Monthly Archives: June 2014

Regenerating Organs for Transplant Interview with David Green

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David Green is Chief Executive Officer of Harvard Apparatus Regenerative Technology, a clinical-stage regenerative medicine company focused on developing life-saving medical devices.

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Methuselah Foundation: Let’s start with Harvard Apparatus Regenerative Technology (HART). What are the mission and goals of your organization?

David Green: We want to bring regenerated organs for transplant to patients who need them. HART has been around for about five years, but it’s only really been visible since November of last year when we were spun off as a separate public company from our parent company, Harvard Bioscience.

I founded Harvard Bioscience, which sells laboratory equipment, 17 years ago. And in the course of developing products, we became interested first in stem cells, and then in regenerative medicine. We signed our first sponsored research agreement with Massachusetts General Hospital in 2008, and later that year, Paolo Macchiarini published a paper in The Lancet on the world’s first regenerated tracheal transplant.

I’d never heard of Dr. Macchiarini before, but in that paper he described a bioreactor similar to what we were interested in. So I sent him an email congratulating him on the achievement and asking if he wanted to license his technology. Thirty minutes later, he wrote back and said “yes.” That began our collaboration, as well as our interest in the trachea as an organ for regeneration and transplant.

MF: What are bioreactors exactly, and what do they enable us to do?

Green: Well, the bioreactor for the trachea is basically a cell culture vessel inside of which the tracheal scaffold is rotated a bit like a chicken is rotated on a rotisserie in order to distribute the cells into the pores of the scaffold. You can’t just pour the cells over the top, because most of them will just wash away. You need to continuously feed the cells into the scaffold in order for them to become embedded within the fibers of the scaffold and start to grow. So that’s the purpose of the bioreactor: to feed the cells onto the scaffold, keep them at body temperature, and keep them sterile for two days prior to the transplant.

MF: What challenges are you currently experiencing with this technology, specifically with your tracheal work?

Green: The bioreactor technology is pretty well developed at this point. We’ve used it in about 11 human surgeries so far. What we’ve had to develop in parallel, however, is the scaffold technology.

If you go back to that first paper in The Lancet in 2008, that was using a decellularized natural donor trachea. In other words, a trachea was taken from the donor, someone who had died in a road accident, and then all the cells were stripped off of it, leaving behind a collagen tube in the shape of the trachea. They then took bone marrow cells from the patient and seeded them onto the scaffold in the bioreactor.

That patient is still alive more than five years after the surgery, so it’s been a great medical success. However, she did have complications, one of which was that the scaffold became floppy after the surgery. It eventually stiffened up, and she’s fine now, but she went through a period where she had to be stented in order to maintain the open airway. Because of this, Dr. Macchiarini was very interested in finding synthetic approaches to scaffold fabrication that could be made much stronger and avoid this risk of tracheal-collapse. We partnered with him to do that.

The first synthetic scaffold was used in 2011 on another patient, who had trachea cancer. Prior to the surgery, he was given two weeks to live, and he ended up surviving two and a half years after that. So it was another great medical success story. That was the first use of a synthetic scaffold. Eventually, we developed a new scaffold using a nanofiber approach, and that technology has been implanted in the most recent five patients, starting in 2013.

MF: Are you also working in other areas, or are you solely focused on the trachea?

Green: We are focused on the trachea primarily because we need to get it through clinical trials and onto the market. We expect to start clinical trials next year and then get the product approved by the regulatory agencies by the end of 2017.

Of course, scientific research still goes on, both our own research and that of our collaborators. Our collaborators have also succeeded in regenerating and transplanting both the esophagus and the lungs. So far, those organs have only been done in animals, but one day we expect to be able to do them in humans as well.

MF: Who has done the work with the lungs and the esophagus?

Green: Harald Ott at Mass General, our original collaborator, did that work on lung regeneration and transplant that was published in Nature in 2010. And just a couple of months ago, Paolo Macchiarini published “The Regeneration and Transplant of an Esophagus in Rats,” also in Nature. We’re also working with the Texas Heart Institute on heart regeneration, the Mayo Clinic on heart valve regeneration, and several other collaborators whose names are confidential.

MF: What is the nature of these collaborations? Are they applying your bioreactor technology or your scaffold technology in their lab work?

Green: Usually both. The scaffold technology we have today is only usable with hollow organs—things like the trachea and the esophagus. It’s not really amenable to solid organs like the heart and the lung, so most of the research work being done in heart and lung regeneration is being done with decellularized donor material. Just like I described for the first trachea in 2008, a donor lung or a donor heart is decellularized—all the cells are stripped off it, leaving a collagen shape behind—and then that scaffold is recellularized with cells from the patient.

MF: What have been the largest technical hurdles with the more complex solid organs like the heart, lung, liver, or kidney?

Green: I think there are two main challenges to the more complex solid organs. One is revascularization. So far, we’ve succeeded in generating a scaffold and then cellularizing it so that it’s covered in cells at the time it’s implanted. But it does not have a vasculature. In cases such as the trachea, that’s okay, because the trachea doesn’t have any real metabolic load. It’s not like the heart that’s beating or the kidney that’s processing and filtering the blood, so it can survive with a very limited amount of vascularization. Vasculature still does have to be provided by the body, but that can occur after the scaffold is implanted. But that strategy probably won’t work for a heart or a lung. There’s just too much need for oxygen in the cells.

