Post by Nadica (She/Her) on Nov 16, 2024 3:57:13 GMT
Doing the science ourselves - Published Jan 21, 2024
By Thomas F. Varley, PhD
Paradigm shifts don’t happen over night: societies don’t all wake up one morning and collectively say: “we’re all doing things differently now, here’s the new Way Things Are.” Change happens slowly – cultures ossify and societies can have an inertia all their own. Sometimes, change only happens when there is a shock: not until the system is perturbed from the outside can the crystallized structures break and new configurations be explored.
The COVID-19 pandemic was, undoubtedly, such a shock: one that shook the foundations of the world with an intensity that outstripped any other event in my lifetime. As is often the case following great catastrophes, when the dust settles and the world begins to wobble back towards equilibrium, we can find ourselves disappointed by how institutions we trusted failed us, and inspired by the unexpected quarters in which help and solidarity emerged. The consequences of those successes and failures can set the stage for new ways of doing things, and new technologies can generate opportunities that push the limits of what was previously imaginable.
Here I want to explore a particular facet of how the pandemic has resulted in something astonishing. Specifically, looking at phenomenon of “long COVID”, and how the failures of institutions to deal with post-COVID illness has inspired something like a revolution in biomedical citizen science. In the void of clinical trials and effective therapeutic research left by the United States’ institutional leaders, a large community of sufferers has begun a remarkable movement: they are starting to do the science themselves. Driven by desperation and with no need to go through the byzantine gatekeeping of “legacy institutions”, these groups are pushing the boundaries of decentralized science in a way that has little parallel with anything else in the history of biomedical research. Along the way, some of them have picked up funding directly from their communities (and the occasional cryptocurrency billionaire) rather than institutional grants, and taken their results to scientific conferences. Years from now, we may recognize that they were laying the foundations stones for a new way of doing science; one facilitated by accelerating technological advances and able to succeed where the legacy institutions have so dismally failed.
Long COVID and the Failures of our Institutions
Since SARS-COV-2 washed over the world in the spring of 2020, there have been more than one hundred million cases in the United States (and over a million deaths). While most people recover with no lasting effects within two to three weeks, a subset of people can develop the debilitating condition “long COVID”. The list of possible symptoms is mind-boggling, both in length and severity. Some people develop chronic fatigue so deep that it leaves them bedbound for weeks or months on end. Some people develop catastrophic inability to perform even the most minor exertions without triggering terrible suffering (known as post-exertional malaise, or PEM). Some people develop so-called “brain fog” that leaves them feeling like they have dementia. And that’s just dipping our toes below the surface of a deep well of misery that includes everything from heart problems to neuropathy to tinnitus to hair-loss.
At present, there are no cures for long COVID. There are not even recommended treatments, beyond “talk to your doctor about managing specific symptoms.” Uncertainty around exactly what constitutes long COVID makes it hard to get an estimate of exactly how many people have it, but in 2022 the CDC estimated that approximately 7% of US adults have had long COVID at one point and that 3.4% of American adults had it at the time. I want to be clear: this is not “7% of people who had COVID”, this is 7% of all US adults. If the 3.4% figure holds up, in the United States there would be eleven million people suffering from long COVID on a given day. Of those who do have long COVID, it’s estimated that about one in five cannot work, and nearly half have had to reduce work hours because they cannot manage to maintain a full-time job. There are an estimated 4 million adults out of the workforce because of the illness (that’s about 1.2% of the total US population, for those following along). Other countries have reported similarly worrying trends.
And finally, if all that is not bad enough, a recent study from Canada that examined the risk of re-infection, and found that the more times you get COVID, the more likely you are to have lingering post-acute symptoms. While vaccination seems to reduce the risk of long COVID, they hardly eliminates it: a large study found that vaccine effectiveness against long COVID ranged from 29-52%. Not bad, but not great either: even in the best case scenario, the risk of developing long COVID after multiple vaccinations is still worryingly high.
So, to recap: we have a debilitating disease caused by a still-circulating virus that is only partially managed by vaccines, increases in likelihood the more times you’re infected and (as of this writing) has no cure or treatment.
That’s the current state of play with respect of long COVID.
Despite these alarming statistics, the response to the crisis of Long COVID from American scientific and government institutions has been...less than inspiring. In 2020, the United States Congress allocated $1.2 billion dollars to the National Institute of Health to spearhead the RECOVER Initiative, which was designed to study long COVID and ultimately development treatments. Two and a half years after the fact, however, there is a growing consensus that the NIH doesn’t have much to show for that billion dollars. The medical news outlet STATNews produced a thorough piece of investigative journalism, interviewing scientists, physicians, and patients. They reported widespread criticism of the initiative. The vast majority of the money has gone towards observational studies cataloging symptoms and recovery trajectories (or, in some cases, lack-of-recovery trajectories). While longitudinal studies are important, for patients suffering from severe disability and pain, seeing so much of the money allocated to passively observing their suffering is galling.
Even the fifteen percent of RECOVER funding that has been allocated to clinical trials leaves a lot to be desired. The initiative almost immediately ran into controversy when it announced one of the trials would be for a progressive, exercise-based intervention to treat post-COVID fatigue and exercise intolerance. Many long COVID sufferers can develop a nightmarish syndrome known as myalgic encephalomyelitis or chronic fatigue syndrome (the terms are typically used interchangably and abbreviated “ME/CFS”), a hallmark of which serious post-exertional malaise. Prior to COVID, many ME/CFS patients who were treated with exercise reported deteriorating after graded therapy, sometimes permanently (ending up housebound or bedbound for years on end).
