#8 Exploring the drivers of post-infectious illness, with Harvard Neuroimmunologist Michael VanElzakker, PhD

[Music] Welcome to Make Visible, the podcast shining a light on complex chronic illness. I am your host, Emily Kate Stevens, and I've been living with an energy limiting condition since 2020. Here I will speak to the world's leading experts to bring you the latest science, research and insights into invisible illnesses, including MCFS, EDS, fibromyalgia, pots, long COVID, and more. [Music] Happy New Year and welcome back. I caught some virus at the very beginning of the year, so I am having a very slow start into January, and I encourage you to do the same. Take it one step at a time, listen to your body, and take a listen to this week's really encouraging episode with Mike van Alzacca, PhD. He is a neuro immunologist focusing his work where the nervous and immune systems meet. He is an educator at Harvard Medical School, Massachusetts General Hospital, and Tufts University, but he is also co-founder of the PolyBio Research Foundation, who are making amazing progress in the space of complex chronic illness. He talks about how PolyBio are using this moment of impetus and funding into COVID research to really try and develop a greater understanding of post-infectious disease. So, neuro immunology is actually the focus or the crux point of your work and the conditions in which you work, would you say, because you look at the point at which the neuro system and immune system meet and the dysfunction between those two. Have I interpreted that correctly? Yeah, I think that's fair. We try really hard to not kind of over-specialize. I think that can happen a lot. Everybody recognizes that these conditions can be really multi-systemic, but nevertheless, people have a tendency to focus in on one either mechanism or theory or things like that, and I think it's important to not do that, but yes, the intersection between the nervous system and the immune system, but why does someone subjectively feel sick? Is the focus of, I think, neuroimmunology, and there's a field called psychoneuroimmunology that really focuses on not necessarily the psychology of it, but the fact that it is subjective symptoms that are triggered by immune responses. I like that you're saying we don't want to make it to too specific an area because the immune system, the neurological, the psychological, it's pretty massive and it actually suggests a fairly holistic approach to what you're studying. Yeah. Your main focus is up until 2020 were ME/CFS and PTSD. Could you explain for me the way in which PTSD and ME/CFS both fall within your rematch? Yeah. So both are about long-term consequences. I don't really necessarily think of them as mechanistically similar. There are some mechanistic overlaps, so for example, my focus tends to be vagus nerve. At the very least, I consider that to be an important organ system that's under considered across multiple conditions, and that seems to be central to both of those conditions. But I don't necessarily think of them as the same thing. PTSD is interesting because it tends to be an event or events where that is a true trigger and it can drive symptoms long-term, where with ME, I don't really think that what happens in most cases is that there's a trigger that is then gone, but then has lasting effects. I suspect in the words of the NIH's recent study that I know people criticize, but there were some parts that people should notice like persistent antigenic stimulation. So it's not quite the same thing. One kind of is a long-term consequence, and the other is kind of an ongoing process, I think in most cases. Persistent antigenic stimulation suggests that the immune system has been activated, but is not necessarily stating that there is viral persistence within the system. Is that the correct interpretation? No, it actually would say that there is probably something persistently. Now, whether or not that is low level or something that, an otherwise healthy person would be persistently responding to, is an open question. But the idea is that it isn't necessarily the case. In most cases, that the immune system is just on for no reason whatsoever. It's being driven by something, whether that's in a hypersensitized manner, or whether the response is appropriate is an open question, I think. Okay, so the difference with the PTSD is that there's the one event, not that it resolves that one event, but it doesn't continue within the body, whereas with these post-viral conditions, ME, and then obviously subsequently, you have looked extensively into long-hoved, there is the idea then that there is something consistently trickering that immune system rather than it being. If we think about the polyvagal theory or rather than it being something that has just switched on that element, and then it's remained even though there's not an antigen still. Yeah, I mean, you don't want to oversimplify because there's probably all kinds of caveats, for example, someone with PTSD still might be in an unsafe environment or maybe in an abusive household still, so there's still something going on, right? But in general, the thinking is that with ME, a lot of what we need to do is to figure out what is driving the immune system. It may be the case that in some people, there's some particular vulnerability that causes an ongoing response, kind of in the absence of stimulation, but that doesn't really make sense given that we're not sterile. So it would be difficult to have a lack of immune stimulation in a system where there are immune stimulants just in and on us all the time. So an important question is whether or not people with the ME diagnostic label have a sensitized immune system that's causing