Category Archives: Interviews

Episode 007 – Control Alt Delete Cancer Research into longevity, human health, ageing, New Organ Research including bioprinting liver, kidney, and other medical pursuits

 

Control Alt Del

Hello and welcome to Episode 7!  On this episode, we’ll talk with Dr. Haroldo Silva and David Halvorsen of the SENS Research Foundation.  They’ve launched a new crowdfunding campaign designed to attack and stop cancer using a new approach.  You’ll hear what that approach is, why they think it has a good chance of success, and you can help in the fight.

If you’d like to comment on the show, have a question or want to reach us, write Rod.Wheaton@MFoundation.org

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Episode 006 – Could Cryopreservation for Human Organs Save 700,000 – 900,000 Lives a Year?

 

Transplanting Organs

Join us on this episode of the Methuselah 300 Podcast as we interview Dr. Sebastian Eriksson Giwa;  co-founder and chairman of the Organ Preservation Alliance and co-founder and CEO of Sylvatica Biotech.  Dr. Giwa will discuss how Cryopreservation could transform and revolutionize transplantation Currently at least 1 in 5 people on the organ waiting list die due to the inability of keeping organs viable for transport, resulting in 700,000 deaths a year by some estimates.  Dr Giwa and his team want to change that…

The Defense Department, National Science Foundation and even the White House are beginning to recognize the need and potential of this scientific frontier , and scientists from around the world to an increasing decree are tackling the remaining challenges.  

Will you join us?  You can find out how to become a foundation supporter at  Mfoundation.org.

We thank you for your support now and in the future!

Sincerely,

Methuselah Foundation

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Episode 005 with Dr John Geibel; Yale University How Yale's Team of Researchers are Moving Toward 3-D Printable Organs

 

Faculty portraits
John Giebel, Director of Surgical Research, Yale University

On this week’s podcast, join us as we talk with Dr John Geibel, Director of Surgical Research and Professor of Department of Cellular and Molecular Physiology at Yale University.  Discover how his team is working hard to develop the first iterations of 3-D printable organs, a goal that will revolutionize the medical organ industry and save thousands upon thousands of lives.

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The International Front Interview with David Williams: Part 3

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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.

Click here for part 1 and part 2 of this interview.

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New Organ: Let’s return to the international arena. Why are you so focused internationally?

David Williams: It’s pretty clear that the United States, and a few countries in Europe, and one or two elsewhere, are at the forefront of developments in these medical technologies in regenerative medicine. But they can’t do everything. We have to recognize that there are very good academic, clinical, and commercial entities all around the world. And I think it is appropriate that we interact with them in order to get the best of everything.

Also, when you look at issues of commercialization and clinical translation, we know that here in the U.S., there are—sometimes understandably—many limitations and barriers to how far and how fast we can go. And there are opportunities in other parts of the world where there are different formats and different styles. Part of my rationale is to try to get the best of all possible commercial, clinical, and academic opportunities in different parts of the world.

For instance, I’ve spent a fair a bit of time in China. Ten years ago, when I started going there, I don’t think they were doing very good work, but they’ve now put money and people into some very interesting developments. Now, I’d say that they are almost as good as any other country. In Biomaterials, I publish more papers from China than I do from the United States. I also know the regulators well in all of these countries, and they are not trying to move things faster or do things cheaper or less rigorously, but they have very different sets of principles than both the FDA and the European Union do.

The FDA is risk averse for understandable reasons, because they’ve got Congress looking over their shoulder and they have to be as sure as possible to get things right. If that means delaying or stopping new developments, then so be it. China, Japan, Korea, and Taiwan, on the other hand, have a somewhat different attitude. I work with those regulators and some of the key labs in Beijing, Shanghai and Singapore, and it’s pretty clear that the progression of translation is likely to be faster there. And at this stage, although we obviously have to keep a close eye on it, I don’t think that this will happen by sacrificing any issues of safety.

NO: In terms of international collaboration, what’s missing that you’re working to achieve?

