Last week, the Patient-Led Research Collaborative (PLRC), the research organization led by people with Long Covid, published the second issue of its Patient-Generated Hypotheses Journal. This journal publishes scientific manuscripts that aim to advance research into Long Covid and related diseases by sharing novel ideas about potential mechanisms and treatments. People with these diseases lead every stage of the journal process, including reviewing hypothesis submissions and writing and editing the papers.
“We hope this issue inspires biomedical researchers to use these hypotheses in their research, to partner with the authors and other patients/caregivers in testing hypotheses, and to uplift patient-generated hypotheses as credible sources of research generation,” said Lisa McCorkell, a co-founder of PLRC and co-lead of the journal, in a press release announcing the second issue.
Betsy Ladyzhets spoke to Vijay Iyer, one of the authors of the new journal issue and a neuroscientist who has Myalgic Encephalomyelitis (ME), about his hypothesis, which describes a bacteria family called Streptococcaceae that may be unusually common in the guts of people with ME. Iyer described how he arrived at his hypothesis, what he learned during the Patient-Generated Hypotheses Journal’s review process, and how to get more people with Long Covid, ME, and related diseases involved with leading research.
This interview has been lightly edited and condensed for clarity.
Betsy Ladyzhets: I wanted to start by asking, since your hypothesis is about the gut microbiome, what background information would you want folks to know if they’re not super familiar with this area of research?
Vijay Iyer: It’s well-known that we have a large number of microbial species in our guts, and probably in other body regions as well. But the gut is one that’s been well-known for many years, and [scientists have learned] that it may play a role in number of different health conditions… It’s becoming an increasingly hot area of research for biomedical researchers to explore what those connections may be.
BL: How did you arrive at your hypothesis about the Streptococcus family?
VI: Recently, the NIH [National Institutes of Health] published a couple of studies that looked at the gut microbiome in ME/CFS. (Editor’s note: Betsy covered those studies for National Geographic last year.) And one of the things they noted is evidence of microbiome dysfunction in the early stages of the disease, which they didn’t really comment too much on [in the papers].
However, for my own personal journey — I, in retrospect, most likely have had at least the mildest form of ME since 2015. And in 2016, I had a significant number of GI [gastrointestinal] symptoms… So I became very interested in GI stuff.
Along the way I did my own personal version of something not unlike the Remission Biome project. I’m not a gut microbiome specialist by any means, but I had a startup many years ago for the area of science that I did work in, in neuroscience. And one of the startups next door happened to be forming a microbiome company at the time, and so I stayed in touch with them. That led to me doing a bunch of microbiome tests back in 2018, 2019… I was actually able to do some of the things that are in some of these NIH studies on my own.
I looked for correlations [between the test results and] symptoms, which were fluctuating a lot at the time. And so I collected a fair bit of data. I kept trying to find a “smoking gun” conclusion, and at the end of the day, the only one that stuck was the Streptococcus being elevated.
BL: Was that like, you were able to see a notable correlation with symptoms?
VI: That was the only abnormal result that was consistent across all my tests… Throughout the period of all my serial tests, one thing that did not fluctuate was the elevated Streptococcus.
Also, despite having no knowledge of ME at the time, I did a functional medicine protocol with an herbal antimicrobial called candibactin, which has been tested for IBS [irritable bowel syndrome], which, as many of us know, has been correlated in many cases to ME. I was still pretty mild, then. But I was fluctuating a lot. And it was very clear that I significantly improved while on the candibactin, at least for a short period.
So in that sense, it was also similar to the Remission Biome stories of a big, relatively temporary effects from antibiotics. So that’s how I got interested… I also had multiple opportunities afterwards, to try antibiotics for short periods, and I did get effects. They tended to be short, but they were pretty significant effects.
These things were in the back of my mind and were why I read, with keen interest, some of the papers about microbiome correlations to ME… And then at some point, I came across this paper from Italy, and noticed in their supplementary figures that the Streptococcus was elevated [in people with ME].
That jumped out at me, even though if you read the article, it was not about Streptococcus… So I had this data, my N-equals-one data, combined with this data [from the paper], and those were the dots I connected [in my hypothesis].
BL: I am also curious about the process of submitting this paper, writing it and having it reviewed. What was all of that like for you?
VI: I think the process was quite good. They [PLRC] have established it like a journal. So there’s a review board, there’s multiple levels of review — both editorial review, which is thinking about things from a clarity point of view, and a [science review].
