Cole Hons: Greetings fellow Homo sapiens, and welcome to the third season of The Symbiotic Podcast. This is the last episode of our third season of the podcast, and I'm really excited about our guest today. We'll be introducing him in just a minute. I'm Cole Hons from the Huck Institutes of the Life Sciences, and we're going to have with us today Dr. Xiaojun “Lance” Lian, who is in the department of Biomedical Engineering, as well as the Department of Biology. He holds a dual position like so many Huck people do here at Penn State. And before I introduce him, and I'm very excited to do so, I just want to do a couple of housekeeping things for you. As you're watching, I encourage everybody to chat in and participate with us. There is a chat box either next to you or below, depending on how you're viewing this. It'll be next to you or below the screen. And you can be anonymous, or you can share your name, doesn't really matter. Make up your own name. We don't really care. But we do want you to participate, so please do participate in that chat.
You can put your questions in there for Dr. Lian. And later on in the show we will be taking those live, and he'll answer your questions, and you can also vote on other people's questions. So we'll start with the highest voted questions at the end. This is about a 45-minute show here. We're going to be showing some video that we've been shooting and producing about the amazing work that Dr. Lian's doing with stem cells. We'll be sharing some of that, and we'll be doing some other fun audience participation stuff that you can vote on in the chat. So please do take advantage of that chat and thank you for tuning in. So with that taken care of. Lance, hello?
Xiaojun (Lance) Lian: Hello. Hey Cole. Nice to be here. Nice to see you.
Cole: It's good to see you too. It's been a little while. We were trying to have you on. Boy, it's been a couple months and we ran into some problems here and there.
Lance: That's right.
Cole: Life can be like that. It can throw things at you between Covid, and hiring issues, and all sorts of things in our chaotic times. It took us a while, but we got here.
Lance: Finally, we make this happen.
Cole: Yeah, that's the important thing. And we're very excited to have you here. I was just mentioning the fact that you're in two different departments, which is such a Huck like thing because Huck is all about interdisciplinary collaboration. And we were just discussing before we started the show here that the work you're doing is a beautiful combination. It's a place that you can serve both biology and biomedical engineering. Can you tell us a little bit about that before we get into other things?
Lance: Sure. Yes. I was appointed by biomedical engineering and biology department. That's because my lab research is focused on stem cell engineering and stem cell biology. That's a very natural thing for me to be appointed by these two departments and I can contribute to both departments in different ways.
Cole: And you were saying even some new courses are emerging out of that reality, right?
Lance: That's right. Since I joined Penn State, I develop a cross listing course, which is called stem cell biology and therapy. So this course is open for both BME students and biology students. So during this course, I assign projects to students. So in this way, engineering students and biology students have the opportunity to work together for one project. So engineering students are more good at quantitative biology, such as use calculus and math to solve things. And biology knows better for biological mechanisms. So when I put them together, they can learn from each other. And this is more productive than just a group of engineering or students work together.
Cole: That's fabulous. I mean, that's what we're all about at Huck.
Lance: Right.
Cole: Kudos to you my friend. Thank you for doing that. It's exactly the kind of thing that we're championing and I think that the big complicated issues that we're grappling with, whether it's medical, or environmental, or even economic, you could go on and on with all the different challenges we're up against these days. But it really does take different kinds of people thinking different ways to take that on. So, thanks for your contributions there.
And then of course with your research, it's just fabulous. The amount of innovations, we'll get to those in a minute with what you're doing with stem cells. Just working with you on the video, I've learned so much, and I'm still learning, and there's no end. So that's why we have you on here in our risk taker game changer series as this great end to the season. It's a strong ending with you because there's so much to share that we'll be talking about.
But before we get into the science, I do this with every guest of this season. I want to know a little bit about you, Lance, and you chose the name Lance, right? Xiaojun is your name. You were born in China and took this nickname when you came here to states. So I want to know, Xiaojun, when you were growing up, when you were a kid, were you a risk-taker? Were you somebody who has changed things and what weren't just satisfied with the status quo?
Lance: Right, right. Yeah. So I was born in small town in China, in Jiangsu province. So when I grew up, I definitely liked to take risks. So for example, if I do hiking, I would like to go through these paths that no one else goes before. So the reason for that is because if you go these pathways, you will see unusual beautiful things that as compared to you use the pathways that everybody goes. And I like to see unexpected things. And especially for doing the research, I don't want to do something that everybody's doing. I want to go through these policies that no one does before. And I enjoy a lot about taking risks.
Cole: That's fantastic. I love that. I also love to go where there is no path. Try and find a path right there. I have a quote on a wall at home that says that do not go where the path may lead, set your own path, and make a trail for others to follow. I definitely relate. That's terrific. And Lance, why did you choose the name Lance? Was there any particular reason that you went with Lance?
Lance: Yeah. That's a good question. So in China when we grow up, we take English classes when we were in the middle school. And then usually the teachers will ask you to pick English name for yourself. And I started to think about it, and I was like, okay, I wanted to pick name. By that time, I just started to learn English and I wanted it to start with the letter L because my family name is L.
Cole: Okay.
Lance: I think it would be cool if I got two L, and then I just look at these English books, and I find when I see Lance, and I really like it. So that's why I just pick this one. Yeah.
Cole: It just appealed to you. And Lance Lian, it does sound good, it flows. Yeah, the two Ls.
Lance: That's right.
Cole: I love that. Terrific. Well, Lance Lian, let's talk about your research a little bit here. You've done so much with stem cells and you've taken some risks with stem cells. We'll be watching this in the video in a moment. And one of the things I learned working with you is about this Wnt pathway that we're going to be talking about a little more. And maybe you could share with us, one of the many innovations that hopefully we'll touch on, is that there are many different ways to differentiate stem cells, and there are many different pathways for the differentiation. But you had shared with me that many scientists working with stem cells try to work across maybe 10 different pathways and try to figure out all of them, and you chose one. I see that as a big risk that you took, you chose one single pathway, the Wnt pathway, and went deep deep on that, and it really yielded all sorts of incredible innovations and breakthroughs. Can you speak about what made you choose that one pathway?
Lance: Right. So stem cells, that the stem cell type that we are working on is called pluripotent stem cells. So naturally, if you have the embryo, if we have the stem cells, and in the modest uterus, these cells just naturally differentiate into all different type of cells in our body. So if you examine what signaling pathways, what signaling factors involved in these differentiation, you will find there are more than 20 different cell signaling pathways.
Cole: 20, oh, I was saying 10. There's more than 20.
Lance: Yes.
Cole: ... signaling pathways.
Lance: And if you check how many signaling factors involved, because each signaling pathway may have multiple signaling factors, you may end up with 100 factors. There's just so many things involved in this process. So when we do this in the Petri dish in the lab, if we try to a hundred percent recapitulation of what's going on in vivo, that is almost impossible because there are just so many factors involved in this process. And if you want to optimize concentration for each of them, you may end up with a combination of billions of combinations. You can never do billions of dishes for experiments. Right?
Cole: Right.
Lance: So what I do is, so my logic is, how about we find the most critical one, and if we systemically optimize this most critical one, can we yield similar results as compared to optimization of many of these factors?
Cole: I see.
Lance: To be honest, that's definitely a risk for me because it is quite possible that just optimize one signal pathway may not work at all. Because in nature you need so many different factors, and here you just try to optimize just a single one pathway and hope it's going to work. So I think I take the risk, and I did a lot of work. It took me about four years and it turns out it worked. So I'm very excited.
Cole: Yeah.
Lance: I think there's also a little bit lucky components here, but it indeed worked.
Cole: You did it. Yeah. A little bit of luck and a lot of hard work and sweat.
Lance: Yeah.
Cole: I mean, we talked about the hours that you had to run these experiments over those about four years. Did you just, three, four years?
Lance: Right. In total, it took me about four years.
Cole: About four years. And during the four years, because time is such an important element, right?
Lance: Right.
Cole: That people go in, three in the morning, checking on things, just watching 24/7 and just trying this, trying that.