them to give an overly robust response, but I think in many cases we're simply not testing at the level that we ought to, at least in a huge bulk of patients. So back to that NIH study, which again, like I have to caveat so I don't get yelled at. I know people are critical, and I am too of some components of it. But I think it's important to note that somewhere around a fifth of the people that were recruited for that study, that had seen ME specialist doctors gotten the sort of checkmark saying yes, they do have real ME. Upon deeper investigation in about a fifth of those patients, they found something else that was driving those symptoms. So at least maybe particularly in a place like the United States with our healthcare was people get kind of punted around to specialists and don't really get a really careful set of tests. They have 15-minute appointments with different specialists that don't speak to one another. So at the very least I think a lot of these patients need some careful investigative work by a doctor or a team of doctors. There's a name for that, isn't there diagnosis by exclusion? I was talking to Dr. Lee Sinder-Bateman recently and I think that's one of the things that she was really, really conscious of of ensuring that the majority of her patients didn't have this other underlying condition. Is there a prevalence of certain things that that tends to be? Does it often tend to be chronic? Lime that's been undiagnosed and presents similarly, or can it be a whole host of different things? It can probably be a lot of different things. One of the difficult things is that most of the ME symptoms overlap with other conditions. So it ought not be a default diagnosis or diagnosis by exclusion, but it ends up in practically speaking being that way. Lime is one of the things that can drive that set of symptoms. In some cases, people can unbeknownst to them have a bacterial infection like Bartonella, Babesia, Burelia, that can drive these symptoms. And again, it's sometimes not easy to test for. It's a maddening because you can get into this really difficult world where you say, "Is this really what I have? Is this really what matters?" But yes, testing carefully, I think, is what the careful NE doctors do. But I guess what's interesting with that is that possibly the ME/CFS or the long-caved, you could say actually people do have that underlying trigger. We just haven't actually identified and managed to remove it from their system because, as you say, those people with those underlying conditions present in a similar way to the other ME and perhaps. who just haven't got to the root. You have spent a lot of time trying to uncover the mechanisms of the ME CFS and a lot of the way in which you've done that is been using imaging, functional and structural imaging. Can you tell us what you see in that imaging that enables you to understand that certain people have ME, what we term ME? Yeah, so there really isn't any kind of a brain scan where I can just look at it and say, "Oh, there it is, there's the ME." Yeah, it's not like you go in and you see a tumour or you see something visible. Exactly. We have to compare groups of patients that have been carefully selected to groups of people that are matched but aren't sick. What we tend to study is neuroinflammation. So basically, when you look at a brain somewhere around half of what you're looking at are actually immune cells called GLEA, G-L-I-A. So those GLEA were once thought to just hold neurons in place. The term GLEA means glue in Greek, but it turns out that they're really important in both a new responses and in normal neurotransmission. So when someone is sick with anything, whether it's, let's say, strep throat or whether it's flu, there are a set of symptoms that people feel just sort of across the board. Those largely overlap with the ME symptoms. It's not the exact same thing, but they largely overlap. It's really interesting because strep is a bacteria and flu is a virus and yet both of those can lead to a common consequence of what we call the sickness response. And so that is largely driven by a neuroinflammatory process. And in the short term, that's supposed to happen. Evolutionarily, it's the part of the immune response that is behavioral that's saying, go to bed, you're really exhausted, really tired. You should not spend energy on other things right now because you're fighting something. And you also should not be around other people. It's trying to. It's trying to make you withdraw, doesn't it? When your immune system is suppressed. Exactly. You isolate. It's the reason that a dog might wander off and lie by themselves when they're really sick or dying or something like that, right? With these conditions, but it seems to be that that is happening on a long persistent basis where a short term that makes sense, but long term, it stops making sense. And then we start to have to figure out why and what is driving it? Is it a sensitized system? Is there a persistent driver that's driving it from the bottom up? The fact that ME patients have neuroinflammation is really not. It's important, but it's not really root cause. So what we try to do is to look at that phenomenon and then try to understand what are some of the things that might be driving it. So we take blood, saliva, other behavioral measure skin in some cases. Three plus final fluid, I think you. Yeah, I'm involved in some studies. I've never taken cerebral spinal fluid, but I've been involved in some studies that have done that and understand why? Why is that happening? Because of course, there's going to be neuroinflammation. If people are having a persistent sickness response or at least you'd really expect it. But then the question is sort of what