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By KLG, who has held research and academic positions in three US medical schools since 1995 and is currently Professor of Biochemistry and Associate Dean. He has performed and directed research on protein structure, function, and evolution; cell adhesion and motility; the mechanism of viral fusion proteins; and assembly of the vertebrate heart. He has served on national review panels of both public and private funding agencies, and his research and that of his students has been funded by the American Heart Association, American Cancer Society, and National Institutes of Health
We are now nearly three years into the COVID-19 pandemic. Where do we go from here? According to the powers that be, we are over COVID. No, probably not.
The biomedical establishment (NIH, CDC, FDA, Big Pharma) went all-in on vaccines that were developed from the apex of modern molecular biology. Yes, mRNA-based vaccines make perfect biological sense. Their design is straightforward, and more importantly they are easily “tunable” to new variants, so we can keep up with variants as they appear. Well, yes and no.
The facility with which a modern molecular biology laboratory can pivot to new protein-coding mRNA constructs is astonishing, especially to a scientist who first cloned a gene when virtually all steps were done “by hand” in each individual laboratory: No cloning kits, no cloning vectors with multiple cloning sites, no PCR; the New England Biolabs catalog did not yet exist in its current biblical form, which every molecular biologist has one at the ready on her lab desk.
But the laboratory is one thing. Injecting human subjects with a perfectly designed but unproven mRNA is altogether something else. So, have the vaccines been effective? Yes, but that all depends on the definition.
It was known long before COVID-19 that lasting immunity to coronaviruses is problematic, so when the vaccines neither prevented infection nor transmission, despite various and sundry rationalizations from the politico-biomedical establishment, a new clinical endpoint was proposed: Vaccination prevented severe disease in many of those infected. Reasonably true, but not exactly what the people naturally expected of a vaccine. Nothing new here to the Naked Capitalism community, and I hope to return to this soon.
While there seems to be no rhyme to our collective response to the pandemic, the reasons are plain if largely hidden. What I would like to do here is consider the overall scientific response to COVID-19, as demonstrated by a view of the COVID-19 scientific literature, first from 30,000 feet and then at ground level.
By any conventional measure, the scientific response to COVID-19 has been astonishing. In the 34 months of the pandemic a search of PubMed using COVID as the database query reveals that more than 300,000 scientific papers have been published with COVID (or Covid, case does not affect the search results) somewhere in the body of the publication.[1] By any reckoning, this is a mind boggling number. Compare this, for example, with the scientific literature for another epidemic. A search with using HIV AIDS as the query (the paper included both HIV and AIDS somewhere in the published version) returns 161,633 results, from 1982 through 12 September 2022.
Breaking this down into citations per month, so far, COVID leads HIV AIDS by approximately 9,400 to 340. How can this be?
No sane person has the time to analyze each of papers in the COVID database or the HIV AIDS database, and few would use AI/machine learning to do so (with the latter probably missing critical information). It is difficult for those who were not present to believe how frightening the AIDS epidemic was in the 1980s. Most of my circle eagerly awaited the weekly editions of Science and Nature and the biweekly issue of Cell, and our weekly Journal Club frequently discussed the latest research on AIDS and then HIV-AIDS after the suspected retrovirus was identified by Luc Montaigner and Françoise Barré-Sinoussi.
In many ways, COVID-19 has been more frightening. It became clear early that AIDS, while lethal, was not easily transmitted, especially in the Global North[2]. SARS-CoV-2 was another matter altogether and has caused more than 6 million deaths worldwide over the past 34 months. This, from a virus that causes a version of the common cold according to much of the conventional wisdom.
One might justifiably ask, “If the scientific response to COVID has been so robust, why haven’t we made more progress (neglecting political factors until a later post)?”
What follows is primarily an educated guess based on a 40+ year career of reading the biomedical literature. The answer lies not in the practice of biomedical research.
In my view the apparent outsized response to COVID-19 is a direct consequence of changes in the business of scientific publishing, in the form of open-access “journals”, rather than any fundamental change in the capacity for an “all hands on deck” response to a medical crisis. This response identified risk factors for AIDS and HIV within a few short years.
The response to COVID-19, on the other hand, has swamped us in virtual paper. For a clear description of much of open-access publishing, I will defer to a preeminent authority on the subject, Jeffrey Beall:
When email first became available, it was a great innovation that made communication fast and cheap. Then came spam – and suddenly the innovation wasn’t so great. It meant having to filter out irrelevant, deceptive, and sometimes offensive messages. It still does…The same corruption of a great idea is now occurring with scholarly open-access publishing.