The other main issue is simply fabrication of the scaffolds. At this point, 3D printing is not capable of producing scaffolds with the kind of resolution necessary to make them friendly for cellularization, let alone vascularization. The fibers we make, for example, are about one micron in diameter, which is about one one-hundredth the width of a human hair. But the best resolution you can get from a 3D printer today is about 20 to 30 microns.

The other big issue with 3D printing is the materials that are available are typically things like steel or rigid hard plastics that engineers like to use to make things like telephones and other industrial products. They’re not biological materials. Obviously, to print a scaffold through cellularization, you would need a biological material, or at least a biologically compatible material like we use for the tracheal scaffolds. So there are major issues with 3D printing for regenerative medicine.

MF: With the bioreactor technology, what improvements are needed to move closer toward creating whole organs for transplantation?

Green: At least for a whole heart or a whole lung, I think the issue really isn’t the bioreactor technology at all. The bioreactor technologies we have today are good enough to do what is needed for decellularization and recellularization of hearts and lungs. The challenges lie much more in the vascularization of those scaffolds, and that’s more a biological issue than it is a bioreactor issue. If someone can crack that problem, they will almost certainly win the Nobel Prize.

Solving this challenge would be incredibly beneficial to patients, as well, because it could make organs viable that currently aren’t good enough for transplant. There are about 2,000 heart transplants per year in the US, but there are many more donor hearts than that. There’s just a very narrow window during which a heart can be harvested from someone who’s died before it needs to get implanted in the recipient, and some of them don’t make it in time. However, even if an organ didn’t make that four or five hour window for direct transplant, it could still conceivably be used for decellularization.

There is a limited amount of starting material for making decellularized organ scaffolds, both for heart and for lungs. And once this vascularization problem is cracked, I think it will be possible to commercialize a decell-recell (that’s what we term a decellularized-recellularized organ scaffold) for heart and lung transplants. Ultimately, I think we’re going to have to figure out how to build synthetic scaffolds, both for hearts and for lungs, because the number of patients you can treat through decell-recell is always going to be limited. There just isn’t yet any technology available that can fabricate those types of scaffolds.

MF: What do you think it would take to get us where we need to be with synthetic scaffolds?

Green: Well, you don’t need to go faster than the speed of light to manufacture a synthetic lung scaffold or a synthetic heart scaffold, so it’s not like we’re talking about breaking the laws of physics here. I think these are much more engineering challenges than they are scientific challenges. It’s certainly not impossible to imagine a 3D printer with a one-micron resolution. I think it’s mostly a matter of money, to be honest.

The big 3D printing companies are not that interested in developing 3D printing for biological scaffolds, I don’t think. 3D Systems and Stratasys, for example, want to bring manufacturing back to the US from China. Compared to that enormous trillion-dollar opportunity, I think they view medical stuff as being kind of a sideline.

I’m not aware of anyone yet who has made the commitment of money, people, and resources to seriously try to overcome these challenges for the fabrication of synthetic organ scaffolds. I know Organovo isn’t trying to do it. As far as I know, they’re focused on building organ-type structures directly from cells rather than trying to fabricate scaffolds for further cellularization and vascularization. I’m not aware of any academic groups who are focused on it, either.

MF: On a different topic, what have been the biggest challenges of running a biotech company in your experience?

Green: I suppose everyone would say funding, right? I’m perhaps not quite as paranoid about that as a lot of people are, because HART is very lean, and my criticism of a lot of biotech companies is that they typically waste a lot of money. Clearly, everyone thinks they could do more if they had more money. But putting that aside, I think the biggest challenge for biotech companies in the regenerative medicine space is that this is all so new for the FDA.

If you’re developing a new small molecule drug for pain therapy or something like that, you can just pull the existing user manual off the shelf and follow the regs. There’s so much precedent, and it’s all pretty clearly laid out. You can take everybody else’s clinical trial designs. You know what the end points are going to be. You know how you’re going to evaluate it. You know how many trial sites and how many patients you need. It’s still a lot of work, but there’s not a lot of mystery about it.

When it comes to cell therapies, however, so few have been approved. Even the FDA admits that there is no playbook or user manual that you can follow, and as a result, it’s a lot more challenging. To its credit, I think the FDA has done a very good job of separating itself into the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER), precisely because they recognize they need a different, more flexible approach for working with these new companies. But the lack of a playbook here is a serious challenge. We’re blazing the trail.

MF: In terms of that, what would you say makes HART unique relative to other regenerative medicine companies?

Green: We’re focused on life-threatening conditions, which is really my big criticism of most of the rest of the cell therapy and regenerative medicine industry. If you look at where this industry got started, with skin, the two companies that got FDA approval for skin both went bankrupt. It’s expensive to develop cell therapies, and you have to be able to charge a high price for them or you’re never going to be able to make a return on your investment.

You can only charge a high price for something if you’re delivering a high medical value to the patient, and the highest medical value you can deliver is to save a patient’s life. I’ll exaggerate to make a point here, but when you deliver a patch of skin to a patient for a diabetic foot ulcer, which is the only application that those two skin companies—Advanced BioHealing and Organogenesis—ever got FDA approval for, you’re not dealing with a death sentence. And unless you are dealing with death sentences, I just don’t think you’re creating enough medical value to be able to charge the prices you need to charge to recover and justify the huge R&D investment necessary to bring these products to market.

