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August 30, 2019
Duke professor of biomedical engineering Nenad Bursac is learning how muscles can recover from injury, by using stem cells to create new muscles from scratch.
Ken Kingery: Hello, and welcome to Rate of Change, a podcast from Duke Engineering dedicated to the ingenious ways that engineers are solving society's toughest problems. My name is Ken Kingery. I'm a science writer for Duke Engineering and all-around general nerd.
Michaela Kane: I am Michaela Kane. I am a science writer for Duke University's Department of Biomedical Engineering, and I am also a resident nerd. Today we are going to talk about building muscle.
Ken Kingery: But we're not talking about building the muscle in a gym. We're talking about building muscle in a laboratory, which is actually a lot harder than doing it at a gym, no matter what your personal trainer might say.
Michaela Kane: Growing muscle in a lab has all kinds of different uses. You could use it to test drugs for different diseases, and you could grow a bunch of it to implant into patients suffering from an injury or a degenerative disease, but there's just as many hoops to jump through first before you can even start dreaming about these sorts of applications.
Ken Kingery: To get to some of those, let's find out who we're talking to today.
Nenad Bursac: I am Nenad Bursac, and I'm a professor of biomedical engineering at Duke University. My lab is involved in finding ways to treat different kinds of skeletal and heart muscle diseases. We are growing muscle cells. We either have these cells obtained from patients or from human donors, or we make these cells starting from scratch. In my lab, that's usually done starting from stem cells.
Ken Kingery: Now, when he says stem cells, what he means is induced pluripotent stem cells. These aren't the controversial ones that you usually hear about all over the news. Instead, these are cells that are actually taken from adults and reverted back to a primordial state.
Michaela Kane: The ability to basically take these cells back to square one is so powerful and potentially transformational to medicine that it won the Nobel Prize just six years after it was first accomplished.
News Reel: [The Nobel Assembly at Karolinska Institute has today decided to award the Nobel Prize in Physiology or Medicine 2012 jointly to John B. Gurdon and Shinya Yamanaka. ].
News Reel: [What does this mean, and how great is the potential for using adult stem cells?]
News Reel: [Well, one expert says it's potentially revolutionary. [Trace 00:00:02:18], let me explain to you what we're talking about here. It's called IPS. That stands for induced pluripotent stem cells. That's the technical name, but what really matters here is IPS, one day, might literally be able to save your life.]
Michaela Kane: For reference, it took Watson and Crick nine years to win the prize after discovering DNA, and that itself was one of the fastest turnaround times for the Nobel Prize.
Ken Kingery: Now let's go back to Professor Bursac to learn about how this incredible breakthrough has affected his research.
Nenad Bursac: You go from a cell that's well differentiated. It has its function, it's within the body like a blood cell or a skin cell, and then you add these factors that make it younger, much, much younger to almost an embryonic state where the cells and these pluripotent stem cells can become almost any cell in our body.
Ken Kingery: When you say growing cells, when I think about growing cells, I think about bacteria in a soup, and they just proliferate uncontrollably. Do human cells do the same thing if you just put them in some sugar water?
Nenad Bursac: Yeah, so—sugar water. Yeah, so it's basically like a sugar water. It does have sugars. It has glucose that we all use all the time every day but also has some proteins and some other minerals. The human cells within this soup are actually growing well depends on the soup and depends on the cell type. In our own lab, we are mostly interested in getting it to become skeletal muscle cells or heart muscle cells, so the cells that contract in our body and do the work.
Ken Kingery: Are those two types of cells, skeletal muscle and heart cells, are those harder to get the pluripotent stem cells to get to than other types?
Nenad Bursac: Well, I guess every cell type has its challenges. I think, at this moment, most of the investigators in the world have managed to get almost any existing cell type in the body starting from these cells. Some have more challenges and more steps. Others have less challenges and less cell steps. For example, I would say the skeletal muscle cells, at this moment, are harder to derive than the heart muscle cells.
