Top takeaways from new Yamanaka (山中伸弥) stem cell interview

Dr. Shinya Yamanaka

Dr. Shinya Yamanaka. Photo from CiRA, Kyoto University

Shinya Yamanaka is one of my favorite fellow scientists. His research is creative and rigorous along with having huge clinical implications. At the same time, Dr. Yamanaka sees the big picture and he’s very open about talking about real life as a scientist. I really appreciate both levels. In the past I interviewed him for my blog on the clinical use of IPS cells.

In a new interview with Yamanaka by The Japan Times, he says quite a lot of important things. The field should take note. Below I’ve listed the top bullet points from the interview. Note that he also talks about his father in a touching way and his own efforts to stay healthy with running.

  • Clinical outcomes from IPS cells are going to be broad. “We are now trying to bring iPS cells to patients suffering disease, for example, Parkinson’s disease, Type I diabetes, cancers. I believe that in the next 10 or 20 years, we can come up with many new treatments and therapies by using iPS cells and other related technologies.”
  • Difficulties and challenging times can be a foundation for future success in the biomedical field for scientists. Asked about struggles as a surgeon, Yamanaka said, “The answer was to become a medical scientist. I decided to contribute to medicine and patients in a different way, not as a clinician but as a scientist.” He also talked about challenging times during his training in the US and how things turned around, “in late 1998, human embryonic stem cells were reported for the first time. That was a big hit to me because we could help thousands of patients by using ES cell-derived brain cells or heart cells. That really activated me again. This is one reason how I overcame scientific depression.”
  • The current shift away from autologous use of IPS cells in Japan explained. “…we learned that autologous transplantation is very expensive and also it takes a very long time, at least six months…I think that, for the next five or 10 years, instead of autologous transplantation, utilizing iPS cells from healthy volunteers is the way to go. Such tissues generated from others are called allografts. By utilizing allografts, the cost can be much lower. We can also prepare cells [for transplantation] in advance…While there are many advantages of using allografts, the downside of using iPS cells from non-patients is immune rejection.”
  • Developing the IPS cell bank. “On the basis of a database of all Japanese HLA types, we have calculated that all we need is 140 lines (donors) in order to cover more than 90 percent of all the Japanese population.”
  • Anticipation returning to autologous IPS cell use in 5-10 years.
  • Skepticism on some working toward human immortality. “I don’t think that it will come true. On the other hand, we are trying to expand our “healthy life expectancy.”
  • How to avoid another STAP cell situation. Asked about STAP and misconduct cases, Yamanaka said, “I believe our area, the stem cell field, is very competitive. As many of our research results can lead to medical applications, many people like venture capitalists, venture companies are paying attention to us. That’s maybe one major reason how this kind of problem happens multiple times in our field…after the STAP scandal in 2014, more and more scientists in our field have become very careful. The No. 1 keyword for us is “reproducibility.”

My top takeaways from #WSCS15 so far: IPS cells, #CRISPR, CAR-T, Patients

Mahendra RaoIt’s been a great couple days so far here at the World Stem Cell Summit in Atlanta. You can follow it on Twitter using the #WSCS15 hash tag. S.

I first attended it 5 years ago in Pasadena. One of the special aspects of WSCS is it brings together diverse stakeholders in a way that just doesn’t happen elsewhere. For instance, you can have the FDA, patients, physicians, scientists, and funding agency people all in one room together.

Some strong impressions so far include the following.

IPS cells. There is a great deal of excitement here about IPS cells of course, but Mahendra Rao providing a more sobering perspective. I’m more optimistic than he is. Here are his six “realities” of IPS cells, which I interpreted as his view of the top challenges.

  • Allogeneic therapy is not going to work unless HLA matched.
  • HLA matching requires a larger number of patients.
  • There is not enough cGMP capacity to make all the lines required.
  • The cost of making a line and the time required to make one make this an expensive therapy and probably not useful for a large number of diseases.
  • Cells may not be mature enough for use even if one could solve all of the above problems.
  • No real model for true autologous therapy where manufacturing is involved (no amortization and no comparability).

CRISPR and human germline modification. I was on a panel yesterday on human germline modification that I enjoyed a great deal. I was on the panel with Aubrey de Grey and Aaron Levine, who both gave fantastic talks. The audience asked spot on probing questions as well. There was some disagreement regarding the appropriate level of urgency for developing policies and/or regulations on human germline modification, but overall my sense was that us three panelists perceive that attempts at CRISPR-based human heritable modification are almost certain to occur in the near future.