This is actually the second [hypothesis] I’ve had submitted. And for this one, they seem to have – at least from my point of view – a broader network of reviewers. So they actually brought in one reviewer who had a microbiome background. And that added a lot to the process… They also challenged me to think about tests we might do, which was a section that wasn’t even in the original [draft].
BL: That was another thing I wanted to ask you about, the tests that could follow this. What research would you want to see further pursue this hypothesis?
VI: One of the things that was impactful about PLRC pulling in a bioinformatics specialist was that, in my first version of the manuscript, I imagined scientists would have to get new samples, run new microbiome panels [to validate this pattern about Streptococcus]. But he pointed out, no, you could use existing data and just run it through a different bioinformatics pipeline… I have passed that along to some researchers, at least one said they might look at it. So that was exciting.
BL: So the next step here is validation of these results. And then what, clinical trials looking at reducing Streptococcus?
VI: Yeah, that’s exactly right. There’s validation, perhaps on existing data, perhaps on new cohorts [new patients]. And there’s also validation across techniques [using different types of microbiome tests, including quantitative PCR and next-generation sequencing].
You kind-of need to break up these studies into a search stage and a focus stage. First you scan the overall region, you find some hits, and then you focus there. If we can do things on broad data and really convince ourselves that Streptococcus is one of the better targets, then you can maybe do a targeted battery of qPCR [more specific tests] to look at things that are most variable between a ME and a healthy cohort.
BL: You mentioned Remission Biome also, and I wanted to ask, what do you see as the role of patient-led research, this sort of N-equals-one experimentation that you yourself have done in researching this area?
VI: Yeah, I think we need more. Case studies are underutilized in the medical literature… The honest truth is that [many scientists] don’t have much incentive to publish on this. If it wasn’t leading to some next grant that they were working on, they didn’t really have much incentive to dive deeper and publish [case studies or novel patterns in results]. But we, as patients, have an urgency to publish these things.
It’s the same issue with doctors, like case studies make some of the most interesting medical literature, but there isn’t really ongoing incentive for doctors to publish case studies… If they don’t have an incentive to publish, and we do, we ought to find a pathway to publishing them. I feel very strongly about N-equals-one case studies. If we could create a pathway for more of them, it could actually become a new, powerful tool for medical discovery.
I feel very strongly about N-equals-one case studies. If we could create a pathway for more of them, it could actually become a new, powerful tool for medical discovery.
BL: That seems to me like one of the reasons why the Patient-Generated Hypotheses Journal is such an important project, because it is a pathway to scribing these things. And there are a few others, like I’ve written about the CURE-ID survey from the FDA and NIH… So I think there are a few of these options out there, but you’re right, we definitely need more and a greater scale. Like if you have 100 N-equals-one case studies, you have N-equals-100, right?
VI: And it can build up over time. You don’t have to have it driven by some carefully orchestrated study that was geared to graduate someone’s PhD within a fixed time.
BL: What recommendations would you have for other people with ME, Long Covid, related diseases, who are interested in doing this kind of thing, whether it is self-experimentation, or reading the medical literature and coming up with hypotheses?
VI: One thing that was noted during this recent issue [of the Patient-Generated Hypotheses Journal], as PLRC shared it, was that the group of authors… included folks who had a scientific background and became patients as well as folks who might not have had a scientific background but were motivated to learn the ropes of doing a scientific publication. And I think we need both. There’s more of the latter than the former, and we want scale.
I’ve been brainstorming how to harness both of these groups… There’s also a lot of momentum in the bioscience community, a big trend towards preprints — to get [results] out early. So one thing I’m gravitating towards is having some sort of preprint server geared at the patient-scientist community to get ideas out there. Get it out there, encourage people to comment on it, and we could have people who help [newer folks] learn the ropes, like helping to find citations or expand on ideas. And maybe over a couple of iterations, it turns into something like a patient-generated hypothesis.
BL: That makes a lot of sense. I like how you’re thinking about the systems problem of like, people need ways to share these things that are not just posting about it on Twitter. Which happens a lot, but is not really indexed in the same way as a server.
Is there anything else you want folks to know?
VI: I would just add that… I was so excited about the Patient-Generated Hypotheses Journal because when I first became involved in ME advocacy, my first thought was, I’ve got a scientific background, at least one thing I can do is help connect the dots.
What would be most tragic is if there’s just something sitting there, that is the answer [to understanding this disease], that nobody looked at because nobody bothered to point it out and there was no way to get the word out. So my real impetus is just, leave no stone unturned.
Editor’s note: The Patient-Led Research Collaborative, like The Sick Times, has received support from the Balvi and Kanro funds. Our newsroom operates independently of financial supporters.
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