The Center for Disease Control (CDC) and the National Institute for Healthcare Excellence (NICE) have both removed graded exercise therapy from their list of recommended treatments for ME/CFS, however this did not stop the RECOVER institute from sinking taxpayer money into the trial, prompting an outcry from physicians, patients, and advocates.
The NIH is not the only major institution to make decisions that damaged the trust of patients. The Stanford Medical School’s clinical trial of Paxlovid for long COVID came under fire when trial staff stopped masking, prompting patients to walk out of the study and leading to an outcry on social media. The same study unexpectedly ended early for unknown reasons a few months later, with little explanation or follow-up announcements. Patients themselves, especially early in the pandemic, sometimes discovered that their doctors were skeptical that long COVID even existed (despite the fact that post-viral syndromes have been rcognized for decades), leading to delayed diagnosis, loss of trust in the medical system, and sometime inappropriate interventions (see “graded exercise therapy”, discussed above). Since there is no official treatment for long COVID, any medications prescribed must be done “off-label” and will not be covered by insurance companies, add an additional financial cost on a patient population already struggling to work.
All of this, combined with a general lack of long COVID awareness in messaging from official public health channels (whose position has been sometimes derisively referred to as “vax and relax”) has left patients feeling adrift and abandoned by what should have been a social safety net.
In response to this sense of institutional abandonment, some long COVID patients (as well as patients with existing neglected disorders like ME/CFS) are doing something remarkable: they’re doing the science on their own.
Citizen Science and Long COVID
Generally, citizen science is a pretty low-stakes endeavor. That’s not to belittle it, but by-and-large, the problems that citizen science projects tackle are not typically life-or-death issues. Citizen scientists have done remarkable work contribute to the project of science, but conspicuously absent from summaries of citizen science successes are fields of medicine. We tend to leave that kind of thing to the experts. But what happens when you feel like the experts are doing nothing? Or worse, actively minimizing the risks and severity of your condition? At that point, the calculus changes a bit.
Social Media Bring Sufferers Together…
A disorder like severe long COVID or ME/CFS is an inherently isolating condition. People are often housebound, or even bedbound, for months or years at a time, and even those who are not as severe find their world shrinking down to the bare essentials (as this cartoon illustrates so poignantly).
However, the Internet and the infrastructure of social media has radically lowered the barrier to connection: people who might have been totally unable to find and strategize with fellow sufferers twenty years ago now have access to communities tens of thousands strong at the tips of their fingers. Communities like Reddit’s r/covidlonghaulers (which has 52,000 subscribers) have become online clearing houses for discussions about almost every feature of living with long COVID imaginable. Members can compare notes on their symptoms, track their own recovery trajectories, and suggest different interventions that worked for them. Much of the online culture has grown out of the world of “bro-science” (also very big on mostly-male Reddit): many of the suggestions include various supplement “stacks”, and it’s pretty common to see people swearing by the bio-hacker-bro standbys of cold-plunges, water fasting, keto or carnivore diets, and daily sunlight. You get the sense that a number of participants probably listen to a lot of Andrew Huberman.
None of this is to say that these communities haven’t been productive, however. A whole lexicon of technical jargon has developed, as well as a kind of crowd-sourced model of the different flavors of long COVID. Posters routinely make distinctions between “CFS-type” long COVID typified by post-exertional malaise, or to “MCAS-type” long COVID (MCAS referring to “mast-cell activation syndrome”), typified by food intolerance and aberrant allergic reactions, or “Neuro-COVID”, typified by neualgia, small fiber neuropathy (and of course, these can all overlap and seem to be typically co-morbid). It’s also common to see discussions of the various hypothetical etiologies of long COVID discussed, complete with references to the scientific literature. People debate the viral persistence hypothesis versus the auto-immunity hypothesis, and speculate freely on the nature of the interaction between the immune system, mitochondrial health, and PEM.
And while the signal-to-noise ratio is probably weak, there does appear to be some signal nevertheless. A small number of varied interventions, such as low-dose naltrexone, nattokinase, nicotine patches, and changes in diet seem to have crystallized into a kind of “standard care” regimen often recommended to newcomers.
For someone who feels like their body and lives are suddenly falling apart, and with nothing coming from their doctors, discovering such a community can be like grabbing onto a life-preserver in a storm.
The community has also seen something like an emergent consensus on symptom management as well. While many patients find their physicians recommending exercise, antidepressants, and cognitive-behavioral therapy, the online patient community is quick to warn against exercise and instead recommends “pacing” – an intensive energy-management regimen first developed to manage ME/CFS. This recommendation was recently validated by a study in Nature Communications, which conclusively showed that long COVID patients experiencing PEM had physiologically distinct responses to exertion than healthy controls and that the tendency for physicians to default to “walk-it-off” is contraindicated in this case..
The content of these communities is rich enough that scientists have started to take note: a number of teams have done text-mining analyses of these online forums, often finding overlap between the empirical results and the ad-hoc clusters that emerged in the communities organically. It is impossible to know how robust any of these emergent, community-based recommendations will prove to be without clinical trials, however these communities are nevertheless something remarkable: a kind of decentralized biomedical science, exploring the spaces of symptoms and treatments without any central overseeing body or gatekeeping force. Unlike previous iterations of “biohackers”, who are generally interested in vague and impossible-to-define goals like “beating aging” or “improving performance” (whatever that means), the cases of long COVID are incredibly concrete, with waves of disabling symptoms, a single, known trigger, and observable measures of progress or loss.
