Connecting the Lab and the Clinic Interview with Dr. Jennifer Elisseeff


Dr. Jennifer Elisseeff is Director of the Translational Tissue Engineering Center at Johns Hopkins University School of Medicine. She focuses primarily on tissue regeneration, and is working to develop an artificial cornea.


Methuselah Foundation: Let’s start by talking about the Translational Tissue Engineering Center at John Hopkins. What kind of work are you doing there in your lab?

Jennifer Elisseeff: Well, we named it the Translational Tissue Engineering Center because we’re focused not just on the development of new technologies in regenerative medicine, but on addressing clinical challenges and developing new therapeutic outcomes for patients. In my lab, we’re looking at a number of different applications in orthopedic surgery, rheumatology, and musculoskeletal repair. We’re working on the regeneration of cartilage tissue, which lines the surfaces of joints. We’re also looking at bone repair, which is important for joints and in craniofacial reconstruction, and exploring what can be done with muscle disease to repair tissues and treat the underlying disease.

Then there are the plastic surgery applications—reconstruction of tissues and wound healing in the craniofacial region and soft tissue throughout the body. We’re also in an ophthalmology building, so we’re surrounded by a lot of clinicians focused on the eye, and we’ve begun projects looking at both corneal repair and retinal repair.

MF: What work are you most proud of so far?

Elisseeff: That’s tricky. I’m often most excited about the newest things that we’re doing, but those are still in the early stages, and so their impact is still unclear. Right now, for example, I’m excited for what’s going on in immunomodulation, and how we can use that to promote tissue regeneration.

If I look back at impact, however, I would say that where we’ve been able to translate things clinically, we’ve also gained important knowledge to help us develop things in the laboratory more efficiently. In other words, the translational applications also help us target the right problems in the research. Without that feedback loop, we might be in the lab playing around with what we think are important variables, only later to find out that they actually aren’t that important when you get into working with people.

MF: Is there anything about the center at Johns Hopkins that you think makes it special or unique, compared to other research centers in US?

Elisseeff: One of the big advantages we have is that we are right in the middle of a fantastic clinical environment. There are surgeries happening on the bottom floor of our building. If you walk out of our building and hit anything close by, there’s patient care happening. We’re surrounded by physicians who are keenly interested in seeing the next therapy get out, and can give us real guidance on what is needed to make that happen and how best to design true therapeutic improvements. In addition, we have a great stem cell center, the Institute for Cell Engineering, that gives us capabilities across the whole spectrum from the basic, fundamental science to the everyday needs and challenges of physicians and patients.

MF: More broadly speaking, how would you describe the potential of tissue engineering and regenerative medicine to impact patient care?

Elisseeff: The impact of regenerative medicine in the clinic ranges all the way from the everyday aspects of wound healing—closure, scar tissue reduction, etc.—to the most complex challenges of composite tissue transplantation, reducing rejection, avoiding immunosuppressives, and rebuilding tissues from the ground up. There are so many challenges along that spectrum from the most simple to the most complicated, including treatments for myocardial infarction or heart attacks, minimization of injections that reduce scars and promote solid tissue growth, whole-systems approaches to treating osteoporosis, and addressing multiple factors that influence disease.

MF: What are your overall thoughts about the state of tissue engineering and regenerative medicine today, both in terms of key opportunities and key roadblocks?

Elisseeff: What’s interesting right now is that there seems to be a renewed excitement for cell therapies and gene therapies, both among students and in the commercial sector. These types of industrial investment and commercial excitement tend to go through ups and downs, and I think there’s a lot of excitement right now that we definitely want to get more and more connected with.

One of the biggest gaps in my mind is what happens at the university versus what’s feasible in commercial settings, and there are a number of these so-called valleys of death between the two. There’s a valley of death in the laboratory of moving to proof of concept and actual efficacy in the most relevant pre-clinical models that the FDA will approve. Then there’s another valley of death when you come out of the laboratory regarding how to manufacture and deliver whatever technology you’re working with, and how to make it commercially viable.

MF: Are there particular reasons why there is a lot of excitement right now around cell and gene therapy?

