Recommended weekend reading on stem cells & science

I try to catch up on my science reading over the weekends and evenings. Here’s my recommended weekend reading on stem cells & science.

Did I miss anything especially cool? Let me know in the comments.

Direct reprogramming of skin cells into insulin-producing cells. I love direct reprogramming.

Healios and Athersys Enter Into Regenerative Medicine Partnership. Can they together create regen med success?

National honor for helping “the blind see” comes from CIRM blog.

human animal chimeras

Fun piece on CRISPR language by Ben Zimmer. ‘Crispr’ Breaks Out Of the Lab. If you don’t know what a backronym is, you should be interested in learning more.

Big claims here for zero off targets for a next gen CRISPR system. Zero is a very small number, eh?

The gut microbiome of the 5,000 year old frozen dude turn out to be a goldmine of sorts of info. Nice piece by Carl Zimmer, Ben’s brother. OK, what did these two brothers who are unusually great writers eat while growing up? Wheaties? 

George Church on The Late Show with Stephen Colbert. Wonder what Letterman would think of George’s Top 10 List for genes with interesting phenotypes in humans? See my interview with Church for that list and a lot more interesting perspectives.

Human-animal chimeras, Antonio Regalado, tells us in a nifty article are currently gestating on farms (image above from that piece).

Ed Yong writes that CRISPR’s most exciting applications are in gene transcriptional regulation (admittedly a cool area) rather than in genetic modification. Great piece, but I disagree with the superlative.

Michael Cea’s conversation with Jeanne Loring: frank views on all things stem cell

By Michael Cea

Jeanne Loring of the Scripps Research Institute in La Jolla, California kindly sat down with me at the ISSCR annual meeting for a broad discussion of her history, views on the field and developments in the science.

I found Jeanne a refreshing character, as I did a number of others I was fortunate to meet in Sweden. Her style I can only best describe as natural. It must be the Southern California air or something but there is a definite quality of relaxed confidence about her. I liked her a lot and hope to have the opportunity to meet her again sometime – perhaps at the birth of her “to be” Northern White Rhino! If she invites me 🙂 that would be something.

The format of the interview was free flowing and what was clear to me from her long standing scientific focus and deep knowledge of the sector was it takes determination and a varied set of skills to maintain one’s position in today’s fast paced world of cutting edge science and more so even to successfully translate that to the clinic.Jeanne Loring

Kudos to Jeanne for her efforts to continue the fight to bring forward a therapy for Parkinson’s after near on 30 years and for her passion to help our planet’s most endangered.

Hope you find the interview interesting, as much as I enjoyed it.

Cheers

Interview:

M: Tell me a little about your background

JL:  I was trained in embryology and neurobiology, I studied neural crest cells, which are actually stem cells and I was fascinated by them. Then when I finished graduate school I got a job as an assistant professor at the University of California Davis and I then realized I could either teach or do research but not both. There were not enough hours in my day, so I took the opportunity to join a biotech company in California called Hana Biologics. There were lots of companies around in 1987. I joined specifically because they were planning a stem cell therapy for Parkinson’s disease. I was getting a little bit tired of generating just knowledge. I wanted to generate practical knowledge, which made me a little bit different from most biologists at the time.

Lewy_Body_alphaSynuclein

Lewy Body characteristic of Parkinson’s

M: Was that motivated by personal experience?

JL: No, I didn’t know anybody who was sick at all; it was just I wanted to have more impact than just writing papers. I wanted to do something more important. When you go into biotech there’s a high probability that you’ll not be at the same job for more than 5 years. I didn’t know that at the time but I’ve learned it now- it’s good for learning how to survive. The first company I went to work for (in the late 1980’s) was developing a cell therapy for Parkinson’s disease, but there were no pluripotent stem cells yet so we were using fetal cells -trying to expand them. That was the heyday of the fetal transplants for Parkinson’s disease and it was clear they were working for some people, so why couldn’t we take fetal cells and expand them and treat more patients?

