Founder Stories: Richard Ransohoff, Third Rock Ventures and Abata Therapeutics

Thank you very much for that introduction. So I feel we have a terrific topic and panel today. I've spent a lot of the last 20 years being interested in neurobiology. And if you are interested in the brain, that's one of the highest complexities that I know. The neuroimmune system is almost equally complex. So a few decades ago, it was remarkable when some genetic studies showed that the immune system seemed to rank very highly in many of the neurodegenerative diseases that we had, also the ones that weren't autoimmune. And as you know, in most neuropathology textbooks, they show either dead neurons that were dead or dying, but very little were kind of described about the other system. But recently we've found that many of the neuroimmune systems are involved. You see in the news about COVID Epstein-Barr viruses. And many of the panelists we have here today have been leaders and are leaders in describing how the immune system interacts and maybe even triggers or initiates the pathologies that we see. So the worldview of neurology and neurodegenerative diseases is changing. And I'm really looking forward to sharing this time with these experts. So we're going to start from sort of a very basic science, but all the way to potentially understanding some of these severe diseases by first listening to Rudy Tanzi.

I'm sorry I can't be there. I'm in a situation I call "homocron," meaning a house full of Omicron, and thought I shouldn't come there to share it with you all, but instead just share my words. It's a pleasure to be here. I started my career cloning the first Alzheimer's gene, the amyloid precursor protein, APP. I spent many years in amyloid and the role of amyloid in the disease. Over time, I and many others realized that amyloid comes very early in the disease. In fact, the first point I want to make is that amyloid is to Alzheimer's as cholesterol is to heart disease. You want to manage it, but once you have symptoms, for example, in heart disease, once you need a bypass, you may take a statin like Lipitor, but it may not— it's not going to fix your bypass, your need for a bypass. So I think this explains why so many of the amyloid trials have failed. It's not whether amyloid should be hit, it's when. So the question is, in a patient who has symptoms, what do you hit? What is the bypass for Alzheimer's? What do you hit? And what we're learning is that it's neuroinflammation. It's the innate immune system. It's microglial activation. And when I started first thinking about this was somewhere around 13, 14 years ago, we found from the first family-based Alzheimer's GWAS that we did at Mass General, the biggest hit we came up with was a gene. I didn't know what it was. It was called CD33. And then we had to learn that, hey, CD33 controls microglial function. And then we learned that CD33 is like an on switch for neuroinflammation for microglia. And a few years later, TREM2 came around, and that was the opposite. TREM2 was the off switch. So you have these microglial cells that are normally housekeeping and clearing amyloid, and when CD33 is up, they become killers. They want to wipe that part of the brain out. Choose the opposite. So if you want to— well, I'll end this first statement is that if you want to help a patient, you really need to put out the fire. I like to say amyloid is the match. It comes 20, 30 years before symptoms. Tangles that are induced by amyloid are like brush fires that spread. The resilient brain studies of people who die with plaques and tangles and no dementia suggest that without neuroinflammation, you don't get symptoms, which is good news. When you want to help a patient, you need to put out that fire. It's not enough to blow out the match or stamp out those brush fires of plaques and tangles. And I have to manage microglial cell activation. And the good news is we now know of at least two dozen different Alzheimer's genes beyond CD3 and TREM2 that are controlling that microglial cell state, whether it's going to be a benevolent housekeeper nurturing the brain or whether it's going to turn into a killer believing that it needs to wipe out that part of the brain with inflammation. And so that's just— and I just would end by saying, so it's possible inflammation could come early on and even trigger the amyloid and tangles. There's not one set temporal pathway here. So that's just the opening. Kind of an open statement about the pathology and temporal order of Alzheimer's and how neuroinflammation and innate immunity plays a role.

Thank you. So the idea then that there are active immune cells in your brain that sits and kind of senses the environment and also interacts very heavily with neurons and other glial cells. I'd like to hear from you, Beth, how you see this. One of the leading lights in this field. And you are describing how microglia can be in different states and perform different functions. So what's your perspective on this?