is driving that? And if you're really careful, you can answer those questions using other measures. Okay. And then what are the measures are you using? Because in terms of that glial activation, that is throughout the whole brain, is that correct? Is it certain areas that show more activation than others? Yeah, it tends to be certain areas. So there's really, let's just use PTSD as an example. We call it a circuitopathy. So there's a particular circuit in PTSD that is hyperactive or in some parts hyperoactive. And that is the reason the symptoms look the way they do. And there is a sickness circuitry also where if that particular circuitry is turned on, then that would be the result. And so yeah, you'd expect to see it in a particular circuit or particular brain regions that drive feelings of pain, fatigue, loss of concentration, things like that. Which by the way, at least in our hands, ME pre-COVID-ME and long COVID aren't exactly the same thing. I think it's similar symptoms, overlapping symptoms that are being driven by different things that aren't quite the same thing. Can you tell me about the differences of what you see between those two? Yeah. So in long COVID, it seems to be that it's a little bit more driven by vascular problems, where structures of the brain that have evolutionarily, this isn't like part of a disorder, but they have a diminished blood brain barrier, they tend to be a little bit more activated. We see abnormal clotting-like processes in long COVID that aren't there at the same level in the pre-COVID-ME. Now, it's a reasonable question whether that's a matter of time. Is it the case that someone's been sick with ME for 15 years, that they just have a diminished response and someone with long COVID simply has gotten sick sooner? In our hands, we don't think that's what's happening. We think it's a little bit of a different mechanism. Okay. And you are able to observe, and it's one of your, is it your most recent paper, you're able to observe the vascular dysfunction, via the imaging that you're doing on the brain. Can you explain how you can see that? Yeah. So in patients with long COVID, we just put out a paper a couple of months ago where what we showed was that there was a pattern of glial activation. So the immune cells of the brain were activated, especially in areas where there was the diminished blood brain barrier, right at the top of the ventricle is there's particular types of cells that it's their job to take blood plasma and convert it into cerebral spinal fluid. And this is an area where blood can pass through a little bit more easily, larger molecules. And before the patients got into the scanner, we took blood from them and then test it. And what we did was to test for several measures of vascular activation or vascular dysfunction. And we were able to show that there was a pretty tight correlation between several of these vascular measures and the neuroinflation where the, if you know, statistics, the Pearson statistics were, you know, 0.75 to 0.85, which in biology is pretty high. So it really seemed to be in the case that things like fibrinogen or SL selectin were really correlated with the glial activation. So SL selectin just as an example is a really interesting substance. It's what's called an adhesion molecule. So what this does when there's inflammation in any tissue, part of the inflammatory process is that the blood vessels kind of open up a little bit so that immune cells can get into the tissues. SL selectin causes the adhesion of immune cells onto the vascular so they can get pulled into the tissue. So we think that in these long COVID patients, some of what's happening is that immune cells from the periphery are getting sucked into the brain, especially these areas of somewhat diminished blood brain barrier. And that is what's driving the neuroinflation. And is it that it is pulling in something that it wouldn't normally be pulling in or is it purely the act of it pulling more in than it otherwise would? Yeah, it's, it is a normal and healthy thing for that to happen. Like if there was some problem in the brain, but the issue is that it's persistently happening months and months after someone had an initial COVID sickness. So that is we think evidence that at least in a lot of patients, there's something persistently driving this process and it's possible that you could just address that and it would stop some sort of a feed forward loop, but it's also possible that there's something driving this immune activation persisting. Now you are currently recruiting for a pre-COVID ME/CFS brain scan study. It's part of the reason for that that you're trying to actually pull in some patients who have relatively recently acquired ME/CFS to try and draw comparison with what you've learned about long COVID. That's not to say that we have to look at everything through the lens of long COVID, but obviously you've done a huge amount of work into long COVID and the understanding that we've got from some of that work has implications in other conditions. Yeah, and that's exactly right. And we're doing basically the exact same things in, she want to call it pre-COVID ME, people that were diagnosed, often without really knowing what the trigger was before 2019. And yes, there's two separate related questions. What is the distinction between those two patient groups with the variable being that in the long COVID patients we know what initiated it, in this case the SARS-CoV-2 virus? And we know the course of time generally. We know even now we know it's in the last four and a half, five years. Exactly. And obviously that time period is now getting longer, but even if people didn't know the specific time at which they were infected if it was