Biomaterials and Clinical Translation Interview with David Williams: Part 1


David Williams is the current President of TERMIS. He is a Professor and Director of International Affairs at the Wake Forest Institute of Regenerative Medicine, Chairman of the South African medical technology company Strait Access Technologies Pty and a Master of the DeTao Academy in China.

The New Organ Initiative is hosted by the Methuselah Foundation.



New Organ: What is your background?

David Williams: I’m trained as a materials scientist, but I worked for the last 45 years as a professor of medical engineering and in various aspects of the medical industry, mostly in Liverpool, and now at Wake Forest in North Carolina. Most of my professional life, I’ve been concerned with medical technology, especially implantable devices—hip replacements, heart valves, and many others—and the materials used for them.

About 10 years ago, I transitioned to incorporate regenerative medicine. The reason for this is that we’ve been pretty successful in working with implantable devices, but we’ve had a very limited range of options and functions. We can use synthetic materials to replace parts of the body that have failed for some reason, but we can only replace mechanical or physical functions. We can’t replace biology. Therefore, we can’t address many of the really important diseases, especially degenerative conditions, where we need to restore biological or pharmacological functions. That’s where regenerative medicine comes in.

NO: Between the Wake Forest Institute for Regenerative Medicine (WFIRM), the Tissue Engineering & Regenerative Medicine International Society (TERMIS), the University of Liverpool, the journal Biomaterials, and more, you wear a lot of different hats within the regenerative medicine community.

Williams: Yes, I suppose I do. Most recently, after 40 years as an educator heading up a large research group and chairing the department at Liverpool, Dr. Anthony Atala asked me to come work with him at WFIRM as a professor of biomaterials and also as director of international affairs. So my role is to mentor and facilitate international collaborations.

In everything I’m doing, you’ll find that the words “international” and “global” figure strongly. That’s my role at both TERMIS and WFIRM. And perhaps just as importantly, it’s my role as editor-in-chief of Biomaterials, the world’s major journal in this area. I’ve taken Biomaterials to number one as a major journal, and I’ve done so internationally—encouraging, promoting, and sponsoring research work all over the world, including Asia and Africa. I think advancing this field is largely a global issue, and whether we’re doing research or educating or working in the commercial sector, we should look at it that way.

NO: I want to come back to your international work, but for the moment, let’s talk about biomaterials. What are they, and what kind of work are you doing with them?

Williams: I published a short paper recently called “The Biomaterials Conundrum in Tissue Engineering,” and to put it simply, I think we’ve mostly gotten it wrong. I’m not being too critical, because it was probably inevitable, but the early attempts at tissue engineering involved material scaffolds, and that’s where biomaterials come in. The scaffold is the form in which you’re going to develop an engineered organ, and the originators felt that they needed to get FDA approval for them. Therefore, they needed to use an FDA approved material, and although this was understandable, I think it was misguided.

The sole criteria for FDA approval for biomaterials used in implantable devices was that the material did no harm. It had to be known to be safe. You’re never going to get a scaffold or template material to function properly if all it does is play safe. You need the material to actually stimulate cells through mechanical forces or growth factor delivery, and standard synthetic polymers were never going to do this reliably and routinely.

Because of this, I think we need totally different types of materials that try to replicate or represent the micro-environment of the cell. I’ve been shouting this from the rooftops for a long time now. It can’t be an engineered fabricated structure that looks nothing like the cell micro-environment, or we’ll never be able to make the cell regenerate the tissues that we want.

We do have a number of pretty good hydrogels that do this, especially biologically-based hydrogels. That’s why decellularized extracellular matrix (ECM) is getting so popular. I don’t think we’re there yet by any means, but there are some interesting approaches around. But the key is that we have to have a different mindset regarding how we develop our biomaterials, and the regulators have to have a different mindset regarding how they regulate them. We can’t use the standard tests for safety that the FDA is saying that we still have to use, and that’s a big issue at the moment. For the most part, the regulators still want to play it too safe.

NO: Are you a voice in the wilderness on this, or are there others out there who see it the same way?

Williams: There are some very good labs that are doing what I’m suggesting, but far too many that are not. Sam Stupp in Chicago and Jeff Hubbell in Switzerland are two who are, and there are quite a few others. Steve Badylak’s work on decellularized ECM is also very good. So I’m certainly not alone. I’m just trying to make sure that the community is aware of it.