Williams: One of the key issues is for there to be clear and transparent collaboration between the best in the U.S. and the best in Asia. There’s going to be some good competition there, and that’s just fine. But in key issues, I believe that it is better to be working in collaboration and in joint ventures. Most American companies now have activities in China and in Korea, and some of them have major research offices there. I’m also involved in a couple of cases where a Chinese company would like to have American representation on its Board in order to validate its work; and therefore, to move together to get both Chinese and American regulators on site. To me, this kind of collaboration is a win-win for everyone.

NO: How does your work with the Tissue Engineering & Regenerative Medicine International Society (TERMIS) play into all this?

Williams: TERMIS is about 10 years old now. The first meeting was held in Shanghai, and its purpose was to facilitate not just international collaboration on particular projects, but to shepherd the formation of a growing family of colleagues in regenerative medicine. I think that was a good idea, and I give a lot of credit to the people that started it, like Alan Russell, Bob Nerem, and Hai-Bang Lee. Back then, I was the director of the UK Centre for Tissue Engineering, and saw myself having some role to play in the development of the community. So I went to that first meeting in Shanghai.

There are now three continental chapters of TERMIS, all of which are successful to varying degrees. TERMIS America is now a solid organization. Europe is a bit more disparate, but there was a very good meeting this year, and they’re getting their act together as well. Asia, which is where I spent a lot of time, is more difficult, because there are many different cultures with totally different customs and approaches to things.

When Steve Badylak’s term as president was up, a lot of people suggested that I should run, because of all the people in the world, I probably knew all three continents together better than anybody else. So I did. It’s a three-year position, and my manifesto was, “Let’s try to consolidate TERMIS globally.”

As president, I’ve outlined two basic principles. One was to ensure that regenerative medicine is growing not just in the big countries, but all over the world, because a lot of the smaller countries have a lot to offer this process as well. Part of the subtext for this was that medical tourism, i.e. stem cell therapies, were being carried out in places like Mumbai and Moscow and so on without any evidence whatsoever. That’s a massive danger to us if they get it wrong, and of course, they are getting it wrong. So the idea is that if we can consolidate the academic and clinical communities around the world into one solid organization, that might help to address some of these unfortunate side effects.

The second principle, which I am working very hard at, is to allow TERMIS to become more than just an organization that conducts conferences. We have a World Congress every three years, and in the intervening two years there are three continental chapter conferences. That’s fine, and they bring together those communities, but TERMIS has no other role. I’d like to see us take on more of an educational role, to look at best practices and how we teach tissue engineering, cell therapy, and regenerative medicine, and help to develop a more well-educated workforce. I’d also like to see TERMIS become the voice internationally for regenerative medicine, so that when organizations such as the WHO or the US Congress or the European Parliament want to go somewhere for an authoritative statement, they’d come to us. We’re not there yet, but I’m working to try to get us in that position.

NO: Tell me more about that role, and what kind of impact it could have.

Williams: I’m really talking less about the scientific base here and more about the infrastructure in which regenerative medicine has to operate. And in that space, I think there are a number of different factors that are hugely important in controlling the way regenerative medicine will progress. That includes ethical issues. It includes health economics. It includes the perceptions of the public, all of which I think are immensely important. Public perception is one area where we have to be extraordinarily careful. And it also includes regulation and the regulatory bodies. For all of these areas, if we get them aligned, then things become easier. If we make mistakes, then it becomes more difficult.

We also have to be extremely careful about not overstating or over-hyping what is possible. There’s a natural tendency to do it, especially if you have a camera or a microphone in front of you. I’ve been guilty of that myself. You want to give a positive spin on things. We all do. But there is a danger there when we begin to over-promise. When we look at some of the advances in regenerative medicine, we have to put them in perspective. There have been some tremendous advances in organ tissue engineering, like what Tony Atala has been doing here at Wake Forest, and Paolo Macchiarini in Europe. But we should not expect too much too soon from these developments.