The HIV-AIDS literature long pre-dated the internet. This did not mean everything published in the early days of AIDS or more recently was correct or that none of it was mendacious. But most of the literature could be trusted as a genuine attempt to understand the problem. The pace may have been slower than with COVID-19, but the trail was clear. This is (still) true of early versions of open-access publishing represented, for example, by BioMedCentral (BMC), in which the intention was to make scientific publishing more open and rapid. One of my graduate students whose goal was to get a faculty position in a small teaching college took advantage of the opportunity provided by a BMC journal. Our extensive experience with that journal was that peer review was and remains rigorous at BMC (yes, n = 1, but I have reviewed for BMC and the process was exactly like that for legacy journals).
The basic model of open-access publishing is that the authors pay a fee upfront (typically $1,000 to $2,000 last time I looked; frequently higher to make contributions to legacy journals immediately available without a paywall) and then usually retain copyright.[3] It did not take long for a version of Gresham’s Law to conquer much of open-access publishing.
Thus, predatory journals followed soon after the initial open-access titles.[4] By no means are all open-access journals predatory, but many/most of them were established with the goal of making money, and a problem as pressing as COVID-19 is fertile ground. Not that there is anything inherently wrong with making money in scientific publishing, as long as standards are maintained.[5] One of the most successful open-access publishers is the Frontiers Group, which now “publishes” 178 online journals.[6] According to their website, they are the “3rd most-cited publisher and 6th largest publisher, with 1.9 billion article views and downloads.” Which brings us to one ground level view of the COVID-19 literature.
A recent paper published in Frontiers in Pharmacology is worth consideration: COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms. The first and corresponding author is Dr. Robert W. Malone. The paper has 24 additional authors. Dr. Malone is well known as the self-described “inventor of mRNA vaccines.” But there is little evidence for that. However, he was first author on the first research showing that functional RNA can be introduced into mammalian cells, incidentally using the mRNA encoding luciferase from the firefly Photinus pyralis. As I noted in a previous post, light is very easy to measure! I remember this paper well, although through the corresponding author Inder Verma instead of Robert Malone.
The Malone et al. famotidine paper is very long, with 12 disparate figures and two tables spread over 21 formatted pages. However, this can be one of the major advantages of open-access publication. Space limitations are not a problem when the paper exists in cyberspace only until downloaded as full-text or pdf. The data generally support the conclusion that “new COVID-19 multi-drug treatment strategies based on repurposing well-characterized drugs are being developed and clinically tested, and many of these drugs are available worldwide in inexpensive generic oral forms suitable for both outpatient and inpatient treatment of COVID-19 disease.” But the results can hardly be called more than slightly suggestive. Whether this is true of famotidine, commonly known as Pepcid, remains to be seen.
However, this paper has been accessed 124,287 times, probably due to the identity of the primary author, and cited in papers in PubMed more than 30 times since publication in March 2021. Not bad, and 25 scientists can take credit for contributing to the response to COVID-19!
A second paper from Frontiers in Virology is a bit more problematic: MSH3 Homology and Potential Recombination Link to SARS-CoV-2 Furin Cleavage Site. This paper has 413,026 views, largely because it purports to prove that the presence of a unique19-base pair nucleotide sequence may prove that SARS-CoV-2 was generated in a laboratory. Naturally, it was a hit at the Daily Mail, which is most catholic in its consistently fantastical, but by no means always illegitimate approach to science.
I originally planned to dig deeper into this but found that someone else already had. Not abusing fair use, I trust, here is their take on the matter:
The Daily Mail article received more than 40,000 user engagements on Facebook. Others, such as the Facebook page for the political activist group Young Americans for Liberty and the website Not the Bee, promoted the Daily Mail article, serving as a springboard for such claims by social media users…
The study reported that a small snippet of the gene for the SARS-CoV-2 spike protein was a 100% match with a segment of a modified human gene sequence patented about three years ago by Moderna. The researchers wrote that ‘The absence of [the sequence showing a 100% match] from any eukaryotic or viral genome in the BLAST database makes recombination in an intermediate host an unlikely explanation for its presence in SARS-CoV-2’. They postulated that the sequence was acquired by a SARS-like coronavirus when it infected human cell cultures grown in a laboratory, thus producing SARS-CoV-2. This hypothesis paved the way for renewed claims that the virus was engineered in a lab or was leaked from a lab…
In its headline, the Daily Mail, in the fashion of ‘just asking questions’, implied that the match is evidence that the virus SARS-CoV-2 is manmade, writing of the study: ‘More evidence Covid was tinkered with in a lab?’
As we will explain below, this is misleading and fails to account for the evidence we already have that runs counter to the claim that SARS-CoV-2 was engineered in a lab.
And explain they do. The sequence may not be a protein-coding sequence, and besides, it is not unique, being found in a chimney swift gene and in a mycobacterium genome. which would be expected for a 19-nucleotide sequence in the entire DNA sequence database available for searches, despite the result any probability calculations return.
But this paper, which has a subsequent corrigendum that is half as long as the original paper, took up a lot of oxygen in the COVID discussion arena. It also confuses homology with sequence similarity, but that is a most common category mistake.