asymptomatic, you still knew that it was in a relative time frame. Whereas ME/CFS, you've got some people who haven't known over 15, 30 years what the trigger was. Exactly. So we have sort of two related but somewhat questions between the known and the often unknown onset and then time, where there may be important differences between let's say someone that was diagnosed with ME or had symptoms starting in like 2018 before the COVID pandemic and someone that's been six since 1995. You would expect that and that is actually for what it's worth something that is somewhat similar with PTSD where when someone has somewhat recent PTSD they have a really robust sympathetic activation. Their autonomic system is really disrupted and then with time if you're looking at someone that you know a Vietnam veteran with PTSD for 40 years those systems they're less responsive. They sort of capituate I suppose or become a little bit burned out. So that's an important question with ME that is probably part of why that literature is so messy is that someone that's been sick for a year probably doesn't have the exact same biology going on as someone that's been sick for 15 20 years. Yeah it is so hard for you to be studying this with such unknown parameters. How do you actually try and look at these people look at patients side by side when you don't necessarily know with the length of time that people have had ME so if you do you separate out the studies so that you look at someone who's had it for 15 years and you look at someone who thinks they've only had it for five. That ought to be done for us the scans that we do cost like $7,000 each so I would love to have 300 people in our studies but that's not practical and you would probably need that to really tease that apart but a significant part of what we're trying to do is in the least cynical way possible kind of take advantage of COVID. It's a disaster for humanity but it is a moment that we could pounce on where a lot of the things that we for many years have fought needed to be developed for ME what we call unbiased testing. How do you find something when you don't know what you're looking for? We're trying our best to take advantage of this long COVID moment to develop some of the testing and some of the procedures that just didn't exist before so that they can be used on people that were sick before 2019 or people that have been sick since then that maybe COVID is not the main thing. So it's a difficult challenge but we're trying to use this moment of COVID where we have a unique opportunity where we really do know the onset in most cases. With ME there's probably shared onset within particular outbreaks or maybe within particular families but when you look at everybody that's been given that diagnostic label I just don't pick it's accurate to say they all have the same thing. That's interesting that goes back to you. I think this was in in your 2019 paper that you actually referenced historically various large onset of what is now termed ME going back to Los Angeles 1934, Iceland 1948, Nevada 1984 and you have these groups. Are you therefore suggesting that some of those should actually be I'm not saying that you do that retrospectively but where you have instances that we almost need to identify what the pathogen was to be able to determine what type of ME these people have. I think so and I think that that's a really important point. There are many that don't agree with that that thinks that people have ended up in a shared endpoint. Certainly the symptoms have a lot of overlap among different forms of onset but I personally think that the end point could arrive from different drivers. We call that equifinality and that the driver in this case really actually matters that if you're going to undo that process like unpeeling an onion you kind of do need to know what's driving it and that that's a really important distinction. That's an open question. Lots of people don't agree with that that think that all of the patients with this diagnostic label have a shared final endpoint that they're stuck in or trapped in and I personally think that the drivers in order to get people better it makes sense to me that we understand what the drivers are which is a tough research question. Again if you know what you're looking for it's relatively easy to detect if the pathogen of interest is in your sample. If it's physically in the blood or tissue or whatever that you're looking at but if you don't know what you're looking for that's harder mechanistically methodologically so that's a lot of what we're we've been trying to develop. I mean that's really interesting when you point to covid being a known quantity in terms of what has driven the post-viral consequence. You could say that we have various things that we believe have contributed to ME in that way. If you just consider EBV or other of the happy's viruses and I think there are other quite prevalent post-viral illnesses perhaps they posted Ebola that have a similar similar first one. But again Ebola is one that you could say yes but those people knew that they had a Ebola. That's what separates it. That's what separates long covid that's what separates post-vailer and there are a lot of people who have said well perhaps all of us with long covid have got ME and I think this is an interesting point it's almost if those people who you're able to identify the pathogen are at an advantage because you have a route to potentially alleviating it. Are there currently tests that are done to establish you mentioned before some of the things that rule people out of having ME because you find something that you're able to rule out? Are there some primary things that we could look at finding and potentially