Elisseeff: For one thing, we’ve moved past some critical barriers in the manufacturing of cells. It’s not at all easy to develop reproducible manufacturing and delivery mechanisms for getting cells into patients. And then finding the right diseases where that even makes sense. It might not make sense in orthopedics or for arthritis, for example, but it might be the perfect solution for a disease like ALS. So it’s been challenging to understand which disease targets are most relevant for cell therapies, and there have recently been some exciting successes in cellular immunotherapies that have given us all great hope for the field.

MF: What stands out to you right now as the most promising work in the field?

Elisseeff: Right now, I’m most encouraged by the interface between regenerative medicine and transplantation. There have been some exciting advances in transplantation and microsurgery, for example, with very complex grafts on the face, hands, and arms. And in order to take it beyond that, and make it less of a rare, boutique occurrence into something more widespread and accessible to a larger number of people, I think it could be very interesting to combine the latest work in cell therapy with the latest in both materials and immunomodulation.

Also, I think some of the recent advancements in cancer immunology, which is really a type of regenerative medicine engineering—in other words, engineering the immune system to treat a disease—involve principles that are very promising and can be applied to many other things.

MF: How would you characterize the overall funding climate right now, especially in the US?

Elisseeff: It’s terrible. Many people running laboratories are spending much more of their time trying to fundraise and write grants than they’re spending doing science, education, or mentorship. And I think that’s a huge problem.

The peer review process is a great thing in the US. As much as I complain about it, whether it be for manuscripts or grants, we do get a lot of great input from our peers to help us do better science. But right now, it’s gotten to the point that it’s untenable. I’m on a panel, so I’ve seen how they run, and it’s really impossible to choose between the top X percentage of grants. They’re all great. So you end up just nitpicking, and you lose a lot of good science in the process. Then those researchers have to write up another X number of grants because they didn’t receive money for that very good grant to start with.

Overall, it’s just a very destructive environment for science and future innovation. It’s particularly challenging for junior faculty members, but it’s not a walk in the park for anybody. I often wonder how many hours and how much science we lose because of this. At the moment, at least, there’s actually a much better climate right now in Europe for funding scientific research.

MF: We’ve been hearing this a lot as well. With NIH budgets continuing to drop, how about the social or charitable sectors? Do you see much funding coming towards stem cell science, regenerative medicine, and tissue engineering from the philanthropic side?

Elisseeff: Did you see the article in the New York Times this year about philanthropists and donors taking a far more significant role in the directions of science? There are many interesting ways to perceive whether that’s a good thing or if we’re moving too far away from peer review.

MF: Yeah, we saw that. But either way, there are 1,300 billionaires in the world. Do you see many of them making regenerative medicine a priority right now? If not, why?

Elisseeff: I suspect that it’s a marketing battle more than anything else. Regenerative medicine is such a young field compared to fields like cancer research. It doesn’t have as many celebrity spokespeople yet, but it has the potential to capture interest, particularly with respect to battling aging.

MF: How about the state of patient advocacy around these things? It often seems like people are more inclined to orient promotional efforts around specific diseases as opposed to an entire field like regenerative medicine.

Elisseeff: I think it’s still at a very early stage. For example, if you look at arthritis, you see a lot of interest emerging now in a genetic perspective on treatment via various drugs coming out of regenerative medicine. I think those approaches are just relatively new, and probably not yet fully appreciated as alternative therapies.

Regenerative medicine is somewhat hard to define. It’s tissue engineering—regenerative medicine—immunoengineering—gene therapy—cell therapy—and so on. Because the field is so broad, it’s perhaps a little bit harder to clearly express to people.

MF: Do you think that there are dramatic changes needed in the way clinical trials and regulation currently works in the U.S.?

Elisseeff: Yes. In our first two translation experiences at Hopkins, all of the clinical testing was done outside of the U.S. Right now, we’re trying to work in the U.S., and even for something relatively simple, it’s still very difficult to do. When you are dealing with cutting edge therapies, there just isn’t any clear guidance on regulatory matters. Everybody is trying to figure out the safest way to go about it, and we have such low risk tolerance here. I think something needs to be done about that if we want to improve the chances for regenerative medicine to make an impact in this country.