Lance: Right.
Cole: And just doggedly going forward. And so when you say it worked, check me if I'm wrong here, Lance, if I'm misconstruing anything, but my understanding is that not only did you create a process for differentiation of stem cells into the other cells that you're trying to make, but you're doing it cheaper, you're doing it faster, and you're doing it with a lot greater efficiency, correct?
Lance: That's right. That's right. So the differentiation that we are talking about is called cardiac differentiation. So the goal here is we want to convert stem cells into cardiac myocytes. The reason for that is because cardiomyocytes are very critical for our heart function. And if a person have a heart attack, their cardiomyocytes died. And if we can generate these cells in the lab, we can potentially transplant these cells back into the heart failure patient. And indeed, this is happening. And during the time that I'm doing my PhD and the cardiac differentiation, efficiency is very low. So you do the differentiation, and it took you about three to four weeks, and your yield is about one to 2%. So the efficiency is very low. So my message greatly improved the efficiency. We can generate more than 90% of the efficiency, and we can achieve our goals in about 10 days.
Cole: 10 days.
Lance: So we both shorten the time and also we gradually improve the efficiency.
Cole: And then the cost associated that process too dramatically reduced, correct?
Lance: That's right. So the previous approaches use the serum and gross factors to do the differentiation, and these factors are expensive and not stable. So that's why you have to use these gross factors more quickly. You cannot store them for a long time. And instead, I did not use any serum, I did not use any growth factors. I used two small molecule compounds to do it. So these chemical compounds are more stable and much, much cheaper. So the cost of these chemical compounds is only 5% of the gross factor cost. So if they need a hundred dollars to do the differentiation, I only need $5 to do it.
Cole: That's fantastic that that's something that we do share in the video will be showing a sneak preview here in just a minute of a video about the cardiomyocyte work you're doing and also mentions pancreatic beta cells that are producing insulin. So before we run the clip, let's hear a little bit about that. And which came first, the cardiomyocytes or the pancreatic beta cells? And also I'm curious, is the same process you developed for cardiomyocytes, which are heart cells, is that's the same process then you're using to produce pancreatic beta cells, correct? And it has to do with the amount of activation and deactivation of the Wnt pathway, correct?
Lance: That's right. So cardiomyocytes differentiation happens first. So during my PhD, so I developed this robust protocol for generating cardiomyocytes. Essentially we can generate beating cardiomyocytes across the whole dish. And later, after I joined Penn State, I started to think about what type of projects that I should work on at Penn State because the cardiomyocytes efficiency is already great. So there's not much room for me to further improve it. And so I decided to look around, and see which other stereotypes are clinical relevant, and also very difficult to generate. So I like to take the risks, if no else can do this very efficiently, I want to do it. I want to make it better. So then I pick the pancreatic beta cells. The reason for pancreatic beta cells is they are very, very useful cells for treating type one diabetes. So these type one diabetes patients, their own pancreatic beta cells died because their beta cells under attack by their immune cells.
So basically their immune cells kill their beta cells. So they do not have beta cells. They cannot naturally control their blood glucose concentration. That's why they have the diabetes. So in this case, the stem cell therapy is very good for treating this disease, because if we can generate good amount of functional pancreatic beta cells, we can transplant these cells back into these type one diabetes patients, we can potentially cure the disease as compared to if you just do insulin injection, just treat the disease. So that's why in Penn State I decided to work on this. And it turns out very, very surprisingly that you can still use the Wnt pathway to regulate the stem cells to generate the pancreatic beta cell progenitors by adjusting the amount of activation. So if you activate the Wnt pathway with higher concentration of the chemicals, you generate cardiomyocytes. But if you activate a Wnt pathway at the intermediate level, you generate the pancreatic progenitors, so that's very surprising.
Cole: That's fantastic.
Lance: Yeah, nobody reported that before.
Cole: Now what about neurons? Because I know that neurons are a third very important cell that cannot be produced by the human body. We can produce skin cells and many different cells. We've talked about this, you and I, but heart cells and pancreatic beta cells and neurons are a third. Would you be able to produce neurons then with the same process?
Lance: Yeah, that's a great question. And based on the literature, my lab doesn't work on a lot of neuron differentiation. But based on the literature, it is very interesting that the Wnt pathway is also involved in neuro differentiation. But in this case, you must suppress the Wnt pathway in order to do the neuron differentiation. So in summary, you can regulate one signaling pathway and generate three different type of cells. If you suppress the Wnt pathway, you got neurons. If you intermediate activated the pathway, you got pancreatic progenitor. If you highly activated the pathway, you got cardiomyocytes.
Cole: Fantastic. Amazing. It's a good thing you went to look for a new path in the scientific woods there, Lance.
Lance: Yeah.
Cole: Really found some beautiful things in the process. Let's take a look at our video if we can. This would be a nice time. And I want encourage everybody to chat in with your questions. I'm trying to watch the chat over here so that we have some things to answer later on in the conversation. But right now, let's take a look at a sneak peek. This is three minutes of a video that when it's done will be probably about five minutes. Let's take a look now.
Narrator: The human heart is made of cardiomyocytes specialized pulsing muscle cells. Without them our hearts can't beat. Unfortunately, unlike many other cells in our bodies, cardiomyocytes don't naturally regenerate. That's one reason why heart disease is the number one cause of death in the United States. It's also the reason that stem cell therapy is considered the most promising treatment for repairing damaged heart tissue. As the raw material from which our bodies are made, stem cells have the incredible potential to form new cardiomyocytes or any other kind of cell. But these cells can only be therapeutically viable if we can control what kinds of cells they become, and successfully introduce them into a patient's body.
Lance: In total for human body, we have about 200 different type of cells, and now we can generate at least 50% of these cells, so around 100 different type of cells from stem cells. But many researchers are focusing on these cell types that cannot be regenerated naturally by our human body.
Narrator: Lance Lian is an associate professor of biomedical engineering at Penn State.
Lance: The hottest areas are three different type of cells. There are neurons, cardiomyocytes, and the pancreatic beta cells.
Narrator: At its outset, stem cell research was hugely controversial. When biologist James Thompson derived the first human stem cell line in 1998, he started with cells sampled from human embryos. In 2001, President George W. Bush banned funding of any new embryonic stem cell lines. But in 2006, Japanese researcher Shinya Yamanaka discovered that adult cells could be reprogrammed to become stem cells. An advance that won him a share of the 2012 Nobel Prize in medicine, and removed the need for embryos. With stem cells readily available to labs, researchers began to discover multiple methods to drive cell differentiation and obtain specific types of cells needed to advance new cell therapies.
Lance: Once you have iPS cell lines, one of the property of these iPS cells is they can proliferate almost indefinitely. So then you do not need to worry about the number of cells that you can have.
Narrator: Lian and his team have devised a novel way to produce new cardiomyocytes by manipulating the Wnt pathway, a sort of protein based communication network used by cells. By timing specific activations and inhibitions of this pathway. The Lian lab has advanced the effectiveness of stem cell differentiation from the highly random 1% yield produced by older methods to yield as high as 90%. They've also reduced the time it takes to produce cells from a month to around 10 days, and they've reduced the cost of the process by 99%.
Lance: We publish our paper, and now our methods become like a golden standard method in the field for all the other labs around the world if they want to make cardiomyocytes.
Narrator: In addition to cardiomyocytes, Lian's lab has used their differentiation technique to make pancreatic beta cells that produce insulin, a breakthrough that may lead to new therapies for type one diabetes.
Cole: Well, I hope you like what we did so far, Lance.
Lance: I really like it.
Cole: Oh good.
Lance: Yeah.
Cole: I'm glad. Yeah, we had a lot of fun coming out to your lab and shooting in the real stuff. There was no faking going on there. That was real science happening right in front of us, and just, it's beautiful to capture that. It seems like magic in a way, the stuff that's going on. So what we didn't get to in that video yet that we're going to get to is actually, it's funny, somebody just chatted in with a question. So I'm going to take this first question here, because it fits right in with another thing I wanted to touch on. David H says, Hello, senior biology major here at PSU. When the artificial pancreatic beta cells are administered to type one diabetics, will these patients’ immune systems attack these new cells? And that's what we were just about to talk about it. It'll be in the video later. We're talking about universal donor cells. Let's talk about that.
