Episode 2: Decoding DNA With Dr. Jessica Rexach

Oscar: So much remains unknown in the progression of rare diseases like PSP, CBD and MSA. Looking under a microscope reveals patterns of an unsolved puzzle: compared to dementias like Alzheimer's disease, where abnormal proteins define a clear disease and mutate genes in a predictable way, PSP affects a different region of the brain, leading to different symptoms, and an altered tau protein, which mutates genes in a way that scientists are still trying to understand.

Dr Jessica Rexach and her team at UCLA have been scouring sequencing data from over 10,000 individuals, searching for clues in the DNA that could explain how changes in the immune system might influence why some individuals develop these conditions. They want to find out which genetic factors are common to both diseases and which are unique to each. Identifying these patterns would be a massive step forward in understanding the causal factors of PSP and a potential site for immune-based therapies.

For this episode of The Collective Mind, Dr Rexach spoke to me about her project that is piecing together a picture of the altered messengers of the immune system, which hopes to make these diseases much less mysterious. The project is supported by CurePSP’s Pathway Grant Program, which provides seed funding to support projects studying the fundamental neurobiology of PSP and CBD.

Jessica: I'm a neurologist and a scientist, so I do see patients with PSP and Alzheimer's disease and a bunch of other disorders, and I have subspecialized in my clinical practice in two ways. I've specialized in neurogenetics and in behavioral neurology. So what that means is that I think very much when I see patients about cause at the molecular level of what's going on from the perspective of the human genome. So humans, you know, we've evolved. We're actually a species that, compared to a lot of the other species on the planet, is one of the youngest species. But we do have variation in our genome that contributes to, you know, why I'm different than you or the next person, but that variation can also influence our risk for having diseases. And one of the challenges with neurodegenerative diseases, or adult onset diseases in particular, is that, you know, they kind of start all of a sudden and then get worse over a period of time, and it's hard to figure out where the starting point is for causal mechanism in the trajectory of that individual's life, right? The disease kind of creeps in when you're asking about, you know, when, oh, I had a little bit of this and then a little bit of this. So it's very hard to kind of try to tease out causality in that way. But when you can study the genetic background of a person or groups of people compared to people who have who don't get the disease, you can tease out these kind of molecular posts that give you an idea of what some of the pathways and variation are in how cells work to begin with, that could already start to influence disease down the road. And you can get what we like to call a causal anchor, so you have the chance to actually rationally think about, how do we get from being okay to having this disease? What are the real mechanisms? Where could we think about shifting that trajectory? Does that make sense? Or can I break that down any more for you?

Oscar: Yeah, that's a good start.

Jessica: So you asked about Alzheimer's versus progressive supranuclear palsy, which I can address from this perspective. So Alzheimer's disease is a degenerative disease that affects certain parts of the brain and tends to happen at a point in life and progresses in a certain way. And when you look under the microscope, there's a couple of abnormal proteins that are very characteristic of Alzheimer's disease. So when you put all of those kinds of things together, like where in the brain is the disease happening, what kind of phase in life those couple of proteins you can see under the microscope, you can begin to define a really specific disease that is happening to people all the time. And what's interesting is that when you then look at the genetics of those groups of people, they also have matching characteristics. So Alzheimer's disease patients have a memory problem. Well, think because the memory part of the brain is the part that's affected first, and most affected as the disease progresses. Alzheimer's disease at the molecular level is from these proteins, tau and beta amyloid, those were the things you can look at under the microscope. Why? Well, we don't know entirely why we see those in those patients, but we do understand that there are very rare cases where there's mutations in some of those genes that could be contributing factors. So we think it has something to do with the causal mechanism. Contrast that with PSP. Let's think about those same factors: The where, the when, etc. And we see that, like Alzheimer's disease, cells seem to be getting sick. They seem to be losing their function. But it's happening in a different part of the nervous system. It's happening more in the subcortical regions that affect movement, eye movement, those types of functions which are otherwise not part of the Alzheimer's disease picture, and also includes some of the front of the brain regions that impair thinking, that are also affected in Alzheimer's disease, but it affects them in a slightly different way. It's hitting different cells, and it's affecting those cells slightly differently than Alzheimer's disease. So there's actually something in the brain happening in a different place, and that correlates to why patients present with different symptoms add that extra layer of looking under the microscope. And in fact, the protein tau, which is seen abnormally in PSP, is a slightly different shape of tau than the kind you see in Alzheimer's disease. So even at the microscope level, there's a difference.