…and the Science get Technical.
Anyone who spends time in these online communities will quickly notice that there is a remarkably high level of engagement with the technical, scientific literature around long COVID, ME/CFS, and related issues. Thanks to pushes for open-access scientific publishing, the normalization of pre-print servers like bioRxiv and medRxiv, pirate sites like SciHub and public-access databases like the ClinicalTrials.gov, the average Joe suddenly has access to a tremendous amount of scientific information that would previously have been cloistered away in the hallowed halls of the ivory tower. In 2024, papers which might never have made so much as a ripple in “official channels” can find new lives in online communities (where they can reach far more people than any paywalled Nature paper ever could).
One such an example is a small case-study of using nicotine patches to treat long COVID:
Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration?
bioelecmed.biomedcentral.com/articles/10.1186/s42234-023-00104-7
This paper tells the story of four patients who had been suffering from post-COVID symptoms for varying periods of time, all of whom experienced sustained remission following off-label use of nicotine patches under the care of the author, Dr. Marco Leitzke. Putting on my professional “science hat”, I think it’s fair to say that this paper leaves something to be desired. It’s a small set of case-studies (just four people), and two of the four don’t even follow the regimen set by Dr. Leitzke: one accidentally gave himself a double dose, leading to “intolerable vomiting and diarrhea” and dropped out after a mere 10 hours. The second patient inexplicably took a “let-er-rip” approach and deliberately doubled his dose on the third day, before stopping as well. Nevertheless, all four patients reported sustained remission of symptoms like fatigue and exercise intolerance upon follow-up.
In my professional opinion as a scientist, this is not a paper I would expect to make large waves. Certainly I don’t think it would spawn anything like a clinical trial: clinical trials are complex, expensive affairs, requiring quite a bit of justification to initiate. Four people (half of whom didn’t even take the medicine right) just doesn’t cut it. The patients themselves had also only been sick for a few weeks after the acute infection, causing some to suggest that they don’t even qualify as “long COVID” patients at all.
None of this is meant to be an attack on the paper, Dr. Leitzke, or the patients - the scientific literature is full of this kind of paper: small case studies that might pique the interest of domain experts but never evolve into anything due to the inherent constraints of limited funding, limited time, and limited attention.
So, why then, does Altmetric rank it in the 99th percentile for all papers of it’s age (of the 466,974 tracked articles, it’s ranked 873)? And why has it been accessed 103,000 times? The answer, of course, is: because of the Internet.
Clinical trials are expensive, centralized projects, and if they turn out null results, millions of dollars can be “lost”. But nicotine patches themselves are cheap, and unlike big-money players who are (for better or worse) concerned about the possibility of lighting piles of cash on fire, many long COVID sufferers felt like they personally had little to lose and potentially everything to gain. And so, as this small paper percolated through networks of Facebook and Reddit groups people started “doing the trial” themselves, in a sense.
The result is The Nicotine Test. The Nicotine Test is a largely crowd-sourced resource and science project following up on Dr. Leitzke’s original paper: there’s a detailed FAQ that covers everything from basic questions like “why would you do this” to fairly detailed discussions about how nicotine might interact with other commonly-used supplements. There’s also a set of safety guidelines and protocols for patients to follow, as well as a slickly-produced visual guide for those not interested in (or perhaps too brain-fogged) to wade through pages of size-12 font.
But that’s not what made The Nicotine Project so interesting to me. What really intrigued me was how prospective volunteers were invited to track their own experiences with the patch, and contribute to an on-going data collection project. There is a two-part survey respondents can fill out (a short form, and then a longer, more detailed survey for those that feel up for it – a kind nod to the respondents who might not be up for the full thing). There’s also educational material on the standard, clinical measures of functionality, in this case Bell’s Functionality Score, to ensure that everyone has the same “reference point” when discussing their symptoms. After collecting close to 150 responses, representatives of The Nicotine Test were able to put together a poster to present at an academic conference on long COVID. I have no idea how many respondents have filled out the survey since then, but it’s likely that the final number could be at the upper end of the range of what would be considered viable for a Phase 2 clinical trial (which is typically 100-300 volunteers). For a citizen science project helmed in part by volunteers debilitated by long COVID themselves, it is a remarkable feat.
The Nicotine Project is just one of a family of patient-led, volunteer research projects. There is also The Acid Test, where volunteers with ME/CFS track their own blood levels of lactic acid, based on the hypothesis the extreme fatigue and exercise intolerance are associated with an inability to engage in normal aerobic metabolism, and a group self-experimenting with red-light therapy. All of these various projects are being organized by a group of volunteers (most living with ME/CFS or long COVID themselves). They collectively go by Renegade Research on Twitter/X, and while I can’t find a single, centralized “About Us” page anywhere, but it seems to be an almost entirely patient-led endeavor, which is an astonishing feat for a group of people suffering from an illness that, almost definitionally, makes this kind of intensive labor difficult-to-impossible most days.