I do get frustrated sometimes. I was at a biomaterials meeting in Europe this year, and presentation after presentation and poster after poster talked about a minor modification to an old material that never worked anyway. We academics have to get over this barrier. Why spend dollars and student time working on old science that is never going to work? It’s easy to do, but it’s not going to get us anywhere.

NO: What do you see as the most promising approaches to biomaterials?

Williams: Let me first make clear that even though I’m a biomaterials scientist, I don’t believe that we will always need biomaterials as part of regenerative medicine. There are a number of different approaches and therapies out there, for which a variety of different materials may be appropriate. However, if we do want to create solid organs and achieve reasonable dimensions to tissues, they will have to have some sort of structure, and I think we can only get that by using materials that are capable of elaborating that structure.

I mentioned Sam Stupp in Chicago, who uses peptide hydrogels, and works in both the musculoskeletal and the neural areas. I think his approach is very sound. I work with some groups in China who have made good progress in peripheral nerve regeneration using a combination of materials and growth factors and other bio-molecules. The overall principle, though is that we need a systems approach. It’s not just one issue, but putting many different pieces together that gives the best opportunity for a cell to regenerate the cellular matrix and then for it to be integrated into the host.

NO: In terms of advancing state-of-the-art biomaterials science, what would you like to see happen that’s not happening? What activities would really move things forward?

Williams: One of the biggest questions now has to do with suitable models for evaluation prior to “first in human.” It’s a huge issue. We know that we can use both biomaterials-based therapy or cell therapy in mice, and we can do it in rats or in rabbits. But the first thing you notice is that you get different results in these different types of small animals, and when you go to a large animal, you get even greater variations in the results, especially in vascularity.

We need an appropriate large animal model that will be sufficiently predictive of performance in the clinic to allow regulators and funders to say, “Yes, go ahead and do it.” Without that, we’re never going to be able to commercialize, because any company involved in this will have to follow the proper regulatory rules, and those are just too burdensome at the moment.

For example, the great work that has been done to date on the bladder and the trachea by people like Tony Atala and Paolo Macchiarini has been done under regulatory approval, but not as a commercial entity. And doing these transplants as orphan procedures is not necessarily going to translate into commercial success. The companies that are making money in regenerative medicine, I think, are those that are scaling up on the cell manufacturing side, companies like Mesoblast in Australia.

So far, we don’t actually have a business model or a real clinical translation model that is going to allow for-profit companies to make their profit by treating a significant number of patients. We’ll do it one by one, but to translate that into companies actually coming in, investing, and making money at scale in the manufacturing of tissue is a huge issue. We should never forget the role that health economics plays in all of this.

NO: Do you think we’re more likely to see clinical commercialization success in other countries? In other words, are economic conditions more favorable elsewhere? And if so, will those successes increase the odds of more favorable conditions in the U.S.?

Williams: It’s too difficult to predict that at this stage. Let me give you an example. Ten years ago, when I was back in my lab in Liverpool, we worked on a tissue engineering approach to treating diabetic foot ulcers. We were working with a company and we had a system that was looking pretty good. But it was costing 20,000 euros to develop one product for one person, and that was just never, ever going to work.

From a health insurance point of view, the answer is, “We’ll just put a new bandage on every week. You can have a band-aid.” And I’m not diminishing the impact of diabetic foot ulcers, but that was not the life-threatening issue that New Organ is trying to deal with. That’s why here in the U.S., I think we’ve got huge problems. It’s not simply ObamaCare or the Affordable Care Act. It’s the way in which the insurance provider is now in charge. I think it’s going to be very difficult as long as their priorities are focused on short-term benefits. As far as I can see, long-term solutions are not really in the best interests of many insurers right now, and so the overall health economics in the U.S. are working against us rather than for us at the moment.

In order to change that reality, we have to persuade real decision makers that “Yes, there really is a future in this.” And there are very significant early costs required in order to get to that point. Pre-clinically, for example, we’re nearly there now in the treatment of patients with acute myocardial infarction (heart attack). There are some good cell therapies, as well as some tissue engineering approaches that look as though they may work.

I can also give you a couple of examples from the medical technology area. You may remember the artificial heart, and especially the heart assist devices? They can certainly be successful, but when the hardware and the first-year costs of these treatments amount to almost $500,000, and it saves one life for a year or two, that’s obviously a big health economics issue. It’s the same when you look at the treatment of peripheral vascular disease (when a patient has clotted arteries in the leg). To avoid an amputation, we can put in vascular grafts, and I work with Peter Zilla in South Africa who developed a technology 10 years ago to seed those vascular grafts with endothelial cells from the patient. This improved the performance significantly, and he published paper after paper showing the improved patency rate (i.e., freedom from obstruction). He believes that this is the first type of tissue engineering, which I think it really was, and it improved patients’ lives enormously. But it was just too expensive for any hospital to take it up. You had to take the patient in, harvest her endothelial cells, and then grow them in the graft for several weeks. It just wasn’t going to happen.