addressing in ME or is the problem that we can't then remove some of those things from the system? Yes I think there are some things that the again Bartonella, Babesia, in some people, Orrelia. Those are bacterial infections that people ought to test for and if they have that that is addressable it doesn't make it easy. Some of those pathogens Bartonella for example, especially if it's going years and years without knowing if you get an acute Bartonella or for that matter acute, Orrelia line, let's say that you see a tick, you go to the doctor, you get treatment right away. The outcome for that is pretty good, it is treatable. But the issue happens when someone let's say and I know that the tick-borne stuff is a big controversial area but if someone for example had a little nymph tick that was at their hairline they never even saw it, they feel sick, they feel nauseous, they don't feel good for months and months, they get kicked around. So now two, three, four years have passed without testing, they finally get a test. Now it's probably a little bit harder to address, it's gone into tissues, right? There's definitely advantage of knowing what you're addressing. So Babesia is something that I mentioned that that's actually technically a parasite, more like malaria, that can affect red blood cells. I have seen examples of people that had the ME diagnosis and got testing and figured out they had Babesia, got it addressed and are doing reasonably well, that certainly is one of the things that was really driving it for them. And if they didn't have that testing they could just go years and years without knowing and maybe even unfortunately thinking they have this nebulous thing called ME that is driving their symptoms. But I guess that also invokes the question that has been raised quite a lot with lung cavid, has the cavid virus reactivated a latent virus in the system and I have often wondered about that and then you're potentially with ME looking at two different crossover points because I've often wondered, did I get lung cavid because I had malaria when I was 18? Are there things in the system that have set you up to then have another knock on your immune system that your body can't cope with? And once you start looking at those crossovers of it, it's so hard to untangle because you've got so many possibilities. Definitely. That's why I use the unpeeling the onion analogy because, when the germ theory of disease was finally being established and accepted in around Freud's time, actually 1880s, 1890s somewhere on there, they're emerged coaxed postulates, which at the time, I think, was really helpful in clarifying the way that pathogens relate to disease, where if you have the pathogen, you have the disease. If you have the disease, you have the pathogen. If you give someone the pathogen, they're going to get the disease. The truth is that it's just more complicated than that. It doesn't really work like that. In some cases, it is sort of straight one-on-one, but you're completely right that most of us, 95% plus have multiple herpes strains. But let me just take a single example, which is multiple sclerosis. So it's pretty clear now that Epstein-Barr virus can drive multiple sclerosis. 90% of humans have the Epstein-Barr virus. It is not the case that 90% of people have multiple sclerosis. So what's the distinction there? Well, part of it is location, part of it may be other risk factors where it gets. A big thing for me is having something, it matters where that is, is it in the central nervous system, is it not? So coaxed postulates is really sort of oversimplified, I think at this point. And with these chronic illness patients, it absolutely is the case that there's probably a multiple interacting factors. Some of them, pathogenic, some of them may be a history of injury, some genetic, it could even be like exposure to pollution or diet, things like that. So with any given patient, there really ought to be careful investigative work. So with COVID, the truth is that the large majority of people with COVID would report that they feel fully recovered or largely recovered. So there probably is some risk factor that is in some people that make them not fully recovered. Some of that in the sex with dumb luck of where did it go, how severe was it initially. But let's say that someone has something like malaria, which can persist or aren't nela babesia and they're handling it relatively well. And then COVID hits. Now they're not handling those other things as well. And they can start to cause a bigger problem. So I would never say that SARS-CoV-2 is like HIV. There's lots of differences. But I think intuitively people understand with HIV that one of the things that viruses do is to sabotage or evade host immunity for their own benefit. And then other pathogens take advantage of that. And that's what ends up when people get really sick with AIDS. They end up succumbing to a fungal infection that you or I fight every day and when we're suppressing it just fine. So with the SARS-CoV-2 virus as an example, there are several protein products of the SARS-CoV-2 virus that affect interferon singling. So that's a form of cytokine that is kind of the main antiviral cytokine. It doesn't directly kill viruses but it triggers the antiviral cascade. Interferons on an ongoing basis suppress herpes virus that again 95% of us have and keep them in latency. So most of the time most of us are keeping our herpes viruses in latency. But when something else comes along and sabotages for its own benefit, interferon singling, that's a moment for the herpes viruses to pop back up. Herpes actually means creep in Greeks. They creep around in your nerves and when they have a moment to pop back up because the