Tissue Engineering Collaboration
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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.