I used the skin companies as a case in point, but you could raise similar issues about the knee cartilage repair products that Genzyme has commercialized. Again, knee cartilage repair is not life threatening. It’s very painful, and I’d hate to have that condition myself, but there are many other, more affordable ways of treating defective knee cartilage.

To me, the industry so far has been characterized by too much science and not enough business. At the end of the day, the economics of the product you develop and the price you can charge for it have a huge bearing on which products actually get developed and commercialized.

I mean, it’s not all gloom and doom. We’re doing life-saving stuff with the trachea, but we’re not the only ones. There’s a company called Neuralstem, for example, that is using cell therapy to treat ALS, and ALS is 100% fatal. But there aren’t many of us.

MF: In the big picture, what do you think is the best thing that could be done to increase the prominence of tissue engineering and regenerative medicine?

Green: I think a successful commercial product would go a long way. If you’ve got a successful commercial product, you will have lots of investors who will want to invest, and once you have lots of investors, a lot of new products are going to get developed. I think that would probably be the single biggest catalyst.

Everyone would like more funding for basic research, but I’m not convinced that spending a lot more government money on basic research is really warranted anyway. I think any government funding would be much better spent on translational research, on getting products developed and commercialized that address significant unmet medical needs.

MF: Do you think that’s the case with whole organ regeneration as well—that the issues and challenges are more in the domain of engineering than in basic science?

Green: I do. I wouldn’t say there are no basic science challenges—that would be an understatement. But the big breakthroughs that need to be made are not at the scientific level.

This is actually one of the reasons I’m pretty hopeful about this field in the long term. At this point, I think we’ve reached a kind of critical mass of knowledge about cells, scaffold environments, and patient conditions that whole organ regeneration is within reach. If you asked me this question 20 years ago, when Vacanti and Langer were publishing their papers about tissue engineering, we just didn’t have enough collective knowledge to be able to make confident predictions. But it’s a much clearer path for us now to go from cells to scaffolds to an organ.

With our particular effort, we’ve shown it can be done on the trachea, on three different scaffolds. One was a decellularized donor scaffold in 2008. Another was a synthetic scaffold using a plastic polymer called POSS-PCU in 2011. Then in 2012, we began these fibrous-type scaffold implants in humans. None of them are perfect, but they’ve all given significantly extended lifespans to patients who had very little lifespan ahead of them. So it’s coming. The proof-of-concept is there that organs really can be regenerated for transplant.

MF: How important is public advocacy for advancing the field?

Green: Well, I think it’s very important, but the most important aspect of it is patient advocacy. I think we need an organization like the Juvenile Diabetes Research Foundation (JDRF), which does a fantastic job of pushing research towards the clinic. Unfortunately, there is no equivalent organization for organ transplantation. I mean, I know there are organizations like the United Network for Organ Sharing (UNOS), for example, but they’re not patient advocacy groups. They organize the donation of the organs and the logistics for implant.

MF: What do you think an organization like that should look like?

Green: I’d be hard-pressed to find a better model to clone than the JDRF. I think there’s one for chronic myeloid leukemia (CML), as well. Several of these groups have been very successful, and often they are organized initially around a patient.

There’s a woman named Kathy Giusti, for example, who suffered from multiple myeloma, and who also happened to be a graduate of Harvard Business School and a successful executive somewhere. Following her diagnosis, she quit her job and co-founded the Multiple Myeloma Research Foundation with her twin sister Karen Andrews. She started going around to all the academics who were doing multiple myeloma research and said, “Guys, you have to start working together. This is ridiculous. You’re all competing with each other, and you need to start working together.”

The second thing she said is, “You need standards. You guys are operating as though this is all about academic research, but the FDA has requirements, and the work you’re doing is not up to the standards required by the FDA.” She kinda beat heads together and said, “Stop. Stop being academics. Start thinking about treating patients, patients like me.” And it worked.

I think some sort of patient advocacy organization like that would make a huge difference. A group that is capable of mustering large amounts of resources and playing a coordinating role for bringing therapies from basic science to a particular set of patients. But it’s not like this needs to be invented from scratch. There are plenty of role models.

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On Taking Risks and Thinking Big Interview with Dr. Robert Langer

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Dr. Robert Langer is the David H. Koch Institute Professor at MIT. He has over 1,250 articles, 1,050 patents, and 220 major awards to his name, most recently Japan’s Kyoto Prize. He is widely regarded as one of the founders of tissue engineering.

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Methuselah Foundation: What’s your perspective on the current state of tissue engineering?

Robert Langer: Well, a lot of progress has been made, and there’s still a lot to do. We did some of the early studies in the 1980s with Joseph Vacanti, and I’m very pleased to see how far we’ve come and how many people are working in the field today. Overall, I think things have gone very well.

MF: What do you see as some of the key present challenges, especially with respect to the Holy Grail of regenerating or bioengineering whole organs?

Langer: It depends on what method you use, but some of the biggest concerns are cell death, vascularization, innervation, and rejection. From a practical standpoint, there are others as well—cell expansion, cryopreservation, and so on. Then there are particular issues with each individual tissue or organ you’re trying to do. And beyond the science, you’ve got regulatory challenges, manufacturing challenges, legal challenges . . . . There are plenty of roadblocks.

MF: In your mind, what is the most promising work going on these days in tissue engineering?