Michaela Kane: What specifically makes them harder to derive than the heart muscle cells?
Nenad Bursac: When we start from these pluripotent stem cells and let them become any cell faith just spontaneously, some of these cells will become heart muscle cells, but almost none of these cells will spontaneously turn into skeletal muscle cells. Within almost 8 to 10 days, you can have a heart muscle cell made and spontaneously contracting, and you can see it in a dish. Skeletal muscle cells, it takes weeks. Yeah, it's always been a kind of a puzzling thing why heart muscle cells is much easier to make than the skeletal muscle cell.
Michaela Kane: According to Dr. Bursac, since the pluripotent stem cells were first used in 2006, there's been an influx of tens of thousands of researchers into the field of regenerative medicine, and all of these researchers have been trying to figure out new ways to use these pluripotent stem cells to replicate tissues, organs, and cells within our own body. However, that's no easy feat.
Ken Kingery: With tens of thousands of people all around the world trying to use these things to improve the quality of life, they're not all doing the same thing. There's a lot of work that's being done to create little tiny pieces of tissue that can be used to explore for new types of drugs and also to be used for individual patients to see what types of treatments would work best for them, but Professor Bursac is trying to grow entire pieces of muscle. The question is how many people are trying to do that?
Nenad Bursac: Well, I think there is a significant number of researchers trying to coax cells and make them into functional tissues, right? Being able to make pluripotent stem cells, for example, into heart muscle cells is a relatively standard procedure at this point. Then how you use them after that is a question.
Nenad Bursac: One possibility is to use to study a disease. You can study disease sometimes only on the single-cell level, but sometimes you really need to coax these cells into a functional tissue to be able to study the disease. For that reason, a lot of people will take the cells, try to or coax them into tissues, and for studying disease and especially drug tests, you will actually want these tissues to be the smallest possible so you can test as many drugs as you can in these little miniature tissues. People call these tissues micro tissues or micro physiological systems and then use them for drug tests. This is one of the avenues of research, and this is where I think most or the bulk of the people who make cardiac muscle cells from pluripotent cells, this is the bulk of what they do or try to do.
Ken Kingery: They try to make that as efficient as possible, so by making them as small as possible, you can fit more on a chip. You can spend less time growing them, all those sorts of things.
Nenad Bursac: Exactly. You can test many drugs in the multiplicates and different doses at the same time, so the lot of people is now focused on that work because this is probably a lower-hanging fruit in what you can do with these cells, and pharma industry is interested in this.
Nenad Bursac: On the other hand, a smaller group, now, of researchers is trying to use these cells for regenerative therapy because the reason is, if you are to make a piece of heart muscle that you will try to use to replace the muscle that's lost in the heart during heart attack, you need really a big functioning tissue. In our own lab, we are mostly interested in getting them to become skeletal muscle cells-
Ken Kingery: Little more difficult to do?
Nenad Bursac: Yeah, a little more, a little more and more difficult to do, a little bit more challenging for sure. The reason that it's more challenging is because now you need to generate something that's maybe centimeters large instead of less than millimeters or millimeters.
Ken Kingery: When you say something's that large, are you still looking at just heart muscles or are you trying to then start to introduce other types of cells? Because nothing acts alone. Nothing lives by itself, at least not in the human body.
Nenad Bursac: Yeah, that's a very good point. When we look at a heart muscle, you see, if you look, if you compare the just cell numbers in the heart muscle, heart muscle cells themselves that contract, there are only about 20, 20, 30% of cells. There are all other cells that are present in the heart that support heart muscle function. For example, some of them are, of course, capillaries and vascular cells because they need to bring nutrients to heart muscle cells so they can work hard during the entire life. There are other cell types that probably are very important, especially in their response to injuries, such as immune system cells for example.
