New Interview With Masayo Takahashi (高橋 政代) on IPSC Trial: Guest Piece by Michael Cea

By Michael Cea
Stem Cell Analyst & Advocate
(editor’s note: piece was originally posted on Michael’s blog here; follow Michael on Twitter @msemporda)

 

Having followed closely the developments in programs using pluripotent based therapeutics I was fortunate during ISSCR2015 to have the opportunity to sit down with Dr Masayo Takahashi to discuss her pioneering efforts to translate Shinya Yamanaka’s groundbreaking iPS technology for debilitating retinal conditions.Masayo Takahashi

As most everyone is aware, the first iteration of the program, for advanced Wet AMD, has entered the clinic and been safely administered to the first patient – a milestone achievement for the field, which has been widely covered by the media, especially in Japan. However, as I learned first hand, this first step is but a part of a comprehensive strategy to address most retinal diseases by way of various cultured cell transplantation methods, depending on the patient condition – including suspension therapies and multi-layered organoid developed tissue. This was best described by Masayo “what I have said to the Japanese regulators is that ideally we need all cell types – sheets, suspensions, auto, allo – and the surgeons will choose which to use for each patient.”

Monkey stem cell RPEsBefore relaying the key segments of the interview, I wanted to express some thoughts of how practical and committed to the patient Masayo is. Her clinical practice is at the very heart of her professional vision – to bring relief to those that come to her for help. Disappointment again and again in not being able to help drives her passion for new therapies. She is both confident and open to the process that has already taken more than a decade and a half of her research. The goal being, in time, to have all the tools necessary to deliver on the promise to her patients and fulfill on that hope, that is very real and apparent today – something she couldn’t point to just a few short years ago. Her new message is very clear now “visual impairment is not as bad as they think and you can change that world – so there is hope – yes.”

Cheers

Interview:

Q: There is a lot of hype in the field how have you addressed that?

MT: When I started to do the regenerative medicine work the media broadcast our efforts and many patients came and they expected I could help them. But 10 years ago I was very nervous because after hearing the news they were disappointed in front of me so I started to talk to the media and educate. Every month we worked with media so gradually within this period they learned and suppressed their expectations so in Japan the hype isn’t so high anymore.

Q: Does the Internet makes things easier for patients to understand?

MT: People who can connect with the Internet can understand but the older people still don’t have access to the Internet and rely on the newspaper and TV but sometimes they’re informed wrongly as a result so I still struggle.

Q: Is that due to the technical language and complexity of the science?

MT: Common sense is different from the medical reality but the regenerative medicine area is very focused so we can use the media to inform the public correctly. Regenerative medicine won’t cure everything but if you think in a different way you can do many things. The “hope” should be the correct one. People need to learn the way of thinking of the scientists – in Japan people are very clever and gradually they have understood. So if you teach correctly they can understand gradually. It’s important to relay the correct information. Media sometimes tries to simplify as a need or belief in the communication method yet they lose the true message. Stem cells are a specific area with many unknowns – yes – it’s like a “black box.”

Q: You started using ES neuronal cells then moved to iPS and retinal cells

MT: Yes, a little background. I started in 2000 with ES cells and proved in mid-2000 using primate ES cells that we could treat some retinal diseases but we hesitated to move to the clinical stage because the risk of immune rejection. By that time iPS cells came out and I was very happy as I knew the last hurdle would be solved w/ iPS cells so we immediately started research using those cells and after 5 to 6 years of translational research in preclinical studies we started the 1st patient clinical application last September and we will judge the safety and effect 1 year later this September. We announced mid-term results in March and so far we don’t observe any immune rejection without any immunosuppression, which we expected as a result of using autologous iPS cells.

There was a famous paper in the journal Nature that the autologous iPS cells invoked immune rejection in a mouse model but I think the research design wasn’t very good. They transplanted kind of a tumor which would be rejected – not the iPS cells but the tumor.