The last of the Renegade Research projects I want to highlight is the Remission Biome Project project, as it is both the most ambitious and also the most radically outside-the-norm for business-as-usual biomedicine. The story here is a bit complex and detailed in a fascinating Guardian article, as well as in a piece on Phoenix Rising. Briefly, two ME/CFS sufferers, Dr. Tamara Romanuk and Dr. Tess Falor (who both happened to be PhDs with experience working in science themselves) independently experienced an unexpected remission from their symptoms by taking a mixture antibiotics and probiotics for unrelated infections. After finding each other, they set up the Remission Biome project: a patient-led study attempting to replicate their experience in others, while also untangling exactly what had happened in the first place.
What sets Remission Biome apart is that they are not just collecting data from patient-volunteers like the Nicotine Test or the Acid Test (which is pretty low-overhead, from an organizer’s point of view), but they are raising serious money and investing in an array of medical tests to help untangle how the volunteers bodies are responding to the protocol in real time (five volunteers have already gone through the protocol, replicating the remission events). This is not an inexpensive undertaking: tests are pricey, as well as paying for the drugs, probiotics, and prebiotics out-of-pocket. The community seems to have their back, however: the project’s GoFundMe (which is unfortunately light on details), has raised over $70,000. Beyond grassroots funding, the project has been able to swing impressive private funding, including a quarter-million dollar grant from Vitalik Buterin, creator of the Ethereum cryptocurrency.* This kind of direct philanthropy is increasingly supporting scientists both inside and outside legacy institutions whose research topics are not priorities for the usual funding sources. Another recent example was the anonymous gift that the “Pineapple Fund” gave to the Multidisciplinary Association for Psychedelic Studies to research MDMA for PTSD (despite MDMA’s Schedule 1 drug status).
I should note that the Remission Biome project has not been without its detractors within the community: there is a long thread on the Science For ME forum, which contains plenty of reports of people with ME/CFS who did not achieve any kind of remission on antibiotics, critique the project on a number of fronts. Dr. Tamara Romanuk (one of the two Remission Biome project co-founders) has also separated from the Remission Biome project specifically and the Renegade Research project generally, although has not said why (as far as I can tell). Being neither a physician, nor a person with (severe) long COVID or ME/CFS, I’m not in a position to pass judgment on either the wisdom of the project, nor estimate its likelihood of success, but the scope, vision, and radical nature of the projects is impossible to deny (even if you don’t think they’ll work).
New Horizons of Knowledge Production
This explosion of citizen biomedical science is, I think, just a single facet of a much larger sea change occurring in how humanity produces, and disseminates knowledge. In the 20th century “knowledge production” has largely been centralized in a small number of powerful institutions that control vast amounts of capital: universities, governments, and large corporations. However, as we reach the mid-2020s, it’s hard not to feel like many of these institutions are wavering in their capacity to direct the future of scientific research (at least, in the United States). Americans confidence in academia has fallen 21 percentage points from 2015 and since the pandemic, Americans trust in scientists has gone down as well. Trust of governmental public health agencies like the CDC has cratered.
America’s corporate sector is also looking a little anemic. The biggest pharmaceutical corporations actually are doing very little R&D themselves, instead either opting to acquire intellectual property, or finding new ways to repackage and sell existing drugs. Developments on crucial classes of drugs like antibiotics seems to have stalled, as has development in psychiatric medications. The perverse incentive structure of modern pharmaceutical development means that there is very little interest in running a large scale, Phase III clinical trials for any drug that isn’t novel enough to patent. Even if an existing drug does show promise, it’s hard to imagine a company like Pfizer sinking money into large trials when doctors will just prescribe the generic. However, novel drugs can take a decade to work through the pipeline, leaving long COVID sufferers with little hope of a near-term therapy coming from the private sector.
So, barring some currently-unexpected show of force from the US government, it seems like for the foreseeable future, the kind of decentralized, patient-led research is going to be where things move the fastest. In other, lower stakes, areas of science this kind of shift is also occurring: fellow Substack writer Erik Hoel has written about how newsletters provide a creative freedom that has largely be extinguished in the increasingly bureaucratized and political world of academia.
The writers at Experimental History recently made experimental history by publishing a paper (complete with figures and everything) on their newsletter, bypasing all the usual gatekeepers.
All of these things, from Substack blogs to DeSci conferences are all small potatoes compared to the overwhelming horror that is the ongoing long COVID epidemic. We’re not talking about a few intellectual white dudes trying something new in their own careers: hundreds of thousands, possibly millions of people have, or will get, some form of long COVID over the coming decade. But nevertheless, I think it’s possible to imagine a future where we can leverage this nascent “indie science” structure and use that to scaffold the chaotic, but essential, work that patients have taken on in managing, and curing, their own neglected illnesses. I don’t know exactly what that looks like. I’d like to help be part of building it, but it’ll be a massive undertaking: there’s a lot of inertia to overcome. The COVID-19 pandemic was a pretty massive blow to the status quo, however, and in response the institutions of knowledge production seem to be driving themselves towards a series of further crises. So maybe it’s time to get creative, and see what our communities are capable of.
* This is not the first time that grassroots funding and cryptocurrency nouveau riche philanthropists have stepped in to fund science that institutional funding bodies were ignoring: the first human neuroimaging study of LSD was funded in part by a crowdfunding campaign due to limited interest from the UK government (I personally donated, and still have a framed “thank you” poster on my wall). Also in the psychedelic space, the Multidisciplinary Association for Psychedelic Studies famously received a $5 million donation from the anonymous bitcoin-based Pineapple Fund. (The anonymous philanthropist also gave another $5 million to the Open Medicine Foundation which researches ME/CFS among other rare diseases).