interferon signaling that normally suppresses them is suppressed, they do. And so people with acute COVID or long COVID might have shingles suddenly. And this is a virus that they caught when they were five when they had chickenpox. And suddenly it's got to dance to a mirror. So we think that in a lot of cases people with the ME diagnosis have something like that going on where there may be one or two apex pathogens that are really affecting the ability for the other pathogens to have their effect and just run people down, activate their immune cells, their neutrophils, which when they're activated are quite energetically demanding. They switch into a metabolic state called warburg that is faster but inefficient. So they're burning a huge amount of energy just in their bloodstream on an ongoing basis. So yes, we think that it's often interacting issues that may be driving it and doing a really careful investigative work would be my dream for a given patient. What is happening in that person? Yeah, a very specific one. The autoimmune process, some of that is you just mentioned MS. So driving into autoimmune via a pathogen like that. What about the idea of a genetic autoimmunity that someone has always had? Is that a theory behind an initial hit that in terms of a bacterial or viral infection that drives ME as well? It could be. When we talk about autoimmunity, I tend to give a little pushback on that term where I think that it's something that is kind of current to our to a lot of the current model in medicine that is driven in a for-profit system by what big pharmaceutical companies can do, which is to suppress the immune system. We know how to do that pretty well. So you can suppress the immune system and because feeling sick is part of the immune response, you will make people feel better temporarily. I think most of the time what's called autoimmunity, it truly is the case that the immune system can cause collateral damage and that sort of thing. But it's driven often by factors, for example, molecular mimicry. So when I talked about that multiple sclerosis example, for years, the go-to treatment was just pure immunosuppression. In some cases, you can force stall symptoms, make people feel a little bit better, but basically, it doesn't really work. It doesn't really get people better. And it turns out when more careful molecular work has happened in the last couple of years, that there is a protein, Ebno1, on the surface of the Epstein-Barr virus that has very similar, essentially, size and shape to a glial surface protein. And so there's cross-reactivity, that's what they call molecular mimicry. There are only so many sizes and shapes that can be on the surface of a cell. And if there's a similar overlap, then an antibody that's meant to address a pathogen will cross-react and address something that's self. So it just thought it was the wrong path in coming in? Exactly. And this is, it seems to be the case in multiple disease states. So for example, there's a neuropsychiatric condition in kids where they have a streptococcal infection that can drive neuropsych symptoms. At least in some of the kids, there's a cross-reaction with the dopamine tour receptor and the antibodies that seem to be intended for the strep. Again, it's not coaxed postulate, it's not, it always is this, it's always this. But that sort of phenomenon that that seems to be to my mind in lots of different conditions that are currently considered auto and year. And to your question about genetics, there does seem to be a genetic component to a lot of these conditions. So we talked about multiple sclerosis, lupus, rheumatoid arthritis. Interestingly, all more prevalent in women as well. Probably part of the reason that they're understudied and psychologized just to get a little talking point in there. But interestingly, the way that viruses work is that they connect to the human cells, DNA, hijack it and drive the cell to do what it needs, which is replication of itself. The transcription site of the Epstein-Barr virus is on risk low-sci for those conditions that I just mentioned. So multiple sclerosis, rheumatoid arthritis, lupus. So there's a risk gene or risk low-sci technically that does seem to confer some inborn risk. But that is exactly where the Epstein-Barr virus latches on. So there may be some kind of an interaction between genetics and the environment that is really a little bit underconsidered. And from my mind, we just simply haven't really considered the role of pathogens. Again, possibly because people assume that if 95% of humans have these pathogens, they can't really be a big deal, where I think maybe that is quite true all for time. Again, it's looking at these crossover points. So in terms of your pathogens, your genetics, your other pathogens, but there is so much variety that it is almost impossible to study in a kind of cohesive way. It's not easy, yeah. If ME is from the work that you've done and inflammation in the central nervous system, does that mean that all of the symptoms sets are actually neurologically driven in ME and possibly in long-havid? So things that people think, oh no, that's not my nervous system. I've got heart pathetitions. No, that can very easily be driven by your nervous system. Do all of the symptoms come from a neurological base? I mean, you're probably asking the wrong person because as a neuroscientist, of course, I think that everything, you know, the body is basically just the way that the brain walks around and feeds itself. So I'm very neurosentric. So yes, there is an enormous crosstalk. And to be less glib, I think when science approaches complex questions, biology, we almost have to split things up. You have to split up the digestive system from the