An Interview with Jonas Bergquist, MD, PhD, and Alain Moreau, PhD Transcript

Dr. Danielle Meadows: Alright. Hi everyone, and thanks so much for listening today. I am Dr. Danielle Meadows, OMF’s VP of Research Programs and Operations, and I’m joined today by Dr. Jonas Bergquist, the Director of our Collaborative Center at Uppsala and Dr. Alain Moreau, the Director of our Collaborative Center at Montreal.

And in this series of interviews, I’m talking to our directors in pairs to kind of push beyond talking about individual projects to where we can try to start to draw some connections between different areas of research and start to get at the big picture. So I want to start maybe first with you, Jonas. You’re bringing, you know, this expertise in neuroinflammation and your clinical perspective as well.

So can you give us your kind of brief explanation of your hypothesis of ME/CFS?

Dr. Jonas Bergquist: Yeah. Hi Danielle, nice to be with you today, and hi Alain also, good to talk to you also. So, as, well, we are all biased by our backgrounds I think, so of course, my perspective has been and will be for the future also mostly evolving around the nervous system and the brain and the neurocognitive dysfunction. And of course, what we are trying to penetrate when we do our studies on ME and Long COVID and other post-viral infection conditions that we are studying in the central nervous system, we are of course trying to find out what is decent explanation for why suddenly someone gets affected by an infection that is rather common that most of us has been exposed to, but a few persons every time, that are exposed, get this, get this long-term consequences, right?

My focus has been, as you mentioned, neuroinflammation, so when our immune system starts to be overactivated. And when that happens in the central nervous system, that also leads to severe issues and problems since the central nervous system and the peripheral nervous system, to some extent, is supposed to be a privileged site, as we say, where you don’t expect to have dramatic inflammation and immune activity going on.

But when that happens, it apparently gives these conditions where you have degradation of cellular function, and you also have loss of energy and possibility to restore energy, and you also have the almost like autoimmune reaction and it also connects very much to autoimmune diseases, the signals we see.

So that is my general hypothesis on what we are looking at from my perspective

Dr. Danielle Meadows: Awesome, thanks Jonas. And so, Alain, I’ll turn it to you then, so you had kind of have this insight into epigenetics and approaching things from a precision medicine angle too. So, can you give your kind of brief overview of your hypothesis?

Dr. Alain Moreau: Yes, thank you Danielle, and hello Jonas. As you mentioned, Jonas, we are always coming from some kind of background. Okay, we are well established investigators, so my field of expertise is the development of biomarker and their validation in complex diseases. So previously working on idiopathic scoliosis and other musculoskeletal diseases.

So, there’s a natural connection, I would say with what I’m doing since 2015, in the field of ME/CFS, and more recently in Long COVID, and my field of this expertise is molecular genetics of those complex diseases, and I realized rapidly that even though that there are some kind of genetic predispositions, the main player is certainly the epigenome.

So, what is happening around our genes? So, there are many ways to affect the gene without creating a mutation. And that’s why we pay more attention, and due to the well-known interaction between viral infection and what is happening during the post-viral situation where some people will recover perfectly rapidly, this is the majority of us, I would say, but there are some circumstances that some people will develop persistent symptoms and sometime new symptoms.

And this is where we are engaging in the wrong path, if I may say, and that’s where epigenetics may be a more important player here. And this is also maybe the future of molecular medicine. So microRNA, DNA methylation change, even histone modifications are not novel, they are well known, and often associated with those very severe chronic diseases, and we need to figure out the best way to understand and how can we modify and change those aspects by using different omic approaches to understand and my difference may be is that I try to have the larger toolbox possible to put all the omics, not just proteomic or metabolomics, and when I don’t know enough, I work with colleagues like Jonas, and that’s why we developed, I think with quite success, DOMINO-ME project, and that allowed us to compete and get a major funding for the Patient Led Research Incentive for the Long COVID.

So, that’s why it’s important that we work together and combine our different expertise to develop a new approaches, but also more importantly, new solutions.

