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The Good Question Podcast
Detecting Chronic Fatigue Epigenetic Biomarkers & Breakthrough Blood Testing
00:35:00
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- [00:01]
A
You're listening to the Good Question podcast with Richard Jacobs. Our goal is to make each of our guests exclaim, hmm, that's a good question. I don't know the answer. Because when that happens, it means you, the listener, may be inspired to learn more beyond the interview and to ask great questions yourself that lead to new insights. In this podcast, we cover historical and current anthropology, comparative religion and history. Welcome. And let's get started.
- [00:36]
B
Hello, this is Richard Jacobs with the Food Question podcast. I have two guests today, Alexandre and Dimitri. We're probably going to stay on a first name basis because their last names I would probably laughably pronounce them. But what we're going to talk about today is these two scientists have helped develop a revolutionary blood test for chronic fatigue syndrome. And from what I understand about chronic fatigue, it takes a long time to diagnose. It's just like this nebulous condition that affects so many people that no one seems to have a handle on until now. So I think this will be really great material. Just quick bio. Alexandre is a chief science officer at Oxford Biodynamics. Dmitri is a professional research fellow at Norwich Medical School. So welcome both of you.
- [01:15]
C
Thank you.
- [01:16]
B
Thank you. Well, if you guys would tell me a bit about your backgrounds, you know, briefly, and how you got involved in chronic fatigue syndrome.
- [01:22]
D
I'm molecular biologist by training. I'd actually spent some time in United States, Robert Wood Johnson Medical School, started the lab up in Oxford, Sir William Dunn School of Pathology. And we started looking at very fundamental biology, but realized it has very important implications to clinical diagnostics. In simple terms, looking at things at molecular level allowed us to tell things more accurately about outcomes in all things clinical diagnosis, prognosis, all the other things. All of that is in the space which is quite popular lately, epigenetics and functional genetics. We can talk about it later. But at some point we realized there is a great value in bringing that into clinical practice. So company was spun out of Oxford University. I stepped in as chief scientific officer as one of co founders, and we started building the technology on a biomarker modality, which is. Which was very new in those days. And that is proving itself, first of all, one of the most insightful biologically understanding in terms of insulin disease, coping very well with complex diseases. That's the story of chronic syndrome, really. And giving us actually very actionable tools as a company. We are a public company today. Oxford Biodynamics has several tests, one of which was developed together with Norwich Medical School with mitri, which very accurately looks early in the prostate cancer evidence does it on blood and shows 90 of 94, 95% accuracy. And it's today already practiced in United States and in private health sectors in uk. The other test gives another very important answers, which is usually a very challenging for any clinical diagnostic test. It tells who is likely to respond to immunotherapies, famous keytrude and other checkpoint inhibitors with high accuracy 85%. If you look what's happening now in this field, there are several approved things around tumor burden around and sort of immunohistochemistry staining on biopsies, PD L1 sort of tests, but they are very low accuracy 40% and even less so. In, in a nutshell, we build a platform which was quite mature by the time we started with chronic fatigue syndrome, which proven that we can build a very reliable high accuracy clinical test. And in the process we looked not only in oncology, we of course looked in many inflammatory conditions, autoimmune conditions, which usually very complex by multiple manifestations from molecular level to clinical level. And yet they're very different, respond different to treatments. So worked with rheumatoid arthritis, psoriatic arthritis, neuroinflammation, things that actually happen. For example, one of our signatures was used in Mitsubishi trial for a drug approved in the United States for motoneuronal disease, amyotropic lateral sclerosis, Radicava. It's neuroinflammation in many ways. And so capturing systemic chemically in blood evidence of something going wrong somewhere in the body and capturing the footprint of it, however complex this condition was our bread and butter. And the high point was where Dima from his background approached us, knowing what we already done in let me say, a little bit more straightforward challenges. And the question was, can we actually build at last a diagnostic test which in a matter of days, not years, will identify and reliably capture the footprint of chronic fatigue syndrome. If so, if it's a distinct disease at molecular level and data will speak for itself. And that's what we started doing because in UK it's a high priority. But we also understand for a number of reasons, it's a high priority in the United States. And the moment we started working on it, we got great support from institutions here in uk. London School of Hygiene and Tropical Medicine one one of of leading centers with biobank and great interest from the United States and never looked back since we started looking and published the first results. Dima, all yours now.
