- Welcome everyone to Wednesday Nite @ the Lab. My name is Dyllen Brewer, and I'm a student worker here at the Biotech Center. On behalf of the Biotechnology Center, UW-Madison Division of Extension, Wisconsin Public Television, Wisconsin Alumni Association, and UW-Madison Science Alliance, welcome to Wednesday Nite @ the Lab. We do this every Wednesday, 50 times a year. Tonight, it is my pleasure of introducing Su-Chun Zhang. And tonight, he will be sharing about human stem cells and how far we've come in 25 years. Before we get started, we're gonna ask him a couple questions. Where were you born?

- Ah, [laughing] ask that question.

[Dyllen laughing] I was born in China.

- All right, where in China?

- On the southeast coast of China. 

- All right, and where did you attend high school?

- In my hometown, that little, little, very little town, village town, very small town.

- All right, and where did you go for undergrad?

- That's in Wenzhou Medical University. So it's a town, couple of hundred kilometers away from my home.

- All right, and what did you study while there?

- I studied medicine.

- All right.

- That's my undergrad.

[all laughing]

- And where did you go for any advanced degrees?

- Yeah, I did my master degree then in Shanghai Medical University. So that's another city; probably many of you know that city.

- All right, everyone, please join me in welcoming Su-Chun Zhang tonight.

[audience applauding]

- Thank you everyone for coming in the wintertime. 

[all laughing]

Because this week is somewhat special, and so I'm going to talk about the topic that happens sometime 25 years ago. So relating to the topic, I'm going to mention stem cell research at UW-Madison, and I'm also going to tell you where we are. So why I pick up this topic? As I mentioned, this week 25 years ago, you might notice, some of you, that in our university, we developed the first human embryonic stem cells on this campus. And that piece actually is written by Terry Devitt, and it goes like, "The dream of one day being able to grow in the laboratory an unlimited amount of human tissues for transplantation is one step closer to reality."

So why is that? You know, because at UW-Madison, the person who did that was Jamie Thomson. Many of you probably have heard of him. He developed the human embryonic stem cells in his laboratory here at the Primate Center at the University of Wisconsin-Madison for the first time in the history. And I want to also mention that he actually did many other type of stem cell. One is monkey embryonic stem cell a few years back, and that actually set up the foundation for him to develop a human embryonic stem cell technology. But as I'm going to tell you later on that, several years later, he developed another type of stem cell called induced pluripotent stem cell. 
I'm going to touch a little bit later.

Why the development of human embryonic stem cell caused such a kind of a splash? This is because, you know, the stem cell comes from this little place in the early embryo. It's called the inner cell mass. It's a cluster of cells consisting of a few hundred cells. And these cells actually in the end that produce any kinds of cells in our body, from skin, bone, muscle, to brain cells, all type of cells. And so these are called, you know, stem cells. And what Jamie did was taking this group of cells and then grow them in the Petri dish. And they grow like that, as a cluster of cells. And this cell can be grown pretty much continuously, until today, actually. Today, the cells we are using were actually initiated by Jamie 25 years, more than 25 years ago. 

And so you can imagine that how many cell we can actually produce over that many years. And plus, because of their potential, the capacity to give rise to any kind of cell, you can imagine what the utility would be. So at least at that time, it was imagined in this way. I just want to show you one example. For example, the cells, the stem cell grew in the Petri dish, and you will see they're beating. You almost can immediately tell what they are, right? They are heart beatings there, and if you count, it actually beats around 60 times a minute.

Why is that? It means that the cells grow in the Petri dish. They actually remember who they are, what they should be doing. And if we take, let's say, the same type of stem cell from a mouse, from a mouse, the embryonic stem cell and then they differentiate to heart cell, they will beat how many times, almost 10 times more, like 500 times a minute or something because they are coming from mice. And from human, they beat around 60 times a minute. 
So that means they remember what they should be.

And so if we take stem cell, guide them to become other type of cell, we probably would also be able to do that, right? So, and another part is that the cell, we can, I mentioned that we can continuously grow them. You know, the cells can divide once a day. For example, two days will be two cells, three days will be four cells, you know, and they keep it going, and generate the huge number of cells for any kind of application. You know, has its potential and capacity.