Dr. Danielle Meadows: Awesome, thank you. So I want to start to move into this kind of drawing connections section here and you know, well for the time being, for conversation sake, say, let’s imagine a world where both of you are correct, all of our hypotheses are correct, and we want to try to figure out how they fit together and how our research findings fit together.

So maybe I’ll throw out something to start us off, and then, you know, can comment and evolve the conversation from there. But I want to start, Alain, maybe with a pretty specific molecule that you’ve actually published on pretty recently which is SMPDL3B and so my understanding is that this is a molecule that’s, you know, involved with a lot of things, sphingolipid metabolism being one of them, and toll-like receptor (TLR) signaling being another.

And I want to use that to draw connections to neuroinflammation and some of the work that Jonas does, maybe by saying that, you know, you’re seeing that  SMPDL3B is cleaved from the cell membrane and there are higher levels in the plasma. Right? And so this then can lead to, you know, more fluid membranes, cell membranes, which can be inciting of inflammation at that point.

And then also dysregulation of the TLR signaling can lead to further inflammation signals. And so I’m just, I’m curious if we can start the conversation there and maybe if either one of you want to comment on, you know, drawing those connections to from the SMPDL3B to some of the neuroinflammation and the signals that Jonas, you’ve seen and in your MRIs, et cetera.

Dr. Alain Moreau: So I’ll start there. Okay. So, first, I would like to correct, so I’m not here as an investigator to be right or wrong. Okay, I’m here to figure out the truth. Okay, and again time will let us know that whether or not that, what exactly is the truth? So the truth in 2015 or 2025 or 2035, maybe they’re a bit different because the knowledge changes.

We have better methodologies and methods and, in general, that allowed us, but we discovered, I would say accidentally SMPDL3B by studying identical twin, but this called them for the disease. And, we find that in some male twins that were, especially the one affected, there was a very severe insulation in the promoter of SMPDL3B, suggesting that that molecule will be turned off.

And this is what we saw also in many men suffering of ME that they are producing very low level of SMPDL3B. So, I started to learn about what was SMPDL3B at that time, no clue was very first time that I heard about that molecule. And, and this is where I did the connection with Bob Naviaux own discovery about the importance to the lipid metabolism and the conversion of sphingomyelin and ceramide.

And it appears that that molecule is doing that. So I say, oh, whoa, there is something that I can connect, that start to make a first step to explain other observation by others. And also, as you mentioned, this is a molecule that is well known to inhibit TLR4. So if you remove the membrane anchored SMPDL3B okay, you release the break of TLR4 and TLR4 start to be more activated, release a cytokine storm, and in the lab we are activating that by adding sugar LPS polysaccharide, that mimic the bacteria membrane. And this is also a connection with the gut dysbiosis that is happening also.

So we have a connection with immunity, we a connection with gut dysbiosis that is happening in some patients. And the beauty of SMPDL3B, and now this is, I think what is connecting me and Jonas also is because this molecule, yes, is present in immune cells, is present in muscle cells and is associated with some form of myositis, so we suspect that having aberrant SMPDL3B level in muscles, that will create some, a lot of trouble, but also in the brain.

So that’s why this molecule is particularly important. And also, of course, the molecule is well known for its role in kidney and particularly in podocyte, which are a specialized form of cells that is playing a big role in the glomerular or kidney filtration. And we just got today a paper that’s been accepted showcasing that there are some kidney abnormality in term of functionality in ME patient due to SMPDL3B.

So I think we are in the process to connect the dots here. I’m not saying SMPDL3B is explaining all the symptoms of the people suffering of ME/CFS, but more importantly, we find drugs that we can repurpose to target the enzyme responsible of the release of SMPDL3B from the membrane.

And this is where I think there’s a lot of hopes that we can work with something very specific, at least more specific. And we recently, those are unpublished results, but we were able to fine tune some combination that will allow to use the actual dosing of those drugs to be maybe more potent and efficient and that regular physician can use to initiate some treatment on their own patient.