Examples like these lead me to conclude that health economics presents a very significant immediate barrier to what we’re trying to do. It’s still unclear to me what a successful business model in regenerative medicine is going to look like.


Tissue Engineering Collaboration Interview with Dr. Tahera Ansari


Dr. Tahera Ansari, a Senior Post-Doctoral Scientist at the Northwick Park Institute for Medical Research in the UK, is leader of Team Hepavive, one of the first six teams participating in the New Organ Liver Prize.


Methuselah Foundation: How did you get into liver engineering?

Tahera Ansari: I actually started off looking at how to engineer the small intestine or small bowel, which I’ve been doing now for several years. At the Northwick Park Institute for Medical Research, which is affiliated with St. Marks Hospital, we have a number of patients who have insufficient bowel tissue. We could simply feed them through their blood and through a tube, but there is a lot of morbidity associated with that. In some cases, they could have a transplant, but there just aren’t enough organs to go around, and not every patient is suitable for transplantation anyway. So the small bowel tissue engineering work really came out of a clinical necessity.

A few years later, I was talking with one of my colleagues who works on the liver, professor Peter Friend, from Oxford University. He said to me, “You’ve been able to take the small intestine and turn it into a scaffold. Wouldn’t it be nice if we could do something along the same lines for the liver?” And that’s what we did. We started out quite big, in that we began working straight away with pig livers. Because we are located within a large pre-clinical facility, we already have large animal models around for certain procedures. One of the things the regulatory bodies in the UK like to see us do is to use the whole animal as best we can, so we started harvesting livers out of animals that were being used for unrelated studies, turning them into scaffolds, and working on how to perfuse these scaffolds with blood without the blood vessels leaking or breaking down. We are now at the stage where we are working with the vasculature in the liver itself to be be able to reseed the scaffolds with new cells and turn the liver into a functional organ again.

MF: What’s the most significant challenge you’re currently facing with this?

Ansari: It definitely has to do with scaling up our cell source, because the liver is such a large organ, and you just need an enormous volume of cells. We can take fat-derived bone marrow stem cells and turn them into pretty much any cell that we want, but we need such large quantities that we may have to combine cells from different populations in order to get enough. Plus, when you perfuse these scaffolds, not every single cell ends up attaching and sticking around. Some of them don’t survive, so you have to have a surplus. It’s not just as simple as saying, “Okay, we can work out the density of the liver, and we can work out how we seed it, and that’s all we need.” We’re going to need different populations of cells, and we need to get the ratios of these cells sorted out. There are lots of little pieces of the jigsaw that need to come together before we’re ready to do this.

MF: How are you working to tackle this cell sourcing issue in your lab?

Ansari: Well, we’re going back to how we tackled it for the small bowel, which was to use clusters of cells known as organoid units rather than single cells alone. For the bowel, what that cluster looks like is an epithelial cell outer layer surrounding the specialized stem cell of the intestine—basically, a little ball of cells. One of the beauties of these organoid units is that because all of the cells are together, they’ve already got their natural architecture in place. When you’re working with single cells, they have the unfortunate habit of changing into other cells that you don’t want. The more you can keep cells together, the happier they are. So these already existing cell architectures turned out to be very useful to us.

Likewise, with the liver, rather than using single cells alone and therefore having to figure out how to mass produce them in order to get enough, we’re exploring whether or not we can use these organoid units instead and get them to expand and coalesce into functional tissue. It’s kind of like giving the whole process a head start. Instead of saying, “Okay, two cells need to get together and start talking,” we’re saying, “Can we put 10 cells together and get them to talk to another 10 cells?”

Down the line, we’re still going to have to figure out where these cells will come from. With pigs, I can take the liver from one pig and turn it into a scaffold, and then take another pig and break down its liver in order to get a bunch of little organoid units out of it, which I can then seed back into the scaffold. That’s great, but it’s not clinically translatable. I can’t really go to a human patient and just take out little bits of their liver and start chopping them up, because they need their liver to survive. So it’s a bit of a Catch-22 at the moment.

