| 1 | National Science Foundation News | How Regenerative Medicine Is Rebuilding the Human Body | Podcast | 3376 | 87 | 7 | 45.5 | positive | 21:36 | We could have said, okay, well, then it's not fitting into what we're working on. Let's move on. Let's put it to the side. It's not our business, right? But instead, we really picked our curiosity and we decided, no, we'll throw everything in the kitchen sink at it. We're going to figure out what this is. This is the Discovery Files podcast from the U.S. National Science Foundation. I'm Nate Potker. Truly groundbreaking research and healthcare is occurring all across the country, transforming how we approach tissue repair, disease treatment, and organ replacement. Regenerative medicine focuses on repairing, replacing, or regenerating human cells, tissues, or organs to restore normal function. We're joined by Max and Plycus, a professor of developmental and cell biology at University of California, Irvine, where as lab studies the mechanisms of cell regeneration. Professor Plycus, thank you so much for joining me today. Thank you for having me on your show. So I think we need to start with a little definition as we move into this topic and for people that don't know what is regenerative medicine. So regenerative medicine, at least in my interpretation, is an aspect of medicine that relies on innate ability of our tissues to repair themself. And these innate abilities are then harnessed for the benefit of producing, for instance, new replacement tissues that either diseased or tissues lost to injury could be substituted. Thinking about approaching, re-growing human tissues, how do you do that? I think, obviously, many people are thinking about it. Many people are working really actively on it. I think it's one of the really fast evolving fields with huge potential. So I think a lot of hopes are that it will work the way we scientists promise it will. I think everything is quite, depends on context, right? So I think first question one would want to ask is what is the problem that needs to be fixed and actually depending on a problem, regenerative medicine solution would actually differ quite a bit. We can obviously go into an example. So if, for example, there is a catastrophic loss of skin, such as to a burn, then what one would want to do is to completely replace the lost skin. And then we already, right now, are able to produce skin substitutes that burn victims could be grafted with. But when you look at what we're able to do right now, the skin substitutes, and you compare it to our actual skin, you quickly realize it's really simplistic. It blocks a lot of components that the normal skin has that makes it what it is. So I think the best outcome of use of skin substitutes is a tissue that looks a lot more like scar and a lot less like normal skin. So we still have a long road to go. So we need to build much more intricate substitutes that, for example, contain hair follicles. So in your hair, it can grow or sweat glands so that skin substitute could later sweat and help us in thermoregulations. So we understand that our abilities to build super complex tissues that much in complexity, those that we normally have, is still quite limited. And then of course, there are other applications for regenerative medicine where, I think, a really classic example is type 1 diabetes where Asians lock insulin producing beta cells in the pancreas. So clearly, if something is lacking, you can just put it back. So why don't we make many more insulin producing beta cells and transplant it to diabetes patients? Shouldn't that work? And in principle, it sounds like it should. But the nature of the disease is R and U. So your own immune system will go after transplanted beta cells and kill them off again and again and again. So then it turns out that regenerative medicine solution for diabetes is a little bit more than just transplanting cells or tissues. It's also protecting them from your own immune system. So, and I think one could really go into a list of examples where all these details matter so much for the success of a therapy, you know, once it's ready. Thinking about your research here that we're then to be talking about a bit, what is lipocardilage and where do you find it in the body? This is obviously in its name, lipocardilage, it's some kind of cartilage with some kind of lipids, right? And that's exactly, you know, this name really encapsulates what it is. It's a lipid-filled cartilage tissue. It's really fatty skeletal tissue if you put it that way. Where it's found. That's a good question. It's not found everywhere. So not every single cartilage in our body is a little fat. It's in our facial structures and next structures. So earlobes, cartilage in our earlobes, cartilage in the tip of our nose, also cartilages that make up all airings. So that's where you find lipocardillages. And yeah, so I think that would be kind of like a short answer. And of course, they're so different from typical cartilages, right? So in the typical cartilages, do not contain lipid in the cells. They just contain a lot of extracellular matrix. So this is, you know, prutinaceous substance outside of the tissue. So many questions that arise. Why is the lipid in the cartilages in our ear and nose and larynx? What is it doing there? Is there benefit to it? What's so special about it lipids? So this list of questions can really go on. What research were you doing or what question were you trying to answer when you guys found this? It was quite simple. We identified somewhat in it and asked it. So and we were a little bit puzzled by it because, okay, so the real context is the following. We were looking at pieces of skin that should have a dipacit. So a dipacit, you know, for your audience, obviously, fat filled cells, but very different, right? The ones that make up our fat tissues. They look in a very diverse certain way under the microscope. So you can envision them. They look like a very beautiful pearl that is iridescent. One slide shines on it. It just like really has this iridescent looked at very pretty and very big. So then we were looking at the small pieces of tissue coming from a mouse ear and we're looking at