And eventually the next step will go through clinical trial to really challenge and validate whether or not SMPDL3B is important. I would like to add also, why this study is important because we have a strong independent cohort to replicate the results. So from our colleagues from Norway, again, without OMF, it would be impossible to connect with those colleagues and, and to allow their replication. And I think we are at a stage that making a discovery is one thing, but I think it must be mandatory to replicate in the first paper, if you can, to really establish that this is something that is worth to follow, as opposed to, oh, it’s another molecule. Yeah. But how we can move forward. So replication is the key here.

Dr. Danielle Meadows: Jonas, anything you want to add to that?

Dr. Jonas Bergquist: Yeah, absolutely. I just want to say that I fully agree with you, Alain, and I think the complementary nature of what we are looking at from our different angles actually fits very well together, because I mean, what you said, this dysfunctional regulation of sphingomyelin, for instance, ceramide, it fits very well with what we see on the neuroinflammatory pathways that we are studying in low grade inflammation in the center nervous system.

Our findings in cerebrospinal fluid, for instance, or even now in the periphery where we see markers for low grade inflammation in the patients. So I think that fits the story very well and I mean, as Alain you also pointed out, we are mostly doing focus on proteomics, metabolomics, so the downstream products of what’s happening on the gene side, but even now recently added on some transcriptomic data, which also connects your genomic findings initially to the transcriptome and then the downstream proteome and metabolome.

And it makes sense because since we are studying such a complex nature of change that happened to our patients, I think it’s extremely important to be open for looking at the different fields of the molecular features and then trying to find the big picture and then also target, reasonable drug targets for, for treatment and the treatment trials that will be coming up. So, I think definitely a combination of things and complimentary insight into what is the cause of the issue we have in our patients.

Dr. Danielle Meadows: Thank you both. Yeah. I want to, you know, maybe play off of the genetic side of things for a second too, because, I know Alain, you’ve seen some difference in the haptoglobin genotype, in terms of severity of symptoms in some cases.

And I think there is an interesting connection to some of the work Jonas does because haptoglobin can actually modulate microglia, which is something that Jonas you look at very specifically in your MRI and PET scans. Is that right? Can you comment a little bit on the microglia activity component?

Dr. Jonas Bergquist: Yes, absolutely. I mean, we know that as I mentioned before, the central nervous system is supposed to be rather quiet when it comes to immune activation in the normal state. But when things happen, when we have an insult to the brain, when we have a trauma, when we have an infection that passes the blood brain barrier and start to activate things in the central nervous system, we get this activation of the microglia cells that are in their sleeping state, so to say. There are supportive cells as other glia cells are, but when they’re activated, they start to transform into cells that actually can migrate around in the central nervous system and work as an active immune cell, producing pro-inflammatory cytokines, also send out signals to attract peripheral immune cells, passing the blood brain barrier and entering the central nervous system and starting its action.

And when it comes to that kind of activation, haptoglobin is definitely, as you mentioned, one player of great importance, and the paper we published recently together with Alain is really pointing out that ME patients have considerable, yeah, interesting version of a haptoglobin in presence, also playing to Long COVID patients, cohorts, I would say.

And also that, these activation patterns that we find for microglia could well be a target for treatment also. So that we could potentially go in with selected treatment to try to silence the overactivation of the microglia.

And that which in this, this case now leads to malfunctional immune system activation and a problem with long-term consequences. So what we are studying right now is to see if we can also from noninvasive technologies monitor the microglia activation with imaging. And we are setting up a specific algorithm that is targeting microglia activation with MRI, which is a very non-invasive measurement of the brain activity, so to say.

And we target specifically microglia with, with a specific measurement and in combination with a more traditional and a bit invasive, but still not so difficult treatment with, or not so difficult evaluation with PET imaging. The positron emission tomography where you have a ligand that binds to a certain surface target on microglia, you can then follow that inflammatory reaction with a ligand.

So this is what we really hope for, and in the end of the day, we hope that we can do this examination only with the MRI scan because that would also allow for a more broad use of MRI scans all over the world, and it will be easy, accessible for large population of patients. So that’s what we are targeting right now.