Lance: Sure. That's a great question. Thank you for the question. So, when we generate the pancreatic beta cells in the lab, and then we transplant back into the patient, the patient’s immune cells may still attack our transplanted cells. So the question here is, how do we protect our transplanted cells? So there are two ways that you can do it. The first way is use gene editing approach that we can generate the so called universal donor stem cell. So these universal donor stem cells, we locked out the genes associated with immune interaction with immune cells. So, the immune cells will not treat our transplanting cells as foreigners.
Cole: You locked them out. You locked out, you found those genes that would cause the immune system to react.
Lance: That's right.
Cole: You locked them out.
Lance: I locked them out with the CRISPR gene editing technology.
Cole: CRISPR.
Lance: Yes. So in this way, the immune cells such as T cells will not attack our transplant cells. So the stem cell derived the pancreatic beta cells can survive in vivo for many, many, many times, many, many years. That's one way to protect the transplanted cells. The second way to protect the transplanted cells, which is also going on in clinical trials nowadays, that is you use specific polymers to make the scaffold to encapsulate the beta cells. So these encapsulation devices have small, tiny holes on the surface, but these holes are small enough, they can only allow the insulin to come in and out, insulin, glucose, these small molecules to come in and out. They do not allow cells to come in and out. So the immune cells know there're foreigners are inside of the device, but they just cannot get in to attack them. So, in this way, you protect the transplant with the pancreatic beta cells.
Cole: Very interesting polymers. We're talking nanotechnology here. That reminds me of the whole convergence world of materials and life sciences.
Lance: Nowadays, many of these researchers, many of these problems that we are facing are extremely difficult to solve. So that's why we have to work with both biologists, biomedical engineers, and material scientists. We work together to solve these big problems.
Cole: Right on. And if we return back to the method you developed for the pancreatic beta cells to be donor cells, let's also touch on the fact that it's not just pancreatic cells we're talking about, we're talking about all of them, right?
Lance: That's right.
Cole: We're talking about the cardiomyocytes as well. So, if people watching this think about a heart transplant.
Lance: That's right.
Cole: And that's always a problem is you put the new heart in, but will the body reject that heart? And the same thing is happening on a cellular level with these differentiated stem cells. The cardiomyocytes into the, say, like a heart attack victim, like a patient who can't, like the body can't regenerate, just like it says in the video. They can't regenerate these cells. But if you put the cells in, that's another instance where the body could reject them. But this process you've developed with CRISPR and tricking it, it's almost like stealth cells.
Lance: Right.
Cole: That are not rejected. And you had shared with me that since you published that paper, and put the method out there, which is patented by the way, right?
Lance: Right.
Cole: Now, there are clinical trials going on right now in three countries with heart patients who are using these universal cardiomyocyte cells that derived using your methodology, correct?
Lance: So for the stem cell nature, you can use two different type of cells. One is called embryonic stem cell. So another one is called induced pluripotent stem cell, iPS cells. So for the cardiac therapy, if we use patient's own cell, so for example, we take a little bit of their skin biopsy and generate iPS cells and then generate a cardiac cell. If you transplant these cardiac cells back into the same patient, you may have much less concern about immune rejection. The reason for that is because the cells are coming from their own skin cells. So, in this case, you may not even need the universal donor stem cell.
Cole: Okay.
Lance: Yeah. In this case, in this specific case.
Cole: Got it.
Lance: But for pancreatic beta cell even you use patient's own cell to do iPS cell generation to do beta cell differentiation, and a transplant back, you may still have the problem.
Cole: Oh.
Lance: Because the patient, their immune cells just attack their own sale, so these are a little bit different. So for example, if we take the cardiomyocytes as an example, why cardiomyocytes, we may still need the universal donor stem cell? Why not do we just customize iPS cells for individual patients? The reason for that will be, the reason why the cost will be extremely high. That is every time I got the new patient, I have to generate a specific iPS cell line for that patient. And then I need to do differentiation. I cannot make the off the shelf product.
Cole: Got it.
Lance: The reason too, in some accurate situations, for example, heart failure, you didn't have time to do that. So the patient come to hospital and they may die in four to five hours. You cannot just say like, wait, I need to generate iPS cells, and that take about one month. The patient just didn't have time for you to do that. So then also for business and these pharmaceutical companies willing to do this, they don't want do personalized medicine because that cost, it's just too high, just no one can afford it. But if you can generate a universal donor stem cell, and then you can generate billions of cardiomyocytes, and then you freeze in the liquid nitrogen tanks, and it's like the off the shelf product. The patient come to the hospital, you immediately saw one valve of the cells and then you do the transplantation. That is more feasible business model to do this.
Cole: That's phenomenal. And I know that you do have some industry partners and when working with some iPS, do you want to talk about that? I know it's an important thing for Penn State, and one of the reasons we're doing this podcast is to tell some stories to others in the community who may want to do similar things. So, could you speak about what that experience has been like for you?
Lance: Sure, sure. So since I joined Penn State, my lab has filed through Penn State five to six patents. So they are covered different things. So for example, one patent is focusing on how to generate pancreatic beta cells from stem cells. Another one is related to how to generate these universal donor stem cells. Of course, we can combine these two patterns together to generate the so-called universal donor beta cells. But the universal donor stem cells has more broad applications than just beta cells. If you use universal donor stem cells to generate cardiac cells, to generate neurons, these cells after transplantation will also not be rejected by the patient’s immune cells. So that's why we are very interested in combining the universal donor stem cell and pancreatic beta cell protocol go together. And then we start a new company. And then I work with a business partner from New York and we try to recruit the funding to support our company. And then we try to push this forward for clinical trials using these universal donor beta cells for therapy.
Cole: Fantastic. Love it. Now I'm checking my notes because you've done some other things as well, even on top of that. When we talk about where stem cells come from, I want to make sure we touch on this too. In the little video that we showed, there's a quick and dirty little timeline there of embryonic stem cells were where the cells began. And it was very controversial, because people talk about the cells from embryos and the ethical dimensions of that, but then we were able to take these from adult humans. But you've taken it even further to the point where you don't even need blood or a biopsy, just from a urine sample, you're able to derive cells?
Lance: That's right. That's right. So I really want to talk about this topic because many times the audience may think all the stem cells are the same, but they are not. So we have the embryonic stem cells, they must derive from human embryos. So that's why they are ethically debatable. So that's why different people have different ideas on these cells. But the induced pluripotent stem cells do not need any embryos. We can use the adult person's skin cells, blood cells, but if you think about it, these processes are still painful. So you needed to draw some of the blood or you needed to donate some of the skin biopsy. So at Penn State, I decided to generate our own induced pluripotent stem cells or iPS cells for our lab. And we think about it, we were wandering, what about we just take the cells from the urine samples?
So we did that. We take some urines from one of our lab member, and then we applied the IRB through Penn State. Penn State agreed with our approach, and we spin down the urine, and then we collect the cells. So you got about 10 cells out of 100 ml of the urine samples. No a lot of cells, just 10 cells. But the good news is, these cells, once they attach to the Petri dish, they can proliferate. One cell become two to become four, become eight. And then after 10 days, we got about a couple thousand cells. And then starting from these sales, we use reprogramming technology developed by Dr. Shinya Yamanaka who won the Nobel Prize in 2012. And then we use similar technology and reprogrammed the urine cells to iPS cells. So, this process that's developed by us is a non-painful process at all because we just need to collect a little bit of urine samples.
Cole: Right.
Lance: That's it.
Cole: And the people who can collect a urine sample versus the training it takes to draw blood or get–
Lance: That's right.
Cole: So there's also the cost and the time and the effort. And so again, you're changing the game, I mean, in all these different dimensions of stem cell engineering and stem cell differentiation and even the sample collection, it's quite phenomenal. So what the heck are you working on next? What's on your agenda right now?
