Scientist Stories: Mathew Blurton-Jones, Stem Cells to Treat Alzheimer's

Good morning and thank you for joining UCI MIND today for a live discussion and Q&A on how stem cells are being used in Alzheimer's disease research. I'm Chelsea Cox, Associate Director of Education at UCI MIND, which is an Alzheimer's disease research center designated by the National Institutes of Health. We're a collaboration of over 100 researchers at the University of California, Irvine, who work together along with colleagues across the world to try to solve Alzheimer's disease and related dementias. This episode is part of a monthly Q&A series where live viewers have the opportunity to ask questions of our nation's leading experts in Alzheimer's and related dementia research. And today I'm thrilled to be joined by Dr. Matthew Blerton-Jones, who will talk on the topic of stem cell research in Alzheimer's disease. So I'm going to add him here onto the screen. Hi, Dr. Blerton-Jones, how are you? Very well, thanks, Kelsey. Good. Thanks so much for joining us today to speak on this important topic. Before we get started, I'd just like to take a couple minutes to introduce Dr. Blerton-Jones. He's an associate professor of neurobiology and behavior in the UCI School of Biological Sciences, and he leads the induced pluripotent stem cell core of the UC Irvine Alzheimer's Disease Research Center, which he'll tell us a little bit more about in a bit. He received his PhD in neuroscience from UC San Diego, And the primary focus of his research is to examine the underlying mechanisms that drive the development of Alzheimer's disease, as well as Parkinson's disease, the two most common forms of dementia. His lab uses patient-derived induced pluripotent stem cells to study the role of neural and immune cell populations in these disorders. So I see we have quite a few live viewers right now, so thank you for joining us. If this is your first time attending this series, I will get us started by asking Dr. Blerton-Jones some questions on the topic, and then as you have questions that come up, please do type them right there into the comments box that's accompanying the video, and Dr. Blerton-Jones will address as many questions as he has time for. Please do note that whatever you post on Facebook will be linked to your name, and visible to others. So we ask that you please post responsibly. All right, so let's go ahead and get started. Um, Dr. Blerton-Jones, thanks again for joining me today to discuss stem cell research in Alzheimer's disease. First, um, there's been a lot of controversy and uncertainty around the use of stem cells in research and what that looks like and what it means. So could you first just tell us a little bit more about this and explain how your team uses stem cells at UCI MIND.