Langer: I think there’s a lot of it—everything from IPS cells to stem cells to new materials. There’s a lot of very good basic and applied work going on. People are trying to understand and design bioreactors, factors that affect cell growth, new kinds of biomaterials, decellularized constructs. There are all kinds of animal and clinical trials going on. And then in each particular area, I think there’s been exciting work—skin, lung, eyes, kidneys, pancreas, vocal cords, spinal cords, etc. There’s just a tremendous amount of good work being done.

MF: Would you say this field has one foot in basic science and one foot in applied science, or are both feet mostly in the applied science domain, where it’s more about, time, money, and the translation of existing knowledge?

Langer: I think it’s both. It depends on how you define it, but I see both basic science and applied science as being important, and I think they have been from the beginning. Sometimes it’s not so obvious that one is doing something for a particular goal. Work that people may do in areas like embryogenesis may be very useful for regenerative medicine, but it may not be the intent of the people who are doing that work to apply it that way.

MF: What do you think about the state of cross-institutional collaboration in tissue engineering and regenerative medicine? Is it strong enough?

Langer: I think it’s pretty good. At least, I don’t think it’s a big roadblock. We collaborate, for example, with many hospitals like Mass General. I mentioned Dr. Vacanti in tissue engineering and also Dr. Zeitels in tissue engineering. We collaborate with the Brigham, we collaborate with Johns Hopkins, we collaborate with lots of places, and we collaborate with companies too. Whatever is going to advance the science, I’m absolutely in support of.

MF: You’ve founded and been involved with a lot of biotech companies. What have been the biggest challenges to success, especially in the U.S.?

Langer: The key is raising money, because it’s just so incredibly expensive. I think they estimate now that it costs well over a billion dollars to create a new drug. So raising money is crucial. You also have to have mitigation strategies for things that don’t work out. You don’t get that many shots on goal. Doing good science and having good intellectual property are the foundation, but anything in the medical area is a very, very expensive proposition. It’s not like the internet.

MF: How do you feel about the state of IP in biomedical engineering? Is it sufficient?

Langer: I think it’s okay. One of the problems is that when you do things that are highly advanced, you only have finite lifetimes. Vacanti and I filed some patents in 1986, for example, that have expired by now, and those are very broad patents. You’d think that 20 or 21 years was a long time, but when the research takes so long, then by the time actual products come out, it’s not such a long time.

MF: Are you happy with the amount of funding that tissue engineering is receiving?

Langer: No, I think it needs a lot more. To me that’s a huge issue.

MF: How do we change that situation?

Langer: Well, it’s very hard. For example, I think what you’re doing with New Organ is great, but you’re doing it on the back end, and the problem is that we need more funding on the front end. Government grants are really the key, and it’s very hard to get them. And I’m not limiting it to this area. Barack Obama asked me about stem cell research for his book, The Audacity of Hope, and I said to him that it’s really important and it would be great if there were more funding. But the fact is, there are hundreds of areas of research for which you’d like to have more funding. They’re all getting hit. That was true when I talked to him in 2006, and it’s even more true today.

MF: Do you have a sense of the scope of funding that the NIH is providing right now for tissue engineering and related work?

Langer: I don’t know all the grants that are given and spread across the many different institutes of the NIH, but I know a lot of people, including us, that have grants from NIH funding basic work in stem cells. We’ve gotten grants in different biopolymer work, intestinal research, craniofacial research. I think they’re quite diverse. But the question is: If they only fund 5% or 10% of all the grants they receive, that means there’s going to be a lot of good grants that don’t get funded. The overall problem is the limited amount of funds for medical research, period. And in particular, what happens when money is tight is that really long-range projects don’t get funded at all. Projects that are being done by younger researchers are often not funded, as well.

MF: The philanthropic sector seems to be underfunding these areas as well, and has been for some time.

Langer: I think that’s probably fair. I would agree with that.

MF: Why do you think that is? For example, when I look at the Giving Pledge signers list—100 plus billionaires committing 50% or more of their networth toward charity—it’s hard to find many of them who are allocating funds toward tissue engineering or regenerative medicine.

Langer: I think people do things on a fairly disease-specific basis. Cancer and heart disease are still the number one killers, and people usually support things they’ve seen close relatives die from.

MF: That seems right. Let’s talk a little bit about your lab, which has a tremendous reputation and a prolific level of output. What do you think makes it so special?

Langer: Well, our lab is very interdisciplinary. Our people have backgrounds in many different areas—MD’s, chemical engineers, material scientists—and they are all bright and self-driven. I see it as a training ground for people to become future leaders, inventors, and scholars.

MF: In developing New Organ, we’ve had more conversations with people saying that they came out of your lab than anywhere else.

Langer: Yeah, that might well be.

MF: Looking back over your career, what do you think are some of the main factors that have enabled you to build such a significant, collaborative network that has been so productive over the years?

Langer: I like to think it’s treating people well. It’s thinking out of the box. It’s trying to go after big problems. Those kinds of things.

MF: If one of your students told you they wanted to follow your example and aspired to reach a similar level of accomplishment in his or her career, what advice would you give them?

Langer: Well, I think when you’re young, it’s best to learn the fundamentals well. Learn a single discipline well. When you get a little older, like for your postdoc, maybe then it’s good to really learn something different. I’m a risk taker. I dream big dreams, and I am very, very persistent. I don’t give up easily. I get discouraged, but I’ll keep plugging along. And my goal has been not just to come up with ideas on the blackboard, but to take them all the way to the patient, to make a difference in peoples’ lives.