Lance: Yeah. Great question. So in my lab, we talk a lot about stem cells. Actually, in my lab we also work on gene editing.
Cole: Gene editing.
Lance: Yeah. Let me explain why gene editing and stem cell research are a very good match. So there are many, many patients that have diseases because they inherited the disease causing mutations from their parents.
Cole: Right.
Lance: Yes.
Cole: Hereditary.
Lance: So that's why we are very dedicated to develop gene editing technologies to correct these mutations in the patients. So recently, my lab published a newspaper in Cell Reports Methods. We showed that we can greatly improve the gene editing efficiency by using the so-called chemical and modified RNA. So this is a technology that used to generate the SARS Covid RNA vaccine. So we use this modified RNA technology to encode gene editing enzymes. And we find this method is much high efficiency as compared to traditionally people use DNA to encode these factors. So our efficiency can achieve about 85%, and the traditional efficiency is only 10 to 15%.
Cole: Did you say modified ions?
Lance: Modified RNA.
Cole: Modified RNA. RNA. I'm sorry. Yeah, I'm just making sure. Okay. RNA, that makes sense, because we've all heard about RNA with, as you said, the Covid vaccines.
Lance: RNA vaccine. That's right.
Cole: So now we're completely moving away from stem cells together, right?
Lance: No.
Cole: But you bring it back into the stem cell round.
Lance: No, not moving away from stem cells. Let me explain why this is still closely relates to stem cells.
Cole: Okay. Okay.
Lance: Because if you have a patient, that patient has a mutation, you can take that patient's urine cells and make iPS cells. So, the iPS cells will have the same mutation as the patient cell, because this is from the patient.
Cole: Got it.
Lance: So, it has a mutation.
Cole: Okay.
Lance: The question here is how do we correct the mutation? You cannot directly test your gene editing in the patient, but you can test with iPS cells derived from the patient.
Cole: Oh.
Lance: That's why it's a perfect match.
Cole: Wow. Yes. Okay.
Lance: So this is why we are working on in the lab. So we take the patient's urine cells, make the patient's iPS cell, and we deliver the gene editing into the iPS cell. And we want to see if we can correct the mutation. Yeah. I already receive many emails actually from different patients asking me to see if we can help them for this type of disease. Yeah.
Cole: Phenomenal. It's got to be a lot of fun working in your lab.
Lance: Yeah. We always work on different new projects and at take the risk steps. Yes.
Cole: Yeah. Never a dull moment. That's how it is around Huck and a lot of the Huck labs. Never a dull moment. Well boy, we're coming up pretty quick on time. I'm surprised at the number of questions I'm not seeing, and I don't know if that's because something's malfunctioning on my end with what I'm able to see on my screen, but I'm going to try one more time to check in. Oh boy. Okay. So there is a follow up question here. Okay. I just had to refresh. What are your goals for the clinical application of generated neurons? Are you looking to treat any conditions in specific at this – any specific conditions?
Lance: Right. Great question. So my lab actually didn't work a lot on the neurons, but talking about iPS cell derived neuron application, I think one of the biggest application would be related to stroke.
Cole: Stroke.
Lance: Yes, stroke. Let me make an energy in the heart, the heart of failure causes the cardiomyocytes to die. The stroke caused the neurons to die.
Cole: Yes.
Lance: So basically if you can generate iPS derived functional neurons, you can also transplant these neurons to replace the damaged neuron area. So, then you can have the new neurons grow in that area.
Cole: That's phenomenal. That could just be a whole new world medically speaking. Well, it's fantastic. I'm so glad, I'm checking to make sure that I... Did I miss anything? We talked about patents, we talked about clinical trials, we talked about what's next. Cheaper, faster, more efficient. Deriving, getting stem cells from urine samples, Wnt pathways, insulin producing pancreatic beta cells, neurons, you're all over. And now CRISPR as well. We're going deeper into CRISPR, and addressing some of those mutations as well. Phenomenal. So, there's only really one thing left to do on this episode, Lance, and that is to talk a little bit about our plushies over here.
Lance: Sure.
Cole: I can't let you go without talking about our plushies.
Lance: Yeah. We were looking at–
Cole: Yeah, we've done this all through our entire third season with our Risk Takers and Game Changers. It's just our way of having a little fun. And we're doing our own little research, Lance. I'm researching people like you, this phenomenal risk takers and game changers in science. And I'm trying to find out how you compare, if I give you, it's a social science experiment. If I show you these alternative plushies, we've got a unicorn over here, Dan's going to show our little video so that our audience can really get a good look at these. Let's take a look, Dan, if you can run that clip, we'll really show this off. There we go. It's 2022 people. And we can go deeper into plushy land than just the usual Nittany Lion that everybody's used to. Everybody loves the Nittany Lion, we love him. But if you're not a lion person, you could go with a Nittany unicorn, you could go with a Nittany little bear. I like to call that the infinite indoctrination bear.
And if you have little ones in your life that you want to get into the Penn State community, we also have the old gnome, the wizened gnome in the middle there for watch over your garden and keep the Penn State vibes going. We even have a llama, and see they all get along with our lion. You can see the lion right there. And by the way, I heard the lion's in a 12-step program now. So we're all very, very happy with the lion. He's making up with everybody in his life, doing all his good work and getting his life together. So I want to ask you, what's your favorite alternative plushy, Lance? Are you a unicorn man, a bear man, a gnome, or a llama?
Lance: Right. Great question. So my top one choice is for sure, go with Nittany Lion. Okay, because I'm a Penn Stater. So, the second choice I would go is this, the unicorn.
Cole: The unicorn. The unicorn would be your favorite alternative.
Lance: Yeah. The reason for that is because unicorns are associated with dreams.
Cole: Oh really?
Lance: Yeah. So in China we saw many description about unicorns with dreams. I just hope that I'm a person that want to dream big, want to do risky things. So that's why I like unicorns very much.
Cole: I love that. I like the unicorn too. That's phenomenal. So everybody out there watching before you sign off here, please, please vote. You can go in the chat right there. You can vote llama, gnome, bear, unicorn. And then what we're going to do is we're going to compile all the data. We're looking at which scientists liked which plushy, and then which the audience members of the different scientists, how did the audiences break out? And then we may start our own journal. We're thinking about starting a journal of social science journal just called Plushy. And this will be our first paper, and we'll see. I'm not sure if we're going to be able to apply that to anything practical, but maybe it doesn't matter. Maybe it's just something fun for us. But in all seriousness, Lance, thanks so much for coming down and sharing a little bit about what you're doing.
It's phenomenal. Thank you. One of the reasons that Penn State is great as people like you doing the work and inspiring the next generation and collaborating with colleagues across disciplines to really make a difference in the world. So thank you very much more power to you as you go forward. If people want to follow Lance's work, keep up with the Huck. You could subscribe to our newsletter, The Pulse, at our website, and you'll be getting updates about what Lance is doing and others at the Huck. I encourage you to do that. Also, if you subscribe to our YouTube channel, when we finish our video about Lance's work, that's our Life From All Angles video, the whole thing, you'll be able to watch that and share it with others. This episode will be on the YouTube channel [The Symbiotic Podcast video playlist] as well. So, if somebody missed this and you think they ought to see it, pay attention there.
You can share it with others there. We're also going to be releasing our video about Dr. Sally Mackenzie. We never finished off, there was an animation, we're just finishing up. So her video is also forthcoming. So stay tuned for that. And we're going to take a hiatus from The Symbiotic Podcast. We're taking a little break and we're going to come back with something totally different in the new year. So stay tuned for that. But again, Lance, thank you so much for coming down. It's always a pleasure.
Lance: Thank you, Cole. Nice to be here.
Cole: Take good care. And everybody out there, thanks again for watching and don't stop co-evolving.
Narrator: The Symbiotic Podcast is a production of the Huck Institutes of the Life Sciences at Penn State University.
