a while since I posted one of these postcards. I’ve tried to move on with life, but it’s not always easy. In this post I’ve also include some images from my past postcards.

Today I’m thinking about the question: how did I get here and where is the prostate cancer world going?

prostate cancer

It all started when the cancer came out of the blue for me at age 42 as a dangerous form of prostate cancer. I had surgery. I’m not cured. Instead, I’m in what my doctor calls “long-term remission”.

I still don’t quite know where I belong in the prostate cancer world. I’m sort of a kid in that world. I remember the first time I went to see the urologist and found in the waiting room that all the men also there seemed like parents/grandparents to me in terms of their ages. Being diagnosed at age 42 feels weird when the average age of diagnosis for this disease is roughly age 68. I’ve never met anyone diagnosed at a younger age with prostate cancer than I was. I’m sure they are out there, but it feels a bit lonely in a way.

It’s concerning that I may have more company with other young men in that the rate of prostate cancer in young men has been rapidly increasing and scientists do not seem to know why. It does not seem to be explainable entirely as a case of a change in diagnostic tools.

John Daly Pants

I had a lot of questions when I was diagnosed and frankly I still do not have answers to these for the most part today. Do younger men diagnosed with prostate cancer do better or worse than older men? The literature is unclear. Is prostate cancer in a 42-year old different than that of say a 70-year old man?

cancer myth

In the almost five years since I was diagnosed, unfortunately I haven’t seen any blockbuster new prostate cancer treatments emerge. As both a cancer survivor and cancer researcher, I wish things would speed up. When I read about prostate cancer treatments in the pipeline for recurrent prostate cancer, somewhat depressingly so far the “successes” prolong patient life by a few months, which frankly to me seems pretty disappointing. There is hope for new treatments that could be game changers.

Here are my previous prostate cancer postcards. See if you can match them up with some of the pictures in this piece.

STAP Cell Update: New STAP-like paper, Obokata, Vacanti, Real Origin of STAP cells, & More

The STAP cell mess that began in January of this year has in some ways quieted down.

In a broader sense, I believe that STAP is now and will be in the future viewed as a scandal that revealed some less than ideal aspects to the world of biomedical science and publishing.

Where does STAP stand today?

A New STAP-Like Paper?electric iPSC

The most recent development is the publication of a new paper pointed out by a number of people to me as perhaps STAP-like. It is entitled “Electromagnetic Fields Mediate Efficient Cell Reprogramming into a Pluripotent State”. It was published in the journal ACS Nano.

This Baek, et al. paper suggests that you can dramatically more efficiently create induced pluripotent stem cells (iPSC) by exposing somatic cells to an electromagnetic field (see graphical abstract above). My reaction? Let’s see if another lab can reproduce this, but I’m not terribly optimistic. Derek Lowe weighed in on this paper here. The Pubpeer folks have some concerns too and the authors have responded (which is a good thing) there as well.

STAP stem cellsObokata Thesis in Jeopardy

At this time, first author Haruko Obokata is faced with more immediate issues such as her future at RIKEN and her thesis. She must correct her Waseda University thesis or it may be revoked. The University did an abrupt U-turn on this as earlier they had said that while the Obokata thesis had problems it was not that big a deal. Now they are requiring a correction. Given the apparent massive plagiarism in it and re-used figures, I don’t see how a correction is possible frankly.

Vacanti still believes in STAP, issues new protocol

Obokata’s former mentor at Harvard/Brigham Women’s, Charles Vacanti, recently reaffirmed his belief in STAP and along with his lab member Koji Kojima, published yet another STAP protocol this time detailing that the addition of ATP might help other labs make it work. I’m skeptical. I do find it fascinating that Vacanti still believes in STAP despite all the evidence to the contrary. Otherwise in the STAP news, it’s interesting to speculate that during his sabbatical that he may continue working on STAP.

Nature‘s role in STAP

I still think that Nature has not come to terms with its role in STAP. As has been said many times, no journal, editors, or reviewers can catch all problems in a paper, but given the released STAP reviews of previous versions of the STAP papers including one at Nature that wasn’t initially accepted and received pretty harsh reviews, it sure seems the overall review process at Nature should have done better. All things considered, I kinda doubt we’ll hear anything else from the journal on STAP. If the trend of a surging number of overall retractions at Nature continues, however, there may be more of an impetus for change.

Remaining STAP mystery: where did STAP cells really come from?

If acid and other stressors (now perhaps including electricity) do not really make pluripotent or totipotent stem cells, then where did the alleged STAP cells/STAP stem cells come from that seemed in the mouse assays to have pluripotency or totipotency? There have been some indications that STAP cells have a different genetic make up or transcriptomic profile than they were “supposed to” as the authors reported these features in the retracted STAP papers. Were STAP cells actually a mixture of ES cells and trophoblastic stem cells? Some kind of iPS cells? We still do not know.