M: I attended the pre-meeting symposium @ Karolinska on the aging brain. The eye and brain are related of course but the brain is less accessible.

Lewy Body characteristic of Parkinson’s. Image from Wikipedia.

JL:  The eye is accessible; therefore it is a good testing ground for therapies. Once you put things in the brain you pretty much don’t know what’s happened until the person dies.

M:  Why did the fetal work not continue?

JL: There were two main efforts – Andreas Bjorklund of Karolinska/Lund and two groups in the US who were funded by the NIH to do clinical trials. I think the people in Sweden will always argue that they had a better success rate. The researchers In the US were required to, or decided to, do a double blind clinical trial to assess placebo effects.

M: And surgery?

JL: Yes, they did sham surgeries for the double blind trial.

M: Isn’t that unethical?

JL:  I would never do it but it was the expectation of the NIH-funded trial. The patients did have the promise of treatment if they were part of the control group.

M: You mean opening them up again?

JL:  Yes, but the people who routinely do brain surgery don’t take this issue as seriously as I do, and they know what they’re doing.

To continue, the problem was that maybe 25%-30% of the patients, depending on the study, had an adverse effect that was quite dramatic, called dyskinesia. When they got the cells they had Parkinson’s disease, which was treatable with L-Dopa, but then after they had the cells they started having uncontrollable events, like the opposite of that sort of frozen kind of characteristic of people with Parkinson’s disease. They had to be treated separately and it had obviously been caused by the transplant. The question was…

M: Why?

JL: Exactly. The fetal cell therapies stopped in about 2003. I remember I was at the Society of Neuroscience meeting when the results were discussed and everyone in the room was saying… we can’t do this anymore.

M: But 75% of the patients were…

JL: Were either not helped or they were helped for the rest of their lives and went off drugs. So it was clearly a spectacular therapy.

M: This was so early, late 80s early 90s, wouldn’t you think that with more push in the science?

JL: Everything sort of dropped off the map at that stage and people just didn’t pursue it anymore.

M: Was it ethically charged?

JL: The question was: do you want to do something to people that has a clear probability of an adverse effect? Parkinson’s disease is not a life threatening disease.

M: It is a debilitating disease.

JL: Yes, it is a debilitating disease.

M: I have a relative that has Parkinson’s, in my wife’s family, and it’s not just the disease it’s what it does to you aside from that. Your whole spinal column changes and that makes everything more painful and difficult.

JL: Everything is more challenging and you can never predict whether you’re going to have a good time or bad time today or this morning or afternoon. I have a friend in Texas who has Parkinson’s disease – I talk to him on the phone every once in a while and it has to be at a particular time of day. Otherwise I can’t understand him at all.

M: Devastating disease, all the neuronal diseases are devastating.

JL: That was the whole basis for my Parkinson’s disease focus, after there was a resurgence in interest when human pluripotent stem cells were made. We can turn these cells into real dopamine neurons and do just what we want with quality control.

M: This was the question I had at the brain symposium, why wouldn’t you test the neural stem cells themselves as a method of action and let them stimulate the environment.

JL: People have tried that. There was a whole interval where people were trying to treat Parkinson’s with cells that were not dopamine neurons. Actually it damaged the field because it didn’t work and turned organizations like the Michael J. Fox foundation, an organization that had supported it, against cell therapy entirely. They’re not funding cell therapy now.

M: Were those stem cell originated?

JL: No, this was all before pluripotent stem cells were available. They were either adult cells or fetal derived stem cells, and they didn’t become dopaminergic neurons.

M: Isn’t there a big difference in terms of your understanding of the pluripotent sources in terms of that?

JL: Of course. There’s a huge difference. The cells you get from an adult or fetus have not been successfully turned into the same neuronal cell type that dies in Parkinson’s. They don’t seem to be able to.

M: So what about the pluripotent neural stem cells?