Yeah, thank you. So I've been studying these resident immune cells called microglia, as you just heard from Rudy, for the last decade or so. And I initially got interested in studying them from the context of the healthy brain, because they make up about 8% to 10% of the cells of our brains. And they are— they have a lot of jobs, right? A lot of roles that are both beneficial and detrimental depending on the context. So they're really sensitive to changes in their environment, very local changes and perturbations to something really dramatic like an injury or neurodegenerative disease. So I became interested in one particular function of these cells from an early point in my career. And that is one of the jobs that they do is that they actually help to prune or sculpt synapses, the connections between neurons. Now this back then was kind of an unexpected finding because we know and have known for a long time that one of the strongest correlates of cognitive decline in diseases like Alzheimer's or other age-related diseases or even normal aging is the loss of synapses, right, those connections between neurons. And one of the many roles of these cells is to remove or prune away those synapses.. So during development, when your brain is wiring up, when you're a child, you want to have this remodeling, this pruning. And we've been studying that process in depth. But what we've also discovered is some of the same mechanisms that normally help microglia prune away those extra connections during development can become aberrantly turned on in diseases like Alzheimer's or aging or other diseases. And so we've been trying to understand what it is that tells microglia, prune these synapses or don't prune these connections. And we uncovered a role of a number of different immune-related molecules that, again, are expressed in the healthy brain and have normal function. So you think about immunology in the immune system as a separate sort of entity than the brain. And what we're learning, and you'll hear more about today, is that these two systems are intimately connected. So what we're also learning is pruning is just one of the many jobs of these cells. In one hand, in the context of diseases like Alzheimer's, we want to find ways to stop them from removing synapses, right? And so that's one potential therapeutic target or mechanism. But at the same time, the other thing they're really good at doing, which would be a beneficial thing, is clearing a toxic protein like amyloid or clearing or removing a dying cell. And so the big question for the field now is how do we get microglia to do to, you know, the pruning in one way and then, you know, get them to increase their ability to clear a protein like amyloid. And so that is really, in a way, where we're moving forward is trying to get at ways to specifically target these different states. And I think what's really happened in the last 5 years or so is not only are human genetic studies like what Rudy's just described implicating these cells directly, certain genes and pathways we can think about targeting. But we also now have access to a lot of genomic and single-cell and multi-omic data that are starting to give us an unbiased look at these different states of microglia and other immune-related cells in our brain. So now we're in a position for the first time to develop new strategies to be able to track and target these cells, early stages of diseases, to try to slow down the progression of diseases. And so we've been thinking about, both in the lab and through collaborative efforts, and in partnerships with industry, ways to develop new models to study these cells in a dish, for example, where you can actually grow human cells from patients and grow them into microglia and study them in depth. And we can also start to really take the ability to be able to access human samples of CSF and blood and other data and start to really deeply profile these cells and then bring all that data together to give us new potential targets targets and pathways with which to think about studying more mechanistically. So that's sort of the arc that we've been taking it, but I think it really does take a real collaborative approach to be able to get to that point.

Thank you. And that collaborative approach leads also to drug development. And we're going to hear now from Spyros, who really is a leader in both neurology and in drug development. And in fact, he is working, and he will tell us, I believe, that some of the genes that Rudy mentioned are actually explored and actively used as targets in several diseases. So can you please tell us about your efforts?