But there is also coming with a issue because the cells were initially coming from an embryo. Even though it's in vitro fertilized embryo, the couple no longer need them and they are going to discard it, still, you know, there are ethical issue. One is the people who against it would be, "Okay, killing this helpless human embryo "for scientific research represent an assault to, you know, respect for human life." But on the other hand, that there is also a counterargument that it's immoral not to use, to pursue research on otherwise discarded embryo that has the potential to find treatment and cures for world's most devastating diseases. And so there are always ethical argument surrounding the embryonic stem cell research. 

And I took this Time magazine page, just you probably notice many of the faces, right?

[laughing]

And because of this research having this ethical issue and that for that reason, so at that time, the research on human embryonic stem cell were not funded by any federal government. And so in order for the cell to be utilized for research purpose and for developing therapeutics, we need the support from all aspects. And among those faces, you probably notice one person we are very familiar with, right? Yeah, so Tommy Thompson, another Thompson. He was our former governor and the former Secretary of Human Health and Human Services in the Bush government. And he was very instrumental in persuading Bush government to allow stem cell research go on. And he came to visit us many times to, you know, understand what this stem cell research entails, how the potential it would be, and so on and so forth.

So in the end, I think he persuade the Bush government to allow the research on human embryonic stem cell for at least the stem cell lines that were already generated by that time. But still at that time, the funding, federal funding for research in that area was not allowed. And so that's why the university and the Alumni Research Foundation, many alumni, like many of you here, help us to promote research.

The first thing was done by the Wisconsin Alumni Research Foundation to build the non-for-profit research institute called the WiCell Institute. It started with several of us. So for that, I want to remember one person, Carl Gulbrandsen. And he was the director of WARF. You know, he really championed for the stem cell researcher here at the UW-Madison. And that institute was designed to promote the stem cell research, in particular at that time, to allow stem cell research to work in a building that was not contended by federal fundings, and that was pretty tough at that time. And so that really made the stem cell research here at UW-Madison move forward.

But it goes way beyond that. You know, we trained a lot of people how to grow those stem cell, research on those stem cells, not only UW, not only in the United States, but also people from around the world. And furthermore, with that institute, we actually shipped cells to all over the world, okay? And just to give you some idea, you know, over the past 25 years, we ship cells all over the world. Ship now over 10,000 shipments to over 3,000 investigators in 900 institutions, more than 48 countries in 6 continents, you know. So you can see how a small Madison can contribute to the world in that particular area.

But still, that is not sufficient with just that institute. So we actually, the university, you know, through communication with many entities through public communication and went to Capitol Hill, talking to people, and we even invited many of the celebrity I mentioned that are here, you know. It's Michael J. Fox, you probably know him. He has Parkinson's; he promote stem cell research. The upper one actually is our former governor, Jim Doyle. You know, many of you know them. And so many, many people actually help to promote the research.

So in the end, I think, besides at the beginning, 2001, when the stem cell, the existing stem cell lines were allowed to do research, later on, Obama administration further removed the remaining restrictions to allow the stem cell research to move forward. So I want to tell you this brief history because you know, this kind of initial discovery unnecessarily went through this bumpy road getting to where we are today. But another important part in science is that we have those embryonic stem cell research, but that research actually led to another further discovery that is the development of another stem cell type called induced pluripotent stem cells.

And that was done by two people. One is Shinya Yamanaka in Japan, as well as our old friend Jamie Thomson here at UW. And Shinya actually received a Nobel Prize for that. So again, you see how the embryonic stem cell research here leads to the further development of another type of stem cell. And why this induced pluripotent stem cell, short for iPS cell, why they are so important. Because these cells can be generated from any of us here. You just need to donate a drop of blood. We can generate such kind of stem cell. So it means every of us can have a stem cell bank in our cabinet, right?

And yet those stem cell, iPS cell, are very similar to the ES cells, the embryonic stem cell. They can proliferate continuously, they can generate all kinds of cell in our body, and of course, has less ethical issue because it generally from our own body. And it also means that this cell can be used for personalized regenerative therapy because it's coming from our own body, right? So with this kind of development, you know, our school also establish another center. It's called the Stem Cell and Regenerative Medicine Center to further promote the research on both embryonic stem cell and induced pluripotent stem cells. And what this center is aiming at to advance science in stem cell research and also foster regenerative therapy and maintain the forefront status of stem cell research here at UW-Madison.