JL: Neural stem cells from brain aren’t pluripotent- they can’t develop into all cell types. We use pluripotent stem cells to make neural stem cells, which we then turn into dopamine neurons.

M: Ok

JL: So my next job, because fetal dopamine neuron precursor cells couldn’t be expanded, was to work at a company called GenPharm. This was in the early 90s and we were doing gene knockouts and deriving mouse embryonic stem cells so I got to be at the beginning of one field and the beginning of another field. That company lasted about five years. https://www.gsb.stanford.edu/faculty-research/case-studies/genpharm-international.

M: What technology did you use?

JL: Using homologous recombination, which was a brand new idea at the. Mario Capecchi, who was a scientific advisor to the company, won a Nobel Prize for it in 2007. I like being in the situation where the technology I’m using wins Nobel prizes for people. I kind of think that validates it. We could just about do anything. We could knock-out genes and we could change genes. This was all pre Crispr-Cas, which is the way people are doing it now. So that was early days for that as well.

I made a lot of mouse embryonic stem cell lines. This was the same time as Austin Smith and Rudolf Jaenisch were using, making and knocking-out genes in mouse embryonic stem cells. That’s where our histories all overlapped; we were all doing this in the early 90s, although I was at a company, and they were academics. It was a spectacular five years and we did a lot of amazing work. The work I did then is still some of the most highly cited work that I have ever done. It was really pioneering and it was fun. Then after that company failed (most of them do), I moved on to a company called Incyte Genomics. This was at the peak of the human genome sequencing era, which started around the mid-90s. I worked at Incyte for around 5 years learning how sequencing worked.

M: Uncovering the map

JL: Yes, and the technology was evolving very fast at that time. So I now had three things I knew well – the Parkinson’s neural cell transplant idea, embryonic stem cells and now genomics/DNA.

M: This all was at the same time as the other groups but your work went unheralded?

JL:  It was not a big deal- if you’re going to be heralded you have to stick in one field for a long time. My approach has been to learn something then learn something else and try to put the two things together.

M: and it’s all coming together now?

JL: It is, everything I’ve done is coming together now.

M: Tell me about that, because that’s why you’re back.

JL:  That’s why I’m back. Regarding Parkinson’s disease – we now have human pluripotent stem cells that can be turned into dopamine neurons, so all the things that were wrong with the early work I was doing in the late 80s I can now fix.

M: You’re independent in an academic setting now.

JL: Yes, I’m an academic with my own lab. I have the Parkinson’s history and I have the mouse embryonic stem cell history, which Austin and Rudolf share. You know it’s interesting people who come from a mouse embryonic background and then started working on human ES or iPS cells have been really annoyed that the human cells don’t act like the mouse cells. They’re much harder to grow. So both Rudolf and Austin have been trying to turn human pluripotent stem cells into cells like the mouse.

M: Is this kind of an internal debate?

JL: Yes, this is what they’re focused on now & intensely competing with each other over whether you can make human cells with the qualities of mouse cells. I’m not involved- I just went straight to human pluripotent stem cells and realized they were not going to be like mouse and lived with it.

M: Is that because of the quality and body of evidence in the mouse?

JL: Yes, the history is with mouse ES cells and the kind of things you can do with them. They’re much more robust than human pluripotent stem cells. Human embryonic stem cells have to be babied, but mouse ES cells you can pretty much leave in an incubator and they’re fine. The researchers have moved in the direction of trying to make hESCs be like that.

M: To perform better?

JL: Yes, so that then can take all those techniques they used in the mouse and now apply them to human. As I said, I’ve just bypassed that. My cells can become what I want them to become and that’s it – I’m done. They don’t need to be like mouse cells.

To continue, while I was still at Incyte I started a company and made a bunch of hESC derivations that were on George Bush’s original list.

M: From IVF donations?

JL: Yes, that’s right. I started a company, so I did it in my own company. There were 3 employees. I was the scientist and I had an assistant.

M: You had a number of lines. What ever happened to those lines?