Absolutely. Thank you so much, Ulli. We focus in a very, very well-defined area. Imagine a triangle. On the top of the triangle sits the one cellular population, the microglia, and then We target diseases that are either neuroimmune mediated or neurodegenerative. So this is our particular space and there are multiple targets there. Our favorite target is one that Rudy mentioned, TREM2. And why we're so excited is that TREM2 is a damage receptor. So it goes around and recognizes myelin bits and pieces. It recognizes membrane fragments. It recognizes forms of A-beta. It recognizes ApoE and gives microglia this neuro-friendly phenotype that is so much needed and wanted in neurodegenerative disease. There are many ways to approach TREM2 biology. We chose to start from a rare disease. We are a precision medicine company.. So we like when we know the parts and the bits of the story. We focus on a condition called ALSP. It stands for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. Whoever gave, you know, came up with this term, I need to have a discussion with them because it's completely unpronounceable and it's definitely not ALS. It's a completely different condition. It strikes patients at their about 40. It leaves patients incapacitated in about 3 to 4 years, and it leads to death in about 6 years. There's nothing much that the patients can do other than symptomatic treatments and perhaps hematopoietic stem cell transplants in very, very, very selected cases. And that's kind of a very nice link between cell and gene therapy and neuroimmunity. So there is hope for for modulation of the immune system. How we're using TREM, though, is unique in our case. So we know that ALSP is caused by mutations on a gene called CSF1, and CSF1R is a receptor that recognizes trophic factors and gives microglia their functionality. And what CSF1R does, it shares common pathway with TREM2. TREM2 is a damage receptor. CSF1R is a trophic receptor, but they all signal through DAP12, SIC, and phospho-SIC to exert their functionality. So in a deficient CSF1R microglia, we actually compensate by activating the TREM2 receptor and restoring the dysfunctional microglia. And if you look at the brains of patients with ALSP, they have reduced numbers and reduced functions of microglia. What we've shown basically successfully in human-derived microglia from iPSCs is that we can actually rescue the pathway and give microglia back their healthy phenotype in order to fight disease. So if we can replicate this in patients with ALSP, we believe we have a good opportunity to validate the therapeutic hypothesis. And we're not talking about the future. We're in the clinic and we're going to be conducting human studies in the second half of this year. But there's also the opportunity in Alzheimer's disease. We know that breakdown of this nice microglia sheath or barrier around plaque is associated with impaired amyloid processing. Therefore, through TREM2 agonism, especially in patients that carry variants that have induced, that can induce either accelerated disease or increased risk of developing Alzheimer's disease, intervention with boosting TREM2 agonism and boosting microglia functionality could be really disease-modifying. So very precise approaches in both rare and common diseases with multiple modalities. We're working both with monoclonal antibodies and with small molecules. We're in the clinic with our monoclonal antibody, and we're planning to be in the clinic next year with our small molecule.

Thank you. So we're learning quickly here. So you've already heard about the microglia role in phagocytosis, and it can consume leukodystrophies and other complicated names. But in fact, it gets more complicated. The brain, of course, has many other glial cells, including astrocytes and oligodendrocytes that myelinate tissue. And Richard here is really a world guru, oracle, we heard earlier today, about many of these diseases. And I've known Richard for years. Can you please give us your perspective, for example, on multiple sclerosis, which of course has the autoimmune aspect in addition to its inflammatory component?