Q: Was the surgery difficult for the lady (1st patient)?

MT: Yes the surgery was the most risky part. We were worried a little but the procedure was successful with no adverse events so far.

Q: And the next patient?

MT: We tried, we prepared but decided to go quickly to the allogeneic because the cells are already there from Shinya Yamanaka’s cell line stock. He made the 1st iPS cell line and they have come to our lab.

Q: Have they been approved as clinical grade by the Japanese regulators?

MT: Yes but about the protocol, we will apply within this year for approval. We should reapply as it’s allogeneic, different from autologous.

Q: Will this line be available to others?

MT: Shinya Yamanaka will distribute to various centers with one of the institutions being mine. So there will be a Spinal Cord Injury protocol, maybe the Parkinson’s disease trial will go to an allogeneic protocol, the hematopoietic (platelets) will also. So the various protocols will use that cell stock.

Q: Japan is moving very quickly, is that of concern in the community or is that in your mind appropriate?

MT: Most patients are supportive but some people worry we move too fast but really we prepared, labored and accumulated the data and the people who don’t know the whole data usually say you have the risk – that’s very stressful. So actually we don’t care what they say because they don’t know. Maybe it’s a social balance.

Q: Are you taking the trials overseas, outside of your home market?

MT: In the near future. We made a start-up company, Healios, they made an IPO last week, they plan to do a clinical trial in 2 or 3 years time in the US as they need the time to apply the protocol.

Q: I’d like to get your opinion on the use of a monolayer versus the selection of a suspension protocol.

MT: The people who don’t know the disease think the big sheet is the best but there are many, various situations with the disease, various stages, various lesion sizes, so some patients need a large sheet. Ours is 1 x 3mm, people in the US are preparing a 3 x 5mm sheet, so some people don’t need such a big sheet and earlier stage patients don’t require a big incision, so cell suspension is more feasible.

Q: What is your current disease state target?

MT: Advanced Wet AMD and we pull out the neovascular tissue, so a big defect of RPE, and cell sheets are appropriate but if the neovascular damage isn’t large we don’t want to cut and therefore cell suspension is better.

Q: The market is fragmented – is there a synergy with other programs?

MT: The regenerative medicine area is different than the small molecules, it’s more adaptable, so the judgment should return to the clinical scene and not the big pharma. The clinical reality will determine application and the Japanese government knows very well about this issue and we cooperated to make the new law. The Ministry of Health accepted that regenerative medicine is different than small molecules and that all is needed is a small number of patients to get approval, which is a great advance, a revolution.

Q: Is safety sufficient in a small population study?

MT: Of course the accumulation of the animal data needs to be reconfirmed by 10 or so patients for safety but the statistical significance of the efficacy needs more patients to prove the probable efficacy. Companies can sell the products based on smaller numbers so we don’t need big big pharma for promoting regenerative medicine. Companies can sell but they must register and prove efficacy within 7 years with regular exams. Success will be a collaboration between regulatory and academia with insurance reimbursement playing a commercial role which is incredible and kind of a risky law. The background of that is that academia promoted the regenerative medicine mainly so we cooperate very tightly with government and will decide where to provide treatment after approval with rules later.

Q: Do you plan enhanced cell products?

MT: Manipulated cells can work better, yes. So far natural cells are the most feasible, as regulators don’t like manipulated cells or “supercells.” In future but for now natural cells are good.

Q: Can you speak to the adult cell types?

MT: MSCs are safe. iPS/ES are hard to control so are limited to institutes that can maintain them/control them properly but the industrialization for a standard treatment iPS/ES is very good because we can have one lot otherwise many donors and always a lot of changes so that’s not very good industrially. In the future the ES & iPS cells people can control will be the way to industrialize and standardize treatment.

Q: What are your future plans / next steps?