JL: Well, they got acquired by another company and I have no idea, they’re probably still in the freezer somewhere. They never did anything with them. But it’s not important any more as there are so many lines out here. There are 300 lines or so on the NIH registry of lines that can be used in federal grants.

M: And they’re sufficient to do the science work?

JL: Yes. But my lab doesn’t work much on hESCs anymore. We work with iPSCs because they are equivalent to hESCs and you can get them from individual people. This is where my genome experience comes in because I learned sequencing and genomics when I was at Incyte, so I had an appreciation of the methods used to study the genomes of cells.

M: The translational aspect of what you’re working on is focused on Parkinson’s as a primary program?

JL: Yes. There are a lot of reasons for it. The person who came to me with the idea to do a therapy for Parkinson’s disease is the head of the movement disorders clinic at Scripps Health, which is across the street from me. She thought there ought to be a stem cell therapy for Parkinson’s disease and together we did fundraising to start the project. We want to do a personalized therapy, an iPSC therapy, and genomics is very important as we want to have quality control throughout the process of developing a therapy.

M: This is your approach to it?

JL: Yes. One of the things we’ve learned from studying pluripotent stem cells is that they acquire mutations if they spend a lot of time in culture. You don’t want to put cells with dangerous mutations into people, so that’s where genomics expertise comes in, essentially in assuring the quality control of the cells we want to transplant.

M: Is that the same risk factor in regard to hESCs?

JL: Yes, they will do the same thing. In fact everything we’ve done to date shows that iPS and ES cells are identical. Our approach has been to analyze lots of cell lines, not just one, to learn what to expect from cell lines in general. Almost everything we’ve done was done on 100s of cell lines so we can come up with general principles.

M: I remember you putting out a paper on this recently that was very exhaustive – 2 years of work

JL: Yes, 2 years of cell culturing. The scientist I worked with on that is here at the meeting – I’m going to take him to lunch tomorrow. The whole idea was to try to come up with things that were generalizable to cell lines and different conditions.

M: So if you use 1 cell line that is on the edge of a uniform grouping that will be different than if you select and productize something else within that sequence?

JL: Yes

M: and that’s where we’re at?

JL: Yes, right now. Here’s the challenge. If you have different cell lines we know they’ll have some diversity. They act a little bit differently, a lot due to the personal genomes, of course. The challenge we have is to develop technologies and quality control methods to allow us to know how every one of those cell lines becomes the same thing every single time.

M: Is that a far reaching goal?

JL: I think it’s actually going to work pretty well. A lot of this has been developed already. That’s been a high priority all along. Some people think it’s never going to work but I don’t believe that.

M: Is RNA a part of that process?

JL: Yes, absolutely.

M: So the work presented recently by Yamanaka will factor into this.

JL: Yes. The way we make the cells is important – we’ve investigated that. How you reprogram the cells so that the cells aren’t harmed.

M: Is that Sendai?

JL: Yes, that’s right. We’ve done whole genome sequencing on a lot of cell lines and we’ve discovered that using Sendai vectors for reprogramming is benign. The other methods are also benign, which is important to keep in mind.

M: So looking at this from a cost perspective, autologous patient specific treatments are highly personalized but are highly expensive. Is that part of the process strategically?

JL: Yes, that’s right. It’s part of the process. There’s a lot of discussion on personalized therapy and whether it’s worth the cost.

M: Of course, if it costs $1 million dollars how many people can actually be treated?

JL: Well, more than you think. It turns out for cancer treatments the amount of money that people are paying is similar.

M: Is this about annuities, is that where we’re going?

JL: No. Somebody needs to figure out how to have insurance reimburse for therapies. Right now we’re not worried about that yet. But I can see how it’s going to work because the work that’s being done now with T-Cells, CAR-T therapeutics.

M: I wrote about that 3 years ago.

JL: There you go. That’s about how much it costs for what I’m doing and yet there are multiple companies developing this technology now that it’s been shown to work.

M: There are many now but there were none before.