When Tony Atala was working on the bladder, for example, he did roughly one patient a year, and followed them each very, very carefully. That’s the way you have to do it. Similarly with Paolo, with his trachea and lung. He’s actually had difficulties with that, because expectations rose, and he’s gotten pressure from either individual patients or patient support groups saying, “We need this now. My child has this disease and it needs to be treated now.”

We can make big errors that way. In fact, we’ve seen it happen in medical technology in the past. Even with the best will in the world, trying to get things to patients too quickly can result in real problems. It can end projects, in fact.

In today’s climate, we’ve just got to be careful. For example, you’ll find significant arguments in the literature about work with tracheal tissue engineering, where concerns have been expressed about the clinical translation of some of the concepts. We just have to be mindful of the impression we’re giving to the world. If we have major advances, let’s put them into perspective and make sure we don’t say “We’re going to be doing this in clinics tomorrow.”

The news media do not particularly like that, because they want to tell exciting stories. That’s why we need to make sure to keep things in perspective. So having the ear of important agencies around the world and keeping them informed about what we’re doing will help. Getting more involved in patient support groups will also help. Whether it’s in macular degeneration or Type I diabetes, where there are good patient advocacy organizations, they need to know what we’re doing and what it might deliver, as well as to have a realistic understanding of expected time frames.

NO: Now that you mention patient advocacy, I wanted to ask you about your thoughts on the state of public and patient advocacy as well, in relation to regenerative medicine.

Williams: I think it’s probably average. There are certainly some advocacy programs out there, but I’m not sure they’re pushing us forward that much. What the public hear are the news items, and they tend to be sensational. Sometimes, that’s for good reason—we’ve seen major breakthroughs in recent years, like many of the ones we’ve been talking about. But I don’t often see stories about big breakthroughs in regenerative medicine being channeled through the lens of patient advocacy. I don’t see much related to Parkinson’s or Alzheimer’s, for example.

Maybe it’s there and I just miss it. It’s a little bit like looking at support groups in cancer. When you have a lot of money coming in from charitable organizations and advocacy groups, you tend to go either towards patient treatment management counseling or towards basic research. Sometimes, that dichotomy doesn’t help. You can see this with Alzheimer’s, too. I think we’re so far from a “cure” that most people are far more concerned about how we’re actually going to treat the millions of people who do have Alzheimer’s, and going down that particular route where care is very important. So I think advocacy groups could probably do more. I’m not an expert on this, but that’s my impression.

NO: We talked with David Green of Harvard Apparatus Regenerative Technology, and he commented on how we could use an organization like the Juvenile Diabetes Research Foundation that was focused on the intersection of tissue engineering, regenerative medicine, and organ transplantation. There does seem to be a lack of patient advocacy at the intersection of these areas, and I don’t really understand why.

Williams: Neither do I. Maybe it’s that these organizations are wary of giving false hope to patients who have these diseases? If so, I agree with that. Perhaps it’s a question of balance. Of giving hope by showing how some patients who were blind from macular degeneration can now actually see a little bit, but emphasizing at the same time that we know it’s going to be decades before that becomes widely available. I think many of these organizations are understandably worried about over-hyping good science or good early-stage clinical work.

NO: That makes sense. I have one more question for you, and that’s about the pros and cons of putting forward some kind of “Grand Challenge” initiative surrounding tissue engineering and regenerative medicine in the United States. The Office of Science and Technology Policy, for example, has set up an office dedicated to Grand Challenges, and they’ve been coordinating efforts like the BRAIN Initiative and others in the U.S. Do you think that it would be valuable to see some kind of Grand Challenge Initiative for tissue engineering and regenerative medicine? Do you have any views on how to focus such an effort?

Williams: Yes. Again, a good question. Since I haven’t been in the U.S. that long, I’m not familiar with the process of formulating Grand Challenges. But as I’ve been implying, I think regenerative medicine in all its ramifications is an entirely appropriate area for such a thing. Perhaps the main reason I say this is that regenerative medicine is both interdisciplinary and multidisciplinary in nature, and you need the benefit of scale to be able to tackle these issues.