- [05:57]
C
So I'm an academic clinician, I am a research professor at the university, working in inflammation and epigenetics. And we've been working together with Sasha for many years over various different conditions. And my clinical subspecialty is ME cfs. I lead a medical clinic for ME CFS in Royal Cornwall Hospital. And yes, as Sasha said, we had this really, really interesting technology that kind of can capture a snapshot all over the genome of your epigenetic signatures. And as a result, you can go to something really complex, which is ME cfs, and actually get a very, very meaningful result out of it, not only as a blood test, which is amazing and would be amazing for those patients, but also as the ideas for future treatments. And that would be important because at the moment, there is no proper treatment for this condition.
- [06:53]
B
So what is chronic fatigue syndrome? Is it one disease and what is it? What have you figured out so far?
- [06:59]
C
Well, it's a very difficult question in terms of. I don't think anybody really has the answer. So we know it's classified as neuroinflammatory disease. So the. And research has shown a lot of changes, neuroinflammatory changes in the brain, but it also, you know, it has been shown that there are changes in the energy production by the mitochondria and also so changes in the antibody production, changes in the T cell function. So it looks like a very multicomponent disease. And in terms of one disease or multiple conditions under one umbrella, it's still very much a debate.
- [07:34]
B
Is there an advanced form of IT versus an early form? And can you compare then what systems and cell types and all that have been affected in, you know, in an early or a late stage CFS condition? Is there such a thing?
- [07:46]
C
No, it's not advanced in terms of time, usually, the way it's kind of divers, either by the onset trigger, so what brought it on, or by severity. So it can be obviously mild, moderate and severe. But quite often the, you know, if it is severe, it quite often starts from being severe. So there is no mild phase and then moderate and then a severe one.
- [08:11]
B
So no one overall. I mean, is it, is it well studied or is it kind of ignored as, oh, it's all in people's heads? Like, what is, you know, in the scientific community, what is a CFS considered to be? Is there respect for it? Is there a lot of research into it or not?
- [08:25]
C
I think comparing to most other conditions, very, very little. So for many years, it's kind of one of those obscure conditions that nobody really knows how it works and why it works. Quite Often the people who report symptoms are disregarded because their blood tests and everything is normal. And then kind of, you know, there's nothing, they have nothing to show for it. They don't look different. They, you know, they don't have any kind of physical manifestations except that they feel extremely tired and they kind of just don't feel themselves really. And so for many years, yes, it was very obscure and kind of not treated well by the public, not treated well even by the doctors, and not studied even at the level of medical schools because there was no mechanism to show for it. So there was kind of nothing to study.
- [09:10]
B
So what are the predominant symptoms that people report?
- [09:14]
C
So basically there are four key symptoms of ME cfs, at least according to the British criteria, which we use in our clinic, which is obviously extreme fatigue. The most important one is post exertional malaise. Basically you do something and then you're just knocked out and which could last for days and you really wish you didn't do that thing, whatever brought it on. The third one is a brain fog and the fourth one is a sleep disturbance. And they have to be lasting for more than six weeks. And it is a diagnosis of exclusion. So there has to be no other reason for those symptoms.
- [09:48]
D
I might add something, it might help to sort of to capture where we are in all of this. And Dima very well described the sort of diversity and vagueness of whether it's a disease or not. And the clinical field at a loss almost how to identify or treat it. And that's why in a way, when we were brought in, we de facto were part of the attempts to look at the disease from molecular level, at various level, at the technology, through the technology that we have and try to establish some benchmarks that could last and would be reliable in distinguishing this as a disease and separating it from say long Covid or another disease. We will mention post traumatic stress disorder. And those two, for example, infection, serious chronic infection or stress are two well known triggers that could lead to chronic fatigue syndrome.
- [10:48]
B
So one quick question. If it's stress, what about people that are hypervigilant for maybe their whole lives or for a number of years? Perhaps that's a driver of it. It just, maybe it leads to just an exhaustion of a body's reserves and ability to self regulate because of, well, interesting thing.