MF: Were you more of a risk taker from the beginning, compared to your colleagues?

Langer: Yes, I guess I was. My postdoctoral advisor Judah Folkman was somewhat like that. He took risks, and I think seeing that example was very helpful to me. I think I was probably also lucky. I had a postdoctoral opportunity that put me on an interesting path as the only engineer working in a hospital, and that’s what got me started. It gave me a lot of ideas, and I began to approach things in a different way than others would.

MF: What kind of research is being pursued presently in your lab?

Langer: On tissue engineering, we are working on a range of things—new pancreas, new intestines, spinal cord repair, nerve regeneration. One particular hope has been to design more highly super-biocompatible polymers. But we’re also doing work that is more basic, such as trying to understand how stem cells can be affected by materials in terms of their growth and their differentiation.

We’re also working on things that are indirectly related to tissue engineering, such as: Could we deliver genetic information like siRNA, or mRNA, or DNA to cells to change their character? We’re looking at ways of doing controlled release of different proteins that could modify the cellular environment. So it’s broad based. There’s also a lot of work that is less related to tissue engineering, like work involving drug delivery and new materials.

MF: I’d be curious to hear more about the work on the pancreas.

Langer: Well, the key to it is cell encapsulation. The capsules that protect the cells get encapsulated themselves with fibrous tissue, and that’s a problem. So we’ve been working with Dan Anderson, who is a professor at MIT and one of my former postdocs, to develop what are called high-throughput strategies to synthesize literally thousands of polymers and find ones we can make that are super-biocompatible.

MF: How much have you invested so far into that line of work to get where you are, and how long has the work been underway?

Langer: Six years, and I’d have to check, but it’s probably $6 to $10 million.

MF: Switching gears, what do you think are some of the most compelling reasons to support the case that tissue engineering and regenerative medicine should be a greater priority in society?

Langer: The way that I look at it is that drugs are only going to be able to treat so much, right? Drugs are not going to be able to treat people that are dying of liver failure or heart failure or many other things. To me, tissue engineering is a whole new paradigm for which there really is no substitute. It will change the world in a major way.

MF: Are there other things we could be working toward through New Organ to help advance the field?

Langer: I don’t know the right way to do it, but if we had a Human Genome Project-type effort at the federal level, that would be tremendous. I think tissue engineering is ready for a similar kind of effort to drive the field forward.

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The Promise and Challenge of Stem Cells Interview with Brock Reeve: Part 2

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Brock Reeve is Executive Director of the Harvard Stem Cell Institute, whose mission is to use stem cells, both as tools and as therapies, to understand and treat the root causes of leading degenerative diseases.

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For part 1 of the interviewclick here.

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Methuselah Foundation: In broad strokes, what are your thoughts about the current state of regenerative medicine, tissue engineering, and stem cell science?

Brock Reeve: I think the most interesting change has been that 10 years ago, people were basically thinking about stem cells as replacement parts. For example, how do we grow up enough heart cells to give to someone, or enough blood cells? Now, we’ve realized that cells are really little programmable units. Inserting just four genes out of the 25,000 or so you have per cell will totally reprogram an adult skin cell to an embryonic-like stem cell. That’s amazing. Cells are much more flexible than we used to think they were, and that opens up incredible new windows of opportunity.

It’s not only relevant to the whole drug discovery paradigm we talked about before. People are also looking at in vivo transdifferentiation. What I mean by that is, say you’re short a particular neuronal type in the heart or in the pancreas. Or say you’re diabetic and you have fewer and fewer beta cells. Is it possible to deliver either small or large molecules in vivo into a person and turn a related cell type into the type of cell that you want?

The first test of this kind was conducted several years ago in diabetic mice, and it succeeded in turning a certain type of pancreatic cell into a beta cell, restoring normoglycemia. People have also tried this in the heart. If someone has a heart attack, can you turn the related cells into heart muscle so the heart can rebuild itself? It’s already been done in embryonic mouse brains, turning one type of neuron into another. So, using our understanding of cell plasticity and cell programmability, how can we impact the body’s inherent ability to repair and regenerate, abilities that have either been lost with age or damaged by injury?

There are overlaps with bioengineering, as well. Several years ago, there were a whole bunch of trials about giving people either mesenchymal stem cells or heart cells for heart therapy. One of the things that they showed is that simply putting cardiac cells into people won’t solve the heart problem, because the MSCs don’t transdifferentiate into cardiac cells and the cardiomyocytes don’t electrically couple in the right way. In fact, you can raise the risk of heart attacks. A study done recently in monkeys, for example, showed that after a heart attack, you could give the monkeys more heart cells, but they all had arrhythmia (an irregular heartbeat), and you definitely don’t want to give someone arrhythmia.

It’s a difficult technical challenge to address. Some people are asking, “How do we combine these cells with different biomaterials? How do we put them on thin films or on a patch?” Another approach is looking at how to decellularize organs from a cadaver, and use the extracellular matrix that is left over as a scaffold rather than having to create new biomaterials. Because of what we know about iPS cells and reprogramming, can we repopulate the decellularized organ with a patient’s own cells and grow back a fully-functioning organ?