By Thomas F. Varley, PhD
Paradigm shifts don’t happen over night: societies don’t all wake up one morning and collectively say: “we’re all doing things differently now, here’s the new Way Things Are.” Change happens slowly – cultures ossify and societies can have an inertia all their own. Sometimes, change only happens when there is a shock: not until the system is perturbed from the outside can the crystallized structures break and new configurations be explored.
The COVID-19 pandemic was, undoubtedly, such a shock: one that shook the foundations of the world with an intensity that outstripped any other event in my lifetime. As is often the case following great catastrophes, when the dust settles and the world begins to wobble back towards equilibrium, we can find ourselves disappointed by how institutions we trusted failed us, and inspired by the unexpected quarters in which help and solidarity emerged. The consequences of those successes and failures can set the stage for new ways of doing things, and new technologies can generate opportunities that push the limits of what was previously imaginable.
Here I want to explore a particular facet of how the pandemic has resulted in something astonishing. Specifically, looking at phenomenon of “long COVID”, and how the failures of institutions to deal with post-COVID illness has inspired something like a revolution in biomedical citizen science. In the void of clinical trials and effective therapeutic research left by the United States’ institutional leaders, a large community of sufferers has begun a remarkable movement: they are starting to do the science themselves. Driven by desperation and with no need to go through the byzantine gatekeeping of “legacy institutions”, these groups are pushing the boundaries of decentralized science in a way that has little parallel with anything else in the history of biomedical research. Along the way, some of them have picked up funding directly from their communities (and the occasional cryptocurrency billionaire) rather than institutional grants, and taken their results to scientific conferences. Years from now, we may recognize that they were laying the foundations stones for a new way of doing science; one facilitated by accelerating technological advances and able to succeed where the legacy institutions have so dismally failed.
Long COVID and the Failures of our Institutions
Since SARS-COV-2 washed over the world in the spring of 2020, there have been more than one hundred million cases in the United States (and over a million deaths). While most people recover with no lasting effects within two to three weeks, a subset of people can develop the debilitating condition “long COVID”. The list of possible symptoms is mind-boggling, both in length and severity. Some people develop chronic fatigue so deep that it leaves them bedbound for weeks or months on end. Some people develop catastrophic inability to perform even the most minor exertions without triggering terrible suffering (known as post-exertional malaise, or PEM). Some people develop so-called “brain fog” that leaves them feeling like they have dementia. And that’s just dipping our toes below the surface of a deep well of misery that includes everything from heart problems to neuropathy to tinnitus to hair-loss.
At present, there are no cures for long COVID. There are not even recommended treatments, beyond “talk to your doctor about managing specific symptoms.” Uncertainty around exactly what constitutes long COVID makes it hard to get an estimate of exactly how many people have it, but in 2022 the CDC estimated that approximately 7% of US adults have had long COVID at one point and that 3.4% of American adults had it at the time. I want to be clear: this is not “7% of people who had COVID”, this is 7% of all US adults. If the 3.4% figure holds up, in the United States there would be eleven million people suffering from long COVID on a given day. Of those who do have long COVID, it’s estimated that about one in five cannot work, and nearly half have had to reduce work hours because they cannot manage to maintain a full-time job. There are an estimated 4 million adults out of the workforce because of the illness (that’s about 1.2% of the total US population, for those following along). Other countries have reported similarly worrying trends.
And finally, if all that is not bad enough, a recent study from Canada that examined the risk of re-infection, and found that the more times you get COVID, the more likely you are to have lingering post-acute symptoms. While vaccination seems to reduce the risk of long COVID, they hardly eliminates it: a large study found that vaccine effectiveness against long COVID ranged from 29-52%. Not bad, but not great either: even in the best case scenario, the risk of developing long COVID after multiple vaccinations is still worryingly high.
So, to recap: we have a debilitating disease caused by a still-circulating virus that is only partially managed by vaccines, increases in likelihood the more times you’re infected and (as of this writing) has no cure or treatment.
That’s the current state of play with respect of long COVID.
Despite these alarming statistics, the response to the crisis of Long COVID from American scientific and government institutions has been...less than inspiring. In 2020, the United States Congress allocated $1.2 billion dollars to the National Institute of Health to spearhead the RECOVER Initiative, which was designed to study long COVID and ultimately development treatments. Two and a half years after the fact, however, there is a growing consensus that the NIH doesn’t have much to show for that billion dollars. The medical news outlet STATNews produced a thorough piece of investigative journalism, interviewing scientists, physicians, and patients. They reported widespread criticism of the initiative. The vast majority of the money has gone towards observational studies cataloging symptoms and recovery trajectories (or, in some cases, lack-of-recovery trajectories). While longitudinal studies are important, for patients suffering from severe disability and pain, seeing so much of the money allocated to passively observing their suffering is galling.
Even the fifteen percent of RECOVER funding that has been allocated to clinical trials leaves a lot to be desired. The initiative almost immediately ran into controversy when it announced one of the trials would be for a progressive, exercise-based intervention to treat post-COVID fatigue and exercise intolerance. Many long COVID sufferers can develop a nightmarish syndrome known as myalgic encephalomyelitis or chronic fatigue syndrome (the terms are typically used interchangably and abbreviated “ME/CFS”), a hallmark of which serious post-exertional malaise. Prior to COVID, many ME/CFS patients who were treated with exercise reported deteriorating after graded therapy, sometimes permanently (ending up housebound or bedbound for years on end).