Our video and livestream producer is Dan Lesher. Our sound engineer is Brennan Dincher. Our web developer is Jodie LeMaster, and our marketing manager is Keith Hickey. Cole Hons hosts and directs the show, and original illustrations and animations are provided by Sam Muller and Bethany Seib.
If you enjoy our podcast, we hope you’ll subscribe and share it with others. We’d also love to know what you think about our content, so if you want to get in touch, please email symbiotic@psu.edu.
You can put your questions in there for Dr. Lian. And later on in the show we will be taking those live, and he'll answer your questions, and you can also vote on other people's questions. So we'll start with the highest voted questions at the end. This is about a 45-minute show here. We're going to be showing some video that we've been shooting and producing about the amazing work that Dr. Lian's doing with stem cells. We'll be sharing some of that, and we'll be doing some other fun audience participation stuff that you can vote on in the chat. So please do take advantage of that chat and thank you for tuning in. So with that taken care of. Lance, hello?
Xiaojun (Lance) Lian: Hello. Hey Cole. Nice to be here. Nice to see you.
Cole: It's good to see you too. It's been a little while. We were trying to have you on. Boy, it's been a couple months and we ran into some problems here and there.
Lance: That's right.
Cole: Life can be like that. It can throw things at you between Covid, and hiring issues, and all sorts of things in our chaotic times. It took us a while, but we got here.
Lance: Finally, we make this happen.
Cole: Yeah, that's the important thing. And we're very excited to have you here. I was just mentioning the fact that you're in two different departments, which is such a Huck like thing because Huck is all about interdisciplinary collaboration. And we were just discussing before we started the show here that the work you're doing is a beautiful combination. It's a place that you can serve both biology and biomedical engineering. Can you tell us a little bit about that before we get into other things?
Lance: Sure. Yes. I was appointed by biomedical engineering and biology department. That's because my lab research is focused on stem cell engineering and stem cell biology. That's a very natural thing for me to be appointed by these two departments and I can contribute to both departments in different ways.
Cole: And you were saying even some new courses are emerging out of that reality, right?
Lance: That's right. Since I joined Penn State, I develop a cross listing course, which is called stem cell biology and therapy. So this course is open for both BME students and biology students. So during this course, I assign projects to students. So in this way, engineering students and biology students have the opportunity to work together for one project. So engineering students are more good at quantitative biology, such as use calculus and math to solve things. And biology knows better for biological mechanisms. So when I put them together, they can learn from each other. And this is more productive than just a group of engineering or students work together.
Cole: That's fabulous. I mean, that's what we're all about at Huck.
Lance: Right.
Cole: Kudos to you my friend. Thank you for doing that. It's exactly the kind of thing that we're championing and I think that the big complicated issues that we're grappling with, whether it's medical, or environmental, or even economic, you could go on and on with all the different challenges we're up against these days. But it really does take different kinds of people thinking different ways to take that on. So, thanks for your contributions there.
And then of course with your research, it's just fabulous. The amount of innovations, we'll get to those in a minute with what you're doing with stem cells. Just working with you on the video, I've learned so much, and I'm still learning, and there's no end. So that's why we have you on here in our risk taker game changer series as this great end to the season. It's a strong ending with you because there's so much to share that we'll be talking about.
But before we get into the science, I do this with every guest of this season. I want to know a little bit about you, Lance, and you chose the name Lance, right? Xiaojun is your name. You were born in China and took this nickname when you came here to states. So I want to know, Xiaojun, when you were growing up, when you were a kid, were you a risk-taker? Were you somebody who has changed things and what weren't just satisfied with the status quo?
Lance: Right, right. Yeah. So I was born in small town in China, in Jiangsu province. So when I grew up, I definitely liked to take risks. So for example, if I do hiking, I would like to go through these paths that no one else goes before. So the reason for that is because if you go these pathways, you will see unusual beautiful things that as compared to you use the pathways that everybody goes. And I like to see unexpected things. And especially for doing the research, I don't want to do something that everybody's doing. I want to go through these policies that no one does before. And I enjoy a lot about taking risks.
Cole: That's fantastic. I love that. I also love to go where there is no path. Try and find a path right there. I have a quote on a wall at home that says that do not go where the path may lead, set your own path, and make a trail for others to follow. I definitely relate. That's terrific. And Lance, why did you choose the name Lance? Was there any particular reason that you went with Lance?
Lance: Yeah. That's a good question. So in China when we grow up, we take English classes when we were in the middle school. And then usually the teachers will ask you to pick English name for yourself. And I started to think about it, and I was like, okay, I wanted to pick name. By that time, I just started to learn English and I wanted it to start with the letter L because my family name is L.
Cole: Okay.
Lance: I think it would be cool if I got two L, and then I just look at these English books, and I find when I see Lance, and I really like it. So that's why I just pick this one. Yeah.
Cole: It just appealed to you. And Lance Lian, it does sound good, it flows. Yeah, the two Ls.
Lance: That's right.
Cole: I love that. Terrific. Well, Lance Lian, let's talk about your research a little bit here. You've done so much with stem cells and you've taken some risks with stem cells. We'll be watching this in the video in a moment. And one of the things I learned working with you is about this Wnt pathway that we're going to be talking about a little more. And maybe you could share with us, one of the many innovations that hopefully we'll touch on, is that there are many different ways to differentiate stem cells, and there are many different pathways for the differentiation. But you had shared with me that many scientists working with stem cells try to work across maybe 10 different pathways and try to figure out all of them, and you chose one. I see that as a big risk that you took, you chose one single pathway, the Wnt pathway, and went deep deep on that, and it really yielded all sorts of incredible innovations and breakthroughs. Can you speak about what made you choose that one pathway?
Lance: Right. So stem cells, that the stem cell type that we are working on is called pluripotent stem cells. So naturally, if you have the embryo, if we have the stem cells, and in the modest uterus, these cells just naturally differentiate into all different type of cells in our body. So if you examine what signaling pathways, what signaling factors involved in these differentiation, you will find there are more than 20 different cell signaling pathways.
Cole: 20, oh, I was saying 10. There's more than 20.
Lance: Yes.
Cole: ... signaling pathways.
Lance: And if you check how many signaling factors involved, because each signaling pathway may have multiple signaling factors, you may end up with 100 factors. There's just so many things involved in this process. So when we do this in the Petri dish in the lab, if we try to a hundred percent recapitulation of what's going on in vivo, that is almost impossible because there are just so many factors involved in this process. And if you want to optimize concentration for each of them, you may end up with a combination of billions of combinations. You can never do billions of dishes for experiments. Right?
Cole: Right.
Lance: So what I do is, so my logic is, how about we find the most critical one, and if we systemically optimize this most critical one, can we yield similar results as compared to optimization of many of these factors?
Cole: I see.
Lance: To be honest, that's definitely a risk for me because it is quite possible that just optimize one signal pathway may not work at all. Because in nature you need so many different factors, and here you just try to optimize just a single one pathway and hope it's going to work. So I think I take the risk, and I did a lot of work. It took me about four years and it turns out it worked. So I'm very excited.
Cole: Yeah.
Lance: I think there's also a little bit lucky components here, but it indeed worked.
Cole: You did it. Yeah. A little bit of luck and a lot of hard work and sweat.
Lance: Yeah.
Cole: I mean, we talked about the hours that you had to run these experiments over those about four years. Did you just, three, four years?
Lance: Right. In total, it took me about four years.
Cole: About four years. And during the four years, because time is such an important element, right?
Lance: Right.
Cole: That people go in, three in the morning, checking on things, just watching 24/7 and just trying this, trying that.
Lance: Right.
Cole: And just doggedly going forward. And so when you say it worked, check me if I'm wrong here, Lance, if I'm misconstruing anything, but my understanding is that not only did you create a process for differentiation of stem cells into the other cells that you're trying to make, but you're doing it cheaper, you're doing it faster, and you're doing it with a lot greater efficiency, correct?