- [11:06]
D
And that's where epigenetics comes into play. It's not only level of stress, it's how the particular body, individual body is programmed and set up, set up through previous experiences in its life or even parents to adapt to it and to deal with it. So we know people who can cope with stress very well and people who don't or go into the chronic pathological condition. And by the way, the highest prevalence of chronic fatigue syndrome is in military forces after they go into the war zones, some of them reporting up to 8% prevalence coming back. And it's not post traumatic strength disorder, that's separate thing, but it probably contributes into it. So there are very interesting things there definitely happening. But of course the field of molecular biomarkers been looking at that before and it's always turned into a kind of a noisy mess. Various different genes show various ranges of deregulation, but it never falls together. What was interesting for us is that when we looked at the level of regulation which our biomarker platforms deal with, this is in the hierarchy of all molecular things in the cell is the top of the pyramid, the factor. It's how in a living cell, the acting genome that does all the job, deals with the genetic risks, expresses genes, responds to metabolic signaling, how it actually folds itself in a functional way so that it can allow all the mach to operate in sync as a network regulation across the whole genome. And it turns out today, and that's a big paradigm shift in molecular biology, is that this is another very important heritable feature that our chromosomes and DNA carries in the cell. The way it's organized itself, will reproduce itself. When the cells divide into daughter cells, will reflect a very specific conditional arrangements, different parts of the genome coming close together in this packaging and influencing cooperating on some control of the genes. And de facto it becomes a map of epigenetic and metabolic state of the cell. And if something goes wrong, there would be specific signature of that wrong thing at the level of genome organization. And so when we look, when we build our maps of what is distinguishing statistically significantly, consistently patients with chronic fatigue syndrome in or measured in blood on de facto it's white blood cells. And we're measuring what is conditionally reset in those cel across the patient cohort. We saw that what we see deregulated if you track it to where in genometers and how the products of those genes talk to each other at protein level. It's actually a very tight, big, but very reproducible footprint. It doesn't break into little islands, it's just one cloud. And that cloud, if you start looking which pathways related to it hits multiple time, all the known sort of manifestations, which normally could be very interpreted as very diverse pathological manifestation. But you see suddenly they all together tied up in the knot. And that is not only gave for the first time, that's what we pursuing now. And that's what gives very interesting insight at last, at some molecular level we see in a very distinct footprint of the disease. Gives us more confidence that despite all the complexity, we're dealing with a particular entity in terms of molecular deregulation.
- [14:45]
B
So what is that? What is the center of the, the footprint look like at the core of it, what's being affected?
- [14:51]
D
It's actually not a centralized network. It's almost like Bitcoin system. Right. So they all together and they all pass in this deregulation controls between themselves. But it's becomes very stable. Deregulation, massive footprint within the inflammatory conditions, massive imprint in some of the other neuroinflammatory muscle death. All these things, things that one way or another manifest itself in patients. And most interestingly it does overlap with long Covid a bit and with post traumatic stress disorder a bit. And so you could see how one, when you create this pathology in a patient could actually develop into dysregulation that captures the footprint of the disease we call today chronic fatigue syndrome.
- [15:37]
B
So maybe it's a. It sounds like a pattern of epigenetic change that gets locked in. Yes, because it's persistent for so long. And that creates you know, all these, these dinosaur I guess you can call it, you know, these other problems that manifest.
- [15:51]
D
You describe it very well because the most important thing that it becomes very stable is basically like self sustaining, sustaining condition which in terms of cellular manifestation and body sort of clinical manifestations is pathological. It's not good. But how to knock it out of this pathological state? That's where you start looking what are the hubs? How potentially we can drugs that might be targeting the genes that control the hubs. So looking at it with some of the AI tools that in our technologies referred as ApiSwitch Orion AI platform, we for example identified that one of the targets is quite a well known controller of basically longevity of the cell. MTOR controls some of the key metabolic switches between growth and division in the cell.
- [16:47]
B
And.
- [16:47]
D
And it has a very famous drug which is tested in many different longevity exercises and animal models called rapamycin. And rapamycin at low dose has been demonstrated in some pilots in the United States. This is the work by Cimmeron Mayo Clinic where on particular groups of chronic fatigue syndrome patients in the pilot they had efficacy in reducing fatigue. They had a response rate about 73%. If I remember correctly. So the, there are insights and rapamycinone is one of those drug, there are a couple of others that also coming on our radar screen where we able not only to recognize if the footprint that we identify in chronic fatigue syndrome is present in individual patient, but start looking do they cluster, do they break into subgroups where we can predict that they will respond to low dose rapamycin, copaxone or rituximab? All those known drugs have been shown some of the efficacies in some subgroups of patients.