The Center for Disease Control (CDC) and the National Institute for Healthcare Excellence (NICE) have both removed graded exercise therapy from their list of recommended treatments for ME/CFS, however this did not stop the RECOVER institute from sinking taxpayer money into the trial, prompting an outcry from physicians, patients, and advocates.
The NIH is not the only major institution to make decisions that damaged the trust of patients. The Stanford Medical School’s clinical trial of Paxlovid for long COVID came under fire when trial staff stopped masking, prompting patients to walk out of the study and leading to an outcry on social media. The same study unexpectedly ended early for unknown reasons a few months later, with little explanation or follow-up announcements. Patients themselves, especially early in the pandemic, sometimes discovered that their doctors were skeptical that long COVID even existed (despite the fact that post-viral syndromes have been rcognized for decades), leading to delayed diagnosis, loss of trust in the medical system, and sometime inappropriate interventions (see “graded exercise therapy”, discussed above). Since there is no official treatment for long COVID, any medications prescribed must be done “off-label” and will not be covered by insurance companies, add an additional financial cost on a patient population already struggling to work.
All of this, combined with a general lack of long COVID awareness in messaging from official public health channels (whose position has been sometimes derisively referred to as “vax and relax”) has left patients feeling adrift and abandoned by what should have been a social safety net.
In response to this sense of institutional abandonment, some long COVID patients (as well as patients with existing neglected disorders like ME/CFS) are doing something remarkable: they’re doing the science on their own.
Citizen Science and Long COVID
Generally, citizen science is a pretty low-stakes endeavor. That’s not to belittle it, but by-and-large, the problems that citizen science projects tackle are not typically life-or-death issues. Citizen scientists have done remarkable work contribute to the project of science, but conspicuously absent from summaries of citizen science successes are fields of medicine. We tend to leave that kind of thing to the experts. But what happens when you feel like the experts are doing nothing? Or worse, actively minimizing the risks and severity of your condition? At that point, the calculus changes a bit.
Social Media Bring Sufferers Together…
A disorder like severe long COVID or ME/CFS is an inherently isolating condition. People are often housebound, or even bedbound, for months or years at a time, and even those who are not as severe find their world shrinking down to the bare essentials (as this cartoon illustrates so poignantly).
However, the Internet and the infrastructure of social media has radically lowered the barrier to connection: people who might have been totally unable to find and strategize with fellow sufferers twenty years ago now have access to communities tens of thousands strong at the tips of their fingers. Communities like Reddit’s r/covidlonghaulers (which has 52,000 subscribers) have become online clearing houses for discussions about almost every feature of living with long COVID imaginable. Members can compare notes on their symptoms, track their own recovery trajectories, and suggest different interventions that worked for them. Much of the online culture has grown out of the world of “bro-science” (also very big on mostly-male Reddit): many of the suggestions include various supplement “stacks”, and it’s pretty common to see people swearing by the bio-hacker-bro standbys of cold-plunges, water fasting, keto or carnivore diets, and daily sunlight. You get the sense that a number of participants probably listen to a lot of Andrew Huberman.
None of this is to say that these communities haven’t been productive, however. A whole lexicon of technical jargon has developed, as well as a kind of crowd-sourced model of the different flavors of long COVID. Posters routinely make distinctions between “CFS-type” long COVID typified by post-exertional malaise, or to “MCAS-type” long COVID (MCAS referring to “mast-cell activation syndrome”), typified by food intolerance and aberrant allergic reactions, or “Neuro-COVID”, typified by neualgia, small fiber neuropathy (and of course, these can all overlap and seem to be typically co-morbid). It’s also common to see discussions of the various hypothetical etiologies of long COVID discussed, complete with references to the scientific literature. People debate the viral persistence hypothesis versus the auto-immunity hypothesis, and speculate freely on the nature of the interaction between the immune system, mitochondrial health, and PEM.
And while the signal-to-noise ratio is probably weak, there does appear to be some signal nevertheless. A small number of varied interventions, such as low-dose naltrexone, nattokinase, nicotine patches, and changes in diet seem to have crystallized into a kind of “standard care” regimen often recommended to newcomers.
For someone who feels like their body and lives are suddenly falling apart, and with nothing coming from their doctors, discovering such a community can be like grabbing onto a life-preserver in a storm.
The community has also seen something like an emergent consensus on symptom management as well. While many patients find their physicians recommending exercise, antidepressants, and cognitive-behavioral therapy, the online patient community is quick to warn against exercise and instead recommends “pacing” – an intensive energy-management regimen first developed to manage ME/CFS. This recommendation was recently validated by a study in Nature Communications, which conclusively showed that long COVID patients experiencing PEM had physiologically distinct responses to exertion than healthy controls and that the tendency for physicians to default to “walk-it-off” is contraindicated in this case..
The content of these communities is rich enough that scientists have started to take note: a number of teams have done text-mining analyses of these online forums, often finding overlap between the empirical results and the ad-hoc clusters that emerged in the communities organically. It is impossible to know how robust any of these emergent, community-based recommendations will prove to be without clinical trials, however these communities are nevertheless something remarkable: a kind of decentralized biomedical science, exploring the spaces of symptoms and treatments without any central overseeing body or gatekeeping force. Unlike previous iterations of “biohackers”, who are generally interested in vague and impossible-to-define goals like “beating aging” or “improving performance” (whatever that means), the cases of long COVID are incredibly concrete, with waves of disabling symptoms, a single, known trigger, and observable measures of progress or loss.