Lance: That's right. That's right. So the differentiation that we are talking about is called cardiac differentiation. So the goal here is we want to convert stem cells into cardiac myocytes. The reason for that is because cardiomyocytes are very critical for our heart function. And if a person have a heart attack, their cardiomyocytes died. And if we can generate these cells in the lab, we can potentially transplant these cells back into the heart failure patient. And indeed, this is happening. And during the time that I'm doing my PhD and the cardiac differentiation, efficiency is very low. So you do the differentiation, and it took you about three to four weeks, and your yield is about one to 2%. So the efficiency is very low. So my message greatly improved the efficiency. We can generate more than 90% of the efficiency, and we can achieve our goals in about 10 days.
Cole: 10 days.
Lance: So we both shorten the time and also we gradually improve the efficiency.
Cole: And then the cost associated that process too dramatically reduced, correct?
Lance: That's right. So the previous approaches use the serum and gross factors to do the differentiation, and these factors are expensive and not stable. So that's why you have to use these gross factors more quickly. You cannot store them for a long time. And instead, I did not use any serum, I did not use any growth factors. I used two small molecule compounds to do it. So these chemical compounds are more stable and much, much cheaper. So the cost of these chemical compounds is only 5% of the gross factor cost. So if they need a hundred dollars to do the differentiation, I only need $5 to do it.
Cole: That's fantastic that that's something that we do share in the video will be showing a sneak preview here in just a minute of a video about the cardiomyocyte work you're doing and also mentions pancreatic beta cells that are producing insulin. So before we run the clip, let's hear a little bit about that. And which came first, the cardiomyocytes or the pancreatic beta cells? And also I'm curious, is the same process you developed for cardiomyocytes, which are heart cells, is that's the same process then you're using to produce pancreatic beta cells, correct? And it has to do with the amount of activation and deactivation of the Wnt pathway, correct?
Lance: That's right. So cardiomyocytes differentiation happens first. So during my PhD, so I developed this robust protocol for generating cardiomyocytes. Essentially we can generate beating cardiomyocytes across the whole dish. And later, after I joined Penn State, I started to think about what type of projects that I should work on at Penn State because the cardiomyocytes efficiency is already great. So there's not much room for me to further improve it. And so I decided to look around, and see which other stereotypes are clinical relevant, and also very difficult to generate. So I like to take the risks, if no else can do this very efficiently, I want to do it. I want to make it better. So then I pick the pancreatic beta cells. The reason for pancreatic beta cells is they are very, very useful cells for treating type one diabetes. So these type one diabetes patients, their own pancreatic beta cells died because their beta cells under attack by their immune cells.
So basically their immune cells kill their beta cells. So they do not have beta cells. They cannot naturally control their blood glucose concentration. That's why they have the diabetes. So in this case, the stem cell therapy is very good for treating this disease, because if we can generate good amount of functional pancreatic beta cells, we can transplant these cells back into these type one diabetes patients, we can potentially cure the disease as compared to if you just do insulin injection, just treat the disease. So that's why in Penn State I decided to work on this. And it turns out very, very surprisingly that you can still use the Wnt pathway to regulate the stem cells to generate the pancreatic beta cell progenitors by adjusting the amount of activation. So if you activate the Wnt pathway with higher concentration of the chemicals, you generate cardiomyocytes. But if you activate a Wnt pathway at the intermediate level, you generate the pancreatic progenitors, so that's very surprising.
Cole: That's fantastic.
Lance: Yeah, nobody reported that before.
Cole: Now what about neurons? Because I know that neurons are a third very important cell that cannot be produced by the human body. We can produce skin cells and many different cells. We've talked about this, you and I, but heart cells and pancreatic beta cells and neurons are a third. Would you be able to produce neurons then with the same process?
Lance: Yeah, that's a great question. And based on the literature, my lab doesn't work on a lot of neuron differentiation. But based on the literature, it is very interesting that the Wnt pathway is also involved in neuro differentiation. But in this case, you must suppress the Wnt pathway in order to do the neuron differentiation. So in summary, you can regulate one signaling pathway and generate three different type of cells. If you suppress the Wnt pathway, you got neurons. If you intermediate activated the pathway, you got pancreatic progenitor. If you highly activated the pathway, you got cardiomyocytes.
Cole: Fantastic. Amazing. It's a good thing you went to look for a new path in the scientific woods there, Lance.
Lance: Yeah.
Cole: Really found some beautiful things in the process. Let's take a look at our video if we can. This would be a nice time. And I want encourage everybody to chat in with your questions. I'm trying to watch the chat over here so that we have some things to answer later on in the conversation. But right now, let's take a look at a sneak peek. This is three minutes of a video that when it's done will be probably about five minutes. Let's take a look now.
Narrator: The human heart is made of cardiomyocytes specialized pulsing muscle cells. Without them our hearts can't beat. Unfortunately, unlike many other cells in our bodies, cardiomyocytes don't naturally regenerate. That's one reason why heart disease is the number one cause of death in the United States. It's also the reason that stem cell therapy is considered the most promising treatment for repairing damaged heart tissue. As the raw material from which our bodies are made, stem cells have the incredible potential to form new cardiomyocytes or any other kind of cell. But these cells can only be therapeutically viable if we can control what kinds of cells they become, and successfully introduce them into a patient's body.
Lance: In total for human body, we have about 200 different type of cells, and now we can generate at least 50% of these cells, so around 100 different type of cells from stem cells. But many researchers are focusing on these cell types that cannot be regenerated naturally by our human body.
Narrator: Lance Lian is an associate professor of biomedical engineering at Penn State.
Lance: The hottest areas are three different type of cells. There are neurons, cardiomyocytes, and the pancreatic beta cells.
Narrator: At its outset, stem cell research was hugely controversial. When biologist James Thompson derived the first human stem cell line in 1998, he started with cells sampled from human embryos. In 2001, President George W. Bush banned funding of any new embryonic stem cell lines. But in 2006, Japanese researcher Shinya Yamanaka discovered that adult cells could be reprogrammed to become stem cells. An advance that won him a share of the 2012 Nobel Prize in medicine, and removed the need for embryos. With stem cells readily available to labs, researchers began to discover multiple methods to drive cell differentiation and obtain specific types of cells needed to advance new cell therapies.
Lance: Once you have iPS cell lines, one of the property of these iPS cells is they can proliferate almost indefinitely. So then you do not need to worry about the number of cells that you can have.
Narrator: Lian and his team have devised a novel way to produce new cardiomyocytes by manipulating the Wnt pathway, a sort of protein based communication network used by cells. By timing specific activations and inhibitions of this pathway. The Lian lab has advanced the effectiveness of stem cell differentiation from the highly random 1% yield produced by older methods to yield as high as 90%. They've also reduced the time it takes to produce cells from a month to around 10 days, and they've reduced the cost of the process by 99%.
Lance: We publish our paper, and now our methods become like a golden standard method in the field for all the other labs around the world if they want to make cardiomyocytes.
Narrator: In addition to cardiomyocytes, Lian's lab has used their differentiation technique to make pancreatic beta cells that produce insulin, a breakthrough that may lead to new therapies for type one diabetes.
Cole: Well, I hope you like what we did so far, Lance.
Lance: I really like it.
Cole: Oh good.
Lance: Yeah.
Cole: I'm glad. Yeah, we had a lot of fun coming out to your lab and shooting in the real stuff. There was no faking going on there. That was real science happening right in front of us, and just, it's beautiful to capture that. It seems like magic in a way, the stuff that's going on. So what we didn't get to in that video yet that we're going to get to is actually, it's funny, somebody just chatted in with a question. So I'm going to take this first question here, because it fits right in with another thing I wanted to touch on. David H says, Hello, senior biology major here at PSU. When the artificial pancreatic beta cells are administered to type one diabetics, will these patients’ immune systems attack these new cells? And that's what we were just about to talk about it. It'll be in the video later. We're talking about universal donor cells. Let's talk about that.