Yes, Kelsey, I think that's a really important question to unpack. There's really a couple of main controversies that have surrounded stem cells, and in order to discuss them, we need to start by just understanding that there are several different types of stem cells. So there are stem cells within our body right now that are localized to different organs. So for instance, in our brain, which we obviously study, There are a type of stem cell called neural stem cells, and they persist throughout life. And what— how we define a stem cell is that they can make copies of themselves. They can divide and make copies of themselves, but they can also what we call differentiate, which is mature and change into a more mature cell. So our neural stem cells in our brain can give rise to neurons or to some of the other cell types like astrocytes in our brain. So that's one type of stem cell. And we have those in virtually all of our organs. Types of stem cells that can do that—muscle stem cells, liver stem cells. But then there's another type of stem cell that we refer to as pluripotent stem cell, and pluripotent means it can give rise to any other cell type in the brain—in the body, sorry. So it could give rise to nervous system cells, it could give rise to muscle cells, it could give rise to heart cells. That's what—how we define pluripotent cells. Now, when chloroquine cells were first discovered, their origins were where one of the potential controversies lie, which was they were first discovered from looking at very early stage embryos, so what we call blastocysts. And these were actually gathered from in vitro fertilization clinics where the parents who had gone through in vitro fertilization no longer wanted to have additional implantations done, and those were going to be discarded, and scientists started working to see, try and understand the characteristics of those cells. And they were able to show that they could grow and expand pluripotent stem cells, and that those cells could give rise to any cell type in the body. So you can understand that there's some controversy there, because these are coming from human early-stage blastocysts, which are about 7 days after conception. But these are, you know, I think it's an important point out, these are blastocysts that were going to be discarded because the parents no longer wanted to keep them. Now, move forward about 7 or 8 years, and some, some really amazing science was done by studying those pluripotent stem cells to figure out a way to make pluripotent stem cells almost from scratch from any cell type in our body. And so those initial studies were done with skin cells. So a patient would donate a little bit of skin cells, and they were allowed to be told about the experiments and decide whether they wanted to participate or not. They donate those skin cells, and work from Shinya Yamanaka, who ended up earning the Nobel Prize for this work, figured out a few genes that he could add to those skin cells that would change them back into a stem cell state. And those stem cells we now call induced pluripotent stem cells, and they're essentially very, very similar to the earlier embryonic stem cells in that they can give rise to any cell types. The other exciting thing about these iPS cells, aside from that, it sort of overcomes any of this controversy. And I should say that Shinya Yamanaka was actually appointed about 8 years ago to, to a papal scientific board. And so that kind of shows you that religious groups are fully in favor of these iPS cells. One of the things that it allows us to do is to actually make cells from patients who have a given disease. And that's one of the things we're doing and we'll talk more about at UCI. We were actually the first Alzheimer's center to begin collecting skin cells from our patients who were incredibly generous. And we really couldn't do this research without our dedicated patients who would agree to donate a little tiny little bit of skin cells. And then we would reprogram them, as we call them, into these induced pluripotent stem cells., and, um, then could start to make different cell types like brain cells, for example. So, so that's one of the controversies surrounding stem cells, is, is the origin of them. And, um, sorry, I'm moving closer to my microphone because I hear that some people are having a hard time hearing me, and I'll try and talk louder. Uh, so that's one of the potential controversies which I, I feel, uh, you know, has really been largely resolved through the development of induced pluripotent stem cells and our ability to to really start using those. And the work we're doing is entirely with induced pluripotent stem cells. The other controversy that I think we all need to be aware of is the idea that stem cells can cure every disease. Unfortunately, stem cells are a very hot topic, and there's some, some groups who have sort of taken advantage of that to, to suggest or propose that they can cure almost any disease. And so what I'm talking about are these, for lack of a better word, clinics that have popped up that offer to treat multiple sclerosis, Alzheimer's, Parkinson's with some sort of a stem cell. And they're really, they're not FDA approved. They've not based on really any scientific evidence. And what is actually happening in these clinics is not totally clear, but it's really become rampant. And unfortunately, these clinics will often charge patients patients, you know, their life savings, $30,000, $40,000 for a therapy that is unlikely to work. And so, unfortunately, that's given stem cell research a bit of a bad name. And I should say that I, as a scientist, and virtually all scientists who study stem cell research, are really trying to fight this problem, this, and help to educate people that for certain things, there are not yet cures for stem cells. We absolutely think that stem cells stem cells can be developed to provide treatments one day for some of these devastating diseases, and that's why we do our research. But a lot of them are not there yet, and these unregulated clinics are sort of taking advantage of the hype of stem cells, and so one needs to be a little cautious about that.

That's very interesting and concerning, and, you know, thank you for sharing that. It's like you said, incredibly important that we're researching these things thoroughly before we're using them in any sort of clinical practice. And then just going back to the use of induced pluripotent stem cells, you mentioned that they're donated from research participants, from their skin samples and blood samples, and what an incredible gift that is given to us by our research participants at UCI MIND. Could you tell us a little bit more about how, you know, how these induced pluripotent stem cells donated from our participants have really changed the field of Alzheimer's disease research?