There’s real promise for CRISPR-based therapies in the future for rare genetic diseases (not to mention all the great in vitro CRISPR research on humans cells in the lab that should continue), but to get from point A where we are now to point B where we might as a field hypothetically be ready to responsibly use CRISPR in the germline for humans is a long road. Thus, irresponsible clinical attempts in the next few years would be very dangerous and could be harmful to the field and society.

Still, patients in the audience passionately pointed out that in many cases there is a profound need for helpful therapies now and in the immediate future. That “patient drive” as it was termed at the Washington DC meeting last week on human germline modification is powerful and must be part of the discussion.

Innovation in brain cancer treatment including CAR-T. We also heard earlier about transformative approaching such as stem cells loaded with toxins and CAR-T therapies for cancer. Very exciting stuff!

Patients and stem cell clinics. In a session today that I chaired, we heard much more from patients. They articulated better than anyone else could about how difficult it is to get reliable information. How does one know if a certain therapy is legit, safe, and worth getting? Where are sources of information? I’d recommend some of the websites list in the link section of this blog (scroll down the right side of the page).

Dr. Steven A. Davis, co-founder of SymBioSys, Inc. gave a great talk using the example of the Texas stem cell clinic CellTex, now operating in Mexico, as a test case and as a way to introduce the key issues that need discussion more broadly. We then spent a good 45 minutes have questions and discussions. It’s clear that there are many gray areas and difficulties in this arena.

The leader of the Mexican Stem Cell Foundation (unfortunately I didn’t catch his name, but if I find it I will add it in here later) gave some helpful context for understanding where things stand in Mexico. His sense was that the Mexican equivalent of the FDA (COFEPRIS) is not currently equipped to carefully evaluate all the stem cell clinics there (often clustered on the border and catering mainly to American patients). However, he did indicate that his perception was that things are improving.

Overall. I have to thank Bernie Siegel, who is the organizer of this amazing meeting, and his team at the Genetics Policy Institute (GPI). They do a phenomenal job every year on the WSCS.

More talks are ongoing right now including a fascinating one on cord blood and its potential use for neurological disorders….stay tuned.

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 also 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 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 in contact 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.

Was Fujifilm CDI acquisition a good move by the companies?

The big stem cell news already this week is the acquisition by Fujifilm of Cellular Dynamics International (CDI) for a whopping $307 million dollars or about $16.50 per CDI share. You can read the press release here.

It was less than two years ago that CDI did its IPO with an initial offering of about $46 million.Cellular Dynamics

Fujifilm reportedly has a multibillion-dollar war chest for buying into the life sciences sector and a growing interest in regenerative medicine. Note that there’s some fun, but perhaps over the top speculation going on in terms of whom they might snap up next.

CDI is an unusual company in the sense that it began about a decade ago with a very sexy idea of using human pluripotent stem cells to cure disease, but now as xconomy.com refers to it is focused more in the “unsexy” business of manufacturing cellular products from stem cells.Fujifilm Logo

Although the production side of regenerative medicine may not sound very innovative, it turns out that the reality is that making high-quality, functional, and pure differentiated cell products from pluripotent stem cells is no easy task. Throw in making such products from human induced pluripotent stem cells (IPSC) and it starts to become very exciting and important.

So was this a good move by Fujifilm and CDI?

Good news for the stem cell/regenerative medicine field overall?

My sense is an initial “yes” all around overall, but with some remaining questions.

If Fujifilm wants to grow a presence in IPSC and more generally the regen med arena, it now has made a big step forward. CDI has worked with CIRM, NIH, and a number of biotech companies. Again, the process of making the “real deal” pure, functional cellular products from IPSC is very important and valuable. The evolving CDI “superdonor” IPSC bank is very cool and could have huge value.

Perhaps something we could learn more about is how Fujifilm will make use of the unique IP of CDI specifically. Also how does the fact that CDI has to license IPSC technology via the Yamanaka Patents come into play? What about the overall price tag just over $300 million?