I heard a great description of the medical translation challenge once from a Congressmen who is also a medical doctor. He said simply that there is no one in Washington whose job it is to promote and stimulate innovation in health technologies, to shepherd things through and promote the innovation process. There are people responsible for regulating products and making sure that people are safe, but nobody with the real objective of stimulating innovation and translation. How can we promote as much innovation as we can, but in as safe and efficient a manner as possible? Particularly with new therapies for which, despite all the pre-clinical testing, we don’t know much about what’s going to happen in a clinical environment? We need to be actively asking these questions.

MF: If you were master of the universe for a little while, what would you do to greatly accelerate research in regenerative medicine, in order to save and improve lives as rapidly as possible?

Elisseeff: If we can enhance our methods and strategies for translation, it will create a positive feedback cycle in which more and more translatable technologies lead to better and better research, and ultimately, greater and greater impact. To me, a big part of that has to do with better education of academic faculty in how this process works. On the other side, it also depends on demonstrating the potential to those who are in a position to translate, either from the investor end or the commercial end.

We also need to cultivate more of an appreciation for the unique challenges, and unique value, of multi-disciplinary research. One of the major hurdles today for regenerative medicine strategies, including research proposals, is that there’s not enough appreciation for the fact that no single investigator is ever going to be an expert in everything at once—in stem cell biology, in the particular disease under consideration, and in all the other relevant fields.

This sort of universal domain expertise is not only impossible, but unnecessary. In our peer review panels, for example, what we’ll often see is that a proposal will come in that might be able to satisfy one particular domain expert, but there will inevitably be three others, all in different fields, who are each unhappy with some aspect of the proposal. It’s really hard to make all the experts in all the relevant fields happy, and I think more of us need to learn that the complexities of multi-disciplinary research require different considerations.

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Methuselah Honors Dr. Huber Warner Summer 2014 Newsletter

Dear Friends,

We hope you’ve been having a productive and satisfying 2014.

If you haven’t seen it yet, definitely visit our new Methuselah Foundation blog and let us know what you think. We’ve been publishing weekly posts, including a primer on the science of organ regeneration and a regenerative medicine news roundup from around the web during April and May.

We’ve also posted several recent interviews there, with Dr. Alan Russell of Carnegie Mellon, Dr. Takanori Takebe of Yokohama City University, Dr. Eric Lagasse of the University of Pittsburgh, and Brock Reeve of the Harvard Stem Cell Institute. In the weeks ahead, look out for part 2 of the Brock Reeve piece, a new interview with MIT’s Dr. Robert Langer, and more.


On May 30th, at the 43rd Annual Meeting of the American Aging Association in San Antonio, Texas, we awarded a $10,000 Methuselah Prize to Dr. Huber Warner for founding the National Institute on Aging’s Intervention Testing Program (ITP), a “multi-institutional study investigating treatments with the potential to extend lifespan and delay disease and dysfunction in mice.” Dr. Warner is a former program director for the NIA Biology of Aging Program and former Associate Dean of Research for the College of Biological Sciences at the University of Minnesota.

Kevin Perrott, Huber Warner, and Randy Strong at the 43rd Annual Meeting of the American Aging Association

According to Kevin Perrott, Executive Director of the Methuselah Prize, “The vision Dr. Warner showed, and his persistence over years of resistance to establish the ITP, is truly worthy of recognition. This program is going to provide not only potential near-term interventions in the aging process, but hard data to support claims of health benefits in a statistically significant manner. Science needs solid foundations on which to base further investigations, and the ITP provides the highest level of confidence yet established.”

“I saw lots of papers from grantees of the NIA about slowing down aging and extending lifespan,” said Dr. Warner, “but they were rarely backed up and given credibility through testing. Research over the last 25 years has been characterized by great success in identifying genes that play some role in extending the late-life health and longevity of several useful animal models of aging, such as yeast, fruit flies, and mice. The next challenging step is to demonstrate how this information might be used to increase the health of older members of our human populations around the world as they age.”


With New Organ, we’ve been busy growing our partner alliance, garnering endorsements (for example, from the Founding Fellows of the Tissue Engineering and Regenerative Medicine International Society), defining criteria for our upcoming heart prize, and working toward an official announcement of our first group of teams participating in the liver prize. We’ve had good initial interest, with five teams committed so far, and we’re currently in dialogue with many more.