Absolutely. And I can't reiterate enough what you just said, Chelsea, about how amazing our dedicated patients are that are participating in providing these cells. So when they come into our lab after they make a donation, I have some very talented scientists who go through this process to reprogram the cells. They add a couple of key genes, and they follow these cells for about a period of a month as they start change and they turn into these stem cells, these pluripotent stem cells. At that point, one of the great things about pluripotent stem cells is they can be expanded and grown almost indefinitely, and that really allows us to share these invaluable resources with as many scientists as want one. And in fact, that's one of our goals at UCI MIND within our Alzheimer's Disease Research Center is to share as much resources as possible. We've actually been able to make these cells from about 80 different patients and then to send them out to labs across the world. We've sent cells to London, to Australia, to Germany, and of course to many, many universities and institutions in the U.S. And so that allows sort of an expansion and a rapid movement in, in science so that what research we're doing at UCI, which I'll obviously tell you about shortly, we can continue to do, but other groups can do other research with these cells. So it's a really invaluable resource that kind amplifies as it gets out into the scientific community. So in terms of my lab, what we've really focused on over the last few years is a cell type called microglia. Now, microglia are the immune cell of the brain. They're sitting in our brain ready in case there's any sort of an infection to deal with it, but they do a lot more than that. They actually help to keep our neurons functioning properly. They kind of survey the environment. There's evidence that they are important in the connectivity of neurons, so they can help neurons connect and form synapses. They can also help break up those synapses. And so microglia are a very interesting cell of their own right. But a number of studies from geneticists in Alzheimer's have really helped point it towards microglia as being very important in Alzheimer's disease. So there's a number of different genes that can contribute to Alzheimer's disease, and many of those genes are part of what microglia do. They have those— those microglia are expressing those genes at high levels, and those genes are affecting the function of microglia. And so what that suggests is genetic differences in how our microglia act may be underlying a big part of Alzheimer's disease and may be able to give us a clue as to how we can start to develop treatments and cures for Alzheimer's disease. So in our lab, we can make these induce pluripotent stem cells, grow them up, distribute them, but then we can also mature them into microglia. And that was some of the work that we did just about 4 years ago by a talented graduate student in my lab who developed an approach to add different types of reagents to gradually mature these cells into microglia. And we've done a lot of studies to validate that these are indeed human microglia. And now we can study those microglia and compare how do the microglia act if they came from a patient who had Alzheimer's or a patient who doesn't have Alzheimer's disease. How are those different? How are those similar? And we can better understand how microglia are influencing the disease. And we can even start to look at specific genes. So probably many of you have heard in the news of this, this idea of CRISPR. It's an ability to change a gene very specifically. And we're at UCI using CRISPR to change some genes. So we can take a patient's line that we know has a mutation that might influence Alzheimer's, and then we can use CRISPR to fix that mutation. And now we've sort of got the perfect pair of cells to compare, one that has the mutation, one that doesn't, and we can see what does that mutation do, how does it change microglial function, and can we start to use that to develop new therapies.

So it sounds like you're doing some amazing work in terms of developing new models, new stem cell models to be shared with researchers really worldwide, which just speaks to the capacity of this type of research to really make a difference and an impact. And you touched on it a little bit, but what are some of your most important findings related to Alzheimer's disease so far, would you say?

Yeah, so it's a great question. So one is really validating how important these cells So obviously, and you've probably heard about in some of these other Facebook Live interviews, that one of our tools as scientists to study Alzheimer's is to use mouse models. So we have mice that will develop some of the pathologies of Alzheimer's, some of the memory impairments, and we've done a lot of work and there's been a lot of progress made by using these mouse models. But one of the things we've actually quite recently found is that when you look at microglia, mouse microglia and human microglia are quite different, especially in their way that they respond to Alzheimer's pathology. So when in Alzheimer's you have the accumulation of these amyloid plaques that we think might be driving a lot of disease, and microglia will respond to these plaques. They'll migrate, they'll surround the plaques, they'll try to wall them off to reduce some of the damage, and they'll change their gene expression, they'll change their function in response to that pathology. But the way a mouse microglia does that and the way a human microglia do it, the that is different and quite different. And so that really reassures us that we should be studying human microglia to better understand this human disease. So that was one of our important findings. The others, as we move forward, we've now started to dig deeper into some of these important genes. So there's a gene called TREM2 that one can have mutations in that will increase the risk of developing Alzheimer's by about 3 to 4-fold. And we've been able to get iPS lines generated from a few patients that have this mutation, and then, as I mentioned, using CRISPR to correct that mutation. So now we have these pairs of lines that either do or don't have the mutation, and we've been able to study them and find out what does this mutation do to microglial function. And it does a lot of interesting and problematic things. It can impair the ability for microglia to what we call phagocytosis. And this is one of the things microglia do is they eat stuff, they eat debris, they eat waste material. And in the case of Alzheimer's, there's evidence that they eat some of that amyloid, and this TREM2 mutation will impair their ability to eat that amyloid. The other thing we're finding that this TREM2 mutation does is it impairs the ability of these cells to actually sense the amyloid, to migrate and move towards the amyloid. So it's as if they don't realize there's something going wrong when they have this mutation. So that's telling us a lot about what we do need microglia to do to be protective versus what we don't want them to do. And you can imagine that once you see these things, the next step is we can start to test drugs in our dishes of cells and see, can we rescue, can we improve this problem and make these microglia act the way they ought to that could be beneficial and slow the progression of the disease.

Before I ask my next question, I just want to remind our viewers we'd love to hear from you. So if you have any questions that come up, please feel free to type them in the comments box, and I'm sure Dr. Lorton-Jones will be happy to answer them. So you mentioned that you're taking this knowledge gained to develop possibly potential treatments for the disease. So what is the potential of stem cells for Alzheimer's disease treatment, and are there any studies related to treatments that are currently underway? Yeah, fantastic question.