And then finally, we talked about genetic makeup, right? So when we look at the genetic makeup of people who are at risk of Alzheimer's disease, we see a certain pattern. When you look in progressive supranuclear palsy, it's a very different pattern. So that suggests that the actual causal pressures in the cell level when met with disease, give way and contribute to disease progression and clinical disease. Those causal factors are actually also different for PSP, so in those ways, they're very different disorders, but at the end of the day, both hurt the brain. You hurt brain cells. So things start to happen in a very reproducible way. So there's also a lot of shared mechanisms, too.

Oscar: Yeah, so thinking about causal factors that lead to symptoms and disease progression, I'm wondering how, very basically, the immune system is connected to the health of our brains? Could you maybe just describe a little bit of what that's like, from the stuff that you see in the immune system to the symptoms that people feel.

Jessica: Absolutely, so this is a completely new horizon in brain science. There's a lot of fundamental questions that we still are asking. For a long time it was thought that the immune system doesn't interact very much with the brain, which I guess is kind of naive, because we know that it really does regulate infections and cell health throughout the body. So why would the brain be any different? The brain and the immune system interact with each other in a very different way, it seems, than the way the immune system interacts with cells in the rest of our body. And we know it's different. We know that there's a role for the immune system in the brain, but we don't know quite exactly what all of those components are. So it's an exciting time where there's a lot to be discovered. We know that the most. So I'm going to go back to the discussion we were having before about genetics. Okay, we know that genes vary from person to person, and that ultimately that contributes to our risk of getting diseases, particularly, you know, kind of later onset chronic diseases, and importantly, the immune genes are our most varied genes in the human genome, so they often get picked up on these comparative studies where we say, hey, let's map the genome of people who have Alzheimer's disease compared to people who don't, or let's do that for Parkinson's disease, or let's do that for multiple sclerosis, or let's do that for cancer. There's a lot of studies like this. They're called GWAS studies, or they also do whole genome sequencing. There's just so many different ways we can do this now, and a lot of the time there's a big signpost sitting in the immune part of the genome, and we can see that in these studies over and over again. And sometimes it's a difference, a slightly different signal that's getting picked up. But that's not enough for us to really understand that signal, it just tells us that it's there. So it tells us the immune system, and the way the immune system varies appears to have some causal contribution to the risk of these diseases. It's not black or white necessarily saying, “Oh, the immune system is the whole story,” but we can imagine that the immune system, which really modifies six cells in our body and regulates how sick cells are restored or cleared from the body, how variations in that could impact these diseases, right? You can easily imagine that that would not be an unreasonable expectation. But again, we don't know the details of how, particularly in the brain, and we see this signal in the immune part of the genetic signal that tells us that there's something there that we need to learn more about.