- [17:53]
B
You know what I would do to get some longitudinal data is who has been have a cohort of people that are newly diagnosed with it and have a cohort of people that were diagnosed with it 10 years ago and look at the epigenetic profile of both. Because again if that theory holds that it's epigenetic change that gets locked in, you would see more and more things happening once it's, once it's locked in, let's say over a 10 year period. Maybe that way you could, you could see, you know what's quote unquote long term CFs versus newer CFs.
- [18:22]
D
Well, longitudinal analysis always gives brilliant insights and it's a very good idea. Now how to organize that, how to look at that because as, as we discussed already, some of those settings might be already present people in, in some people without manifestation, early pre symptomatic diagnosis. And then you go through a couple of tipping points and then the full footprint comes into play. So there are lots of very fascinating stories that we see predisposition of some people to develop cond Chronic fatigue syndrome or several others. And how early you start looking for it. But you always start from extreme cases, people who never leave their home and sort of pass sort of the, the very high threshold of manifestation of chronic syndrome. And you walk back through molecular readouts trying to see where you, how early you start seeing it, how it comes into play, how all the parts of that domino fall into one hip, that trigger disease as such. A lot of these things for example demonstrate that not every long COVID patient will convert into chronic fatigue syndrome. But in UK we have certified demobile control. Correct me if I'm wrong, almost under half a million patients certified chronic fatigue syndrome patients. A lot of it being attributed to Covid epidemics that we had.
- [19:49]
C
Well in general you could see. So the whole idea about that something just you know shifts and, and the person is not themselves anymore is very of similar to how it develops clinically. People are not born with me CFS Nobody's born with me cfs, so. And they develop it not in response to their first infection or second infection or even their hundredth infection. It just happens to some people for some reason. And usually there is a very pretty abrupt onset if you kind of dig further into the history. And it is, yes, longitudinal. This is always possible. The only problem confounding the longitudinal studies is that many of the people who present for the first time to the CFS clinic already had it for years. Years. And the very fresh patients are kind of more, more a rarity because by the time they pass through the primary care and have all, everything else tested in them, it takes quite, quite a long time.
- [20:42]
B
Do you see anyone that goes into like remission from it that, that now feels better all of a sudden, or does that never happen?
- [20:48]
C
Yes, no, it does. But that's the difference between the long Covid and the CFS. Statistically speaking, long Covid has 75% remission, while CFS up to only 20. So 6% of CFS people almost complete remission, about 20% can go into partial remission, and the rest either plateau or actually worsen with time. So it's, there is definitely a very. And that's why they say the COVID sort of goes into two different ways. There is a cohort of people who go into remission and that's not like cfs. And then the cohort of people who become like cfs, although they, although it's a post Covid syndrome. But yeah, that's, that's, that's what happens clinically and for what it takes, it quite often can worsen. So there are some people, for instance, who had it for years. CFS maybe kind of, you know, on a moderate scale. They could work part time or something. Then they have covered and then it drops even further. And then they, and then they say, oh, I thought that was bad.
- [21:43]
D
And another puzzle is, of course there's quite a lot of very young patients with chronic fatigue syndrome. So we're not talking about accumulation of some hits that eventually tip the whole balance over. There are certainly cases where very prescribed, precise targets obviously involved that trigger the whole system into chronic fatigue syndrome, even in the young age.
- [22:06]
C
Yes. There are teens and twenties and definitely they did not have too much exposure to anything. They kind of had their first glandular fever and that's it.
- [22:14]
B
It seems similar to cancer in a way. You know, the wound that won't heal and the maladaptation leads to cancer and metastasis and et cetera is cfs. A degenerative condition or is it just you have it and it doesn't seem to go away?
- [22:29]
C
Well, the whole point is. Point is that all your blood tests and everything are perfectly normal. That's the, that's the, that's the hallmark of cfs. You don't have, you know, kidney damage, liver damage, your full blood count is full. Your inflammatory markers, you know, your CRP SR are perfectly normal as well. You don't have any classic autoimmunity or anything like this. And that's, that's what, what I'm saying, that they actually have nothing to show for. It's the patients, they look normal, their bloods are normal, and yet they feel totally not normal.
- [22:58]
B
Have you ever seen anyone with CFS for 20 years? Maybe it just takes a long time to manifest in a degenerative way. I don't know.