So there's really two ways that stem cells are being considered for treatments for Alzheimer's, or really for any disease. One is the idea of modeling, and that's sort of the work I just described, where you can take the cells from patients, see what's wrong, and start to understand the disease better. And the more we understand about the disease, the more we can be able to develop therapies. One can take that a step further, which is to take these cells and test drugs on the human cells and try and see, can those drugs rescue that? And so, in fact, we recently finished a study that was sponsored by the Orange County Community Foundation to test a whole lot of drugs that we already know are safe in people. So they've already been approved by the FDA for various different diseases. And we tested those drugs to see, could they change the function of my. And that particular function that we were looking at is something called synaptic phagocytosis. So let me just unpack that a little bit. Synapses are the connections that neurons make, and they're very important in how our neurons function. And with Alzheimer's disease, one loses synapses. And the more synapses you lose, the more the dementia progresses. There's some really exciting work suggesting that one of the functions of microglia is to kind of prune and eat those synapses that we no longer need. But in Alzheimer's, there's some evidence that they get a little out of control and they overeat those synapses. And so what we've been looking at is, can we slow them down? Can we stop, stop them from eating so many synapses? Because that might provide some benefit in Alzheimer's disease. And so we've certainly identified now several drugs that we know are FDA approved and safe in in people that are able to slow down the amount of synapses that are being eaten. And so there's obviously many next steps to go, but we like to think that we might be able to move forward with the clinicians and the trial design experts at UCI MIND to move these into a clinical trial to see if this might have benefit in patients. So that's one way is the sort of drug screening approach. The other possibility, which is maybe a little further off, is the idea that transplantation of cells may be beneficial if done in the right way. And so in the case of microglia, we don't necessarily want more microglia, but we want— what we might want is microglia to act a certain way, or to, for example, I mentioned the microglia will surround these plaques and wall them off. We actually know that is a good response. That is the kind of response we might like to do. By studying these cells, we can figure out how to promote that response, and we might even be able to sort of modify these microglia to make them do that more. And so one could potentially envision a sort of a transplant type approach in which these cells made from the patient's own blood, for example, turned into stem cells, turned into microglia, could be made to actually provide better benefit to really help to get rid of the amyloid and to improve some of the other functions. As I said, that's sort of a little further away. That's going to take a lot more work to develop, but I think both of those have potential.

You touched on some of these things already. I wanted to go back to one of your current projects where you mentioned that you're testing drugs that are already approved in humans for other disorders and diseases to be tested for Alzheimer's disease through these stem cell models. Which is pretty neat. And you mentioned that it is being supported by the Orange County Community Foundation, which is philanthropic funds that have come in to support this type of research. And so that's pretty cool. And I also— it gives me an opportunity to plug that if you're interested in learning more about philanthropy and how it can support this type of cutting-edge innovative research that's happening at UCI MIND, we're actually holding our annual gala tomorrow, Saturday, December 5th, and it's going to be virtual online. So if you want to learn more about these types of projects and how philanthropy can support them, you can visit our gala website at gala.mind.uci.edu. So Dr. Blerton-Jones, you talked a little bit about that project. You talked— could you speak a little bit more to to some of your future goals in stem cell research for Alzheimer's disease?

Yeah, absolutely. So first, before I say that, I just want to reiterate what you just said in terms of philanthropy has been so critical for this work. Even our stem cell core that we developed was initially funded by some very generous philanthropy. And the reason that's so important is NIH, National Institutes of Health, the fund a lot of research, they're a little bit risk-averse. They want to see some proof that their money is going to work. And so that does take some seed money, some philanthropy for us to do some of these a little more crazy ideas like developing these cells. But we were able to do that with philanthropy and then be able to go to NIH, and they loved the idea and have continued to fund it ever since. So that's an example of how philanthropy can really move this research forward. And take a somewhat risky idea to allow us to make some real progress. So in terms of other studies that we're doing, as I mentioned, there's this gene TREM2 that we've studied, but there are actually several other genes that are implicated in Alzheimer's disease that we know the microglia express that are affecting their function. And so we're really trying to dig into those using our cells, using CRISPR to try and understand what the function of those genes are, and even how those genes start to interact together to affect function. So that's one way. The other thing is that in Alzheimer's, there's two main pathologies. There's the amyloid plaques I've talked about, but then there's also neurofibrillary tangles, which are an accumulation of a different protein called tau that occurs within the neurons themselves. And we do know that microglia respond to that pathology too. And so we've actually developed new ways to start to study the interactions microglia and the tangle pathology. And we're finding some very interesting aspects of this. And we're really trying to understand where microglia fit in the sort of projection of Alzheimer's disease. So we know that amyloid accumulates first and the tangles come a little bit later. And we actually, and I think a lot of the field is thinking this way, think that microglia may fit somewhere in between there, that they may be trying to slow the amyloid progression and slow its ability to lead to the tangles, but sometimes it doesn't work. And so how can we encourage the microglia to do a better job of slowing that progression? And so that's one of the big things we're trying to look at is the interaction between the amyloid and the tau and where microglia fit into that story.