JL: Well I remember the first time I heard about it I thought I had no idea you could do that. I didn’t know the immune system could do that.

M: The immune system is a powerful force to employ.

JL: Yes it is, and that’s one of the reasons we’re using autologous therapy. We want the cells to be matched and don’t want them to be rejected.

M: Isn’t there a movement towards allogeneic?

JL: It’s hard to say. Yes, probably because of the effort in characterizing cells, but let me put it this way. As soon as we demonstrate we can make the same cells from 8 different patients and they all work, then the story’s over. Autologous therapy and the price point will be worth it. It will be like CAR-T therapy. It will be what you have to do for the best possible therapy.

M: Wouldn’t you want to test an allogeneic source?

JL: I don’t want to as others are doing it. I’m going to let them go ahead and do it.

M: and who are those others?

JL: The Studer Lab in the US. Actually there’s one other autologous therapy which is being done in Japan by Jun Takahashi.

M: Coming out next year.

JL: Yes, his and my projects are very similar. We’re trying to collaborate but I don’t think it’s going to work, as it’s almost impossible to exchange materials between the US and Japan.

M: Really I thought we were friends in many ways.

JL: We are but when it comes to scientific IP, it’s very hard.

M: They do want to license a lot of their underlying technology, Japan Academia, Healios.

JL: and I would be licensing it if I were a company but I don’t have to as an academic and that’s another strategy of mine.

M: Don’t they have underlying patents?

JL: Oh yes, and if I decide to commercialize what I develop I’m going to have to license patents from Japan. But I’m going to worry about that later. I know a bit about patents too.

M: I remember that.

JL:  I think we have a good strategy. The thing is you can never be certain, but the science makes sense, the strategy makes sense.

M: To be clear on this patent issue – you don’t need a license to do clinical trials.

JL: No. I don’t need a license to develop anything, as long as I’m an academic and I’m not commercializing it,

M: The concept is Japan Academia is licensing for research purposes because they deliver a package.

JL: Yes – and I don’t need it yet because I’m a non-profit. They will license their technology for research purposes to companies but they won’t let anybody sell the iPS cells.

M: The process of development can happen independently using Sendai without a license.

JL: Yes that’s correct. I was in biotech and I was affected rather negatively by patents at times. I remember this very clearly: my friends and I wanted to challenge the WARF patents that gave them ownership of all human embryonic stem cells, and we worked on this for many years. The patents expired just before we asked the Supreme Court to hear the case for overturning the patents, and they declined to hear it. When I became an academic, as I liked to say to the WARF attorneys as many times as I could, I had the freedom to operate and not require a patent from them to do embryonic stem cell research. Our patent challenge was very interesting and very educational; as a result of our challenge, WARF narrowed the claims of their patents to limit them specifically to embryonic stem cells. Their original patents claimed all pluripotent stem cells, so if we hadn’t challenged the patents, they could have retroactively claimed iPSCs.

M: There are a few words in there which are specific to embryo derived.

JL:  What happened was, we challenged the patents, the patent office rejected all of them, and in order to get the patent office to reinstate them they had to change the language for their primary patent.

M: It was their intent in the first place.

JL: I think we caught them by surprise. I met some really great people as a result of the patent challenge. The attorney who was with me was the same attorney who brought the challenge to the Myriad patents. He was at the Supreme Court for that case and I went to the Court to watch them argue that case.

M: Interesting isn’t it?

JL: It was fascinating

M: The legal system is a world apart

JL: It’s so bizarre

M: Somewhat like the science world?

JL: No, well in theory yes. What really struck me was the fact that the Supreme Court justices, and I think lay people, need metaphors in order to understand science.

M: They do and communication from science to the world is vital as the boxed view of old school scientists just doing experiments to publish needs to change.

JL: I don’t know why people would do that, to tell you the truth.

M: I think there is a value. My curiosity brought me here. So I think there’s a great value in curiosity and the maintenance of that throughout your life

JL: I agree.