Okay, so, as we start to dig, and as we've dug, particularly so far, into Parkinson's and Alzheimer's disease, we're really finding some interesting stuff implicating immune cells that play a role, again, in really cell and tissue surveillance, but also viral infection, and we're finding these absolutely new interactions that are opening the field to questions like, “Well, can we boost the immune system or dampen certain aspects of immune system as a possible therapeutic?” Which is very exciting, because the immune system as a target for therapeutics has been revolutionized in cancer and autoimmune disease. So there's a lot that we can do there, if we can just figure out how to translate that into these degenerative diseases. So we're thinking about this from the original contrast that I made in your first question about Alzheimer's disease versus progressive supranuclear palsy, where I said different parts of the brain are affected at slightly different times in our lives, and different proteins are sitting there, and the genetic difference, right? But we don't know how some of these findings in the immune genetics that have been made in Alzheimer's disease and Parkinson's, we don't know if those are different or those are the same, because to understand that requires digging deeper into the data. So that's what we propose to do here, is start from the genetics perspective, it's called immunogenetics, and apply some specialized analytical techniques to existing data to understand whether the pattern in those regions suggests there may be a link with PSP and whether there's a difference between the length seen in Alzheimer's disease and what we see in PSP, right? Because there's been more progress in this space, in Alzheimer's disease, which has been kind of a leading edge, as you can imagine. There's been a lot of work, and the PSP now has a big genomic study that provides the opportunity to say, well, how does this compare?

Oscar: You mention Alzheimer’s being more understood. I'm curious, just to get a scope of how much we know or don't know about PSP and atypical parkinsonians, how much would you say we know about PSP compared to Alzheimer's or another dementia that’s more popular or well-known?

Jessica: So we've done a recent and heavy lifting collaborative study involving a lot of people that actually compares these disorders head to head in human brain tissue, and this was a study that profiled progressive supranuclear palsy versus Alzheimer's disease and another disease called Pick's disease, which is a kind of frontotemporal dementia that also has tau, and we did this in multiple ways, including single cell sequencing of gene expression, but also the way that genes are regulated. We profiled by single cell sequencing, looking at DNA structures, and we also looked across seven different brain regions that are all differentially affected by disease. So this was a big study, and in this study we found that there are some very, very distinct differences between PSP and the other disorders. The first thing to say is that most of the changes we see in the brain actually are shared, suggesting that they're probably related to cells being injured or reacting to the general phenomenon of neurodegenerative changes. But there's a few sets of changes that really separate out from the rest as being distinct by disorder, including some in the PSP space that we had no expectation of and need to be now scrutinized in more studies, because this is brand new stuff, right in science, when you make a new discovery that's the beginning of then trying to replicate that broadly before you know if you have a truth. But what we found, for example, is that astrocytes, which are these really important support cells in the brain that help neurons function, were actually looked to be injured or vulnerable or lost in the PSP brains in unexpected brain regions compared to the other disorders. We also saw some fundamental changes involving the inflammatory response and also the way that neurons were signaling that were kind of brain-wide in PSP and reproduced some previous studies trends, but this was the first time we looked at enough brain regions to say confidently that it's not just a matter of if you picked one spot and didn't see the same thing. We looked throughout the whole brain, and we see that these are really happening differently throughout the whole brain and PSP patients. So we have some new observations to support thinking about differences in PSP at the molecular level. And it's helpful to do this where you're taking a common disorder and contrasting it with the atypicals or rare disorders. Rarer you know, PSP is not that rare, but it is a rare disorder because it allows you to kind of do, like a quick catch up and say, Okay, well, we know all this stuff about Alzheimer's disease that's emerging. If we can kind of lift some of that reasoning over to the PSP space, can we kind of do a catch up with PSP? So that was part of this, but also this study was again rooted in genetics. So if we see that there's a different genetic predisposition to these different diseases, does that translate to actually different molecular changes that you could see under the microscope or in the brains? And if you can find an intersection between them that might be kind of where causal disease is happening in the human brain. So we did actually find some intersections that we're going to be following up on that might help us understand not just what is different in the PSP brain, but why is it different? So we're really excited about this work, and we're going to be taking this forward into the lab.

The proposal that we put in for this CurePSP grant is one complementary aspect of that, because in order to do the “why is what different” question we have to understand the genome, and there's been a beautiful project work recently to map the PSP genomic changes, but it just didn't take care of this immune portion that we're very interested in based on some of the findings that we had. So we're kind of taking the opportunity of this funding to fill that gap so that we can really comprehensively ask, how could the immune part maybe describe or help us understand the differences that we see in the human brain tissues, and can we translate that more broadly into just broader differences that we see?