The pre-release construction phase of our beautiful marble and granite monument installation in the U.S. Virgin Islands, to honor all of the major donors who are part of the Methuselah 300, will be completed by August. We’ve got some cool surprises in store, and our goal is to formally dedicate the monument in the first quarter of 2015, during the peak tourist season—with as many of you in attendance as are able!

Finally, don’t miss the SENS Research Foundation’s upcoming Rejuvenation Biotechnology Conference, taking place on August 21-23 in Santa Clara, CA. All the details are here.

And as always, please don’t hesitate to contact us with any questions, comments, and feedback.

Warm regards,

Dave Gobel

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Regenerating Organs for Transplant Interview with David Green


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


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


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.


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


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.


For part 1 of the interviewclick here.


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


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.


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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On Livers and Lymph Nodes Interview with Dr. Eric Lagasse

Dr.-Eric-Lagasse_circleDr. Eric Lagasse is Director of the Cancer Stem Cell Center at the University of Pittsburgh’s McGowan Institute for Regenerative Medicine.


Methuselah Foundation: What first motivated you to work on solutions to end-stage organ failure?

Eric Lagasse: Well, it’s a natural continuation of what I was already doing, which is cell transplantation and regeneration, particularly in the liver. I was using stem cells, and I realized that they might not be the solution for a lot of patients. That moved me to think about doing ectopic organogenesis.

MF: What is ectopic organogenesis exactly?

Lagasse: Patients with end-stage organ failure have a very diseased organ that is failing, and so the concept is to try to generate a similar organ somewhere else. The liver is an extraordinary organ. It can regenerate very well, so we asked the question, “Can we regenerate a liver outside its normal environment and have it function like an auxiliary organ that would assist the diseased organ?” This approach ended up being quite successful, and we’ve been able to demonstrate that we can transplant liver cells in the lymph node and regenerate an ectopic liver that functions very similarly to a normal liver. We’ve done this in mouse models, and we’re working now with larger animal models to reproduce what we’ve done with mice.

MF: How long do the mice survive this procedure?

Lagasse: As long as you want them to. The mouse basically has two livers now, one that is defective and another that is functional, and we haven’t seen any limitations on their survival.

MF: Is there any issue with tumor formation in this approach?

Lagasse: No, we don’t see any tumor formation. I think the problem that people are worried about when you transplant embryonic stem cells or induced pluripotent stem cells is that they might generate teratocarcinoma. It’s a question I get asked a lot, because the lymph node is also a site of metastatic cancer. But we’ve never seen it. The tissue growth that we generate is that of a normal organ. The transplanted hepatocytes don’t migrate to other lymph nodes, and when they grow, they don’t form tumors. As the liver grows, it basically allows the vasculature and the lymphatic tissue to grow around it or sometimes even inside it, and the segregation progresses normally. There’s nothing even close to tumor development.

MF: What challenges are you facing in translating this work to a larger animal model?

Lagasse: The first major challenge is that there really are no good large animal models of liver disease. So you have to deal with a normal animal, and then induce a liver disease that resembles, to a certain extent, what a patient might have. This is very expensive and difficult.

The liver is an essential organ. You can’t live without it. I always joke that you can live without a brain, but you cannot live without a liver. So if you create a liver injury that mimics the extent of what a human patient would have, then you have a very diseased large animal, and the animal needs to go into something like an ICU just to keep it alive. It’s very costly to take care of an animal this way 24 hours a day, to make sure that it doesn’t die and doesn’t suffer and so on. In our experience so far with large animal models, like the swine model, each animal probably costs $20,000 to $30,000 to do.

And you can’t do just one. You have to do a whole set in order to cover all the parameters necessary to demonstrate that what you have is applicable to human patients. So it can build up pretty fast. I mean, 10 animals might cost you half a million to a million dollars eventually.

MF: What’s the funding situation like right now for this kind of work?

Lagasse: There is some funding available from the NIH, but it’s very hard to get. At the moment, they’re interested in how things work. They want to see studies of molecular mechanisms, gene proteins, and so on. They’re not as interested in applications to patients without first clarifying molecular mechanisms. So approaches like ours are very challenging because we don’t have that. But if you don’t do large animal models, the probability of translating whatever we’ve found in mice into patients is low to non-existent. When you eventually go and ask for a clinical trial, the FDA will probably ask you to show a large animal model study that demonstrates proof of concept.