In the end, I wonder whether we may have to figure out how to harvest a smaller portion of organoid units from small biopsies of a patient’s liver, seed them into a scaffold alongside other stem cells, and then somehow get those organoid units to turn the adjacent stem cells into liver cells. We do have a little bit of lab evidence that this could work, because we’ve taken bone marrow stem cells, co-cultured them together with epithelial cells from the trachea, and these stem cells have shown signs of turning into epithelial cells themselves. But this still needs to be explored in a lot more detail.

MF: What’s your ideal vision for this work in the future? If I was a patient with liver failure, how would my experience change?

Ansari: Well, a lot of it would depend on what the underlying cause for your liver failure was. In general, we’d eventually like to be able to say to you, “Here’s a fully seeded new liver, and you can have a full transplant.” Before we get to that point, however, it may also be possible to use a partial tissue-engineered liver to make some kind of dialysis machine, much like we do for the kidney. This would give us the opportunity, step by step, to offer an intermediate form of treatment that would give your liver a chance to regenerate a little bit and regain some of its function.

MF: How far away would you say the full transplant is?

Ansari: Based on the work we’re doing now, I think we’ll need another four to five years at least before we’re ready to find our first human patient and do a serious pre-clinical GLP study, which is the completely audited study that the regulators would approve of. And that’s for the dialysis treatment. Once you got the dialysis up and running, from there it may just be a case of scaling it up to full engineered organ transplants. I don’t know how long that will take.

MF: Above and beyond the various scientific and technical challenges we’ve been talking about, what else would you say is currently inhibiting progress in tissue engineering?

Ansari: I think there’s probably a couple of things. First, everyone is going to say they’d love more funding. And of course we could all use more. I started my own career in maternal-fetal medicine, and one of the reasons I moved away from that was the lack of funding. Comparatively, things are a lot better in regenerative medicine. It’s taken some time, but there’s been a groundswell of government support over the last couple years. In the UK right now, for example, there’s a lot of emphasis on commercialization and getting things to market. In tissue engineering, if you have a good idea and a good study plan, I think there are people who are willing to listen to you. You may not get all the money in one go, but enough is available to get over certain hurdles that were just insurmountable five years ago.

Another point I’d make is that I think it would be nice to involve more patients at earlier stages in our work. At some point, we’re going to have to start asking people, “Okay, we’ve got these cells, we’ve got these scaffolds. How many of you would be happy to receive a porcine product? How many of you would be bothered by that?” Those issues will definitely need to be explored.

Finally, because this field is relatively new, we don’t yet have a standardized regulatory body, and we’re going to need one. There just isn’t enough information available yet to outline meaningful criteria for approval. There are certain things we can say. For example, if an organ scaffold comes from a non-human species, there has to be complete viral clearance. It must not mount any immune response. Then there are all the regulations from the stem cell side: Where do the cells come from? Will they cause cancer or not? Etc. But the whole area is still a bit woolly.

MF: One of the things that we’re particularly interested in is how to encourage more partnership and collaboration among various scientists, funders, and institutions. I also know you’re part of a team made up of people from several different organizations. What’s the current competitive environment like in tissue engineering in the UK? How important do you think collaboration is in the grand scheme of things, and what has your experience been like so far?

Ansari: I think collaboration is key because no single facility has enough expertise on its own to get things done. Our little unit is very good at doing pre-clinical studies, for example, but we needed the guys in Oxford for all the human stuff, and so on. So I purposely set up our New Organ team to cross over as many different disciplines as I could in order to make sure the whole project coalesces and fits together as well as it can. The challenges are so complex, you just can’t do it all yourself.

One concern I do have is that when large research centres come together, they often end up with disproportionate amounts of power. In the UK, we have what we call “Centres of Excellence,” and the majority of the funding goes to them. Quite often, there are other research facilities that have good ideas and get good ratings, but if you’re not connected to one of these Centres of Excellence, you just can’t get funding. Of course, I appreciate the value of concentrating limited resources at times, but I am also cautious about too much consolidation. Sometimes, ideas from out in left field end up coming along and making huge differences, and I don’t think we should be excluding anybody. We need as many heads as we can get working together in order to solve this.

MF: That makes a lot of sense. I’m curious—have New Organ’s prize criteria shaped or altered your research direction at all?

Ansari: Yes, I think it has. One thing it did make us do is to concentrate our minds on the functional outputs of our work. Up until now, we’d been thinking more broadly about how to find the cells, and how to get the scaffolds working, and how to put the two together, and the prize has shifted our focus somewhat toward defining what specifically we’re looking to measure in order to assess whether or not these livers are actually functional. We might get the cells to attach to the scaffold, for example, but if they’re not achieving certain levels of functionality, they’re not much use to anybody. So the prize has encouraged us to think several steps ahead, and to do so earlier on in the project than we otherwise would have.