Lance: Sure. That's a great question. Thank you for the question. So, when we generate the pancreatic beta cells in the lab, and then we transplant back into the patient, the patient’s immune cells may still attack our transplanted cells. So the question here is, how do we protect our transplanted cells? So there are two ways that you can do it. The first way is use gene editing approach that we can generate the so called universal donor stem cell. So these universal donor stem cells, we locked out the genes associated with immune interaction with immune cells. So, the immune cells will not treat our transplanting cells as foreigners.
Cole: You locked them out. You locked out, you found those genes that would cause the immune system to react.
Lance: That's right.
Cole: You locked them out.
Lance: I locked them out with the CRISPR gene editing technology.
Cole: CRISPR.
Lance: Yes. So in this way, the immune cells such as T cells will not attack our transplant cells. So the stem cell derived the pancreatic beta cells can survive in vivo for many, many, many times, many, many years. That's one way to protect the transplanted cells. The second way to protect the transplanted cells, which is also going on in clinical trials nowadays, that is you use specific polymers to make the scaffold to encapsulate the beta cells. So these encapsulation devices have small, tiny holes on the surface, but these holes are small enough, they can only allow the insulin to come in and out, insulin, glucose, these small molecules to come in and out. They do not allow cells to come in and out. So the immune cells know there're foreigners are inside of the device, but they just cannot get in to attack them. So, in this way, you protect the transplant with the pancreatic beta cells.
Cole: Very interesting polymers. We're talking nanotechnology here. That reminds me of the whole convergence world of materials and life sciences.
Lance: Nowadays, many of these researchers, many of these problems that we are facing are extremely difficult to solve. So that's why we have to work with both biologists, biomedical engineers, and material scientists. We work together to solve these big problems.
Cole: Right on. And if we return back to the method you developed for the pancreatic beta cells to be donor cells, let's also touch on the fact that it's not just pancreatic cells we're talking about, we're talking about all of them, right?
Lance: That's right.
Cole: We're talking about the cardiomyocytes as well. So, if people watching this think about a heart transplant.
Lance: That's right.
Cole: And that's always a problem is you put the new heart in, but will the body reject that heart? And the same thing is happening on a cellular level with these differentiated stem cells. The cardiomyocytes into the, say, like a heart attack victim, like a patient who can't, like the body can't regenerate, just like it says in the video. They can't regenerate these cells. But if you put the cells in, that's another instance where the body could reject them. But this process you've developed with CRISPR and tricking it, it's almost like stealth cells.
Lance: Right.
Cole: That are not rejected. And you had shared with me that since you published that paper, and put the method out there, which is patented by the way, right?
Lance: Right.
Cole: Now, there are clinical trials going on right now in three countries with heart patients who are using these universal cardiomyocyte cells that derived using your methodology, correct?
Lance: So for the stem cell nature, you can use two different type of cells. One is called embryonic stem cell. So another one is called induced pluripotent stem cell, iPS cells. So for the cardiac therapy, if we use patient's own cell, so for example, we take a little bit of their skin biopsy and generate iPS cells and then generate a cardiac cell. If you transplant these cardiac cells back into the same patient, you may have much less concern about immune rejection. The reason for that is because the cells are coming from their own skin cells. So, in this case, you may not even need the universal donor stem cell.
Cole: Okay.
Lance: Yeah. In this case, in this specific case.
Cole: Got it.
Lance: But for pancreatic beta cell even you use patient's own cell to do iPS cell generation to do beta cell differentiation, and a transplant back, you may still have the problem.
Cole: Oh.
Lance: Because the patient, their immune cells just attack their own sale, so these are a little bit different. So for example, if we take the cardiomyocytes as an example, why cardiomyocytes, we may still need the universal donor stem cell? Why not do we just customize iPS cells for individual patients? The reason for that will be, the reason why the cost will be extremely high. That is every time I got the new patient, I have to generate a specific iPS cell line for that patient. And then I need to do differentiation. I cannot make the off the shelf product.
Cole: Got it.
Lance: The reason too, in some accurate situations, for example, heart failure, you didn't have time to do that. So the patient come to hospital and they may die in four to five hours. You cannot just say like, wait, I need to generate iPS cells, and that take about one month. The patient just didn't have time for you to do that. So then also for business and these pharmaceutical companies willing to do this, they don't want do personalized medicine because that cost, it's just too high, just no one can afford it. But if you can generate a universal donor stem cell, and then you can generate billions of cardiomyocytes, and then you freeze in the liquid nitrogen tanks, and it's like the off the shelf product. The patient come to the hospital, you immediately saw one valve of the cells and then you do the transplantation. That is more feasible business model to do this.
Cole: That's phenomenal. And I know that you do have some industry partners and when working with some iPS, do you want to talk about that? I know it's an important thing for Penn State, and one of the reasons we're doing this podcast is to tell some stories to others in the community who may want to do similar things. So, could you speak about what that experience has been like for you?
Lance: Sure, sure. So since I joined Penn State, my lab has filed through Penn State five to six patents. So they are covered different things. So for example, one patent is focusing on how to generate pancreatic beta cells from stem cells. Another one is related to how to generate these universal donor stem cells. Of course, we can combine these two patterns together to generate the so-called universal donor beta cells. But the universal donor stem cells has more broad applications than just beta cells. If you use universal donor stem cells to generate cardiac cells, to generate neurons, these cells after transplantation will also not be rejected by the patient’s immune cells. So that's why we are very interested in combining the universal donor stem cell and pancreatic beta cell protocol go together. And then we start a new company. And then I work with a business partner from New York and we try to recruit the funding to support our company. And then we try to push this forward for clinical trials using these universal donor beta cells for therapy.
Cole: Fantastic. Love it. Now I'm checking my notes because you've done some other things as well, even on top of that. When we talk about where stem cells come from, I want to make sure we touch on this too. In the little video that we showed, there's a quick and dirty little timeline there of embryonic stem cells were where the cells began. And it was very controversial, because people talk about the cells from embryos and the ethical dimensions of that, but then we were able to take these from adult humans. But you've taken it even further to the point where you don't even need blood or a biopsy, just from a urine sample, you're able to derive cells?
Lance: That's right. That's right. So I really want to talk about this topic because many times the audience may think all the stem cells are the same, but they are not. So we have the embryonic stem cells, they must derive from human embryos. So that's why they are ethically debatable. So that's why different people have different ideas on these cells. But the induced pluripotent stem cells do not need any embryos. We can use the adult person's skin cells, blood cells, but if you think about it, these processes are still painful. So you needed to draw some of the blood or you needed to donate some of the skin biopsy. So at Penn State, I decided to generate our own induced pluripotent stem cells or iPS cells for our lab. And we think about it, we were wandering, what about we just take the cells from the urine samples?
So we did that. We take some urines from one of our lab member, and then we applied the IRB through Penn State. Penn State agreed with our approach, and we spin down the urine, and then we collect the cells. So you got about 10 cells out of 100 ml of the urine samples. No a lot of cells, just 10 cells. But the good news is, these cells, once they attach to the Petri dish, they can proliferate. One cell become two to become four, become eight. And then after 10 days, we got about a couple thousand cells. And then starting from these sales, we use reprogramming technology developed by Dr. Shinya Yamanaka who won the Nobel Prize in 2012. And then we use similar technology and reprogrammed the urine cells to iPS cells. So, this process that's developed by us is a non-painful process at all because we just need to collect a little bit of urine samples.
Cole: Right.
Lance: That's it.
Cole: And the people who can collect a urine sample versus the training it takes to draw blood or get–
Lance: That's right.
Cole: So there's also the cost and the time and the effort. And so again, you're changing the game, I mean, in all these different dimensions of stem cell engineering and stem cell differentiation and even the sample collection, it's quite phenomenal. So what the heck are you working on next? What's on your agenda right now?
Lance: Yeah. Great question. So in my lab, we talk a lot about stem cells. Actually, in my lab we also work on gene editing.
Cole: Gene editing.
Lance: Yeah. Let me explain why gene editing and stem cell research are a very good match. So there are many, many patients that have diseases because they inherited the disease causing mutations from their parents.