- [23:05]
C
No, people live with CFS very long time. Yes, I've seen patients who had it for, for a long time. Usually they kind of gradually worsen in terms of their symptoms, but they are. Again, they, they have repeated blood tests and they're all perfectly normal. There's nothing, there's nothing deteriorating physically in terms of something that we can point a finger on, saying, oh, you know, like the, you know, their muscle markers, their creatinine kinase is up or something. Nothing.
- [23:28]
B
We have there old people with it, or is it?
- [23:31]
C
Yes, there are. Yeah, there are some old people it, and there are people who had it for many, many years. Old people. And there are old people who just got it now after Covid or something.
- [23:40]
D
From the cases we dealt with in UK and US, there was a US case where someone, after 25 years of something being wrong, been finally confirmed to be a chronic fatigue syndrome. That's the record, at least in my experience.
- [23:55]
B
That's very mysterious, very difficult.
- [23:57]
C
Yeah, yeah. Because usually what happens, they go to their doctor, they say, I'm tired all the time, I'm sleeping, I wake up, I'm not refreshed, you know, go for a walk and then I have to sleep for five days and, you know, and what's wrong with me? And they do all the blood tests and they say, your blood tests are perfectly normal. So kind of having this false reassurance, they go back and obviously the symptoms are the same. So they keep coming to the doctors and the doctors have nothing to show for it and they've got nothing to offer. So quite often if the CFS does not come into the picture, this dialogue goes on for years. And quite often they blame mental health for it. But there is a very big difference. People with CFS usually have a lot of motivation, they just can't do things physically while people with mental health usually have problem with motivation. But if they were to put their mind to it, they actually can do it physically.
- [24:43]
B
See if that's people, are they still motivated or are they demoralized by just being tired all the time?
- [24:47]
C
They are demoralized in terms of. It's extremely frustrating because in their mind they don't feel different. In their mind they feel like they're normal 30 year old, 20 year old, 40 year old person, they don't look different and that obviously adds to it. But they just can't do things and they're extremely frustrated but they're horribly motivated to actually do stuff. They really wish they wake up one day and especially because it's so mysterious and so kind of invisible condition, they wish they wake up one day and feel normal again. And they always try. Trying is, is a really kind of a bad thing in CFS because usually it causes post exertional malaise and then you crash and so then you kind of spend in bed the next five days because you just overdone it and then from time to time they just repeat the same thing. But yeah, they're very motivated.
- [25:33]
B
So what your blood test, the test that you guys have come up with, what is it showing?
- [25:37]
D
So it looks at very specific three dimensional architect across the whole genome and looks at 200 arrangements that basically control quite a significant number of genes in terms of modulating their regulation in synchronized way. And when we look at those arrangements we see very consistent presence of those 200 markers. So there is a sort of statistical analysis classifier, looks at then picks up the measurement. But it's a very strong with the statistical power distinction between, between everything else that we looked so far and those patients with chronic fatigue syndrome. We basically know the names of those genes. But it's the game is in how the whole system is synchronized and coordinated in its deregulation. That's what brings it a little bit of everything that never shows in the blood tests by standard testing as Dima just described. And yet altogether it throws the organism in terms of physiology, metabolic thresholds and everything into clearly abnormal pathological state.
- [26:48]
B
Do animals show cfs? Any animals?
- [26:52]
C
That's a hard question. There are actually animal models of fatigue and they. Yes, they're kind of used. I don't know how much they're representative in terms of, you know, the. So basically I think scientists make, made rats swim to exhaustion and then see what changes in their, in their blood and in terms of biomarkers and you know, cytokines and things like this. But I don't think there's, it's kind of represents the exact human model, let's say like this.
- [27:20]
B
Well, that's the model. I would think a constant stress model would unfortunately wouldn't be nice, but that would, that would maybe recreate it more.
- [27:28]
C
It probably would. And there are plenty of actually patients who did not have any viral illness as a trigger for their cfs, but prolonged stress. And as Sasha said initially, it's, it's a, it's a puzzle that a lot of people can live with stress for years without any manifestation of any physical trouble. While some people develop this fatigue as a response.
- [27:49]
D
Stress as a biological feature, of course also could lead to a very different manifestation. It could be also oncological conditions, it could be things related to neurophysiology. And so in a strange way in different people, it manifests very differently. So there is certain profiles of predisposition on top of which inputs from outside and maybe some viral and genetic contributions altogether create that play around chronic fatigue syndrome.
- [28:21]
C
That's why looking at one biomarker or two biomarkers would be very kind of non productive in such situation. You actually have to look at the whole change in the whole genome because that only will give you the proper response in that regard.
