Monthly Archives: May 2014

On Livers and Lymph Nodes Interview with Dr. Eric Lagasse

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

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

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

MF: What is ectopic organogenesis exactly?

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

MF: How long do the mice survive this procedure?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr.Takebe_circle

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

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

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

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

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

3. Exploring potential applications to other organ systems.

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

5. Developing preclinical animal models of liver disease.

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

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

MF: How are the prospects for clinical adoption?

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

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

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

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

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

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

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

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

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

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

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

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

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LEARN MORE:

Visit Yokohama City University Advanced Medical Research Center online.

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

Nature: Miniature human liver grown in mice

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

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

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Visit us at mfoundation.org.

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

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

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

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

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

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

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

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

MF: You mean the Xi’an Papers?

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

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

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

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

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

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

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

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

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