Exploring the drivers of post-infectious illness

Emily Kate Stephens (0:07): 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 VanElzakker, PhD. He is a neuroimmunologist 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 neuroimmunology 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?

Michael VanElzakker (42:50): 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 fibre 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 nociceptive C fibres way out at the level of skin at the border of the dermis and the epidermis. So we are establishing a pipeline. I actually have a sample here. 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 fibre neuropathy, and we're establishing a pipeline to really carefully investigate what is happening there. So far, most of what that 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? Why? 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 on to people that have had that problem since they had Lyme, or since they had the ME diagnosis, or something like that. So that's kind of the goal.

Emily Kate Stephens (44:07): 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 that 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.

Michael VanElzakker (44:26): 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 old or so at this time. But just for perspective, when the first human genome, which was J. Craig Venter's genome, was sequenced, we work very intimately with the J. Craig Venter Institute. The first human genome was sequenced between 1990 and 2003, so it took 13 years. 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, cerebrospinal 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.

Emily Kate Stephens (46:07): And that's because of technological advancements in terms of being able to actually run it through the computer rather than the

Michael VanElzakker (46:15): 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. Just as a simple example, when someone has persistent UTI, they tend to use culture-based approaches, which are already optimised for E. Coli. And so, what do they find over and over again? E. Coli, because they're using a medium that is optimised to detect E. Coli.

Emily Kate Stephens (46:43): Talk about confirmation bias,

Michael VanElzakker (46:44): Exactly, which is understandable. I mean, it's not like it's wrong, but it's just more complex than that. Again, back to Koch's postulate. It's not one thing, one disease, one thing. So now, if you can take that sample and do next generation sequencing and run it against libraries, somewhat biassed 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 behaviour 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 millilitre of blood taken from the left forearm, right? Yeah, 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 biassed or unbiased techniques. That's the holy grail of testing that we're hoping to pull together.

Emily Kate Stephens (48:19): That is really exciting.

Michael VanElzakker (48:21): I hope so. We'll see,

Emily Kate Stephens (48:22): 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. In that, 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 exciting.

Michael VanElzakker (48:46): I hope so. We're hoping that this really can be transformative for some people if you can really figure out what is driving it in this particular patient.

Emily Kate Stephens (49:00): 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 VanElzakker operate never fails to stop me in my tracks. The work that people like him and the team at 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 100,000 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.