From the press release comes the Fujifilm perspective:

Commenting on the transaction, Shigetaka Komori, Chairman and CEO of Fujifilm, said, “We are delighted to be able to pursue the business from drug discovery to regenerative medicine with CDI, which develops and manufactures iPS cells. We have optimal scaffolding material, ‘recombinant peptides’, for cell generation and technologies useful for regenerative medicines such as material science and engineering. Our group company, Japan Tissue Engineering, markets regenerative medicine products in Japan. By welcoming CDI to the Fujifilm Group and by combining the technologies and knowhow of both companies, we will seek synergies and efficiencies to be more competitive in the field of drug discovery and regenerative medicine.”

From a CDI perspective, this seems like a major win for their team, who will benefit greatly financially from this deal. Although Fujifilm intends to maintain CDI as a Wisconsin-based subsidiary, as xconomy.com points out it’s not clear what this deal means for the employment of the 150+ CDI workers there longer term. “Synergies” and “efficiencies” after an acquisition can mean reductions in employees. It seems likely that Fujifilm will continue the momentum of CDI and help to give clinical meaning to the efforts of the CDI scientists:

Robert J. Palay, Chairman and CEO of CDI, added, “CDI has become a leader in the development and manufacture of fully functioning human cells in industrial quantities to precise specifications. CDI and Fujifilm share a common strategic vision for achieving leadership in the field of regenerative medicine. The combination of CDI’s technology with Fujifilm’s technologies, know-how, and resources brings us ever closer to realizing the promise of discovering better, safer medicines and developing new cell therapies based on iPSCs.”

For the field overall, this deal is good news. It would seem a clear, strong indicator of the great, concrete value of regenerative medicine and cellular therapies. Nearly a third of a billion dollars is nothing to sneeze at. Notably, this is not about clinical trials or that kind of specific pipeline, but more about concrete cellular products and technology. That’s an important distinction because in this sector oftentimes most of the value and growth emphasis is placed on rapid bedside potential.

Disclaimer: this post is not financial advice and the author has no financial interest in either company.

Can Hearts Repair Themselves Via Stem Cells: More on Hot Topic

Can hearts repair themselves via stem cell-like mechanisms?

Sometimes what we scientists all know to be true turns out later on to be wrong and there are clear instances of this in the stem cell field.

For example for decades the dogma was that the adult mammalian brain did not have stem cells, but now everyone knows that the adult brain does have stem cells. What we perceive as factual can change over time.

Yamanaka disproved the entrenched notion that differentiated cells were permanently locked into that differentiated state with his revolutionary findings on induced pluripotent stem cells.

Today the cardiac stem cell field finds itself at an interesting crossroads with a hot, controversial question:

Can damaged heart muscle repair itself via stem cells?

heart stem cells

Some say “yes” there are cardiac stem cells and that they can mediate repair. Others feel just as strongly that there are not such cells.

I recently asked cardiac stem cell expert, Deepak Srivastava for his thoughts on this in a previous post and found his answer compelling.

My sense is that the view that there are some heart stem cells, but perhaps not enough to mediate significant repair predominates today. That’s my current view too.

You can see the diversity of papers in PubMed with “Heart Regeneration” or “Cardiac Regeneration” or “Cardiac stem cells” in their titles.

It seems that a lot more people believe that there are a small population of cardiac stem-like cells (perhaps mobilized and/or reprogrammed by injury) than support the bolder notion that these cells can mediate clinically significant endogenous repair of the heart.

One of the biggest advocates of endogenous cardiac stem cells and repair, Piero Anversa of Harvard and Brigham and Women’s Hospital, has become one of the most controversial as well. His papers have come under fire and one has been retracted. Anversa is the subject of a Harvard investigation and is suing Harvard for how it has conducted the investigation and other matters related to his work.

Could his work still be right that hearts can indeed repair themselves? At this time I am very skeptical.

Still there are glimpses of interesting stem cell activity in the mammalian heart.

A November 2014 Cell Stem Cell paper from the lab of Juan Carlos Izpisua Belmonte, entitled “In Vivo Activation of a Conserved MicroRNA Program Induces Mammalian Heart Regeneration”, argues for endogenous mammalian heart regeneration in part via dedifferentiation of cells into stem-like cells. You can take a look at its graphical abstract above.

Even if the endogenous stem cell-like activity in the heart is not enough usually to mediate clinically significant repair, the good news is that by deciphering the molecular basis of this activity the field could still open the door to powerful new treatments for heart disease. For instance, if the heart naturally replaces 1 in 200 cells per year, perhaps cardiac researchers can find a way to boost that by an order of magnitude with a drug and have a meaningful impact for patients.