On Livers and Lymph Nodes
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Dr. 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.
Eric Lagasse’s Lab at the McGowan Institute for Regenerative Medicine.
Article: Turning Lymph Nodes Into Liver-Growing Factories
Video: Ectopic organogenesis in lymph node
Paper: The mouse lymph node as an ectopic transplantation site for multiple tissues.
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