endocrine system, from the nervous system, from the circulatory system in order to study it. But the tool is that those are human-made false divisions. Doesn't really work like that. That's why you can make a whole career at those intersections of the false divisions. Neuroimmunology. You will say starting in your endocrinology lab. Is that not true? Exactly. I began in neuroendocrinology, which of course, and even endocrine and immune are false splits. And there's a reason if you have a rash on your arm, you essentially wipe it down with a stress hormone, right? And that is an, you know, suppressive and it drops the immune response. So those systems are intimately interlinked. Nature doesn't think that they're separate. So yeah, the the nervous system to my mind is really the central regulator. I recognize that I have my own bias there, but I think that that a good argument could be made that that really is. If you have something like tackycardia, we know the nuclei in the brain stem that ought to address a postural adjustments, there ought to be a symphony of vascular effects when someone goes from lying down to standing up. If that's not happening, it could be happening out there. at the level of vasculature in the feet, on a percent, and it could be happening in the brain, and it's not even mutually exclusive at its water, the other. You are an assistant professor, rather than necessarily being a patient-facing doctor. However, you have taken on a huge responsibility in terms of patient advocacy and patient education in the creation of PolyBio. Can you tell me a little about your most recent work with PolyBio, and for those people that don't know, your co-founder there is Amy Pral, who I have spoken to previously, but she came at it from the perspective of someone who has the lived experience of chronic condition. Yeah, yeah. So, PolyBio, there's definitely a lot going on. We definitely, again, are trying to kind of take advantage of this moment with COVID in the least cynical way possible to establish some testing and research programs that the goal from the start is whenever it's appropriate to move in ME diagnosed patients, post-treatment line diagnosed patients, into the pipelines that we have established. Huge part of what we do, what part of Amy's brilliance is that she's very outgoing and a good networker, and she's able somehow to just call some of the top researchers in the world and get them all. I love it when I look at your website. I don't know how she begs. All the people who are at the top of the game are involved with you. It's absolutely fantastic. She did it to me not to put myself in that same realm, but that's how we connected as well. She's somehow able to just call people and get them on the phone and talk, and then she clearly knows a lot about the topics and shows people that she's a serious scientist, and gets them interested, talks to them about the human problem. Essentially, what we tried to do with Polybio was to establish a really good research community of people that are open-minded, thoughtful, have access to top methods, prioritize careful research above publication number, things like that. The goal is because we were able to get some money from COVID, from some generous donors, in some cases, at least in the old large. The goal very explicitly is to establish research pipelines that will then be used for MECFS. Some of it is developing things, so we can't do it immediately. I completely understand the impatience and frustration of people that have been sick for a long time, but we're trying to build something that hasn't really been built before to be totally frank. But you are also making leaps and bounds that people within the MECFS community have not seen for a long time in terms of just that speed with which we've moved because of the impetus of COVID. I hope so. It's never fast enough. It's never enough. It's never clarifying enough. But the goal is to, for example, small fiber neuropathy is something that can be really debilitating. It's in a subset of people with the ME diagnosis that's a large subset of people with fibromyalgia diagnosis, where there's some kind of a reduction in the density of no-septive C-fibers way out at the the level of skin at the border of the dermis and the epidermis. So we are establishing a pipeline, actually, have a sample here. In this is a tiny piece of skin that we took from someone that it's only here because I'm going to mail it right after this call, that we took from someone on Monday that has small fiber neuropathy and we're establishing a pipeline to really carefully investigate. What is happening there so far, most of what that has been has been the diagnosis. Yes, they show this problem in the nerves, no, they don't. But there's been a relatively limited amount of what's happening. Why is that? And so that's one of the pipelines that we're establishing. And again, we use the moment of long COVID, some available funding to establish that. And now we can move it onto people that have had that problem since they had Lyme or since they had the ME diagnosis or supernipidase. So that's kind of the goal. Can you tell me what you are outside of Polybio? What are you seeing out there in terms of research that is most exciting to you or the you feel might really make a difference in this space? It might be difficult because so many of the so many of the researchers are actually involved in Polybio. The reason we brought them in is because we thought they were doing top work. So at a really macro level, I think that some of the most exciting stuff is with next generation sequencing approaches to genetics, where this isn't, it's not brand new. It's maybe nine years older or so at this time, but just for