Thank you. I'm going to change the script a little bit and talk about a disease in which it— there's truly a prototype neuroimmune disease. It's one in which the immune system is the problem, not part of the response. So as Willie mentioned, multiple sclerosis is an autoimmune disease, and so rogue T cells orchestrate an attack on central nervous system myelin, and it is that attack which causes the symptoms of disease. So what I'm going to tell you briefly is progress towards resolving an approximately 150-year-old mystery in multiple sclerosis, and that is what's going on in progressive multiple sclerosis. Progressive MS is simply what happens after the initial phases of MS called relapsing MS. People get relapses developing relapsing MS around age 30, and they have symptoms that wax and wane. They get worse and then they get better, and they often have long periods of stability and apparent disease quiescence. Around the age of late 40s, early 50s, the phenotype dramatically changes. They no longer have attacks. Instead, they have slow, steady worsening that doesn't get better. And this is called progressive MS. And it's been a curiosity ever since the disease was described about what's going on. Another thing that happens in progressive MS, which is regrettable and unfortunate, is that the medicines that have been developed, which are now more than 15, for relapsing MS, and which are incredibly, incredibly effective and change the lives of patients, no longer work. So there's something different about progressive MS. The first thing you might guess is that the immune system sort of burnt out this autoimmune process, and that damage to the brain that occurred early on is simply playing itself out. So there's a pure neurodegenerative process. You can imagine that that might be the case, but the neuropathology won't support you. If you look at the brains of people dying with MS, and people who have MS do not have shortened lifespans, so typically they will have had MS for 30, 40, 50 years at the time of autopsy. And what you're gonna find is not a picture of burnt-out inflammation and sort of scar-like lesions. What instead you find very often is continuing, ongoing, chronic damage to myelin. And the question is, how can that come about? So beginning of resolution of this mystery, insofar as we've begun to understand it, comes in the late '90s and early 2000s when a number of neuropathologists began to see that there are collections of inflammatory cells—T cells and B cells and macrophages—in the meninges, the lining membranes around the brain where the spinal fluid circulates. And Hans Lossmann was really the thought leader in this area, said that this compartmentalized inflammation, as he called it, might be driving some of the progression and might in particular be driving the ongoing demyelinating tissue injury. The field then took a very large step forward right around 2019 when Danny Reich at the NIH developed an MRI imaging technique that could visualize these chronic active lesions. And he was able to show— so now we're working in living patients and we can correlate what happens at the tissue level with what's happening to the patient. And what he was able to show was that people who have more of these lesions do worse. And so you could see that, yes, there is some amount of neurodegeneration going on because nerve fibers that are demyelinated chronically will in fact degenerate. So there's neurodegeneration, but there's also active inflammatory tissue injury., and that is pushing the disease progression. And so very recently, obviously after 2019 is going to be recently, Danny and colleagues at the NIH did single-cell sequencing of the cells at the lesion edge and showed that they are responding actively by their transcriptomes to T-cell cytokines.. And so the idea began to emerge that maybe the products of those meningeal inflammatory aggregates are driving tissue injury deep in the brain of people with MS. And then the last piece of the puzzle is just about a month ago when Amit Bar-Or at Penn and Jen Gommerman in Toronto and Inge Heutinger in the Netherlands and a variety of other colleagues were able to show a direct relationship between the amount of meningeal inflammation and chronic active lesions. So now you have a fairly complete picture. And the question is, can you test this hypothesis in the clinic? Because I mentioned that all of the other existing treatments fail to affect the course of disease for these individuals. And so at a Third Rock company that I was involved in starting called Abata, we're engineering regulatory T cells to take up residence in the meninges and try to quell this inflammation so that we can directly ask at the therapeutic level whether this hypothesis is correct.

Thanks a lot. So I hope you got through all that. So what we're learning here, right, is that in the brain, which we all think of as a nerve conduction system generating output, we have several cells that actually are sensing immune functions. Not just the microglia, but as I mentioned, astrocytes and also cells in the meninges, the capsule of the brain. And that they are talking, and if they're dysregulated, can create kind of havoc. But again, damaging neurons in the process. So if that's not complicated, I don't know what is. However, our next panelist is a pioneer in artificial intelligence, and Colin Hill here will describe to you another method to deal with complexity. And he will describe to you something very obvious, which is causal inference, I believe it's called, in mathematical modeling. But what he does, and he will describe it better than I do, is to try to find links upstream of these events that we see. And working with patient data to find links to these sometimes immune system actors that could help us find different ways, both targets and biomarkers for the system.