M: I like that analogy the Salk Professor, Rusty Gage, presented. He spoke of a running an experiment where brain cells develop due to vitality, even in disease states. I’m not sure how a Parkinson’s patient can actually get on a treadmill but….

JL: Exercise does help Parkinson’s patients, physically and mentally. Our funding mechanism is patient advocacy based, a partnership with patients.

M: I’m not aware of your funding mechanism.

JL: The funding comes from a private foundation that we started to fund this project

M: I remember this – just recently you did a drive. How did that go?

JL: It’s gotten enough money to get us to the pre-IND stage.

M: Did CIRM ever come in?

JL: CIRM will come through the next round, I believe. We’re certainly going to apply for CIRM money. We’ve been working up to this for a long time. The patients have been going to CIRM meetings so we can educate the panel about the importance of this.

M: How far are you away from the IND

JL: About 2 to 3 years

M: That’s pretty similar to some of the others – Malin Parmer for instance mentioned 2018. Of course the Japanese are coming on fast next year.

JL: They’re on a fast track – there are some positives and negatives about that.

M: Tell me about that. There is I guess a Japanese societal push, an industrial push. They have a tendency to like to do that in industry and it’s been beneficial in the past. Do you see that as a mechanism to dominate?

JL: Yes, absolutely.

M: and will it open up things potentially or will there be a downfall?

JL: The good thing as far as I’m concerned, is if Jun Takahashi gets his therapy through the regulatory agency, he gets to transplant his cells to people and they’ll be doing that before I do. It’s unlikely that our FDA will let me do it sooner. So if nothing bad happens to the patients in Jun’s study, that will help me. However, if somebody else pushes through a therapy because of this fast track, a scientist who are not as careful as Jun Takahashi, there could be issues. Stem cell therapy, just like everything else, if it is strongly promoted, can have setbacks. In Japan we saw what happened with the STAP problem. As soon as there’s a lot of pressure from the Japanese society and Government to move forward there are going to be people that make mistakes. There will be people who are not careful.

M: Masayo Takahashi is trialing iPS cells.

JL: Yes and she has published preclinical work. Essentially she is trying to show equivalency of iPS to ES cells. I think that’s very important, as the FDA is still worried about iPS cells.

M: They are it seems. There was some planning to file an IND for Platelets.

JL: Yes.

M: Do you know that story?

JL: I do, yes.

M: Will you tell it?

JL: I probably can. I can publicly say I was a consultant for them [Ocata/ACT] and that I attended their pre-clinical meeting as a consultant. So I know about the reaction of the FDA about that.

M: This was back 3 years ago?

JL: Yes, I think 2 to 3 years

M: 2013

JL: It turned out that I wasn’t really necessary as an advisor. I didn’t say a word but it was fascinating to see the FDA’s response.

M: The concerns they had were GMP compliance related.

JL: Yes, but they’re getting over that. They’ve approved ES cells that were not made with the intent of using them for therapy. One of the cell lines that they approved was derived in 1998 using bovine serum, which was a concern before the safety trials showed that it wasn’t important.

M: Yes even the Ocata/ACT cell line comes from some time ago on MEF.

JL: Yes, and I’m not concerned about that. There are some issues with using xeno reagents but they are really related to whether you’re making the cells make the wrong kinds of sugars. If you were to put mouse embryonic cells or mouse iPS cells on mouse embryo fibroblasts (MEF), viruses could be transferred into the cells, but this doesn’t happen with human pluripotent stem cells. Nobody has ever shown any kind of viral infection in human cells that comes from the MEFs.

M: That’s why the safety is intact.

JL: Yes, exactly. The process is to imagine bad things that might happen, then prove that they don’t happen.

M: It’s only a transitory process as well.

JL: Yes, you’re not putting mouse cells into people. But you’re also not infecting the cells so there’s no lasting change.

M: There are a lot of other technologies that are far more dangerous – virus delivery for instance.