Oscar: So you see the immune system interacting with and implicating the genome?

Jessica: Yeah, well, the genome is at the heart of everything. And when you know that, the genome starts off already different, and then you see differences at the molecular level that are reproduced over, you know, 10, 15, 20 people, group them all together, and they all still have this one or two differences compared to Alzheimer's disease. There's something really fundamental driving that, right? So when you see these differences reproducibly across people, it's something very fundamental that's causing that it could be some acquired thing, like an environmental thing that we don't know, or it could be something from the genome, or it could be a combination. So you have to break it down and understand the parts to figure out how to build it back up again. And if you can do that, then you understand causality. So that's what we're making an effort to contribute piece by piece. There's a very clear roadmap in front of us. It's a very logical concept here of understanding causal mechanisms, understanding how cells differ in this disease, putting it all together. And making a logical framework in which to understand these diseases and where their key trigger points are, it takes a lot of steps to execute that, and to execute that in a way where you can really say you have something, because we're doing all this work directly out of patient samples, right? So this is human research. You have to really do it with a lot of people before you're sure of what you have. But we're working on that broader goal with this project is a key piece.

Oscar: This might be a silly question but can a genome be altered?

Jessica: Yeah, they're working on that now it's called gene therapy.

Oscar: Oh okay, we definitely have some studies related to that.

Jessica: But you know, in gene therapy, you're kind of making a single edit. The way you want to think about the genomics here is maybe more like this. I'm going to try to make a parallel with this: So let's say that you've got a factory and you have factory workers, and you're seeing that some people are having a hard time getting to work on time, and you don’t know why. So you look at the people, and you look at their genetics, or you look at their traits, right? And you separate them out, and maybe you find that the people who are getting to work on time have some genetic variations at various spots in their genome, but it's making it so that they're five to 12 inches taller than everybody else. So whoa, okay, the people who are coming to work late are taller than the people who are making it on time. And then you look at the factory, and you go, “Wait, we have this door to get in that's actually really short, and maybe the tall people are having a hard time figuring out how to get their bodies through the door.” So the solution to that is not to chop their heads off, right? That’s what you’d see in gene therapy. The solution is to get them through another way. It's to say, “Okay, let's make the door bigger,” or “let's give those people some kind of sled so that they can get through on their knees,” or whatever that might be, right? But there's going to be a lot of different solutions to how to get that group of people past there.

The trouble spot once you've defined it may not be just making the difference go away. So here, let's say that you found that people who have an immune variation makes them more likely to tolerate certain kinds of abnormal proteins, right? That would be the kind of thing we might be able to find from a study like this. So, okay, so their immune system’s working, but there's a certain part of the immune system that maybe is different from the people who don't have this. How does that match up with what we see in disease? Hey, look, in disease tissue, there's a protein that looks kind of like what their immune system can't recognize. Maybe we need to do something about that protein, or give it the immune system a boost against that protein by giving it a vaccine or something like this, right? So then you start to solve the problem, but first you have to line up and figure out what is actually causing the problem. And if it was as easy as looking at everybody and figuring out who was tall and who was short, we would have done that already with PSP. But in the same way, we expect that there's probably variations in people that are contributing to whether or not they're going to get this disease, and if we can figure out how and where that intersects with their risk, then we can come up with great solutions for that problem. We already know that there is one really strong genetic component to PSP, which is a way that our genome is arranged. If it's arranged a certain way around the tau gene, then the risk for PSP can increase by four or five fold. So we already know that, and there's already a lot of really incredible work going on to understand that, some work going on in our lab to try to understand how that relates, so that we can make a solution for that problem. So it's really strong to find these differences, because then you can track them down, understand what they relate to and start to solve those problems.