So can you tell us more about that? Thanks, Ole. So what we've just heard really represents the vanguard in terms of initiatives to get at the underlying causes of neuroinflammation. And it's truly amazing, the discoveries that are coming out that we just heard about. However, they are pieces of a very big puzzle. They are the tip of the iceberg. And the question is, how big is the puzzle? Turns out the puzzle is really, really big. Like not billions and billions, it's astronomically big. And so therefore, if we want to be able to get at the discoveries of the true drivers, we want to get there in the next several years versus several decades. I think it's important that we complement expert-driven, hypothesis-driven approaches By data-driven hypothesis-free approaches, right? After all these years of molecular biology, we know 5% of the circuitry of human disease. 5%. That means we're missing 95%. Now, what we have today is now the opportunity to generate large-scale clinical genomic data. We heard about some of that data generation from Beth. With— when you combine that with advances in the science of causality, a new special kind of AI that's attempting to find the relationships between variables, you now get to the point of being able to reveal the hidden circuitry of human disease. A different way of now generating and testing hypotheses that is leading to the creation of virtual patients. Essentially digital twins that allow us to now conduct experiments on the computer much faster, much cheaper than was ever thought possible before. With these virtual patients, we're now able to simulate gene and protein knockdowns across the whole system one by one by one, as if we were doing siRNA experiments in the wet lab to discover completely novel targets. We're able to also use these digital twins to to simulate clinical trials ahead of the trial. So imagine instead of the 17 failed base inhibitor trials that were conducted for Alzheimer's, that we were able to figure that out ahead of time, years earlier. And so that's exactly what we've done at GNS. And we have examples now where we've managed to discover a number of drivers of neuroinflammation, things that are upstream of cytokine pathways like IL-6. A number of these have now been both validated, discovered and validated in brain tissue directly as well as in blood. I think the punchline here is that we're dealing with systems that are incredibly complex and even the smartest amongst us, this is beyond the complexity that the human brain can deal with. So we have to complement these great ideas with completely data-driven hypothesis-free methods so we can accelerate and short-circuit the discovery process to get at the real culprits of these diseases.

Thank you. So there you have it. So this is sort of the basics. As well as some of the translational aspects of chronic neuroinflammation that could be really a part of the disease process rather than just the final pathology. So there's been a lot of interest in the field, of course, for chronic inflammation, which may be generated even from your microbiome. There's a blood-brain barrier you may have heard about that's very important. Important for this signaling between cytokines and the brain. And my team actually have worked in parallel to some of the work we do in cell therapy on cytokines. So for example, in Parkinson's disease modeling, if we block a cytokine called IL-1 beta, we can make the immune system or the cellular context in which Parkinson-like toxicity, we can block that, right? But we were told immediately that, well, you know, I'm sorry, Ulla, we can't deal with that because we don't know which patients we should treat. Shall we treat the Parkinson patient or the ones that may get it? So that's one of the biggest dilemmas for this chronic neurogenic condition. So I'd like to know if anybody on this panel would like to speak about some of these trigger mechanisms, for example cytokines, or in terms of long COVID, there are many mechanisms that are being postulated. There are autoantibodies that people have found at some of the Yale teams, but also the potential that there are the same mechanisms that we have heard about from several of the speakers, that your hippocampus would deal with memory, starts to show atrophy in people who have been exposed to COVID. And it's a pretty frightening view, at least to me who's been involved in this science, to think about what that may do long term. But I don't know if anyone would like to comment on that on the panel? Any volunteers? Well, then I will ask you, Richard. What do you think about, for example, Epstein-Barr virus, right, which, you know, seems to be a virus that can trigger the initiation, I guess, or the risk for initiating MS? What's your view on that kind of neuroimmune interaction or trigger?

Yeah, so to put EBV, Epstein-Barr virus, in context in terms of pathogenesis of multiple sclerosis, it's important to sort of take on the fact that there is a genetic component to multiple sclerosis and there's an environmental component. And almost all of this can sort of be visualized first by thinking about a twin study.— these are real twins, not virtual— that was reported in the mid-1980s. So all across Canada, the MS clinics got together and they looked at their patients and they asked if they had twins, and if they did, were they monozygotic or dizygotic. And it turned out that if one twin has MS and has a monozygotic twin, a monozygotic twin, the concordance is 30%, and if it's a dizygotic twin, the concordance is 3%. And so that tells you two things. It tells you there is a genetics, and it tells you that genetics is not everything. So what is coming from the environment? One of the great leaders in understanding this has been Alberto Ascarrio of Harvard Public Health, and he has clarified the fact that of all the viruses that might be triggering whatever is going on to launch the MS disease process, the one that stands out is Epstein-Barr virus. And he's shown this in multiple ways and multiple very, very large studies in cohorts like all of the US servicemen. Or the National Nursing Study, which is 600,000 people, and so on. And so if you accept his conclusion, which is inescapable, that Epstein-Barr is involved, then the next question is, what's it doing? And there are at least 3 possible answers, and the right answer has not yet emerged. Emerged. One possible answer is that there is some direct way that Epstein-Barr virus infected cells, which are going to be B lymphocytes, get in the brain and trigger some process that leads to MS. Another possibility, and this is being followed up by a company called Atara that's trying to attack those cells with T-cell infusions that recognize Epstein-Barr-infected cells. So we'll see. They're testing in the clinic. Another possibility is that Epstein-Barr modifies the behavior of B cells in such a way as either to co-opt them into the disease process by some non-antibody involving function or causing them to make pathogenic antibodies. And both of those, I think, are up for grabs as possibilities. But it illustrates the host-pathogen genetic sort of complexity involved in neuroinflammation.