Dr. Danielle Meadows: Yeah, and I would imagine there would be some really interesting complimentary information, like with the scans that you get. And then looking at, for example, the haptoglobin levels, or even the FGF-21 levels, I think can also modulate microglia. And you’ve looked a lot at that, Alain. So anything you want to add to that, Alain?

Dr. Alain Moreau: I would like to add for the haptoglobin. Discovery is that first it’s a genetic paper. So, we have only two allele, the one or the two, and when they are combining, there are what they call the phenotypic variant. So this, you cannot extract that just by looking at the genome.

There’s no way that you can see those phenotypic or what we call proteoform, which is a complex word to see that the assembly of the protein itself by combining alpha chain and beta chain differently will bring a new behavior for the molecule. So, for instance, the haptoglobin 2-2 is very, very less efficient to detoxify and remove hemoglobin.

And by the way, in this paper we use what we call near-infrared spectroscopy measuring hemoglobin in the brain. So again, we are very connecting with the center of interest of Jonas, and we saw that there’s more hemoglobin in the brain blood. And because in the individual having the haptoglobin 2-2 they have less capacity to detoxify.

And, and surprisingly we saw that the worst situation, which also impaired the cognitive function is the 2-1. Intuitively, you should expect that 2-1 should be a bit better than 2-2, but was not the case because by investigating why 2-1 is even worse than 2-2 is because there is a second player called soluble LRP 1, which is also part of another molecule, hemopexine that is like a.

Your plan B to detoxify your hemoglobin when haptoglobin is too busy or not at the level that it should. And LRP-1 must be anchoring the membrane. And of course, in that case there is more soluble. So we have less the right one doing the job. So that explain why individual with ME/CFS, having the haptoglobin phenotype 2-1 have the worst cognitive function, more severe PEM also, which makes sense.

And, and again, this study is also well connected with Ron Davis study about the red blood cells abnormalities, affecting the membrane, which will be part of a process that will lead to more hemolysis and more release of these hemoglobin. Hemoglobin outside the cells are very toxic.

So, on the short run, we could probably propose to do some intravenous infusion of recombinant haptoglobin 1-1 to reduce the intensity of PEM on the very severely affected individual. I don’t think that will become a solution for everyone suffering of ME/CFS.

First of all, there are few, I think 1-1 and they’re doing much better than those, having the 2-1 or 2-2 form. And we need also to understand that, even though that looks very simple, say, oh, you are 1-1, 2-1 or 2-2, but the proteoform, the variant forming the different protein there assemblies, it is different between ME and healthy people that, being 2-1 or 2-2 , and we don’t know why.

So, so there is something also inside the body, inside the cells that is contributing to altering. So probably maybe some post rational modifications that can add some, some additional. In that case, we suspect it’s not glycosylation, but it’s something else. So, so again, if we understand that we might have a more precise solution for the individual.

And, and as you mentioned also FGF 21. It is also, important molecule that is not, I don’t think it’s a causal factor, but it’s a certainly what we call a disease modifying factor. And again, depending your background, if you’re suffering of ME or ME plus FM or having only fibromyalgia FM, being low or high will modify your disease.

And, and the solution that we can propose to normalize your FGF 21 will be different. And again, we are, we need to stick with precision medicine for this complex disease. There is no way that we can, we can find the magic bullet to everyone. I don’t think that will be possible because clinically speaking or molecularly speaking, we can separate patients.

There’s a good reason for that. And, and rest assured is not to make sure people. We don’t, we don’t want to make sure that anyone will be between two chair. We are taking care of everyone, but because we are sensitive to their safety and we want to propose a virtually the most efficient way to treat them, we need to integrate precision medicine.

Dr. Danielle Meadows: Absolutely. I think that that’s it. That’s a great thing to wrap us up on is, you know, the emphasis on working toward precision medicine to try to get everyone better as quickly and as best as we can. So thank you both so much for taking the time to talk to me today. I think we got some really good discussion on how both of your work is fitting in with each other and with, you know, other research going on in the field.

And I will leave it there. Thank you. Thank you, Danielle. Thank you, Danielle. Thank you, Alain.