MF: What role does the public play in all of this? Some of the regulatory challenges to addressing HIV/AIDS, for example, were only overcome once broad public will had been generated.

Lagasse: Yes, I think the public has a very important role to play. In addition to AIDS, diabetes is another disease where I think people have successfully challenged the administration and been able to get more money funneled toward solutions. Whereas in fields like the liver, for example, you have fewer people voicing their concerns about the research, and so you have a lot less money. So it’s very important that the public helps push politics forward and encourages the administration to move on this and bring more money to the table.

MF: We’ve been thinking recently about how to encourage more partnership, collaboration, and strategic alignment among scientists, funders, and research institutes, beginning in the US. With respect to these things, what does the current environment in the US look like to you? What are you encouraged by, and what would you like to see change? For example, we’ve been hearing a lot of people say that they’d like to see more mandated collaborative grants to better encourage information sharing across institutions.

Lagasse: Well, the first thing is more access to money, of course, because without the money, you can’t do the research. If this access to money is via collaborative efforts, why not? Organogenesis and cell transplantation is a complex approach, and often one investigator cannot do everything. So it seems logical to me that having a group of collaborators in different fields working together toward one goal would be an efficient way of doing this. But the money is the essential part of the process.

MF: If you had a coalition of funders committing, say, $25 or $30 million to this area that could be allocated any way you wanted, how would you do it?

Lagasse: Well, that would be incredible, because we’d be able to translate this really, really fast. It’s only a question of time. With that kind of money, you could shrink the time to get to clinical trials from five years to maybe two.

In our large animal study, for example, we did a set of experiments that were very successful, but we ran out of funding and everything came to a standstill in the past nine months. I’m still looking for the funding to continue. After I find it, we’ll demonstrate our proof of concept in large animals and then go to the FDA and say “Look what we have, we’re ready for clinical trials.” But then I’m going to have to find the next stage of support to do feasibility studies. That might take another year or two.

There’s no technological challenge; all we have to do is experiment. But the money is kind of the oil for the engine. If you don’t have any oil, you just have to stop the engine and wait till you get more. That’s the way it is.


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Transforming the Treatment of End-Stage Organ Failure Interview with Dr. Takanori Takebe


Dr. Takanori Takebe of the Yokohama City University Graduate School of Medicine is Team Leader of one of the first participating teams in the New Organ Liver Prize.


Methuselah Foundation: You made a big splash last year with your “liver bud” paper in Nature. What has developed with this line of research in the last nine months?

Takanori Takebe: I’ve tried lots of different things, but you can group them roughly into five research areas:

1. Studying the mechanisms underlying our liver bud forming process.

2. Establishing the mass scale production of micro liver bud in culture.

3. Exploring potential applications to other organ systems.

4. Optimizing transplantation procedures to maximize therapeutic potential, including orthotopic transplant (i.e. replacing the native liver).

5. Developing preclinical animal models of liver disease.

MF: What is the most significant challenge you face in taking this work forward?

Takebe: The most important challenge is simply how to make enough liver bud to transplant into patients. The liver is one of the largest organs in the body, requiring approximately 10 billion hepatocytes to restore sufficient functionality. So we have to produce huge amounts of liver bud at a reasonable cost, including the cost of safety evaluations. Currently, using conventional 2-D inefficient approaches, we estimate costs of more than $10 million per person, and we are working to reduce that number significantly with several technical modifications.

MF: How are the prospects for clinical adoption?

Takebe: It will take approximately seven years before we can start clinical studies to assess the safety, rather than the efficacy, of liver bud transplants.

MF: What is your ideal vision of the future? If I’m a patient with liver failure, how do you imagine my experience would change?

Takebe: I hope to see the day when we do not need to use dead bodies for transplant organs. As a patient, all you’d need to do is provide a drop of your blood, and we could make an alternative rudimentary organ for you.

MF: At age 26, you became one of the youngest professors in Japan. What first motivated you to work on solutions to organ disease?