Michaela Kane: Immune cells are actually what we're here to talk about today. Most people recognize immune cells as white blood cells or T cells. These are cells in the body that help us fight off infection. Before we learn about why immune cells are so important to professor Bursac right now, we have to start at the beginning with cells called satellite stem cells.
Ken Kingery: Satellite stem cells are stem cells that are native to most organs and muscles. They just sit around. They live there. They're there when you're born and, when you get an injury or when you work out, they activate, and they spread throughout the tissue that needs repairing, and they repair it. Basically, what I'm saying is that they're essential for healing. That's a lesson that Nenad learned back in 2014 when he published a study that actually ended up on the front page of the internet and broke Duke Engineering's website.
Speaker 7: Scientists in the US use animals to test drugs for safety and effectiveness before they can be approved for patients, but they hope that, one day, the use of animals could be reduced and the search for more customized treatments for patients made easier by testing drugs on lab-grown human tissue. Scientists at Duke University have now come a step closer to making that a reality. They say they've created the first lab-grown human skeletal muscles that contract in response to electrical and other stimuli.
Ken Kingery: Just to recap a little bit, back in 2014, Nenad Bursac took small pieces of muscle from little baby mice and got them to grow into fully-functional, self-healing adult muscle tissue, but if you listen closely, I said baby mice.
Michaela Kane: We all know that children are resilient, among other adjectives, and this resilience is actually because of these native stem cells that they're born with. When they're first born, these native stem cells are incredibly potent, and they're able to heal them very, very effectively, but as they grow up, these stem cells are replaced by blood-derived stem cells, which just aren't as potent.
Ken Kingery: That brings us now to his latest development.
Nenad Bursac: When we started working with adult, now, muscles and trying to do it from adult muscle, we made the muscle that looks exactly as what we've done with it from these two-day-old rats. Functionally, it looked the same. You did contain some of the same stem cells in the muscle, which is what I mentioned, and then when we injured it, as we did with neonatal muscle, instead of regeneration, we saw only death and degeneration. It was very opposite result from using the neonatal muscle.
Nenad Bursac: We thought that about another... potentially adding some of the growth factors and some of the molecules that could help with this regeneration, and we basically did all of the usual suspect molecules that people are known are pro-regenerative and help regeneration. We put them in, and we injured the muscle, and we couldn't see anything again, so we realized that these factors are probably not enough, and that it should be... potentially, we should think about adding a another cell type that is important for regeneration and, in particular, for muscle regeneration as well as for regeneration or like a healing of many of our tissues in the body, immune system cells are very important.
Ken Kingery: I wouldn't necessarily have thought of that. I don't think of the immune system as something that helps you heal necessarily. It stops you from getting sick. How does the immune system help you heal?
Nenad Bursac: Yeah. For example, if muscle gets to be damaged, if you just exercise in the gym and get sore muscles, that what that means is that, actually, some of the muscles are being damaged. Muscle fibers have died. In that moment, as soon as that happens, an particular cell type that's called monocyte, from the blood, is attracted to the site of injury. These monocytes come into the injured muscle, and then they differentiate into cell called macrophage. Macrophage is a cell that actually, in our body, serves primarily to remove all the debris and all the damage, the remainders of these dying muscle fibers.
Nenad Bursac: At the same time, while that cell is removing the damage, the fibers, it's also releasing other factors, and those factors can attract other cell types and, in particular, different types of immune system cells. In this point, they are bringing other types of macrophages that will then... can help proliferation of stem cells to regenerate the muscle and further help with the muscle regeneration.
Ken Kingery: The amped-up sugar water wasn't working for you, so you decided you needed some immune cells. How does that work? How do you put immune cells in with this tissue that you've already been growing? Do you just take a syringe and go suck some up from a rat and stick it in there or-
Nenad Bursac: Yeah. Bone marrow is a source of many of the system cells, immune system cells in our body and, especially, as I said, macrophages, and so we can derive it from starting from those early cells. Whilst they are derived, once we have the macrophages, then we actually optimize the conditions to mix them together with muscle cells. We can come to basically designing a muscle that now has both muscle fibers, stem cells, and macrophages all in the same mixture and with the same functionality as it was without macrophages. This was our goal, and this is what we...