Can I add to this? Sure. Please go ahead. Yeah, I'm thinking about the work of my late colleague Rob Moyer and showing that years ago that the A-beta, the amyloid beta protein in Alzheimer's disease, is actually an antimicrobial peptide that is a host defense peptide. So it can bind to pathogens, and like an antimicrobial peptide or AMP does, the sticky peptide binds to the pathogen the pathogen, the microbe, it agglutinates, wraps around it. In this case, it's a plaque that's been seeded, and this protects the host cells. And along that process, you generate oligomers of amyloid beta protein-induced tangles. And more recently, the folks in Rob's lab who now join my lab have shown that the tangles themselves in axons can be roadblocks for viruses. So, there's this picture emerging that in addition to microglial cells and neuroinflammation, that's an obvious host defense response, can cause a lot of friendly fire and collateral damage, that even plaques and tangles may have evolved as a host defense system to trap and prevent the spread of pathogens, including viruses. And so, when, you know, just picking up on Richard's, you know, excellent synopsis just now. In Alzheimer's, even today, I believe that it's mostly genetics that's predisposing to the disease. It's possible that these gene mutations and variants that predispose to a greater susceptibility for plaques or tangles or neuroinflammation, there may have been evolutionary pressure on these to be conserved because by driving the biology over the last tens of thousands of years, this may have led to survival during great epidemics of brain infection, be it encephalitis and meningitis. So this is something we're working on quite actively now. What is the interplay of environmental factors like infection versus genetics, where the genetics may have been driven by the host defense properties of Alzheimer's pathology, not just neuroinflammation, and protecting against infection. And I just wonder how, you know, this may apply to other diseases where you can look at infectious etiology as well as genetics.

Yeah, that's an excellent point. And so what we're hearing from the panelists is really there is almost a seesaw effect in which even evolutionary processes that Rudy just mentioned may be playing out chronically and actually are performing their job, so to speak, but under certain conditions, as we tend to live longer and longer, they become part of this dynamic. So maybe, Beth, you've been thinking about that for a long time. And as you said in your introduction, the sculpting of the nervous system, you discovered sort of how this immune system was part of that. And I don't know what your most recent findings are, but certainly the complement system seemed to be the way that microglia kind of spearhead or point out which pieces should be removed.

Yeah, I think that's a great example. The complement system is a very, very old and evolutionarily conserved system, a way that if you had a pathogen in your body, this is secreted proteins in your periphery and in tissues that essentially tag it for removal by these macrophages. So it's really kind of your first line of defense to remove debris or pathogens. And what we, and now others, have shown is that these complement proteins are also in the brain normally, and that they not only could respond to an infection, like a pathogen in the case of a virus or a bacterial cell, but they can also tag other things for removal, including things like synapses. So while that's super interesting to think about how the same system can have such diverse effects depending on the context, it also makes it a bit challenging therapeutically, right? Because you want to be able to target, you know, certain specific aspects that are beneficial and try to protect things like synapses, but you definitely don't want to dampen the ability to clear a pathogen or to remove dead cells. So I think this is one of many examples where the systems that have been studied in the body or in the immune system are also playing locally within the brain and vice versa. And I think the other emerging theme, as just discussed here with viruses, is just like we need to better understand how these different pathogens, whether it be a virus or a bacterial infection, how that's signaling from the periphery to the brain. And Richard mentioned the meninges, these sort of borders, the brain borders and the barriers. That's where this rich repertoire of immune cells that live there, that are patrolling, right, the barriers between the periphery and the brain. And so they have important roles to be able to keep things in homeostasis, in check. But at the same time, with aging and with genetic risk, then suddenly, you know, that system goes out of control and then inflammation can ensue. And then it's hard to kind of get it back to homeostasis. So I think one of the challenges is how do we detect these changes early and how do we get at some some of the common pathways that we could think about targeting even from the peripheral side of things. And maybe that's a question for the group here, because in some ways it would be a lot easier to think about targeting the periphery than to target things in the brain.