Okay, so I have introduced to you what stem cells are and the brief history of stem cell, particularly from embryonic stem cell, to induced pluripotent stem cell. So next, I'm going to tell you, what do this stem cell do? So I will just give you a couple of example from what we are doing in our laboratory. So I'm working mostly related to brain functions. So I will tell you a few things relating to stem cell in terms of neurological or psychiatry disorders. So one thing, in order for the stem cell to be utilized, the first thing we need to do is to guide this stem cell to specialized cells. 

So in this case, I'm showing you is the nerve cells. So we can actually develop technology to guide the stem cell to nerve cells, either in a 2D, two-dimensional culture, or we can actually make them almost like a brain-like structure we call the brain organoid. And recently, we even further developed a technology to 3D print them. So because we have stem cell, we can guide them to become many kinds of specialized cells, and we can actually take those specialized and print them.

And so this is a piece of brain tissue. And they're alive, by the way, and they talk to each other. And so. . .

[clearing throat]

And with those specialized cells, now you can do a number of interesting things. You can look at the, you know, how our human being is developed in early time because we could not study in the past. We can only use animals, right? Now, we can actually look at directly. The second is if we take the cell from patients or we genetically modify them, and we can actually look at how they change in the disease process. And if we have that, we can also use this as a platform to test the drug on those patient cells directly, not necessarily going through animals.

And finally, we can actually have this cell as a source to replace the cells that are injured in our body or lost in our body, so as a cell therapy strategy. Okay, so I'll give you one example, for example, we can guide the stem cell to specialized cell, motor neuron, it's called motor nerve cell, meaning the nerve cell controlling our movement. And that research was initiated by an ALS patient when he called me from Texas over the phone, saying that, "Doctor Zhang, you need to work on this." And I said, "I never worked on that." "But it doesn't matter, you have to work on this." 

[audience laughing]

And I actually started working on that project. It turns out that we were still the first in the world to guide the stem cell to become motor neurons. And this is just one example. And over the years, actually, in my lab, we have guided stem cell to retina cell, brain cell, many, many different kinds of brain cell. I listed over a dozen of them. This all specialized. And those cells are either injured or diseased in many of the disorders like retinal disorder, Parkinson's, Huntington's, Alzheimer's, ALS, and so on and so forth. And this is just from my lab, but there are many other labs at UW-Madison.

And so in our campus, actually, there are many other type of cells generated. For example, I mentioned that neural cell, but there are blood cells, vascular cells, cardiomyocytes, and so on, so forth. So what I'm trying to say is that we actually have developed the technology to guide those stem cells to many, many different kinds of cell in our body, you know, from skin, muscle, bone, to brain cells. 

Now because we have so many type of cells, so now we can actually make it very standardized platform, like using 3D printing. I just want to show you one example. We actually recently developed a technology to print a piece of tissue layer by layer. This is a brain tissue, and they can actually talk to each other. And if I give you a 3D kind of look, you can see this nerve cell with nerves connecting to each other. And I use a different color to show a different type of nerve cell. They actually handshake each other, talking to each other essentially. And so these are all alive. And so we can really begin to understand in our brain how these nerve cells talk to each other.

And I mentioned that if we take cells, the stem cell generally from patients; for example, if some patient or any of the people give a drop of blood and we can generate these iPS cells, and then we can guide them to, let's say, nerve cells. And say, give you an example, if I take a ALS patients, ALS, probably many of you have heard of it. It's called also called Lou Gehrig's disease. Those patients, you know, the nerve cells, the motor neurons died, and so they get paralyzed, and in the end, they could not breathe and they die from that. And see, when we took those patients there and then look, look at the nerve cells we generated, and you can see this, this is from patients. And those nerves there, you have swirling of this called the neurofilament at the cytoskeleton of the nerve. And because they swirl instead of the normal when they line up in parallel, so that really jam the nerve so they could not transduce the signal along the nerve. And that really shows you how powerful, you know, when you take patients and you look at them.

And you can also use this technology to look at some of the unknown disease. We recently discover a family of patient in Middle East, and this family, the kids in that family show this premature aging, you know, when they are kids, when they are teenager, they actually show these aging sign, gray hair and skin, white color skin, all these kind of things. And then they also have a very severe neurological and cognitive deficit. These kids, when they get to teenager, they could no longer move and become paralyzed. What happens to this?