…and the Science get Technical.
Anyone who spends time in these online communities will quickly notice that there is a remarkably high level of engagement with the technical, scientific literature around long COVID, ME/CFS, and related issues. Thanks to pushes for open-access scientific publishing, the normalization of pre-print servers like bioRxiv and medRxiv, pirate sites like SciHub and public-access databases like the ClinicalTrials.gov, the average Joe suddenly has access to a tremendous amount of scientific information that would previously have been cloistered away in the hallowed halls of the ivory tower. In 2024, papers which might never have made so much as a ripple in “official channels” can find new lives in online communities (where they can reach far more people than any paywalled Nature paper ever could).
One such an example is a small case-study of using nicotine patches to treat long COVID:
Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration?
bioelecmed.biomedcentral.com/articles/10.1186/s42234-023-00104-7
This paper tells the story of four patients who had been suffering from post-COVID symptoms for varying periods of time, all of whom experienced sustained remission following off-label use of nicotine patches under the care of the author, Dr. Marco Leitzke. Putting on my professional “science hat”, I think it’s fair to say that this paper leaves something to be desired. It’s a small set of case-studies (just four people), and two of the four don’t even follow the regimen set by Dr. Leitzke: one accidentally gave himself a double dose, leading to “intolerable vomiting and diarrhea” and dropped out after a mere 10 hours. The second patient inexplicably took a “let-er-rip” approach and deliberately doubled his dose on the third day, before stopping as well. Nevertheless, all four patients reported sustained remission of symptoms like fatigue and exercise intolerance upon follow-up.
In my professional opinion as a scientist, this is not a paper I would expect to make large waves. Certainly I don’t think it would spawn anything like a clinical trial: clinical trials are complex, expensive affairs, requiring quite a bit of justification to initiate. Four people (half of whom didn’t even take the medicine right) just doesn’t cut it. The patients themselves had also only been sick for a few weeks after the acute infection, causing some to suggest that they don’t even qualify as “long COVID” patients at all.
None of this is meant to be an attack on the paper, Dr. Leitzke, or the patients - the scientific literature is full of this kind of paper: small case studies that might pique the interest of domain experts but never evolve into anything due to the inherent constraints of limited funding, limited time, and limited attention.
So, why then, does Altmetric rank it in the 99th percentile for all papers of it’s age (of the 466,974 tracked articles, it’s ranked 873)? And why has it been accessed 103,000 times? The answer, of course, is: because of the Internet.
Clinical trials are expensive, centralized projects, and if they turn out null results, millions of dollars can be “lost”. But nicotine patches themselves are cheap, and unlike big-money players who are (for better or worse) concerned about the possibility of lighting piles of cash on fire, many long COVID sufferers felt like they personally had little to lose and potentially everything to gain. And so, as this small paper percolated through networks of Facebook and Reddit groups people started “doing the trial” themselves, in a sense.
The result is The Nicotine Test. The Nicotine Test is a largely crowd-sourced resource and science project following up on Dr. Leitzke’s original paper: there’s a detailed FAQ that covers everything from basic questions like “why would you do this” to fairly detailed discussions about how nicotine might interact with other commonly-used supplements. There’s also a set of safety guidelines and protocols for patients to follow, as well as a slickly-produced visual guide for those not interested in (or perhaps too brain-fogged) to wade through pages of size-12 font.
But that’s not what made The Nicotine Project so interesting to me. What really intrigued me was how prospective volunteers were invited to track their own experiences with the patch, and contribute to an on-going data collection project. There is a two-part survey respondents can fill out (a short form, and then a longer, more detailed survey for those that feel up for it – a kind nod to the respondents who might not be up for the full thing). There’s also educational material on the standard, clinical measures of functionality, in this case Bell’s Functionality Score, to ensure that everyone has the same “reference point” when discussing their symptoms. After collecting close to 150 responses, representatives of The Nicotine Test were able to put together a poster to present at an academic conference on long COVID. I have no idea how many respondents have filled out the survey since then, but it’s likely that the final number could be at the upper end of the range of what would be considered viable for a Phase 2 clinical trial (which is typically 100-300 volunteers). For a citizen science project helmed in part by volunteers debilitated by long COVID themselves, it is a remarkable feat.
The Nicotine Project is just one of a family of patient-led, volunteer research projects. There is also The Acid Test, where volunteers with ME/CFS track their own blood levels of lactic acid, based on the hypothesis the extreme fatigue and exercise intolerance are associated with an inability to engage in normal aerobic metabolism, and a group self-experimenting with red-light therapy. All of these various projects are being organized by a group of volunteers (most living with ME/CFS or long COVID themselves). They collectively go by Renegade Research on Twitter/X, and while I can’t find a single, centralized “About Us” page anywhere, but it seems to be an almost entirely patient-led endeavor, which is an astonishing feat for a group of people suffering from an illness that, almost definitionally, makes this kind of intensive labor difficult-to-impossible most days.