In some cases, it won’t be giving people new organs at all, but using degradable biomaterials and giving them growth factors that will stimulate internal growth and regeneration. So there are multiple strategies being explored, and I’m not sure how it’s all going to play out.

MF: I often hear things like “biology is becoming an information science.” Do you think that’s true? And if so, what does it mean?

Reeve: Yes, I do think it’s true. When I was talking about genes being able to reprogram cells, that really is an information processing question. From the stem cell perspective, a lot of the information that we see is at the intersection with genomics. And at HSCI, we’ve set up a bioinformatics core facility for people to share bioinformatics data across experiments.

There’s a lot of work to be done to understand what genes get turned off, and when, and where, in the course of development of a particular cell type. How are cells comparable to one another? How do we manipulate their genetic backgrounds and capabilities? People used to say, “If we understand the gene, we understand the disease.” Now, we know that isn’t true, even in monogenic diseases.

Understanding the environment in which genes are expressed, as well as all the different feedback loops, is crucial. Which genes are upstream? How are cells signaling to each other? How do cells affect their neighbors? How does the substrate in which they’re laying affect things? How does physical stress in the body, such as blood flow or mechanical stress, impact cells, or in some case turn genes on and off?

Even simple things like exercise can be understood as information flow systems. There are all sorts of beneficial effects of exercise, but in many cases we don’t know why that is the case. There have been genes that have been identified that get turned on and off, but the complexity of information is everywhere, from the systemic level all the way down to the level of single cells.

I was just talking about cystic fibrosis with someone the other day, which is a gene that was identified back in the ‘80s. It’s a single gene, but it has hundreds of mutations, and those mutations manifest in very different ways. Some of them are misfolded proteins, some of them have to do with calcium signaling, etc. And that means you can’t have just one drug for cystic fibrosis. Even though it’s a monogenic disease, any particular drug will only help a certain subset of the population.

MF: When you look at regenerative medicine overall, what are some of the main road blocks for moving the field forward as a whole?

Reeve: Well, one of them is simply funding for basic science, because there is always pressure from the NIH just in terms of budgets. Most early-stage research in this country is funded by the NIH, and it’s getting harder and harder to get that money. As people try to commercialize these technologies, windows like the IPO market open and shut periodically. The pharmaceutical industry is getting more engaged, but as it comes under increasing pressure in terms of its own R&D pipeline and productivity, it’s getting pickier and pickier about deals with academics. So funding for early-stage research is a big bottleneck in the U.S.

To cite one example, California passed a bond act in 2004 that funded theCalifornia Institute of Regenerative Medicine (CIRM), which was driven at first by changes in federal funding of embryonic stem cell research. So there you have a state putting in $3 billion over 10 years to advance work in this field. But will that get renewed? I don’t know. It’s not looking good, right?

Countries like the U.K. have funded central facilities such as stem cell banks. Just last year, they funded several catapult centers, one of which was a cell therapy catapult. Other countries in Europe have various funding projects as well, including IPS cell banks. Years ago, Singapore put a bunch of money into the stem cell space. So as you look around the world, you see various pockets of funding emerging, where governments are trying to drive behavior and investment in particular directions.

One positive change is that the political bottleneck about the ethics of embryonic stem cells has really gone away. These days, I think the politics have more to do with questions of funding than questions of ethics. Of course, there are also technical bottlenecks. I was talking with someone recently who’s struggling with how to create biomaterials that won’t induce a fibrotic response, so that you can put them inside people without creating scar tissue that gets in the way of the cell signaling.

The fundamental science questions will always be there, in one form or another, and we’ll tackle them. But it always comes back to the money. One researcher here had an ambitious project recently to try to create custom humanized mouse models for diabetes—to basically take human beta cells, and blood cells, and thymus cells, and put them into mice in order to turn them into living test tubes for people. But the NIH doesn’t want to fund “blue sky” projects. They more or less told him that it was too innovative, and too risky. So he had to turn to private philanthropy.

MF: What do you think it would take for better funding conditions to emerge? What would it take to really move the needle on this?

Reeve: Well, in this country, the disease foundations have been very important in funding research in their fields of interest, where either the government or the companies were taking a “wait and see” attitude. And one of the things that I think would be highly useful for our field would be to figure out how to get disease foundations and companies and academic institutions all working together in what I call a “pre-competitive space.”

As an example, we’ve been talking with some people about this idea of creating neurons of interest for particular diseases, and how to get it done. We can make mostly mature dopaminergic neurons for Parkinson’s, for example, but not yet for schizophrenia or autism or Alzheimer’s. There’s still a lot of research necessary to get to the point where we can really model human disease in a dish. And you want to do it at scale. But that’s not something that a typical academic lab would do. It also extends beyond the boundaries of what any disease foundation is interested in. Nor is it proprietary to what a pharma company would want to do, because the real intellectual property would be the drugs you could build using those tools, rather than the tools themselves.

So we need to develop some kind of pre-competitive consortia that will allow us to take common problems, share them across groups that are interested in them—companies, foundations, academics, hospitals, etc.—and band together behind the notion that a rising tide is going to lift all boats. I think that’s still a stumbling block for the field, and you could really accelerate some interesting research efforts by picking chunks of that off.

MF: Is there a role for increased patient/public advocacy in all of this? There are historical examples—Parkinson’s, cancer, HIV/AIDS—that demonstrate how public involvement has played a key role in stimulating change. What’s your take on the temperature of public engagement right now?