And this disease, up until today when I'm talking to you, it's not diagnosed. And when we took a skin punch and generate this iPS cell and then guide them to brain organoid. This is a piece of brain tissue-like structure. And you see, the top one is the normal one. Under the lower low is from patients. And you probably can tell, I specifically using color to label different cell types. You can tell the difference. The cells at the bottom, the green cell, many few are not line up evenly, right? These are dividing cell; they're supposed to divide to produce enough cell to form the brain, but those kids do not. Yet when we look at the upper part of the brain organoid, you see the normal one is that thin, yet the patient are much thicker, so that means they prematurely generate the nerve cell. 

So they divide less, but they prematurely become nerve cell. So that's why those patients have a smaller brain and have a defective brain connection. So that's why those patients have neurological problem and cognitive deficits. And so you can see that we can use this technology to even help us diagnose those diseases and potentially come up with a strategy for therapeutic development. And with this kind of stem cell platform, particularly those from patients, we can actually modify it to a platform for drug testing.

Just give you one example. So I mentioned that we can take a drop of blood from a patient and then generate iPS cell, and then guide them to stem cell and then do screening. And we, for example, we develop a platform for SMA, spinal muscular atrophy. This is also a devastating fatal disease. You know, when babies have such kind of a mutation and their muscle, that nerve cell controlling the muscle do not function appropriately, so they cannot move or they cannot even suck milk and so on and so forth. And so they usually, it's usually a fatal disease. And we actually developed this platform and screening drug in collaboration with NIH. And you see, this is the reference drug. And we actually identified several of them. And later on actually, two of them were in clinical trial. So it's quite powerful in identifying drug because you can test directly on patients' target cells.

And so for that reason, the, you know, I created a small startup several years ago in response to the call from the University. It's called for Discovery to Product program, D2P program. And so we develop this startup to generate the human nerve cells for drug company or biotechnology company to look at the disease process, look at the drug development, and so we can produce now many, many different type of cells I listed here, you know. And not just me; there are many others. And so I took a statistic from WARF. Over the past two decades, you know, WARF license the patent. Many of the discoveries here relating to stem cell technology and licensed them, and actually, the income is $50 million. But that's just for the licensing and mostly targeting, you know, these well-known pharma and biotech companies. But they also created startups within Madison area, and I listed a few of them. This list of the companies built here within Madison.

So, so far I've told you that this stem cell can be used as a technology platform for looking at the disease process for screening drugs, right? You still have not heard from me that, in the first page, that the stem cell will be used for therapeutics, right? So I'm going to tell you a little bit in the last part on that part. So cell therapy. So how can the stem cell be used for treating many debilitating disorders? When, of course, you can take the cell, generate a specialized, let's say, nerve cells, and replace the cells that are lost in the disease. But you can also use these cells as a vehicle to carry molecules that are missing in our body. So that's the second way.

The third way is to remodel the environment of the liver or spleen or kidney or brain to promote regeneration. Finally, in the brain in particular, you still need to, not only the cells you need to replace, but also you need to reconnect or rewire the network, so it's much, much more complicated. And I mentioned that with the iPS cell technology, the induced pluripotent stem cell technology, we can actually generate cell from our own body so that we can actually use these cells for personalized therapy because these are coming from our own body. So if you use it, they will not be rejected, not like many of the transplantation many of us have heard. You know, let's say kidney transplantation. You have to use immune suppressions throughout life, right? But here, if we use the own cell, our own cell, so you don't need the immune suppression.

So I will give you one example. Let's say, many of you have heard Parkinson's disease, right? It's a very common neurodegenerative disease. And this disease actually is caused by degeneration of the dopamine nerve cells in the midbrain. And this nerve cell degenerated, and so our movement is not controlled, so have trembling, instability, and so on and so forth. Now, we have treatment options. We can use medication like L-Dopa, or using surgical approach, like deep brain stimulation. And they are actually quite effective in improving the symptom, to minimize the symptom.

However, all these treatment actually do not stop or even slow the progression of the disease. So the disease still progress as-is. So in the end, those medication or surgical approach, they lose their efficacy. So that's why we need the new approach to deal with this kind of disease. And so cell therapy is one potential possibility. And this area actually quite interesting because in the past, actually over the past few decades, people have tried to use fetal tissues to treat the Parkinson's disease. Some are effective, some are not. The reason is because you cannot standardize the treatment. Plus there is ethical issues.