JL: Yes, of course, and viruses used for early gene therapy have actually been shown to be dangerous in some cases.

M: There have been a lot of adverse events and people have actually died in the CAR-T trials and no one talks about it.

JL: That’s right.

M: My feeling is the xeno movement is a good thing for standardization and some of the work shown here, the BioLamina work and the Thermo Fisher work, these are very good protocols that need to be adopted and the expansion occur.

JL: That’s fine. As long as they are necessary and they work well, I don’t really care what methods are needed. I’m not too worried about the xeno issue because the cells won’t be interspecies transplants.

M: Are they requiring it now, is that the new standard?

JL: Not yet, no. We just had a meeting with our regulatory consultant a couple of weeks ago, but of course you never know.

M: So when the Israelis and BioTime and others in the field are touting the xeno-free, it’s just marketing?

JL: Perhaps, but don’t let’s push that too far; I mean the FDA is never perfectly predictable and they could decide at any time that they think it’s dangerous to have xeno reagents.

M: But the products will be approved without a line switch.

JL: Right, that’s right.

M: What are the programs in the pluripotent space you think will reach the market within the next 5 years?

JL: Obviously there’s a lot of interest in the reagent business and there are a lot of companies that are joining in, especially in Japan. I really didn’t realize how much was involved in Japan in creating reagents for taking the cells to the clinic.

M: ReproCell?

JL: Yeah, ReproCell and others.

M: Takara?

JL: Yes. I’m giving a talk at an innovation showcase tomorrow for another Japanese company. One of my friends asked me to do it for him because he can’t make it here. They’re a very large chemistry company. They’ve been in business a long time and now they want to start to apply what they’ve done to stem cells.

M: Interesting how some of the non-scientific power houses in Japan are involving themselves now. A change in strategy perhaps. Digital is affecting their main lines of business and there’s an opportunity.

JL: Absolutely. They have a lot of bandwidth. Fuji Film just bought Cellular Dynamics. I mean you’re not making film anymore so you might as well make stem cell reagents.

M: I don’t want to press on the point of who’s going to come to market soon but success needs to be translated and your view on early access as being a component of adoption, proof of clinical concept, is that in your view an essential part of regulatory review & language?

JL:  Japan has fast tracked cell therapies, but I think our FDA is not going to fully adopt such regulations. Perhaps this is because the Japanese regulatory authorities have decided to trust their scientists more than the FDA trusts us.

M: In my view Japan also has a symbiotic relationship with the other parts of the system, you know, it works all together – the insurance, the legal, the funding, the university/academic and business community.

JL: I know, it’s really amazing. I’m really envious.

M: Anything else on the program front? I wanted to talk about the Zoo work.

JL: I know that’s what you actually wanted to talk to me about.

M: Yes, it was fascinating that you’re doing that work.

JL: Yes, we decided that we should try to reprogram endangered species cells, so in 2011 we published a paper to say we can – Rhinos, using human technology. We hope to use those cells to help restore the species.

M: The egg/sperm combination?

JL: All that stuff is coming. At that time we just made iPS cells from the animals and the project lay dormant for a while because the zoo we were working with thought it was a bit little creepy, too Jurassic Park. They’ve now decided to embrace it.

M: Weren’t there a number of international groups working on that before?

JL: Yes but not a lot, not in this particular thing. There was a group in Australia that was reprogramming other animals.

M: Interestingly in Spain also.

JL: Yes, that was different though, replacing one animal with another in a habitat.

M: Using an animal to host?

JL: Well they’ve done that too. The essence of our approach with endangered animals is to use the technologies that have been developed for mouse and for humans to make gametes out of the iPS cells. Then use IVF technology, that is also in development for these animals, and have a surrogate host that we’ll be able to put the embryos into and regenerate the species. Just a small thing! I’m doing this with the Northern White Rhino, as there are only 5 of them left. There’s only one male and the females I think, with one exception, are beyond reproductive age and they’re dying. [Note: another Northern White Rhino died in late July, so now there are 4].