the dipacits and we were finding them. So yeah, there was all this iridescent cells there. But once we start stating them for markers, we kind of realize, wait a second. Only a small portion of the cells labels with markers of an adipacit. And the larger portion, even though they look exactly like a dipacit, they don't label. So first up was like, we must be looking at rather very unusual, maybe different type of an adipacit. And then as we started digging a little bit more and more trying to define this adipacit, we came to this realization, wait a second, these are not adipacit at all. There's actually cartilage cells that masquerade themselves as in the dipacit, they look like a dipacit, but molecularly, they're completely different. And at that point, when it sort of kind of hit us, we realized, oh, we are dealing with the distinct skeletal tissue, lipid fill cartilage. And at that point, we're really put into a high gear trying to learn more. Was that an exciting finding for you guys? Like why did this go over, looked for so long? It was kind of super exciting. You could imagine it's pretty rare. And 20, 25, you stumble upon a cell that nobody else have seen before described. So you immediately start to question yourself, wait a second, I must just know something very obvious. And if you ask experts in cartilage, they'll say, oh, come on, of course, you know, you're missing something, you should go back to your medical textbooks and read them, right? So we did that. So we just couldn't believe that nobody else saw them before. And long and behold, people did. And the first person who actually described this cells in the ear cartilage of a rat was this really well-known scientist and contemporary Charles Darwin, his name is Francis Leidick. So he worked in, you know, what is now Germany in middle 19th century. So in 1854, he first described it in his book. And you know, I don't remember like the exact word to word translation of, you know, his description in German. He drew it, by the way. So we knew he was looking at the same thing. But basically it said, when you're looking at the cells under the microscope, you think you're looking at a dipacite, sad cells. But you know that this cannot be because what we put under the microscope was cartilage. So it does. We might be dealing with fat-filled cartilage, just case closed, moved on. And then he moved on to other things. And the rest of his book is just like a wide, you know, exploration of everything that he could potentially find and put under the microscope. So you know, contemporary Charles Darwin already found it. And then for almost like a hundred years, nobody seemed to have looked back and realized that there's this cartilage that has all the slip it in it. And then in the 1970s, there were a few papers, descriptive papers, when a electron microscope became actually fairly affordable. And people start sticking all kinds of stuff under electro-microscopes now and sure enough, somebody put ear and sure enough, they realized that, oh, there's this very beautiful lipid vacuoles in the cartilage, let's describe it. And so they did. And you know, people working at that time were also quite diligent because they went back and they dug out Francis Leidick, original description. They, you know, they gave a credit to it. And then in like early 90s, all of a sudden nobody's talking about it again, right? So we essentially were like a third wave of rediscovery. But now, you know, to our advantage, we have all this molecular tools and methods available. So then we, you know, other than just like describing how they look, we start starting the molecular biology, the physiology. And as we were doing it, we realized that there's so many unique aspects about this issue and about the cells, I know. We still know they're little, but therefore we are actually super excited because of what's possible, what's lying ahead. So thinking about those possibilities a little bit, does the lipocardilage cell lend itself towards regenerative medicine potential usage? I would argue that yes, there are many instances where cartilages of our face and neck need to be replaced because, for example, they poorly develop due to bird defects, bird defects of earlobes actually really common. Trauma of the ears, face and neck is common. There are certain forms of cancer that could locally invade into like structures of the nose and neck. And to save patients' life, that needs to be all cut out. And you know, surgeon would have to remove large portions of this cartilage. And then what you're having at that point is big defect in a say so neck. So this all calls for replacement strategies. So and of course there's like the there's category of you know, elective plastic surgeries where it might be beneficial to produce new cartilage because you know, selecting nasal augmentation and things like that. So then the question is like, okay, well, where do you source this type of cartilage? Turns out cartilage is one of the stages that, you know, if you're talking about autologous cartilage, you can cut pieces of the rib cartilage. And then shade it and that's exactly how it's done. Then you can kind of shade it and then place it for example into the tip of the nose or the ear. But you can, but just like touching your rib, you know, it's not a soft right? You can touch your ear and see how just pliable and elastic and bouncy it feels and then touch the rib, right? And it's totally different. So by mechanics of tissues, I like nod the same. So you're not really doing one to one replacement. You know, top of it, you know, cutting out cartilage of the rib is on its own very invasive. So it's not a joke. Because you know, try to do something like this. And then any substance to choose, you know, people will say, okay, well, can we go to like synthetic materials? Can we replace cartilage with say silicone implants? And yes, you can put a silicone implant that is shaped, for example, I like a year, but silicone is a foreign body. And our body knows that this is a foreign body and it will try really, really hard to reject it. And it will like encapsulated it all from a capsule around it. So so longevity of the synthetic implants is actually