MF: That’s great to hear. Do you think this increased focus is going to accelerate your research generally, or help it be more aligned toward clinical translation?

Ansari: Personally, I do think the prize targets are going to focus us on more measurable clinical outcomes. One of the hallmarks of the Institute here is that we’re very much driven by solving specific clinical problems. We’re trying to get away from the habit of just making products in the laboratory and then looking around after the fact for something to use them for. At the end of the day, there are patients out there who need a liver because theirs is failing. You can always sit in the lab and fine tune these technologies to the nth degree, but in order to solve the problem, you might not need to do that. I think having that focus is vital, and the prize has given us an additional incentive and a strong rationale for prioritizing things.

MF: If there was one thing you could say to the average person who might not be at all familiar with regenerative medicine—still a relatively young, unknown field—what would it be?

Ansari: If I had to go out and talk to the average person who didn’t know anything about tissue engineering, one of the things I would like to ask them is, “If you needed a transplant of some sort, what kind of product would you be happy to receive? Would you be happy with an organ that we had made in the lab, or would you only want to receive one that came from another person?”

I think a lot of people, when they hear about what we’re working on in my lab, think it sounds a bit like Frankenstein. And I suppose we probably could eventually put together some kind of Frankenstein, because of all the different body parts we’re making here. But unless we can get across to the average person that these body parts are honestly quite crude, yet have the potential to solve very significant clinical problems, then in some sense we’ve failed.

The fact is, whether we like it or not, we have an aging population, we have a significant shortage of organ donors, and tissue engineering may offer potential solutions. We’re going to have to do something. We can’t just sit back and say, “Oh well, something will eventually come along.” Something won’t come along. We need to take a very proactive approach, because we simply don’t have enough organs, and we have more and more patients that need them.

MF: That’s great. On the flip side, what would you say to your peers and colleagues within the field? What’s the one thing you feel is most underappreciated, even among the experts?

Ansari: Honestly, I guess I would say something similar to them, too. I think a lot of my professional colleagues don’t fully understand the strengths of tissue engineering, either, and how much it can actually deliver on once we get some of the technology sorted out. It’s quite difficult to appreciate just how new this field is, how rapidly it’s expanding, and how many different components are coming in from the periphery that have the potential to deliver major transformations, perhaps even more so than the stem cell field. We’re still dealing a little bit with the legacy of over-hyping stem cells, so there can be this feeling of “Oh great, here we go again.” Stem cells were going to come along and solve everything, and it just didn’t happen. But tissue engineering is still in its infancy.

To me, one of the greatest strengths of tissue engineering is actually that it’s tailor-made for collaboration, because it simply requires it. So many different components have to come together. You need biological scientists talking to materials scientists. You need stem cell scientists and bioengineers and clinicians all working together. The jigsaw puzzle just isn’t complete without them. They are all crucial pieces. The stem cell field, by contrast, could initially just happily go along on its own, and I think that kind of isolation was probably detrimental.

This is certainly the first time in my professional life that I’ve had to go out and talk to people who make polymers and hybrid materials, or electronic engineers with no biology background. We often have to sort of explain our disciplines to each other on the fly, simply out of necessity, in order to figure out how to make what we need.

MF: It sounds like it must be an exciting time for you.

Ansari: It is. By nature, I’m quite curious and I quite like dabbling. And this is like the first time I can do this legitimately! I can go and play with something without being told, “What are you doing that for?” If you have this natural curiosity and tendency to want to dabble in different things, tissue engineering is wonderful because there are so many different avenues that can be, and need to be, explored. There are still a lot of hurdles in front of us, but it is definitely an exciting time. I’m very hopeful for the patients of the future.


Six Teams to Compete for New Organ Prize Fall 2014 Newsletter

Dear Friends,

Great news! Today, we’re announcing the first six teams to officially compete for the New Organ Liver Prize. These teams represent scientists from Harvard Medical School, Massachusetts General Hospital, Northwick Park Institute for Medical Research, University College of London, University of Florida, University of Oxford, University of Pittsburgh, and Yokohama City University, and are being led by:

  • Dr. Tahera Ansari (Team Hepavive): Pursuing the ‘decell-recell’ approach to bioengineering a liver.