Reeve: There’s an association called the Alliance for Regenerative Medicine, and they introduced a bill in Congress called the Regenerative Medicine Promotion Act in April. In general, though, people are motivated by tackling a particular disease, as opposed to regenerative medicine as a whole. If we go back to CIRM in California, they obviously had to do a lot of public awareness campaigning in its early days. But I think they may have oversold the benefits that were going to come from cell therapies and regenerative medicine. Part of how they sold it to the state was by saying, “You’ll save on your healthcare bills.” And the science was too early to promise that.

One of the big things I don’t know is what degree of backlash there might be. Last month, someone sent me an op-ed from the San Francisco Chroniclethat basically said, “Look, we backed CIRM when it first started, but we’re not going to do it again because we think taxpayer money shouldn’t go for this any more.”

MF: Do you think that’s more of an education challenge? Working to advance a frontier is such a tremendously complex endeavor. It seems we lack broad understanding about the challenges, and that our expectations are not properly calibrated. Isn’t it one of those cases where the journey is worth it even if you don’t arrive precisely at the expected destination?

Reeve: Yes. That’s totally true. However, if you promise people you’re going to get to a certain place, and you forget to emphasize the value of the process itself, then I do think that’s an issue.

On the other hand, what’s also increasing is a general understanding, whether it’s for Parkinson’s or organ transplantation or simply healthy aging, of just how far reaching the impacts of regenerative medicine are on different disease areas. This whole issue of repair and regeneration is a broad one, and as people understand that, then I think it plays out well.

MF: Is there anything that you’re not currently seeing on the public advocacy side that you would like to see over the next three to five years?

Reeve: Not really, no. In terms of public policy, we just need more funding. When Mahendra Rao stepped down from the NIH Center for Regenerative Medicine about a month ago, he said: “Look, I had been promised funding to do five clinical trials. I got funding to do one. If we’re really going to do this, we need to do this at scale.” So I think the real public policy issue is the funding.

This is where groups like the NIH play into it. And then, how do state and local groups support that? CIRM is only for California. New York has something roughly equivalent called NYSTEM, and they’ve funded some large projects. They are funding a Parkinson’s study right now. I think they promised up to $1 billion over 10 years. Massachusetts set up a life sciences center, but it was more broadly focused on life sciences jobs in the state rather than just regenerative medicine. Also, in 2006, Maryland established the Maryland Stem Cell Research Fund, with over $110 million committed to date. It would be incredible to see a lot more of these state-level efforts.

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Collaborative Science at the Harvard Stem Cell Institute Interview with Brock Reeve: Part 1

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Brock Reeve is Executive Director of the Harvard Stem Cell Institute, whose mission is to use stem cells, both as tools and as therapies, to understand and treat the root causes of leading degenerative diseases.

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Methuselah Foundation: How did the Harvard Stem Cell Institute (HSCI) get started?

Brock Reeve: It started about 10 years ago to take advantage of the new technology of stem cells and explore how to use them as curative tools for disease. At that time, federal policy was limiting funding amounts for research in embryonic stem cells. So Harvard said: Look, this technology is at an interesting stage. We have a huge research capability here between the schools of Harvard and the Harvard-affiliated hospitals. We also have a unique footprint within the Boston life sciences ecosystem, with a critical mass of both clinicians and researchers. Let’s organize around that opportunity.

Rather than building new labs, we used existing labs and formed the Institute as a virtual research organization. We raised money from private philanthropy to fund work across the network, and our goal was not just to do basic research and publish papers in scientific journals, but ultimately to get beyond the lab and focus on finding cures. As a result, we’ve been able to reach beyond the purview of single departments and disciplines. These aren’t just developmental biology questions. They’re not just clinical care questions. We bring together biologists, chemists, clinicians, bioengineers, etc., in order to tackle these inherently multidisciplinary problems together.

MF: Can you give me an example of a recent project?

Reeve: A couple weeks ago, there was all that publicity about youthful bloodreversing aging in mice. Two of the people who were mentioned in that are involved with Harvard. One was Lee Rubin, and the other was Amy Wagers. Lee did the neuroregeneration piece, and Amy did the muscle regeneration piece. Actually, a year before that, Richard Lee also published on heart regeneration. And all three of them were working together on a common project to understand aging processes in different organ systems.

That project was an example of several things. One is the value of collaboration, because Rich is at the Brigham and Harvard, Amy’s at the Joslin and Harvard, and Lee’s at Harvard. Amy’s a developmental biologist working in muscle, Rich leads our cardiac program, and Lee is a neuroscientist with a deep knowledge of chemistry.

The project originally came out of work Amy did years ago at Stanford using a parabiotic mouse model where you’re joining a young mouse and an old mouse together to share circulatory systems. She had also done some work looking at skeletal muscle repair, and Rich said, “Let’s look for commonalities. Let’s think about how this plays out in the heart.” It’s an example of taking a model that had been used in one disease and asking if it can be applied to another disease, and whether this will reveal any underlying factors in these different systems.

Now, as we start to go down the path toward therapeutic applications, we’re working with one of the local venture firms to make it happen. It’s at the project stage right now, but if it’s successful, it could turn into a company spinning out of this work.

MF: Have you run into any intellectual property conflicts in getting these different institutions to collaborate?