not very high. They also just not ideal. So they needs to be new solution that is, you know, I think one solution that we envision can we generate a lot of face and neck specific cartilage, which is lipocartilage from, let's just say, flu, report and stem cells in large numbers and then shape this cells into tissues that match exactly what we're aiming to produce like, you know, I think over the year. And that would be if, you know, this works really a regenerative medicine solution for the scholars and make a would make a lot of difference for a lot of people that are suffering from those kind of issues. I would agree with that. I would like to pull out a little bit and look at the kind of regenerative medicine field in general. Like I think last year I heard a story about being able to regrow teeth a little bit. What kind of things can actively be regrown at this point in time? I teach a class to my undergraduates, old advances in the regenerative medicine. In every year, I feel like I have to go back and change something because over a year or a span of time, things have advanced dramatically. All the time, there is just new research that came out a month before I have to start teaching in class that would completely change the lecture because what I taught last year is always an out of date. And that really means that this is such a vast evolving field. Almost every month there are some new discoveries, some new advances in regenerative medicine have been reported. So it's really exciting. And at the same time, like, you know, it's really hard to stay on top of this to be current. But you know, a lot of understanding has now exists of what can we do? At this point in time, and what else we need to learn to do to really translate all this very promising stem cell based approaches into real therapies that could help people. And I think that turns out to be multifaceted problem. There's a lot of things that we still need to learn. I can't go into some of them. But I think there were just so many questions that we still need to get answers to you. I think the bottom line at this point in time scientists have learned for the most part how to use really potent stem cells, such as blue-repotent stem cells, and how to direct them to make cells that we intend. Okay, so for example, can we make cartilage cells, can we make contractiles, can we make skin cells, caroteno-sized, and on and on? I think the answer to those questions is like, yes, we've learned. So there are essentially molecular recipes when we call it your cells. You know, we can direct them toward these outcomes that we desire. At the end of it, though, what we have is really a suspension of cells. Okay, but our tissues are for the most part not suspension. They highly intricate, very large and morphologically really well organized. So then the next challenge is that how do we put the cells into this microarchitecture of tissues? How do we generate tissues that are not just tying the microscopic we need, magnifying glass to see them? How do we make them big? Because we are fairly large organisms. So how do we make something that's like 10 by 10 centimeters? And that turns out these are the challenges, the scaling of things, you know, the micro-patterning of things. It's still often, you know, we don't really know how to go about it. But a lot of research isn't this area. So thinking about research, I want to ask you about how NSF support has impacted your career so far. And the set of support was absolutely fundamentally essential for us to be able, you know, to think outside of the box and feel like, you know, we can, you know, support our efforts. Because at the point in time when I mentioned in my earlier answer, when we were looking at a dip aside because, you know, the project that we were working on, it wasn't the dip aside. Right. And the pointing time on to realize that, oh, this iridescent per looking cells, actually, contrast size, there's some kind of interesting colors that nobody knows anything about. We could have said, okay, well, then it's not fitting into what we're working on. Let's, let's move on. Let's put it to the side. It's, it's not our business, right? But instead it really picked our curiosity and we decided, no, we'll, we'll throw everything in the kitchen sink at it. We're going to figure out what this is. So it was in many ways, like just disability, could you research in a completely new direction? Fantastic. So for my last question today, I want to ask you circling back to the lipocardilage. And I want to ask you about what's next. What are you excited to learn about it in the next couple of years? Many things, but amongst those so many things is bio mechanics. I think that's really interesting because skeletal tissues is about biomechanics, right? But our bones, our cartilage, those they provide our bodies with, you know, support. And then when we, when we, meaning scientists, typically think about biomechanics of cartilages, almost always we think about molecular properties of the extracellular matrix, like things such as collagen, you know, how this bendable molecules and Dow cartilage with its properties, like such as elasticity stiffness. But now in lipocardilage, there's very little of this extracellular matrix. And instead, there are very large cells filled with lipid droplets. So then a question that was really, really want to get the answer to is, what is the role of intracellular lipid droplets in tissue biomechanics? We already have clues suggesting that they play essential role. And then so that really suggests that the lipocardilage biomechanics, they're a composite material made by nature. It's the intracellular lipid droplets working together with extracellular, extracellumatrix proteins, producing this composite tissue, which is biomechanical properties, derive at this symbucinergy point. So trying to learn that is what we really want to do next. Special thanks to Max and Plykis for the discovery files. I'm Nate Potker. Please subscribe wherever you get podcasts. And if you like our program, share with the front and consider a link we will review. Discover all the US National Science Foundation is advancing research at NSF.gov. | ↗ |