  • Dr. Stephen Badylak (Team Badylak): A pioneer in biologic scaffolds using extracellular matrix.

  • Dr. Eric Lagasse (Team Ectogenesis): Grew mini-livers inside the lymph nodes of mice with liver disease.

  • Dr. Bryon Petersen (Team Petersen): An authority on the role of hepatic stem cells in liver pathology.

  • Dr. Takanori Takebe (Team Organ Creative): Created tiny ‘liver buds’ that grew and functioned in mice.

  • Dr. Basak Uygun (Team HepaTx): First proof-of-principle transplantation of engineered liver grafts.

For full bios, please visit the team page at our website. Additional teams are also under review and will be announced in a future update.

Good luck to all!



On July 29th, New Organ facilitated a meeting hosted by the Department of Health and Human Services that brought together 10 federal agencies and other stakeholders to explore current efforts in tissue engineering and regenerative medicine (TERM) and the role that incentivized innovation can play in advancing specific challenge targets.

We’ve also submitted a proposal for a workshop entitled Building a TERM Roadmap for Organ Disease” to several potential convening partners. The outline proposes a gathering of 50 scientific, government, industry, and philanthropic leaders committed to advancing biomedical engineering and regenerative medicine breakthrough technologies to address organ disease. Participants will define key challenges at the science and system level; identify enabling technologies and quantitative milestones that can be used to inform future research efforts and challenge prize targets; and examine tools and innovation models that can be applied to advance specific goals. Please contact us if you’re interested in supporting this effort.

New Organ’s close collaboration with the Organ Preservation Alliance (OPA) continues. OPA has proposed key ideas and facilitated input for several Small Business Innovation Research and Small Business Technology Transfer proposals on tissue and organ cryopreservation, currently under review. OPA also secured basic underwriting for the first global “Grand Challenges in Organ Banking” Summit, to be held in Palo Alto, CA in February of 2015. They’ve also updated draft rules for the proposed Organ Banking Prize: a challenge competition to demonstrate long-term storage of a solid organ and subsequent transplantation into a human or large animal.

Finally, New Organ is considering the possibility of a new Vasculature Prize to stimulate the vascularization of thick, functional tissue. Details on this effort, which is currently being explored in coordination with a federal agency, will be forthcoming as discussions progress.



Our bowhead whale DNA sequencing project, funded by Methuselah donors and led by Dr. Joao Pedro de Magelhaes at the University of Liverpool, has now been completed. Thank you for your generous support of this important work.

To facilitate further research, Dr. de Magelhaes’ team eventually plans to make their data available online. Here’s the abstract from their manuscript, currently in submission:

“The bowhead whale (Balaena mysticetus) is estimated to live over 200 years and is possibly the longest-living mammal. These animals should possess protective molecular adaptations relevant to age-related diseases, particularly cancer. Here we report the sequencing and comparative analysis of the bowhead whale genome, accompanied by two individual transcriptomes. Our analysis identified genes under positive selection and several bowhead-specific mutations in genes known to play a role in cancer and ageing. In addition, we identified instances of gene gain and loss with potential phenotypic effects, including in genes associated with DNA repair, cell cycle regulation, cancer and ageing. Our results open new perspectives concerning the evolution of mammalian longevity and provide insights regarding possible players involved in adaptive genetic changes conferring cancer resistance. We also found potentially relevant changes in genes related to thermoregulation, sensory perception, dietary adaptations, and immune response, among other relevant bowhead adaptations.”



We’re excited to report that we recently funded a new study exploring the effects of c60, a potent antioxidant, on human cancer proliferation. This research is being conducted by Ichor Therapeutics, Inc., a pre-clinical biotechnology company focused on age-related pathologies and based in Syracuse, NY. The full press release is available here.

Construction is now complete on phase one of our beautiful monument to the Methuselah 300, located on the Caribbean island of St. Thomas. Stay tuned for more details on this—we’re solidifying plans to officially dedicate the monument and open it to the public in February of 2015, and we’ll be sharing more with you this fall.

If you haven’t seen our new blog yet, please check it out and let us know what you think. Now called “The Bristlecone” and fully integrated into our main website, it has continued to feature interviews with leading scientists and innovators in regenerative medicine, including:

Up next on the blog will be an interview with Dr. Basak Uygun of the Center for Engineering in Medicine at Harvard Medical School, one of our six prize team leaders. Look out for it later this week.

As always, best of luck in your own endeavors, and please don’t hesitate to stay in touch.

With warm regards,

Dave Gobel


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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