Ken Kingery: Getting closer and closer to the real thing then.
Nenad Bursac: Exactly, getting closer and closer, yes. Then what we've done, we actually went to injure it to see whether that would really help this healing that we mentioned, and it was really a... We saw unbelievable injury response where everything regenerated, as you know, for the neonatal cells without presence of macrophages. It obviously told us that that component of muscle or being in the muscle, that immune system component is very important for muscle, adult muscle, to regenerate.
Ken Kingery: This is the first time anybody's been able to pluck muscle fibers from an adult, proliferate them into a larger functioning muscle, and be able to have those resulting muscles heal themselves after being injured.
Nenad Bursac: Yes, that's exactly it, yes.
Ken Kingery: This is only for animals at the moment?
Nenad Bursac: Yeah. We are working to do the same thing with human muscle cells. We can make a human muscle from starting from human pluripotent stem cells or just from biopsies from human muscles. One of the differences with the human and the rat is that, actually, when we want to test for regeneration, the same toxins, the toxins that injure a rat cell do not seem to, as equally, injuring human cells. We are actually now working on finding good ways to be able to test this regenerative potential of the human muscles containing the immune system cells with a good injury model, so testing-
Ken Kingery: You can't just take a bat to them or something?
Nenad Bursac: No. Yeah, well, that's a possibility, the crash injuries, but for now we are trying to do it in a more controlled fashion, yes.
Ken Kingery: Yeah, right. Can you tell about what you're working on next? Where does this go from here?
Nenad Bursac: We are actually, again, working in terms of trying to develop further our human injury muscles. We are making a regenerative or trying to make self-healing muscle from human tissues. Those kind of muscles could be used for drug tests for a lot of diseases that involve degeneration of human muscles as well as, potentially, muscle atrophy. We are developing this as a system to be able to study different diseases. We are now making pluripotent using pluripotent stem cells, and we've been the first group to actually make the human functional muscle from these cells, so now we can test rare muscle diseases in addition, so this is one of the directions that we have in the lab.
Ken Kingery: Are you also working with collaborators over at the Duke Medical Center to try to start making these platforms actually a reality for testing actual diseases?
Nenad Bursac: Yeah. We are working with clinicians from Duke to obtain muscle biopsies such that we can have a source for engineering muscle, both from healthy donors when there are some surgical discards as well as from a patients with specific diseases. We are also working with cardiothoracic surgeons for our cardiac muscle engineering works to be able to test some of these heart patches that I mentioned, so the large indigent heart muscle tissues in pig models of heart attack. We have a lot of close collaborations with clinicians at Duke. As you know, Duke is one of the unique places where I think engineering and medicine are so closely and tightly connected with the goal of translating these discoveries from bench to bedside.
Ken Kingery: Okay, last question because we're running out of time. With either of these projects, you're a pretty young faculty member still. You could be doing this for decades. Where do you hope to leave this off when you retire?
Nenad Bursac: Well, I mean the most I would love to happen is that we see some people really treated using what we do in the lab. Where I would like it to leave, I would love, maybe when when I retire, there are people with heart attack or some of the pediatric patients or having a Bursac therapy for the some of those really devastating diseases.
Ken Kingery: Also, a Nobel Prize maybe wouldn't be too bad.
Nenad Bursac: Well, I don't know about that, but I think primarily goal is to really help someone, and then we'll see for the rest, yes.
Ken Kingery: All right. Well, we'll look forward to seeing the Bursac procedure then.
Nenad Bursac: All right. Thank you.
Ken Kingery: Thanks for listening to Rate of Change. If you want to learn more about Professor Bursac's research, please visit pratt.duke.edu, and please subscribe for more updates from Duke Engineering.