When I was back in Europe, I headed a major European program known as “STEPS,” which was essentially a systems engineering approach to tissue engineering. It was a five-year program funded by the European Commission, and it involved 27 organizations in 15 different countries working through various systemic issues. We had health economists, regulators, scientists, modelers, manufacturers, and more all working to coordinate solutions to very specific tissue engineering processes and challenges.

This field is enormously complex, and I don’t think we’ll actually get where we need to go without that benefit of scale. So I think the Grand Challenge direction is a great idea. In the end, the STEPS program was too big and complex to achieve finality in anything, but it enabled us to build a very good infrastructure in Europe, and that infrastructure has now led to a number of other networks across Europe that are all flourishing pretty well after I left.

NO: That’s an encouraging outcome. Thanks so much for taking the time to talk with us. I’ve admired the unique role that you play in this space for some time now, and appreciate the chance to learn more about your work and better understand where you’re coming from. In shaping programs like New Organ, the systems approach you’re describing very much resonates with what we’re trying to do.

Williams: I appreciate that.

Core Principles and Challenges Interview with David Williams: Part 2

Williams_David_headshot

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.

Click here to read part 1 of this interview.

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New Organ: How would you express the core values or principles that guide your aspirations for regenerative medicine?

David Williams: I could talk about the importance of honesty and so on, but I think the critical piece is that we make sure that the products of science and technology are translated for the benefit of humankind. That is fundamental.

Of course, as I’m sure you’re aware, there are some dangers in overstating things, and perhaps in underestimating the difficulties. But my core principle is to address in an honest way—initially scientifically, but also from an infrastructure point of view—those issues which we can’t ignore if we want to get to successful clinical translation.

You cannot translate bad science. You also cannot translate no science. If we honestly want to address unmet clinical needs, we have to have the appropriate science, whether that’s stem cell, or biomaterials, or bioreactors, or immunology. We have to put all these areas together to give us the best chance of succeeding. So my core value is this: Let’s take fundamental principles and work to develop them for the benefit of patients for whom there is no existing successful treatment.

NO: Absolutely. But here’s another question: Your values are probably shared by most of your colleagues, and yet people often operate within environments that make it difficult for their values to be expressed. If you agree with that view, what’s getting in the way?

Williams: Yes, I do. That’s a hugely important point, and I have a lot of sympathy, especially for young scientists who share these core values. I mentor them. I teach them. And they’re seeing significant barriers to their own progress.

We know about the difficulties with the NIH in getting grant funding. There’s also the whole incentive structure with rewards based upon metrics and not necessarily on alignment with core values. By this, I mean building up CVs for the sake of CVs. This is something I’ve been very focused on. You see it time and time again if you’re the editor of a journal—the rationale motivating people who want to be published in your top journal, and who are being forced down this route because they’re putting in a grant and have to be able to quote three good papers in order to get to the next level, or need at least five papers of a certain impact factor on their CV to get promoted from assistant to associate professor.

The metrics are driving things, and we’re all to blame here. But the grant-giving bodies and the select panels at universities are far too driven by metrics and ticking boxes and far too little concerned with the core values of how good a person’s science is and how good his or her philosophy is. I think even at its best, it’s very tough for young scientists. It takes a brave man or woman to stand in the way of these rules.

NO: A related concern is that if tissue engineering and regenerative medicine are built upon the existing bedrock of healthcare economics without significant improvements to that bedrock itself, it’s going to leave a tremendous amount to be desired. We have the opportunity to influence the initial conditions by which the frontier-to-industry transition happens for this field. We want to be working to optimize that transition for maximum societal benefit.

Williams: I agree. Broadly speaking, I think there are two different levels to consider. First, as I said before, you can’t translate bad science or no science, so we still need a big effort on the science side, especially in the handling of cells and their ability to express new tissue. We don’t fully understand that yet, and everything has to flow from there.