The last of the Renegade Research projects I want to highlight is the Remission Biome Project project, as it is both the most ambitious and also the most radically outside-the-norm for business-as-usual biomedicine. The story here is a bit complex and detailed in a fascinating Guardian article, as well as in a piece on Phoenix Rising. Briefly, two ME/CFS sufferers, Dr. Tamara Romanuk and Dr. Tess Falor (who both happened to be PhDs with experience working in science themselves) independently experienced an unexpected remission from their symptoms by taking a mixture antibiotics and probiotics for unrelated infections. After finding each other, they set up the Remission Biome project: a patient-led study attempting to replicate their experience in others, while also untangling exactly what had happened in the first place.
What sets Remission Biome apart is that they are not just collecting data from patient-volunteers like the Nicotine Test or the Acid Test (which is pretty low-overhead, from an organizer’s point of view), but they are raising serious money and investing in an array of medical tests to help untangle how the volunteers bodies are responding to the protocol in real time (five volunteers have already gone through the protocol, replicating the remission events). This is not an inexpensive undertaking: tests are pricey, as well as paying for the drugs, probiotics, and prebiotics out-of-pocket. The community seems to have their back, however: the project’s GoFundMe (which is unfortunately light on details), has raised over $70,000. Beyond grassroots funding, the project has been able to swing impressive private funding, including a quarter-million dollar grant from Vitalik Buterin, creator of the Ethereum cryptocurrency.* This kind of direct philanthropy is increasingly supporting scientists both inside and outside legacy institutions whose research topics are not priorities for the usual funding sources. Another recent example was the anonymous gift that the “Pineapple Fund” gave to the Multidisciplinary Association for Psychedelic Studies to research MDMA for PTSD (despite MDMA’s Schedule 1 drug status).
I should note that the Remission Biome project has not been without its detractors within the community: there is a long thread on the Science For ME forum, which contains plenty of reports of people with ME/CFS who did not achieve any kind of remission on antibiotics, critique the project on a number of fronts. Dr. Tamara Romanuk (one of the two Remission Biome project co-founders) has also separated from the Remission Biome project specifically and the Renegade Research project generally, although has not said why (as far as I can tell). Being neither a physician, nor a person with (severe) long COVID or ME/CFS, I’m not in a position to pass judgment on either the wisdom of the project, nor estimate its likelihood of success, but the scope, vision, and radical nature of the projects is impossible to deny (even if you don’t think they’ll work).
New Horizons of Knowledge Production
This explosion of citizen biomedical science is, I think, just a single facet of a much larger sea change occurring in how humanity produces, and disseminates knowledge. In the 20th century “knowledge production” has largely been centralized in a small number of powerful institutions that control vast amounts of capital: universities, governments, and large corporations. However, as we reach the mid-2020s, it’s hard not to feel like many of these institutions are wavering in their capacity to direct the future of scientific research (at least, in the United States). Americans confidence in academia has fallen 21 percentage points from 2015 and since the pandemic, Americans trust in scientists has gone down as well. Trust of governmental public health agencies like the CDC has cratered.
America’s corporate sector is also looking a little anemic. The biggest pharmaceutical corporations actually are doing very little R&D themselves, instead either opting to acquire intellectual property, or finding new ways to repackage and sell existing drugs. Developments on crucial classes of drugs like antibiotics seems to have stalled, as has development in psychiatric medications. The perverse incentive structure of modern pharmaceutical development means that there is very little interest in running a large scale, Phase III clinical trials for any drug that isn’t novel enough to patent. Even if an existing drug does show promise, it’s hard to imagine a company like Pfizer sinking money into large trials when doctors will just prescribe the generic. However, novel drugs can take a decade to work through the pipeline, leaving long COVID sufferers with little hope of a near-term therapy coming from the private sector.
So, barring some currently-unexpected show of force from the US government, it seems like for the foreseeable future, the kind of decentralized, patient-led research is going to be where things move the fastest. In other, lower stakes, areas of science this kind of shift is also occurring: fellow Substack writer Erik Hoel has written about how newsletters provide a creative freedom that has largely be extinguished in the increasingly bureaucratized and political world of academia.
The writers at Experimental History recently made experimental history by publishing a paper (complete with figures and everything) on their newsletter, bypasing all the usual gatekeepers.
All of these things, from Substack blogs to DeSci conferences are all small potatoes compared to the overwhelming horror that is the ongoing long COVID epidemic. We’re not talking about a few intellectual white dudes trying something new in their own careers: hundreds of thousands, possibly millions of people have, or will get, some form of long COVID over the coming decade. But nevertheless, I think it’s possible to imagine a future where we can leverage this nascent “indie science” structure and use that to scaffold the chaotic, but essential, work that patients have taken on in managing, and curing, their own neglected illnesses. I don’t know exactly what that looks like. I’d like to help be part of building it, but it’ll be a massive undertaking: there’s a lot of inertia to overcome. The COVID-19 pandemic was a pretty massive blow to the status quo, however, and in response the institutions of knowledge production seem to be driving themselves towards a series of further crises. So maybe it’s time to get creative, and see what our communities are capable of.
* This is not the first time that grassroots funding and cryptocurrency nouveau riche philanthropists have stepped in to fund science that institutional funding bodies were ignoring: the first human neuroimaging study of LSD was funded in part by a crowdfunding campaign due to limited interest from the UK government (I personally donated, and still have a framed “thank you” poster on my wall). Also in the psychedelic space, the Multidisciplinary Association for Psychedelic Studies famously received a $5 million donation from the anonymous bitcoin-based Pineapple Fund. (The anonymous philanthropist also gave another $5 million to the Open Medicine Foundation which researches ME/CFS among other rare diseases).