MT: Our next steps are to have combined stem cell sheets – not only RPE but RPE with Photoreceptors and perhaps the vessel layer. Like a dream in our institute, that has a very high developmental biology focus, we talk about the whole retina with blood vessels and will try to deliver the entire retina for retinal disease conditions that destroy all the layers. For now we are working on monolayers, suspension, photoreceptors, combined layers and ganglion etc with 2016 for the allo, 2017 for the Healios overseas suspension and 2018 for the photoreceptors.

Q: Are you collaborating with other institutions – is that part of your plan, UCL for example?

MT: We are not actually collaborating. We have a communication and information exchange, like a think tank. We know how they promote and we are doing very well. We don’t have to hide. They use similar technology adapted from our work. The aim is to make a standard treatment.

Q: Is ownership not an issue?

For the company it’s an issue – I don’t care. Patients don’t care. Healios is very good and they are connected with the NIH group and the Ali group (UCL) – maybe they collect good procedures from the world.

Q: Are companies in Japan are looking at this sector as a team approach – does this help?

MT: Yes, society of regenerative medicine companies in Japan are maybe 100 companies now under the F.I.R.M association. Fuji, industry, pharma – all diverse companies. Not as a Keiretsu but more an association. Companies are now interested unlike 5 or 6 years ago. I told many companies to help us but they didn’t in the beginning but now they do. The government has helped a lot having supported the industry 10 years ago but they see the reality now as we have the clinical application.

Q: How do you see yourself, as a leader, role model – is there pressure?

MT: Shinya Yamanaka is like an Emperor now – everyone adores him. About the pressure, we have accumulated the data so I don’t fear anything. I have a scheme for 10 years plus and a plan. I know all – from the cells, the pluripotency, genes, animals, disease, patients and social and no worries only a process to move along. There are some against us but if I listen to their talks I’m not convinced by them, I mean persuaded, something wrong in their logic. As a role model – maybe I should behave myself! Patients happiness is what I believe – not papers or money, not interested. Patients first, outpatient clinic is very important to me.

Q: How do you view Lucentis/Eylea?

MT: Wonderful – we saw AMD 25 years ago and there was nothing at all. So we just explained the disease as incurable for 10 years but finally it came out, it was wonderful. We knew AMD very well and knew Lucentis wouldn’t cure everything. The treated patient had 10 injections before surgery and her condition deteriorated from 0.3 to less than 0.1 even though she had the available treatment, so we stabilized her visual acuity with radical treatment without any injection.

By way of disclosure: I have no conflict of interest, financial relationship with anyone or company mentioned in this article.

Interview with transhumanist Maria Konovalenko on the movement and human modification

Maria KonovalenkoThe transhumanism movement has been garnering attention lately for a variety of views including embracing aspects of heritable human genetic modification. Earlier this year I interviewed geneticist and transhumanist, George Church.

In this post I interview molecular biophysicist and transhumanist Maria Konovalenko. She is the program coordinator at the Science for Life Extension Foundation. In addition she has a blog.

Paul: Where does transhumanism stand today? Is it a growing movement? Who would you say are the top leaders in the movement?

Konovalenko: If we separate transhumanism from scientific advances, then I don’t think I see any significant chances recently. Although, Zoltan Istvan’s work makes an amazing impression. Zoltan managed to get the most media attention transhumanism has ever seen by declaring his candidacy for the President of the US. He has enormous potential.

I also don’t see powerful resources on the topic on the internet. It’s as if transhumanism is spread all over all media that write about the future. I’ve recently done an AMA on Reddit and I was quite frankly surprised how well the audience knew the topic.

Speaking of the people who could be most useful – that’d be the young billionaires of the Silicon Valley, but they are only mentioning living forever. No one has yet stepped forward and said: «We will do this and that in particular to reach the goal».

Transhumanism hasn’t yet found neither its unique way to enroll new members, nor the intellectual core of the movement.