- [28:34]
B
Yeah, it's like you guys just, you know, you found 2, 200 different sites I guess that are affected, but it's still a huge knot that you can't untangle yet. It's, it's. You just dipped your toe in so far at least to understand it. But there's so much more. It's crazy.
- [28:49]
D
It is. And, but I think we're learning, we're learning how to deal with complex diseases. And chronic fatigue syndrome is very important. It's almost like an icebreaker for all of us. Because if I talk not as geneticists, but as epigeneticists, I would say whatever the trigger of the disease, there always would be an extended network of deregulation that will sustain the disease and push it it into more progressive states. And so how do you work with network of deregulation? How do you recognize network of deregulation? It needs different stats, it needs biomarkers that has a very strong readout against the noise and it needs analysis. What do you target if it's a kind of a bitcoin like chain, if you want to knock it out so that.
- [29:35]
B
Have you looked at Other regulatory. So other epigenetic changes that act as regulatory changes for other sets of epigenetics. Epigenetic change after like once this one, you know, gene is methylated or then all it. It'll regulate the. The ability of a whole subset to be changed, to be regulated.
- [29:54]
D
Unfortunately a lot. First of all, classical epigenetic sort of DNA methylation histone modifications there are about 50 of historically have a very important component which is really a white noise. It's a very important sensing mechanism at molecular level. So when you look at these profile classical terms of epigenetics, stochastic noise is something that makes it very difficult to build classifiers that actually in clinical practice give you low number of false positives. There's always some noise crumb significant noise coming in. And that's because a lot of molecular events that we read like DNA methylation actually carry information in the dynamics of it turnover of methylation and we capturing a little snapshot in time. And biological organisms are driven by very dynamic processes. So that's why three dimensional organization of genome is actually at the top of pyramid. It offers a much more static conditional redout where it's a binary. Suddenly instead of chasing gene expression that sort of goes up and down and degrades halfway through. You're looking at presence or absence of interaction between two different faraway genes that come in a very particular way together under specific condition. Which means that those two genes tied up in two different pathways coordinate each other and it feeds back into two pathways. So we capturing some network regulation which is turns out to be critical level of controlling these phenotypes, these conditions like chronic fatigue syndrome. It's very interesting in terms that we get into the level of dealing with how biological systems organized in such a way that that def the earlier sort of simplified trivialized version. Let's find the one gene that is responsible for the disease. There's about four diseases, four diseases known with a sort of single genetic driver. It's always some interplay between a group of genes. And of course what is very important in our story is that we're looking at the organization of genome which is a functional feature. It's very important how the whole thing is organized. But 98% of it is non coding. And it's still very important. It's regulatory a lot of things happening there. And it's very important why one need to pay attention to how that part of the genome contributes into disease profile. Because chasing this very relatively small group of what, 20 to 24,000 genes in itself. Making proteins or sort of related controllers is a small fraction of how biological. Biological system builds phenotype of the cell, controls it and genome is active and functional in every aspect of it, including this huge non coding part.
- [32:55]
B
Well, very good. Where can people find out more about your work? Keep tabs on it?
- [32:59]
D
We will, we will.
- [33:00]
B
Oh, but where, where can people go? Should they just google your names or how can they find out more?
- [33:05]
D
We're running very actively a number of programs as a public company. We have our website oxfordbiodynamics.com which post all the official announce. So currently we of course working after we published all together in collaboration with Dima the results of first validation, proof of concept and everything. We're working on making this test commercially available through our clinical lab. When it will happen, it will be announced on the stock market. These are the rules for public company and it would be on the website. We involved in a number of collaboration and programs. Once they reach the results, it's also also would be announced. So I think one of the easiest anchors is just to monitor the news through our website, oxfordbynamics.com and we certainly will be covering all the progress on our work in this disease.
- [33:59]
B
Okay.
- [33:59]
C
And information for, for patients on, on my website, on my clinic website. You know, like a kind of more in. In lay terms and more kind of related to their illness.
- [34:09]
B
Well, very good. Alexandria and Dimitri, thank you so much for taking the time to explain it. And you know, it's very complicated but I think it, you know, more sense can make any more sense. So you know, thank you again for coming on the podcast. I appreciate it.
- [34:22]
C
Thank you so much, Richard.
- [34:23]
B
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- [34:30]
A
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