M: So how would you approach that?

JL: The Southern White Rhino has a very similar reproductive cycle. The Northern White Rhino are a different species but they’re very similar. No one really knows if you can cross them yet. We want to make the gametes from the Northern White Rhino, inseminate the eggs in a culture dish and transfer the embryos to a Southern White Rhino.

M: The egg would come from the endangered species also?

JL: Yes, from the pluripotent stem cells.

M: Both gametes.

JL: Yes both gametes would be produced from iPS technology.

M: Have you proven that yet?

JL: No, we had no money, so we essentially have been generating more iPS cells and we’re getting better at it. But now there’s going to be an investment, that’s what they tell me. The zoo has decided.

M: Which zoo is that?

JL: The San Diego Zoo.

M: Wonderful.

JL: They’ll be announcing that when they want to, it’s not up to me.

M: Very good, I wish you luck with that.

JL: Thanks, it’s one of those things which seemed obvious at the time.

M: Well worth doing.

JL: Yes, it is worth doing and it was just a matter of timing. I think a lot of this is like that. If you’re too ahead of people’s understanding of what you’re doing then it will just sit there dormant until they understand it.

M: I think in most fields if you’re pioneering something you have a responsibility to educate.

JL: Yes but people also have to accept it. I’ve seen a lot of changes in the stem cell world since we started this in 1998 so it’s been a while.

M: The %s are way higher now.

JL: Yes, they’re higher, that’s right, and it does have to do with education and our patient advocacy approach means we educate patients and the patients educate other people because they’re motivated. They may have not wanted to be scientists but they’re driven to understand it because they want to get cured, they want to get treated.

M: Thank you Jeanne

JL: Ok

###

Ref: Parkinson’s review by EuroStemCells

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.

Stem Cell Person of the Year 2014: Masayo Takahashi (高橋 政代)

Masayo Takahashi

Dr. Masayo Takahashi,  Asahi photo

Congratulations to Masayo Takahashi (高橋 政代), MD, PhD, the winner of the 2014 Stem Cell Person of the Year Award.

Dr. Takahashi received this award including the $2,000 prize for her exceptional achievements in stem cell research in 2014. She was selected as the winner from a stellar group of top 12 finalists this year.

Takahashi leads a team doing high-risk, high reward research that is conducting the first induced pluripotent stem cell (IPSC) clinical study in humans ever. I interviewed Takahashi at the beginning of this year and you can learn more about her research and vision for the future from reading that interviewMonkey stem cell RPEs

The Takahashi team clinical study is intended to examine the safety of a human retinal pigmented epithelial cell (RPE) product made from each patients’ own IPSCs. You can see at right RPEs produced by her team from monkey pluripotent stem cells.

In an astonishing feat of speedy clinical translation, Takahashi’s team transplanted its first macular degeneration patient recently on September 12, only 7 years after human IPSCs were first ever published. The usual timeline for such translation would be 20 years. In that regard, in a recent interview I did with him, Nobel Laureate Shinya Yamanaka had this to say of Takahashi and her work:

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.

Her achievements extend beyond this year to an outstanding long-term track record in vision research including a very impressive track record of highly-cited publications. Takahashi is physician scientist, who is a faculty member and Project Leader at the Laboratory of Retinal Regeneration at the CDB at RIKEN. Some of her nominators for the Stem Cell Person of the Year Award described her as a “transformative” and “courageous” stem cell scientist. Below you can see a TEDx talk from just a few months ago by Takahashi explaining her work.

Takahashi joins previous Stem Cell Person of the Year Award recipients Roman Reed and Elena Cattaneo as outside-the-box thinkers who to take risks to make outstanding new developments in the arena of stem cell research with the goal of helping others.

More about the Stem Cell Person of the Year Award. I fund this prize myself as a way of giving back to the stem cell community and recognizing transformative people who take risks to help others. It is to my knowledge the only annual, international science-related prize personally funded by a professor.