Takebe: My trainee day at the transplant center was eye-opening. I saw many catastrophic examples of the organ shortage, in which a lot of patients were excluded from transplantation or simply died before transplant surgery. Before that point, I had dreamed of saving many lives as a surgeon, but I saw that this was possible only when one could get the donated organs.

This motivated me to establish an alternative approach to saving lives that didn’t depend on waiting for a matching donor to die. To tackle this problem, a regenerative approach using stem cells is one of the most fascinating approaches, and I resolved to start my career by studying regeneration medicine using human cells (Takebe, et al. Proc. Natl. Acad. Sci. USA, 2011; PLoS ONE, 2011; Nature, 2014).

MF: How would you describe the funding climate right now in Japan for regenerative medicine and tissue engineering? Is the government making these areas a priority?

Takebe: The funding volume is increasing, but only a small fraction of the most senior scientists can access such big money for the realization of emerging approaches. The government does prioritize the translational research of regenerative medicine, and it distributes between one and ten million dollars each to five large teams led by very famous professors. Challenging research done by young scientists like me, on the other hand, is very difficult to get funded in Japan.

MF: At New Organ, we’ve been thinking a lot recently about how to encourage more partnership, collaboration, and strategic alignment among scientists, funders, and research institutions in the U.S. With respect to these things, what’s the current environment like in Japan? What are you encouraged by? What would you like to see change?

Takebe: That sounds very good! The Japanese funding community is not always good at promoting emerging technologies. (Japan is much more conservative than you might imagine, and often resistant to change.) This is especially true when it comes to highly risky and challenging fields such as regenerative medicine. So I think more collaborative international relationships, both in terms of funding and human resources, would dramatically accelerate our and others’ ability to conduct clinical trials.

MF: We’re delighted that you’re participating in the New Organ Liver Prize. How do you intend to approach the challenge?

Takebe: I hope to demonstrate the therapeutic efficacy of liver bud transplantation first by using subacute type infantile liver failure, and then by trying to expand the indication to adults. Also, I want to examine the adaptability of other organs like the pancreas and the kidney. My hope is that organ bud (rudimentary organ) transplantation therapy will revolutionize regenerative medicine and transform the treatment of end-stage organ failure as we know it.



Visit Yokohama City University Advanced Medical Research Center online.

MIT Technology Review: A Rudimentary Liver Is Grown from Stem Cells

Nature: Miniature human liver grown in mice

Explore applications for Takebe’s work and beyond at Knoepfler Lab Stem Cell Blog.

Jeremy Hobson and Carey Goldberg, host of WBUR’s CommonHealth blog, discuss stem cell grown liver buds on NPR’s here & Now.


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The Great Potential of Regenerative Medicine Interview with Dr. Alan Russell

Dr.-Alan-Russell_circleExcerpted from a recent conversation with Dr. Alan Russell, Highmark Distinguished Career Professor at Carnegie Mellon and former Founding Director of the McGowan Institute for Regenerative Medicine at the University of Pittsburgh.


Methuselah Foundation: In your opinion, what are the most significant barriers to progress in organ bioengineering right now?

Alan Russell: That’s a bit like asking me “how long is a piece of string?” It’s a huge, unending discussion. A new textbook just hit the market on regenerative medicine, and it’s about 2,000 pages of answers to the question you just posed. In very broad strokes, I think it’s a mixture of money issues, business issues, and scientific barriers that for years have gotten in the way of the broad application of organ engineering to successfully replace transplantable organs.

MF: We’ve recently been exploring the idea of creating a kind of “moonshot” document for organ engineering and regeneration in order to build greater alignment and fuel collaboration among various researchers, institutions, funders, etc. Is this something that you think would be useful to pursue?

Russell: A lot of people have tried similar things. There have been government-led initiatives all over the world to try and create helpful collaboration between groups. The AFIRM program (Armed Forces Institute of Regenerative Medicine), for example, is one that has included a whole organ approach. The founding documents of the California Institute for Regenerative Medicine seemed to play a role in helping secure its $3 billion public investment. There’s also a document out calling for a Federal Initiative in Regenerative Medicine that’s been reasonably impactful.