perspective, when the first human genome, which was J Craig Ventures genome, was sequenced, we worked very intimately with the J Craig Ventures to the first human genome was sequenced between 1990 and 2003. So it took 13 years. It took several billion dollars. Within the last two years, they just set the record and I think they were able to do a full human genome sequencing in like five hours. What first took 13 years? So one of the things that we can do now, and that's the human genome. So you can also get the entire, all of the genetic material from a given sample, whether that's blood, cerebral spinal fluid, tissue, tears, whatever it is. And normally what researchers have done is to throw away everything that's not human to focus on the human genome. But what we're trying to do, what our collaborators are doing is to not throw that out, to take a look at what is not human in the sample, and then you can compare to libraries in which they've done a full sequencing of lots and lots of viruses, archaea, fungi, bacteria, phage, etc. And you can run your sample against those libraries and figure out everything that's in your sample. So this is what I mentioned before of looking for something when you don't know what you're looking for. So we're getting a lot better at that. And that's a huge part of what we're trying to push. And that's because of technological advancements in terms of being able to actually run it through the computer rather than. The sequencing isn't just happening kind of linearly now. It can happen in a massively parallel way. And that can include the non-human, what we call non-human reads. It just is a simple example when when someone has persistent UTI, they tend to use culture-based approaches, which are already optimized for E. coli. And so what do they find over and over again? E. coli because they're using a medium that is optimized to detect E. coli. To confirm confirmation bias. Exactly. Which is understandable. I mean, it's not like it's wrong. But it's more complex than that again, back to Cokespossilant. It's not one thing, one disease, one disease, one thing. So now if you can take that sample and do next generation sequencing and run it against libraries, somewhat biased libraries where you know a series of pathogens that might be driving this, you can say, okay, in this patient, it looks like there's an interaction between these six pathogens, one of which is only there at a 1% level. But that's a really important pathogen that can drive the behavior of other pathogens. So if you can start to really address and figure out, okay, in this person, yes, E. coli is there, like it is in most UTIs. But then there's these other five or so pathogens that are interacting. You can really start to address thoughtfully and in a targeted way. So that's kind of the dream that we can do that in other samples. Again, tissue is to me kind of the holy grail pathogens. If they're floating around in your blood, you're quite sick. But a lot of times they don't. It's not a smart place for pathogens to be. And yet most of our testing comes from a milliliter of blood taken from the left forearm, right? Yeah. They may not be there. But if we can start to get into tissues and do somewhat non-invasive biopsies and look for things when we don't already know what we're looking for, again, we're developing these techniques with the knowledge of SARS-CoV-2 being our target. But the idea is to expand to these less biased or unbiased techniques. That's the holy grail of testing that we're hoping to pull together. That is really exciting. I hope so. We'll see. And we will have to see what happens. But I just think that it is hopeful that we have teams of people like you who are that invested in that unbiased research. Because obviously everyone's research has a certain amount of bias. But at least being aware of that and trying to open it up to say what are we not seeing yet? What have we not yet identified? Is it exciting? Yeah. I hope so. We're hoping that this really can be transformed it for some people. If you can really figure out what is driving it in this particular patient. If you're not familiar with the work of the Polybio Research Foundation, do take a moment to go and look them up. They're linked in the podcast app information. On their website, you will find a who's who of scientists, doctors and researchers operating in the space of post infectious and complex illness. And they have some fabulous resources. The generosity and humility with which people like Mike Bantel's Acro operate never fails to stop me in my tracks. The work that people like him and the team of Polybio are putting into developing understanding is astounding. And his final point is something from which I think we can all learn it highlighted the complexity of these conditions and the interactions of potential pathogens for which we don't even know that we're looking. I'm really looking forward to seeing the work that comes out of this space because I think that it's by approaching things with that open mind with the idea that we don't necessarily know what we're searching for that we might be able to gain greater understanding at large. Thank you for listening to Make Visible. Please do like, follow or subscribe to listen to our next episode where we'll be uncovering more insights into complex chronic illness. This was brought to you by the team at Visible, a group of scientists and engineers whose lives have been affected by energy limiting health conditions. We're building wearable technology that's helping a hundred thousand people measure and manage their complex chronic illness. To find out more about what we're working on and how visible could help you visit our website at MakeVisible.com.