Then from a higher vantage point, even if we get to the place where it looks like we are getting the science right, we still need to tackle all the problems of translation through manufacturing. I know a few big companies are making progress—like Mesoblast, as I mentioned—but there are still a number of confounding issues to deal with. One is the communication between regulators and the scientific commissions. I’ve got a lot of sympathy with the regulators, but at the moment, they are serving as more of a barrier rather than being of assistance. Secondly, as I also mentioned, it’s still unclear how regenerative medicine is going to be profitable. Is it a product? Is it a service? Who’s going to pay for it? Is the payer here in the U.S. the insurance companies? Private pockets? Who is it?

NO: All great questions.

Williams: One of the things that has struck me over the last couple years is that research funding in the U.S., especially through the NIH, is in a diabolical situation. I’m not sure I have an answer for that. The NIH has a big budget, and maybe we’re just trying to spread it too thinly. I don’t know. But when you have a success rate of 10% or less, that gives rise to circumstances that are very difficult and inefficient. For the amount of time that professors have to spend writing grants, a 10% chance of success is a pretty desperate situation.

At the same time, put that alongside the fact that for most of the large hospitals with medical schools, the last few years have not been kind to them in terms of their own economies. They’re making their academic doctors do more clinical work just to pay the bills, and so they have less and less time for research. I’ve known several senior clinicians who have recently decided to retire because they were, even at very high levels of seniority, being forced to go on call and spend all their time in the clinic with no time whatsoever to even think about research. So I think these things together are working against us.

The other issue is that if this area is eventually to become commercially successful, then you might reasonably expect to see investment from big companies, and right now, most companies in the medical technology sector are more or less closed to R&D. None of the big companies—Medtronic, Boston Scientific, Johnson & Johnson, St. Jude’s—do R&D any more, or hardly any.

They used to. Good medical technology discoveries were funded by the big companies, either in their own labs or extramurally, and that funding came out of revenue from their existing products. Now, companies have stopped doing that, and in the regenerative medicine area, of course, there are no revenues. What they’re doing these days is more or less sitting back and waiting till they see a discovery being developed in a small university startup, and then going in and buying it. But the startups in universities have their own set of problems. They have no revenues, and this area is expensive, and the investors putting money in want their rewards sooner rather than later. It’s a huge trap.

NO: It’s definitely indicative of a general problem that’s been going on for a while. We just don’t have that many Bell Labs or Xerox PARCs around the U.S. anymore.

Williams: Exactly.

NO: And we’ve been seeing multiple valleys of death (i.e. funding gaps in translating research into the market) emerge over time, in different areas. How do you think we might get a handle on this funding conundrum?

Williams: Well, there’s been a lot of discussion about NIH funding, and there was a significant increase in NIH funding for research for a period of time, but it’s leveled out again. Personally, I think there is good funding here in the U.S., but it’s being spread too thin. When you have a hot topic like tissue engineering and regenerative medicine, a great many universities and medical schools wish to get into that space, and therefore the number of proposals coming in has increased. In turn, people are without a doubt having greater difficulty in finding funding.

Without naming names, I’ve talked to some really good people in this area over the last few weeks who are no longer getting support, and they used to be just two or three years ago. Once you get down to a 10% or 12% funding level in any study section in the NIH or NSF, then issues other than basic science or clinical outcomes become important, which means politics. That’s where regenerative medicine is right now. It’s difficult, and probably will get more difficult, and I don’t think the national politics are going to help over the next few years.

NO: If you were master of the universe for a little while, how would you change funding allocations to better advance the field?

Williams: That’s a very good question. One important angle to mention is that the Department of Defense has been a major funder of research in the U.S., primarily aimed at servicemen and women and veterans who have been very seriously injured. That’s been a huge issue. As you know, the Armed Forces Institute of Regenerative Medicine (AFIRM), which is now spread out across the whole country, is a coordinated effort to look at regeneration in areas of large-volume muscle loss and craniofacial issues and so on.