Yeah, it sounds like microglia plays a pretty important role in this disease, and researchers like your team are just really trying to figure out where exactly it fits in the cascade of Alzheimer's disease. Now, Dr. Blurton-Jones, I always like to learn about how our researchers got started in this field. I'm sure you didn't always focus on— maybe you did, but I always focus on induced pluripotent stem cells and microglia. So how So what has been your path that has led you to this innovative work?

Yeah, so as is often the case, I had a relative affected by Alzheimer's disease. So while I was in undergraduate college, my grandfather was diagnosed with Alzheimer's disease and I watched him sort of continue to decline and it's heartbreaking. And it was heartbreaking to watch my grandmother having to try and take care of him. And so that really sort of got me more and more focused Alzheimer's disease. I was already a biology major. I was interested in biology, but I didn't know what area, and that really started to focus my interest on Alzheimer's disease. So then I pursued a neuroscience PhD, as you mentioned, at UC San Diego, working in a lab that had a component that was studying Alzheimer's disease, so I could really start to dig into that. And at that point, microglia were just sort of an aside. We didn't know really much about how they might be involved in Alzheimer's disease. So I wasn't studying microglia. Take a step forward, I moved to UC Irvine to pursue a postdoc with Karl Kauppmann, who is an amazing scientist who really helped to establish UCI MIND initially. And then I subsequently also worked with Dr. LaFerla, who's continuing to move UCI MIND forward, working on mouse models of Alzheimer's disease to trying to understand these pathologies and how they're occurring. And it really wasn't until I started my own lab in 2011 that I started to become interested in stem cells. The technology was coming online, the iPS cells had been invented, so I was starting to study them with the concept of being able to study neurons. I figured neurons are very important in the brain, we can study neurons, and we started that way. But as the genetic information came, out saying that microglia are the key cells that are being implicated by the genetics of Alzheimer's disease, I became very interested in trying to start to study microglia. And really, again, this is an example of having to take a little bit of a risky step, which was we'd been working on neurons. No one at the time knew how to change a stem cell into a microglia, but we figured it needed to be done. And so we tried working on that and we were successful. Fortunately. And so we were able to make those cells and then really start digging into all the things that I've been talking about.

Well, it's incredible work that you're doing, and it sounds like it comes from personal— your motivation and drive comes from your personal experience with the disease, as it does for many of us who work at UCI MIND. So thank you for sharing that about your family and about your, your journey to this important work. And thank you for joining us today, Dr. Flirtin-Jones. That's, um, that is all we have time for today. Um, we appreciate you taking the time to answer our questions and look forward to seeing you again soon. So I'll let you leave the screen as I make my closing remarks.

Okay, thanks so much.

All right, take care. Thanks to all of you, um, who joined us live today. This is our last episode of our 2020 series, um, but we will be back in 2021. With more topics, more experts, and we're actually going to have more viewing options, including we will be broadcasting on YouTube Live next year, and we may be converting some of these episodes to podcasts to help reach more people. So please do stay tuned for details. All of our past 2019 and 2020 Q&A episodes are archived on our Facebook Live video page and on our YouTube channel. So you can visit those links that'll be posted here to view past Q&A episodes. And then again, if you're interested in attending our annual gala tomorrow, December 5th at 5:30 PM, you can visit gala.mind.uci.edu to register. And lastly, if you want to help UCI researchers by participating in important studies, that might be right for you, you can visit our UCI Consent to Contact Registry to learn more, and that website is c2c.uci.edu. Thank you again so much for joining us, and we will see you for this live series again in the new year. Take care.