And so if we have the stem cell, now we can actually guide them to become, let's say, dopamine nerve cells and we can standardize them. Then it become a drug, right, a medication. And so that is what we have been doing over the past many years. And we actually have developed a way to guide stem cells to this dopamine nerve cells. And I use many panels because these dopamine nerve cells are very specialized dopamine nerve cell. They have to have certain kind of features, including the expression of those genes and not other genes. And when these cells are transplanted back to the mouse brain-- experiment, we can only use the mouse. And so we, let's see, we transplant the cell into the mouse brain, also midbrain area. And then you ask, you know, "What this nerve cell do?"

These are the human stem cell-derived dopamine nerve cell. And you'll see here in the brain section, and that's where we transplanted. And the dark area are where the nerve goes. And you see the nerve goes to all the way here. This is a magnified view. It's straight in the area that controls our movement. And that is what exactly these nerve cell do in our brain. It's just mind-boggling because those nerve cells are generated in a Petri dish, and you put back into the mouse brain, not even human brain, they know where to go. They actually find their way, find their home, and reconnect the neural network. 

And so that's why this animal actually recovered. Their motor deficit is mitigated. But in order to demonstrate that this motor recovery actually is coming from the transplanted cell, we actually engineered the stem cell before transplantation. We built a switch into it. So how do we do that? And so we can turn on or turn off the function of the transplanted cell. Let's see, if we turn off the function of the transplanted cell, so the therapeutic effect will be lost. And so it will be indicated by the mouse turning to the left side. And so, with remote control, the mouse turn off the function of the transplanted cell. So when you let the mouse move freely, and you can see it always turn to the left. So that means it loses the effect of the therapeutic function. 

But if you want the cell to function more, and you can beat them, you know, beat them to work harder. And then, what's your expectation? What goes to the right side? This is just a read out. And so when we turn the positive switch, they turn to the right side. And so that demonstrates that this cell indeed do what they are supposed to do. And because of that, we are moving to the preclinical to a larger animal because you know, you can cure hundreds of thousands of mice, but it doesn't necessarily mean it will be effective in human, right? You have heard so much in news that the mice are cured, but when we move on to human, that's another story. And so we decided to move on to the larger animals using the non-human primate.

And so how did we do that? So we took a skin punch from the Parkinson's monkeys and generate the stem cells from them and guide them to dopamine nerve cells, and then transplant them back into the same Parkinson's monkey. And this was done in collaboration with the Primate Center and the imaging done at the Waisman Center. Now, and we follow those animal exactly like we follow the patients. Do all the tests on patients, on those monkey in the exact same way as for patients. 

And you see, this is just the PET imaging to look at whether the transplanted cell release dopamine or not. So the top part panel is the animals that before receiving transplantation, you can see the right side is empty, right? The left side is red. Now, the lower panel is after transplantation. You can see that the right side, there is a signal on the right side of the brain. So that's the transplanted cell release dopamine. And when we look at the behavior, symptom, and those animals actually recover and they move freely. And so this set of animal tells us that, hey, this approach can be safe and can be also effective actually. And more importantly, because those cells are coming from the same monkey, so that means it's autologous. So we actually didn't use any immune suppression. After surgery, they are free, you know. 

And also, because we did a number of animals, so we can actually come up with many of the parameter so that we can use those parameter for application in patients. And so that's why we are now moving toward patient application. Now the final part, how do we move from the lab to the clinics? I mentioned briefly that nowadays, we can use a different approach, either from your own cell or from somebody else. So I would just use your own cells. Let's say you take a drop of blood, generate stem cell, and then we can generate many different kinds of cells, right? Let's say blood cell. You can use it for blood disease like leukemia and so on and so forth. You can generate the insulin cell for example, for diabetes. Maybe retina cell for eye disease or the nerve cell I mentioned for many of the neurological disorders.

Just give a couple of example. One is the blood cells. I took Dr. Igor Slukvin's lab slide, and they actually develop a technology to guide the human stem cell to many, many different kinds of blood cells, from neutrophil, macrophage, T-cell, you know, in case these lymphocytes. And this cell can be used to treat many of the leukemia blood disorders. But he's also developing technology to help avoid immune suppression because when we use cell transplantation from one person to another, this is called allogenic transplantation, which would need immune suppression. And sometime, it can create a reaction because the immune reaction to the transplanted cells, and it can create the so-called graft-induced reaction. And he's now developing the mesenchymal cells from those stem cells and to regulate this response. So that can minimize the risk for this kind of cell transplantation therapy. And that they have already, you know, gone through the phase one clinical trial. At least it shows that it's safe through his company, Cynata.