Oscar: Yeah, So it almost seems like it's pre-intervention, figuring out what you want to change. You mentioned gene therapy as something like chopping off their heads, what would be some of the different types of interventions?

Jessica: There's so many different kinds of treatments that are available now. There's small molecules that are still incredibly important, and there's always new chemistry coming out and new strategies to manipulate cell machinery with small molecules. So I always think small molecules are a key kind of drug, a key kind of therapy. But particularly if you start to address things like the immune system, you can start to you can start to consider some of the newer, alternative types of therapies, like cell therapy, or, you know, immunomodulators, like antibodies that change the way the immune cells function, or vaccines that change what the immune cells see or how they respond to those things, etc, etc. So it opens up more space.

But just to be clear, we're at the early days of just trying to figure out how the immune system may even be happening, may even be contributing here, which really needs to be answered, because of how potentially important those questions could be. But until we answer those questions, we don't know where the opportunities are going to be.

Oscar: Right, and you might have already answered this, but as you said, what do you hope answering those questions about the immune system, how would that influence treatment and care for patients?

Jessica: We have to turn every leaf on the genomics to understand the risk factors going into disease so that we can take advantage of the incredible progress that is being made in functional genomics and data science to translate those into new new targets. Once we have targets, which means something in the disease space that we think that those genes are influencing, we can actually start to go after them and find out if there's therapies there. So this is the way that almost all progress is being made in neurodegenerative disease research right now is by following genes and that's because there's just so much that happens in these diseases that if you don't have some kind of anchor causally, it can be really hard to know that your change is going to be in the right way. Is going to be in the right direction. If you have genetics to support your ideas, you can actually rationalize from the onset. This is going to be the right direction to change things, to cause the right impact that I'm trying to make. So this is the way that these disorders are finally starting to see therapy. We see our first examples of therapies coming out just in the last years for diseases that previously had nothing, that are following mostly from this kind of logic. So we just need to complete that and then continue to understand the molecular level what is happening in PSP so that we can begin to figure out which of those differences are key areas for therapies.

And it sounds like an enormous amount of work to do, to get to a therapy, but I can tell you this, when you don't know how to articulate how to get there, that's where you want to be worried, right? If we don't even have a game plan, or we don't even know what it's going to take to get there, that's when you don't have a lot of hope. I have an enormous amount of hope, because we know much more now about PSP than we ever have before. We have incredible tools to do this kind of work that I'm describing that was completely unattainable 10 years ago, and it is the right tools for this problem, and we know how to address it. So, I'm articulating that there's a process that needs to be executed, but I have great confidence that we're going to get what we need out of these kinds of processes that are happening now and that this work is contributing to, so it's a very exciting time.

Oscar: Yeah, that's super interesting. Very on-brand as a Pathway Grant. So I have two questions: What is the population you mentioned? You're looking at genomes of patients, what has it been like gathering that population? And, because I know it can be tough sometimes for PSP to gather a population to study, what is yours like?

Jessica: We're standing on the shoulders of giants and a lot of previous work that was enabled by CurePSP and other consortia efforts to actually generate a whole genome sequencing data set for PSP. So we're actually going to work with that data. We also have tools to take other kinds of data to do complementary analyzes, to expand our observations even further. But the real core of this is that whole genome sequencing that was completed and for PSP recently, and where the immune genes haven't undergone the analysis that we propose because it requires a special approach. The immune genes are like super packed together, super tight, and you have to run different algorithms to tease that apart that are not necessarily standard. And we also want to do this in comparison with Alzheimer's disease, because Alzheimer's disease whole genome data is tenfold more people. So we're trying to see if we can translate some of the findings that have already gotten that discovery level from the bigger data sets in Alzheimer's disease, and then just bring them into the PSP and say, do we see similarities or not? So we have a couple strategies on that. But, yeah, all of this is requiring that those cohorts are already existing, and it's an analysis-focused grant, because that analysis alone takes a lot of work. And this is where community is so necessary, and this is where building incredible data sets is important, because they live on. You make the data set, you do your primary analysis, and then you bring into the hands of the next scientist who's going to do even more with it, or do something different with it. So there's a real value in investing and making these high quality data sets.