That’s why my answer is no, it’s not a growing movement. Let’s call a leader somebody who is capable of bringing 5000 people in the streets or to crowdfund a project. So far there is no such person in transhumanism.

Paul: Is anti-aging just one element or strategy of transhumanism?

Konovalenko: First of all, anti-aging is a discredited term. Too many frauds used it. We are talking about reaching radical life extension and physical immortality. Of course it is part of transhumanism, in fact it’s the most important part. Our first goal is to stay alive. The second one is to improve ourselves and expand our capabilities. That’s pretty much it. That’s basically all what transhumanism is about.

Paul: I’m a stem cell and genomics researcher myself. Do you think stem cell technology and regenerative medicine have a role in transhumanism and anti-aging?

Konovalenko: Regenerative medicine is an important part of human longevity research. Therefore it is part of transhumanism. I actually am also studying stem cells, putting a review together on the role of mTOR signaling during aging of stem cells. I think therapeutic cloning and genetically modified stem cell therapy have a lot of potential.

Paul: What’s your view of other self-editing and more specifically gene editing technology’s use in humans, such as CRISPR-Cas9, as a means of making a positive difference? Would you say this is likely reflective of the transhumanist view of human gene editing more generally?

Konovalenko:I am for using any kind of safe technology on humans as a means of making a positive difference. Of course, it is crucial to adjust CRISPR-Cas9 for medical use. Generally, the point of view of transhumanism on gene editing is the following: let’s do it every time when it can be useful for us.

I should add that there is a myriad of CRISPR-Cas9 and applications. For example, we could create new biological systems in deserts, using genetically modified organisms we can reach incredible biodiversity. We could grow whole cities. We will certainly terraform Mars using GMOs. The most unbelievable fact is that we can actually start implementing this task right away.

Paul: Some people like to draw a dividing line between human gene editing in adults (e.g. gene therapy) and germline human gene therapy that is heritable such as correction of a genetic disease in a 1-cell embryo that could grow up to be a healthier person. Do you advocate for both of these kinds of approaches and think that line is unnecessary?

Konovalenko: Yes, I advocate for all interventions that improve human well-being. Is it actually inaction, not providing the help when it is possible, these are the things that I consider unethical and criminal.

6. What about using gene editing to make improvements on the human condition? These would not necessarily be for preventing disease, but rather for conferring “better” traits?

A great idea. Aren’t we constantly trying to improve ourselves with education and physical exercise? It is also an attempt to impact gene expression. It would be great is we could do this directly. You add a gene and boom!, you have an increased motivation towards learning. I would love that.

Paul: Is there a difference between transhumanism and genetic self-editing versus say the Eugenics of the past?

Konovalenko: I don’t quite understand what you mean by “Eugenics of the past”. If this is in any way related to eliminating people, then transhumanism is on the opposite pole. If we are talking about improving human condition of those alive today, then yes, it’s transhumanism. We are saying: “Let’s look for more effective ways of improvements”.

Paul: What are you most excited about in science today in terms of specific projects and technologies that can aid transhumanism?

Konovalenko: All advances of the human mind, breakthroughs in biology, chemistry, and physics inspire us. Although, in the first place the tasks of transhumanism lie in the area of social changes, in the area of politics. I am dreaming of seeing 2,000 people who came in the street to protect their right to live with a demand to increase funding the experiments in longevity. That’s when we can count on acceleration.

Paul: Anything else you’d like to add?

Konovalenko: Generally speaking, scientific progress in the area of aging research is moving forward quite successfully. I have a feeling that in 10 years we will have the first drugs that extend longevity. However, we have problems of a different kind now. The threat of the 3rd world war is staring us in the face. At any moment Putin, who is an autocratic leader who seems to have lost his mind, can press the nuclear button. We have to be able to create the technologies that can neutralize weapons leading to the death of the civilization and we have to do this in time.

Super stem cells meetings, & courses remaining in 2015

Stem Cell Meetings 2015

There are a whole bunch of wonderful stem cell meetings, conferences, and courses remaining in the second half of 2015.