And another part is retina cell, for example. It's from my colleague next door to my office, Dave Gamm; he's in ophthalmology. So they actually generated the retinal cells from the stem cells. And just give you one example, this panel, the middle panel is the retinal cells generated from stem cells in the Petri dish. And the right side is the real retinal cell in our retina. Look at them, how similar they are! Of course, this is just by morphology, but the more important is functionally, they are actually very similar. And so that's why Dr. Gamm also establish a company to help him translating this technology to clinical application. They are also in preparation through FDA approval for clinical trial.

I mentioned the Parkinson's experiment I did over the past two decades, and I felt that we have overwhelming data to support the move for clinical application. So that's why I also set up another startup, BrainXell Therapeutics, and to initiate the clinical trial. And this is the new company, and the first part is to work on stem cell, and in this case, we will use autologous transplantation, basically very much like what I did on the monkey studies, taking patients' cells, guide them to dopamine nerve cells, and transplant them back. And so that's what we expect to get in approval from FDA next year and hopefully start the clinical trial a year later.

But we are also working on a number of other diseases, which we do not have actually any treatment options. One is spinal cord injury because when the person injured, injured the spinal cord, they're paralyzed. We do not have any options actually. And so over the years, we actually develop technology to turn the stem cell, to specialize the spinal cord cells, and they can regulate the pain, spasm, movement, and so on and so forth. And we have already tested in rat models, and they work well. And we are also testing in the monkey model, at least from MRI, showing that they can integrate into the spinal cord. So we are now in the preclinical stage. Hopefully, we'll get to the patient sometime. 

Another also very devastating disease is stroke, and it's also very widespread disease. And you know, when there is a stroke, the brain is damaged and they cannot regenerate. And so we have developed a way to guide the cell to the brain cells. But still, there are many hurdles in this part because if you transplant cell into the lesion, the stroke area, the cell actually could not survive at all. And so we recently engineered a cocktail. With that cocktail, the cell survive, as you see the blue area. This is the lesion area in the stroke area, and with the transplantation, it can heal the stroke area completely, reconstitute the brain. And so we are now also moving to the larger animals before we move on to the patients. I kind of give you only a few examples over the course.

But I just want to summarize that, you know, the first stem cell, human stem cell were generated here in Madison 25 years ago. And that leads to the newer version of stem cell, it's called iPS cell, several years later. And it looks like it takes very long time for us to get to where we want to go. Indeed, it takes very long time to develop technology, particularly in terms of how to guide the stem cell to produce specialized blood cell, pancreatic cell, nerve cell, and so and so forth. But now if I look at the, what's happening, particularly after 2020, you know, in this area, you see the first patient trial in Parkinson's patient was in 2020. And then in the spinal cord injury patients, and then the clinical trial for Parkinson's in many other area in China, EU, U.S., Canada, Japan, and so on and so forth. And also recently, there is also a report showing that the cell therapy is effective for epilepsy. And these are just the neurological disorders. And there are many others. 

You already have heard diabetes, for example, macular degeneration, and so on and so forth. And those things happen actually mostly within this past few years, right? A couple of years. So you can see where the stem cell research is heading. It really gets to the critical stage toward the clinical application. So that's my prediction. But before I end, I just want to come back to tell us how proud we are here. You know, what UW has done has impact the field, particularly in terms of stem cell research and regenerative medicine. And I mentioned that it's the place, you know, where human stem cell originate. But I also mentioned that in the historical perspective that it went through multiple steps, how it impacts the policy funding for stem cell research. And I mentioned that we actually, through this process, we actually trained a lot of people worldwide and distributing cells across the globe and stimulate and nurture the stem cell investigators, including also industry. 

And in the end, it will benefit the people who suffer from many of the debilitating disorders. So I will stop here by acknowledging a lot of people because the work I've done in the lab I mentioned, done by my students, post-docs, undergraduate researchers, and so on and so forth, and of course also from many other labs. And the funding support from federal and non-federal private industries. I mentioned many things not happening in my lab, and those are coming from many of the colleagues who provided all this information. And I also mentioned tht two companies I set up because they are actually very important to take the technology developed in my lab to application in potentially in the future in clinics. Okay, I will stop here, taking any potential questions.

[audience applauding]