I hope I’m not jaded by history, but I’ve personally been involved in so many of those kinds of initiatives and discussions, and very rarely does anything of any substance or utility really come out of it. For the most part, these are all just collections of people that say they’re going to work together in order to generate research money, and they don’t necessarily really work together.

There is one recent, very substantive effort led by David Williams that I could point to. It took place in China last year, and it was really focused on the grand challenges of regenerative medicine. I think the document that came out of it was going to be published in The Lancet.

MF: You mean the Xi’an Papers?

Russell: Yes. That document does everything you’re talking about. But the real question to answer is, did anyone read it? Did anyone change their behavior as a result of reading it?

MF: That’s a good question. I don’t know, but I agree that it’s a good model for what we’re envisioning. Let’s switch gears now and talk about your own work. What do you personally believe are the most promising pathways forward for regenerative medicine?

Russell: I’m a great believer in whole organ engineering, meaning decellularization and recellularization. But if I’m really honest, do I think that it will provide clinical relevance? I think probably not. I see it a little bit like I see embryonic stem cell research. It’s going to teach us a huge amount about how to use cells and stem cells in vivo, but perhaps they themselves won’t be used clinically to a great extent. So I don’t know that decellularization-recellularization is the path to go.

My personal favorite of all of the different approaches is actually called “ectopic organogenesis.” This is the approach that was promulgated by Eric Lagasse, who discovered that you could repopulate lymphatic tissue with different kinds of cells, and through doing that, encourage the transformation of a lymph node into a miniature organ of different kinds. I think this work has much more clinical potential.

MF: What would you say is the single most important thing for people unfamiliar with regenerative medicine to know or appreciate about the field?

Russell: When I talk to the public, I always express it like this: When you go to the doctor and you hear certain words, it can raise great fear. Some words, words like “diabetes” or “Parkinson’s” or “Alzheimer’s,” are very alarming to hear. And there are other words that aren’t—words like “sore throat.” If you went to the physician 100 years ago and they said, “Hey, you have pneumonia,” you would have been scared, because you’d be dead. Then science came along and made those words less fearsome. So I think the great potential for regenerative medicine is that it represents a set of tools that will allow what we currently think of as debilitating, terrible diseases to be less scary. That’s exciting because it’s something that our grandchildren are likely to benefit from. In other words, by the time people being born today are old enough to have to face some of the challenges that you and I might face, these tools will be ready to help them.

MF: That’s great. How about for people within the regenerative medicine community? What’s the most important thing you’d like your peers and colleagues to better understand or appreciate?

Russell: I’ve said this one a thousand times: the need for standardization. Typically, everybody works in their own little way, with their own model, and a lot of the work is unfortunately very hard to reproduce. If you look at industries that have innovated rapidly and successfully penetrated their markets, whether it’s PCs or mobile phones or even the automobile industry, they’ve often been able to do that because different competitors decided to come together and agree to a common set of standards. In our field, we haven’t done that.


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Welcome to our new blog!

Since launching the New Organ Liver Prize at last year’s World Stem Cell Summit (WSCS), we’ve been hard at work growing the New Organ Alliance and reaching out to potential prize teams. We now have four labs lined up to participate in the prize challenge, with more on the way.

In case you missed it, here’s Methuselah CEO Dave Gobel’s announcement speech at WSCS. “It seems to me species insanity,” he says, describing the origins of New Organ, “that we would spend $200,000+ to restore a car like a Shelby Cobra, and yet all that car’s creator Carroll Shelby could get were junkyard parts. His heart came from a dead person—it wasn’t new. His kidney came from his wonderful son, but it wasn’t new. And it didn’t fit. None of these parts fit.”

Right now, we’re also developing the next prize in the New Organ series, which we hope to announce later this year. This time, we’re focusing on the heart.

Coming up in May, at the World Stem Cells Regenerative Medicine Congress in London, we’ll be introducing New Organ to the European audience at one of the world’s leading events for cell therapy and regenerative medicine.

In the meantime, we’re excited to be launching this new blog to keep you more connected to many different aspects of our work as it unfolds in real time. Look out this month for new interviews with several New Organ advisors and participants, including Dr. Alan Russell of Carnegie Mellon and Dr. Takanori Takebe of Yokohama City University.


The Methuselah Team

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