And I wonder what the panel thinks about that idea. Yeah, to maybe rephrase that, because now I really love this part. So even as we heard from AI and Colin, right, When I started doing medical studies or science, the blood was very far away from the brain. But actually, their virtual patients have blood data. And the inflammatory status in the periphery, what we call periphery, the blood other side of the brain, right, is of course influencing many of these things that are happening on the other side of the blood-brain barrier. So I think this idea that we think of systemic inflammation and local inflammation with a spectrum of disease that can happen in many ways. But this idea that we're looking at the patient in a more holistic way and looking for clues to say, how is this patient responding to a situation like Beth just said, the biomarker, can that instruct us how to treat early? We have many drugs actually, but they're usually not deployed because we don't know the status of the patient. So also, I'm looking down here on my tablet for any questions that are from you, the audience, so make sure that you send them to me. We have still a few minutes here.

But maybe you would like to comment on that. Well, I'll just add one comment, a follow-up from what Beth described. We've been surprised in seeing the amount of overlap between targets and networks in the blood from studies like the ADNI study as well as the AMP-AD study, which is We're looking directly at brain tissue. And so, it's telling us that either the blood-brain barrier isn't such a barrier or that a lot of the phenomena that underlie neuroinflammation in the brain happens in other parts of the body at the same time, but we're just simply not— it doesn't play out in the rest of the body in the way it does play out in the brain, which would be a radical but becoming a more plausible idea.

Okay. So, thank you. I— on my screen, it was all blank. Now I have lots of questions here and lots of choices to make. Wow, this is really interesting. So, well, here's one that I think is interesting. What do we know and what do we hypothesize about about the chronic viral infections are drivers of neuroinflammation. What are the mechanisms that play on these triggers? I don't know if there is an answer. So do we know what the mechanisms are? I mean, I can give a few examples. So there are receptors in the brain that we heard of are innate, toll-like receptors, one for bacteria, toll-like 4, and one for virus, toll-like 3. And they sit on these cells. And are kind of evolutionarily placed, right? But as we heard previously, even with long COVID, there seems to be sort of a cytokine drive, right? So maybe anyone on the panel who know about how that communication is done, what is the trigger?

What's the mechanism? Well, I just, just in 2 minutes, you know, just remember these viruses, they can see the amyloid readily, they see tangles Many of these viruses spread neurotropically. So they go down axon and across synapses. So evolutionarily, if you want to stop their spread, you want to block them in axons, which is what phosphotolerant tangles will do, and amyloid will induce those tangles. And you'll also want to take out synapses, and that's what this excessive pruning Beth talked about will do. So it's so easy to see some of the damage that's happening in Alzheimer's disease is so aimed at stopping a viral spreading, whether it's A-beta binding to a herpes virus and agglutinating it in a plaque, or the escaped virus inducing a tangle together with A-beta oligomers inducing tangles to block the neurotropic spread to microglial cells attacking the virus and taking out synapses, which is how they spread from neuron to neuron. And so I look at it as one big orchestrated system where cytokines and complement are playing a key role because they're also inducing astrogliosis, as Beth and Ben Barris showed, that brings other cells into the mix for protecting against infection. But, you know, back to Conal's point, I think we do have to look at this as a system, not one pathology, not one cell at a time, not one pathology alone, but actually look at how orchestrated together and how they may have evolved together and for what reason.

On that very wise note, I would like to thank the panelists for really contributing to this discussion and also for the audience to participate.