That program is still there, but there is a decrease in need now with the scaling down of wars in Iraq, Afghanistan, and elsewhere. And this does allow the U.S. to broaden its focus. I’ve made this point before: the areas of “unmet clinical need” are changing. Right now, I believe the U.S. has a good opportunity to say, “We still should invest heavily in regenerative medicine, but where are we going to get the best value in areas, such as Alzheimer’s and Parkinson’s? How about macular degeneration and diabetes Type I?”

Those areas where we don’t really have good therapies are where I think we need to concentrate. In my view that means the whole of the nervous system. Interestingly, I just saw on the news a major breakthrough in the UK and Poland on stem cell therapy and spinal cord injury. I believe the U.S. should look at that and say, “We’re pretty good at that. Maybe we should see if we could invest more here in the U.S. on those main areas where there is literally no treatment at the moment.”

NO: How about the challenges on the science side? What would you say are the key technical hurdles that still need to be overcome in order to specifically create new solid organs, which many see as one of the holy grails of regenerative medicine?

Williams: That’s another good question. I’m not sure whether there is any one single scientific issue. Again, I go back to the need for a systems approach. Bear in mind that what we’re trying to do is to take a group of cells and persuade them to do something they don’t want to do. That is, to express new extracellular matrix that can then be organized into the structure and function of an organ.

I think many of the different scientific principles are in place. We’ve made big progress already, and to me, the key issue is in putting everything together such that we can develop the structures that function as organs do. We know how to do the little bits, but we still have to explore the complex functioning of the whole.

Another thing we haven’t talked about yet is imaging and diagnostics, and these are both hugely important for regenerative medicine. If you look at Parkinson’s, for example, by the time a patient knows they have Parkinson’s, probably from the tremors somewhere, they’ve already lost 95% of their dopamine-producing function, and it’s too late. So treatment for Parkinson’s is going in the direction of personalized medicine, with better imaging and screening and biomarkers. This is a hugely important step, but like a lot of what we’ve been talking about, it’s also going to be a massive problem as far as the economics are concerned.

NO: One of the scientific rate limiters that we heard a lot about in our work developing the New Organ Liver Prize was vascularization. What are your thoughts on vascularization as a major clinical hurdle that still needs to be overcome, particularly in the context of the heart, liver, kidney, lung, and pancreas?

Williams: Yes, that is still one of the most important issues. There has been a fair bit of progress made in vascularization, especially in using some small molecules and certain growth factors to encourage newer vascularization. So there are encouraging signs in this area, but it does remain one of the bigger challenges.

NO: How would you define the major benchmarks or milestones in overcoming that particular hurdle?

Williams: I’m not sure, but it generally goes back to a point I made before about having a suitable animal model. I think we have to demonstrate sufficient vascularization within a suitable animal model first, and I’ve got a feeling that means we’re going to have to show significant vital vascularity over a period of time in one or more non-human primates. We’re going to have to do that before we get into humans, I think, and that’s going to be very difficult to do.

Overall, I think that scientific progress has been good. There are still some key scientific issues that have to be addressed. But again, more than solving any particular issue, I believe it’s the integration of individual projects that is the most important and most difficult challenge.

Take muscle tissue engineering, for example. It’s already possible to regenerate small amounts of muscle, but the integration of that into a functional muscle regenerative project is much, much harder. We need to address the integration issues more than anything, and we need to start doing it for the areas where our current therapies are weakest. We had to start somewhere, and so skin, cartilage, and bone were good starting points. In most all of these areas, we’ve now had some degree of clinical success in alternative treatment modalities. Where we don’t have good therapies at the moment is in areas like degenerative disease, especially neurodegeneration and musculo-skeletal regeneration, and I’d like to see more effort being addressed in those areas.

Biomaterials and Clinical Translation Interview with David Williams: Part 1

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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.

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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

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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.

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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.

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

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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.

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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.

Regenerating Organs for Transplant Interview with David Green

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

MF: How do we change that situation?

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

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

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

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

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

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

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

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

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

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

Langer: Yeah, that might well be.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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