Reeve: Not in this case, because the PI’s (principal investigators) all knew, liked, and respected each other, and they had the right attitude towards sharing. It’s really driven by that. The IP will reside with three different organizations: Brigham has some IP out of it, Joslin has some IP out of it, and Harvard has some IP out of it, which can get complicated, but the tech transfer officers agree if the PIs agree on how the scientific contribution should be divvied up. It only gets problematic when people start saying, “Wait a minute. My contribution was 80%, and yours was 20%, right?”

MF: So in essence, that’s how you cut the Gordian knot with different collaborators?

Reeve: Exactly. You have to establish that the default assumption is that it’s all equal, unless we agree otherwise. Eight years ago, some of our junior faculty wanted to work on a joint project together, and one of them asked me: “Am I better off building my lab the old-fashioned way?” In other words, should I make it all about me instead of being part of a team?

Eventually, he and the others realized that as part of a team, they could share data earlier and publish earlier, and they all did better work as a result. When other junior faculty saw them, they wanted to do the same thing. So we’ve organized a whole set of junior faculty projects that way, doing team-based science. And it’s working because we didn’t force it from the top down. It bubbled up from the ground. In truth, we’re not only working a science experiment here. We’re working an organizational experiment, too.

MF: When you started out 10 years ago, is there anything you expected to happen that didn’t happen? And on the flip side, have there been any surprise successes?

Reeve: I guess what surprised me initially is how many different organizational affiliations people have here. Sometimes the same person will have four or five affiliations: they might be a Howard Hughes investigator, a hospital employee who belongs to a certain department, and also be a member of, say, stem cell programs at Boston Children’s Hospital or Mass General, all in addition to being part of HSCI. Because of that, getting people to feel that they are a part of a larger whole is sometimes difficult. So we’ve had to do a lot to help reinforce a sense of community.

It’s not all about the money funding these projects, because you’ll never have enough money to fund everybody. But you can get enough to grease the wheels, and you can lower the barriers to people sharing ideas across the network. We hold events like Chalk Talks and Think Tanks, different ways for people to learn science from one another and do better work as a result, in addition to being part of a larger community. And one of the lessons for me, particularly within an institution that has historically been known for being very siloed, is that we’ve been able to change some of that. But it’s an ongoing effort. The virtues of this kind of collaboration aren’t always as self-evident as you might think.

MF: What kind of policies did you originally put in place to test some of these ideas out organizationally?

Reeve: Well, we’re the first organization at Harvard that spans all of the Harvard-affiliated institutions. Harvard had never done that before. And you could argue that the jury is still out on whether that speeds up the research process as a result. But I think we’re getting there. Ultimately, what we’re saying at the end of the day is that we can do better science and faster science than we did before. Those are the two big benefits.

We’re in the third year of a project right now, for example, with four different labs working on Parkinson’s together. The first year, our funders said to us, “Hmmm. We’re not sure how this is going.” But we got together again last week, and they said, “We never thought it would move this far this fast.”

MF: That’s fantastic. We hear figures all the time like, “It takes 15 years to turn a scientific discovery into a new medical solution,” or “It takes a billion dollars to bring a new therapy to market,” or “only one out of every 10,000 discoveries make it to market.” Do you think what you’re doing could impact those numbers?

Reeve: Yes, that’s the hope. What you described is the typical drug R&D pipeline, and one of the promises of stem cell science as a discovery tool is to totally change those economics.

A lot of pharmaceutical discovery is based on using either hamster cells or cancer cell lines. But we set up a stem cell-based screening center seven years ago at Harvard, and now other groups have done that as well. When you combine this with reprogramming and other technologies, what you can ultimately do is put human cells of a particular type in a dish. We’ve now done high-throughput screening on human motor neurons, for example, from both healthy people and those with ALS. You couldn’t do that five years ago. Now, you can do it in 384-well plates in automated fashion, using different chemical libraries, so you can identify which drugs keep motor neurons alive longer from ALS patients with a particular genetic background. And in theory, you can now identify drugs that work on those patient populations. If you have an existing drug that you want to test, you can now do clinical trials only on patients with the right characteristics.

Last year, one of our scientists published a paper in which he studied two drugs that had been pulled off the market in phase 3 because they were found to be ineffective when they went out to broader patient populations. At this point, they had become expensive experiments, because they’re getting up to your billion-dollar mark. And in the paper, he demonstrated that with this in-vitro model, he could have shown up front that both of them were going to be ineffective.

So yes, we could have saved hundreds of millions of dollars for someone that way. You’d never go into clinical trials with drugs like this in the first place. At the same time, we’re about to do a trial—it also happens to be in ALS—where we found an existing drug that was able to be re-purposed. It was approved for a different neuroscience disease, but we realized it would actually work on this electrophysiological response and would keep motor neurons alive longer. So we’re going to do a parallel in-vitro trial with the actual clinical trial. In other words, we’re going to make iPS cells from patients in that trial, and then compare the results from the actual trial with the in-vitro trial.

That’s never been done before. The virtue of doing it is not only to better understand this particular drug, and identify for whom it may be effective or not, but to better understand the enormous potential down the road. You’ll never get rid of live human trials, but if you can dramatically shorten the time or narrow the net that you’re casting, you should be able to speed up the whole process, or significantly sharpen its focus, or both. It’s still an open question, of course, but this kind of thing has the potential to hugely change the economics of the whole drug R&D pipeline.

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