Oscar: Yeah, how do patients and families influence your research, and how can they help your research? Are there any ways they could engage with it?

Jessica: I actually consider my research part of my clinical job. I don't see myself as having two jobs, being a scientist and being a doctor, but it's more from a real perspective and a very personal level, where I'm inspired by the observations I make for my patients, I'm inspired by what I see of their needs, and what I see of their of their strengths and their courage. And, we take that into everything that we do. I think that for translational science with these kind of disease focus, I think it's always the patients at the center, the samples that we're able to access are because a patient donated those samples. Here we're taking advantage of financial resources that were put together by patients and donors and people who are really driving this. So we're part of that. It's a community effort. But, you know, the patients and their families are at the core, and we need them to kind of drive the work.

Oscar: Yeah, and kind of off that, something I'm thinking about, you interact with a lot of patients, and at a time when there's not really any therapies for them, it feels like palliative care and kind of adjusting, because the disease changes so much so quickly, adjusting based on what they're saying, it seems really important and important for minimizing symptoms. So I'm just wondering, what do you see as the most effective treatments for a disease like PSP that lacks therapeutics?

Jessica: I mean, everything lacks therapeutics, but it makes a huge difference whether somebody with a degenerative disease gets good care or not. It makes a huge difference. The priorities are twofold: Top of the priority list is quality of life. Second priority is maintaining or adjusting to maintain functionality as best as possible, right? So even when you can't cure something, there's a heck of a lot you can do for both of those goals, and they can be incredibly important, and will remain incredibly important in medicine. So it's palliative care because by definition it's care that's not curing, but rather treating and healing, right? But that is at the center of what we do.

I had a patient with a different but related disorder come to me in their case, it was not PSP, it was a genetic disorder that was running in their family, and for generations, the family just said, “Well, we got this,” and when they start to get sick they wouldn't really do very much about it. They felt like there was nothing that could be done. And she came in and was very proud of the fact that she was the first person from her family who said, “No, I can do something to improve my quality of life and my function and my longevity.” And she had or attested to me that her experience was completely different with the disease. And I think by the time I had met her, she had already outlived every other family member by a decade. So these things make a difference in different diseases, they make a difference, more or less, right? Because some of the things we can adapt better for, there's a lot of challenges with PSP and being able to adapt to the particular way patients fall and can get injured. We have special walkers for that. But it can still be a real challenge, and then with cognitive, there's very little that we can do to adapt when somebody's cognitive skills have been affected to a certain extent. But we can still support with what we can do, and offer, not only that technical, whatever it is, DME, or medication to help with bowel and bladder function or whatever it is. But we also can make the patients and families understand that we're with them, and we're walking the journey with them, and that they're cared for. So I try to carry those things with me, because almost universally, with very few exceptions, I can't treat any of my patients curatively for any of the things that they have.

Oscar: And lastly, what do you hope that future studies could take from this? And where do you hope research goes from here?

Jesscia: I just hope we keep going. I think we're at this point where the investments from 10 years ago, five years ago, are giving us completely new and exciting opportunities, and we have to just keep the pressure on, and it can feel like from the outside in particular, that we've gone on this long road and we're still not there, right? But I see that we're getting there. It's still a lot of work. We got to put our foot more on the gas and accelerate and push more research, let the data drive the work and support not just incremental science, but science that's willing to go where it needs to go to have the impacts it needs to have. For patients, all the tools are there, but science takes time, takes energy, takes teams, takes talent, and it takes a lot of resources, a lot of resources. And so I just want to see or encourage others to keep going, because I know we'll get there if we do.