Cole: Right.
Lance: Yes.
Cole: Hereditary.
Lance: So that's why we are very dedicated to develop gene editing technologies to correct these mutations in the patients. So recently, my lab published a newspaper in Cell Reports Methods. We showed that we can greatly improve the gene editing efficiency by using the so-called chemical and modified RNA. So this is a technology that used to generate the SARS Covid RNA vaccine. So we use this modified RNA technology to encode gene editing enzymes. And we find this method is much high efficiency as compared to traditionally people use DNA to encode these factors. So our efficiency can achieve about 85%, and the traditional efficiency is only 10 to 15%.
Cole: Did you say modified ions?
Lance: Modified RNA.
Cole: Modified RNA. RNA. I'm sorry. Yeah, I'm just making sure. Okay. RNA, that makes sense, because we've all heard about RNA with, as you said, the Covid vaccines.
Lance: RNA vaccine. That's right.
Cole: So now we're completely moving away from stem cells together, right?
Lance: No.
Cole: But you bring it back into the stem cell round.
Lance: No, not moving away from stem cells. Let me explain why this is still closely relates to stem cells.
Cole: Okay. Okay.
Lance: Because if you have a patient, that patient has a mutation, you can take that patient's urine cells and make iPS cells. So, the iPS cells will have the same mutation as the patient cell, because this is from the patient.
Cole: Got it.
Lance: So, it has a mutation.
Cole: Okay.
Lance: The question here is how do we correct the mutation? You cannot directly test your gene editing in the patient, but you can test with iPS cells derived from the patient.
Cole: Oh.
Lance: That's why it's a perfect match.
Cole: Wow. Yes. Okay.
Lance: So this is why we are working on in the lab. So we take the patient's urine cells, make the patient's iPS cell, and we deliver the gene editing into the iPS cell. And we want to see if we can correct the mutation. Yeah. I already receive many emails actually from different patients asking me to see if we can help them for this type of disease. Yeah.
Cole: Phenomenal. It's got to be a lot of fun working in your lab.
Lance: Yeah. We always work on different new projects and at take the risk steps. Yes.
Cole: Yeah. Never a dull moment. That's how it is around Huck and a lot of the Huck labs. Never a dull moment. Well boy, we're coming up pretty quick on time. I'm surprised at the number of questions I'm not seeing, and I don't know if that's because something's malfunctioning on my end with what I'm able to see on my screen, but I'm going to try one more time to check in. Oh boy. Okay. So there is a follow up question here. Okay. I just had to refresh. What are your goals for the clinical application of generated neurons? Are you looking to treat any conditions in specific at this – any specific conditions?
Lance: Right. Great question. So my lab actually didn't work a lot on the neurons, but talking about iPS cell derived neuron application, I think one of the biggest application would be related to stroke.
Cole: Stroke.
Lance: Yes, stroke. Let me make an energy in the heart, the heart of failure causes the cardiomyocytes to die. The stroke caused the neurons to die.
Cole: Yes.
Lance: So basically if you can generate iPS derived functional neurons, you can also transplant these neurons to replace the damaged neuron area. So, then you can have the new neurons grow in that area.
Cole: That's phenomenal. That could just be a whole new world medically speaking. Well, it's fantastic. I'm so glad, I'm checking to make sure that I... Did I miss anything? We talked about patents, we talked about clinical trials, we talked about what's next. Cheaper, faster, more efficient. Deriving, getting stem cells from urine samples, Wnt pathways, insulin producing pancreatic beta cells, neurons, you're all over. And now CRISPR as well. We're going deeper into CRISPR, and addressing some of those mutations as well. Phenomenal. So, there's only really one thing left to do on this episode, Lance, and that is to talk a little bit about our plushies over here.
Lance: Sure.
Cole: I can't let you go without talking about our plushies.
Lance: Yeah. We were looking at–
Cole: Yeah, we've done this all through our entire third season with our Risk Takers and Game Changers. It's just our way of having a little fun. And we're doing our own little research, Lance. I'm researching people like you, this phenomenal risk takers and game changers in science. And I'm trying to find out how you compare, if I give you, it's a social science experiment. If I show you these alternative plushies, we've got a unicorn over here, Dan's going to show our little video so that our audience can really get a good look at these. Let's take a look, Dan, if you can run that clip, we'll really show this off. There we go. It's 2022 people. And we can go deeper into plushy land than just the usual Nittany Lion that everybody's used to. Everybody loves the Nittany Lion, we love him. But if you're not a lion person, you could go with a Nittany unicorn, you could go with a Nittany little bear. I like to call that the infinite indoctrination bear.
And if you have little ones in your life that you want to get into the Penn State community, we also have the old gnome, the wizened gnome in the middle there for watch over your garden and keep the Penn State vibes going. We even have a llama, and see they all get along with our lion. You can see the lion right there. And by the way, I heard the lion's in a 12-step program now. So we're all very, very happy with the lion. He's making up with everybody in his life, doing all his good work and getting his life together. So I want to ask you, what's your favorite alternative plushy, Lance? Are you a unicorn man, a bear man, a gnome, or a llama?
Lance: Right. Great question. So my top one choice is for sure, go with Nittany Lion. Okay, because I'm a Penn Stater. So, the second choice I would go is this, the unicorn.
Cole: The unicorn. The unicorn would be your favorite alternative.
Lance: Yeah. The reason for that is because unicorns are associated with dreams.
Cole: Oh really?
Lance: Yeah. So in China we saw many description about unicorns with dreams. I just hope that I'm a person that want to dream big, want to do risky things. So that's why I like unicorns very much.
Cole: I love that. I like the unicorn too. That's phenomenal. So everybody out there watching before you sign off here, please, please vote. You can go in the chat right there. You can vote llama, gnome, bear, unicorn. And then what we're going to do is we're going to compile all the data. We're looking at which scientists liked which plushy, and then which the audience members of the different scientists, how did the audiences break out? And then we may start our own journal. We're thinking about starting a journal of social science journal just called Plushy. And this will be our first paper, and we'll see. I'm not sure if we're going to be able to apply that to anything practical, but maybe it doesn't matter. Maybe it's just something fun for us. But in all seriousness, Lance, thanks so much for coming down and sharing a little bit about what you're doing.
It's phenomenal. Thank you. One of the reasons that Penn State is great as people like you doing the work and inspiring the next generation and collaborating with colleagues across disciplines to really make a difference in the world. So thank you very much more power to you as you go forward. If people want to follow Lance's work, keep up with the Huck. You could subscribe to our newsletter, The Pulse, at our website, and you'll be getting updates about what Lance is doing and others at the Huck. I encourage you to do that. Also, if you subscribe to our YouTube channel, when we finish our video about Lance's work, that's our Life From All Angles video, the whole thing, you'll be able to watch that and share it with others. This episode will be on the YouTube channel [The Symbiotic Podcast video playlist] as well. So, if somebody missed this and you think they ought to see it, pay attention there.
You can share it with others there. We're also going to be releasing our video about Dr. Sally Mackenzie. We never finished off, there was an animation, we're just finishing up. So her video is also forthcoming. So stay tuned for that. And we're going to take a hiatus from The Symbiotic Podcast. We're taking a little break and we're going to come back with something totally different in the new year. So stay tuned for that. But again, Lance, thank you so much for coming down. It's always a pleasure.
Lance: Thank you, Cole. Nice to be here.
Cole: Take good care. And everybody out there, thanks again for watching and don't stop co-evolving.
Narrator: The Symbiotic Podcast is a production of the Huck Institutes of the Life Sciences at Penn State University.
Our video and livestream producer is Dan Lesher. Our sound engineer is Brennan Dincher. Our web developer is Jodie LeMaster, and our marketing manager is Keith Hickey. Cole Hons hosts and directs the show, and original illustrations and animations are provided by Sam Muller and Bethany Seib.
If you enjoy our podcast, we hope you’ll subscribe and share it with others. We’d also love to know what you think about our content, so if you want to get in touch, please email symbiotic@psu.edu.