If you are organizing (or just know of) another one and don’t see it listed here please let me know and I’ll add it in.

I’m starting to collect those for 2016 as well so feel free to let me know about those as well.

July

August

September

October 

November

December

Sexism in Science and Tim Hunt

Tim HuntSexism in science is a very real, big problem.

The Tim Hunt situation is just one example. For a reality check on that particular train wreck and background see this piece by Connie St Louis.

The sexism prevalent in science not only has negatively affected tens of thousands of scientists, but also is quite harmful to science overall and to society.

This sexism manifests at countless levels from words to policies to actions. It can be conscious or unconscious. It can be outright sexual harassment.

In Tim Hunt’s case, I find his words to be very harmful, but what concerns me more is that I believe that his words are an accurate window into his thoughts and mentality. He may have done some positive things over the years for some women in science such as his own trainees, but his particular brand of “man versus girl” mentality reflects a persistent and toxic world view. As a Nobel Laureate and leader in science, over the decades his sexist views may well have infected countless others and harmed many.

I don’t buy the “it was just a joke” attempt to walk it back. I’m not really buying the “this is an attack on academic freedom” gambit either when it comes to the push back against the reaction to Hunt.

Sure, social media can be a hell of a maelstrom and a very unforgiving one. I regularly find myself thinking about that reality as a science blogger and academic. Who isn’t worried they might say or write the wrong thing?  It would be nuts not to be awed and conscious over the power of that maelstrom to explode. At the same time, Tim Hunt himself is responsible for his words and actions. He has a special responsibility in his position and in that regard he failed. Was the reaction to his words an overreaction on social media or appropriate all things considered?

As much as this recent high-profile case has caused understandable concern and even some anger, at the same time there is the at least mildly heartening sense that the overall level of consciousness is increasing. Still is that already translating to major concrete outcomes that are positive and measurable? I’m not sure.

For myself I would say that today as compared to past years I am far more conscious of the gender make up of the committees that I serve on, the meetings that I go to or cover on this blog, etc. and aware of the possibility of unconscious bias on my part. I continue to be committed to the importance of diversity and equality in science.

Battling sexism and other discrimination in science is a long slog of a marathon, but I believe the efforts will pay off overall.

Landmark IPSC clinical study on hold due to genomic issue

IPSC RPE sheetThe pioneering induced pluripotent stem cell (IPSC) clinical study in Japan led by top stem cell clinical researcher Dr. Masayo Takahashi has been stopped reports the WSJ in Japan. This development is confirmed by other sources and in a PDF report by RIKEN (in Japanese here).

One patient was transplanted in September 2014 with their own IPSC-derived retinal pigment epithelial cells (using an innovative RPE sheet, see image) for treatment of macular degeneration.

The study then moved on to a possible second patient, whose IPSC did not pass a genomic validation step. Reportedly, these IPSC contained a mutation, potentially in a known oncogene, which is a serious concern. Thus, the team decided to at least temporarily suspend the trial pending a possible redesign. The new plan could involve a change in how the IPSC are produced. For example, the team is reportedly considering the possible use of allogeneic IPSC as well, which could come from CiRA (Center for iPS cell Research and Application, Kyoto University).

It remains unclear at this time whether the mutation in the second patient’s IPSC was pre-existing in the patient’s skin cells or if it occurred during the reprogramming process itself. This is a critically important question to resolve. If the mutation was caused by/associated with reprograming then that would be a deeper issue.

Overall, this situation is of course a concern, but it also reflects the very rigorous and appropriate degree of caution that this team was using in validation studies. Notably, the first transplanted patient is apparently doing well.

I hope to learn more details from Dr. Takahashi and will pass that along on the blog when possible. She has also been tweeting about this development (you can follow her at @masayomasayo). Until we learn more it is advisable to take a cautious approach in interpreting this development.