This is not the only such paper, and they have been used on all sides of the COVID pandemic arguments… is the spike structure in the vaccine construct really correct, to mask or not, it’s just a cold that everyone will get, there is nothing we can do so we might as well just relax and declare the pandemic over. My several colleagues who have recently had COVID, some with nasty Paxlovid rebound might differ on the latter.
In the long run do papers like this, often published where peer review can be lax, really matter?
I believe they do, and one other view from ground level indicates why. A measured review that is well supported by what we already know of the brain, was published in July 2022 in the Journal of Neurophysiology (American Physiological Society, 1938) by Leslie M. Kay. It asks the question: COVID-19 and olfactory dysfunction: a looming wave of dementia?
That the olfactory bulb is a gateway into the brain is well established:
The OB is particularly vulnerable to infection via the cribriform plate. Some viruses can infect olfactory sensory neurons directly, including many strains of influenza, herpesvirus, poliovirus, and West Nile virus. The transcribriform route is one method used to bypass the blood-brain-barrier for drug delivery. One example is nasal zolmitriptan used to treat migraines. Nasal application diffuses the drug easily into the CNS. Even if pathogens do not directly infect olfactory sensory neurons, they can cross the blood-brain-barrier in the cerebrospinal fluid (CSF) within the fascicles of the olfactory and nerve in the upper recesses of the nasal cavity or via infection of the glial olfactory ensheathing cells that surround these channels.
I would add that the “brain-eating amoeba” Naegleria fowleri also gains access to the brain through nasal passages and the cribiform plate, and that I will never swim in a freshwater river or pond again.
The review is open-access and readily accessible, so I will leave this with another extended quote from Dr. Kay:
This entire story is based on a hunch that comes from my deep knowledge of olfaction and its role in limbic system health. The hunch is (well) supported by confirmatory evidence. Maybe I am wrong. I hope I am wrong. There is not yet proof that infection in the OB will lead to dementia later on. However, there is enough evidence for the current pandemic and the place of the olfactory system in many diseases that result in dementia (e.g., Alzheimer’s disease, Lewy body dementia) that further research is warranted…
In 1920, in the wake of the Spanish Flu pandemic, we did not have the research infrastructure or the technologies that we have now. Although a catastrophe on many levels, the COVID-19 pandemic presents an opportunity to improve human health. We should take advantage of this opportunity (parentheses added).
“Let ‘er rip!” and long covid may have even worse consequences. The key is “deep knowledge.” We do have enough deep knowledge to effectively attack COVID-19, but we are too distracted, as both a scientific community and as a polity, to focus. I hope to return to this subject in a subsequent post.
Nevertheless, these are the scientific issues of COVID-19 the Biomedical Establishment should be discussing and pursuing, in public, not whether SARS-CoV-2 was the result of a lab leak[7] or whether a 19-nucleotide sequence in a patent application is evidence of Big Pharma perfidy, or whether a drug for gastroesophageal reflux disease can be repurposed to treat COVID-19, in the absence of reasonable evidence for why it might[8], or whether new commercial mRNA vaccines to an old virus will work (probably not). The publication of a few hundred thousand papers that are meant to gain credit of some kind just will not do the job.
The evidence seems to indicate that Silvain Lesné thought differently regarding Alzheimer’s disease. Mother nature doesn’t care what we think. But we should, and biomedical science properly pursued can answer our many questions about COVID-19.
Finally, one small bit of considered advice, which is unneeded in the NC community, but spread the word. When reading the scientific literature, dig deeper than the headline, the author(s), the title, and the journal. It is often difficult for a scientist, much less a layperson, to parse a journal title, if not its contents.
Open access journals always look and sound legitimate, which is the key to their persistence and profitability. A pdf from one will look exactly like a pdf from Proceedings of the National Academy of Sciences. But legacy journals are not blameless by any stretch of the imagination. The Lancet, which is one of the very best biomedical journals, has led the way on many COVID-19 issues. It also loosed Andrew Wakefield upon the world. Caveat emptor, alas.
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[1] On 12 September 2022, the search returned 289,698 results. When results from 2019-2022 are summed independently the total was 320,485.
[2] Nevertheless, it has been estimated that AIDS still may cause up to one million deaths per year, worldwide, despite the availability of HAARTsince 1995.
[3] Note that in traditional legacy journals the author(s) also pay commercial publishers, generally out of a line item in their grant support, in the form of page charges and added costs for color figures and diagrams. Page charges have required that the paper be identified as an “advertisement,” which is fairly ugly to contemplate. Fees are sometimes waived in extraordinary circumstances. These costs can run to more than $2,000 in some journals. Which is why my previous research in biochemistry was often published in Biochemistry, which is a journal of the American Chemical Society. No charges, at the time, and color was free if the editor agreed that it was required. A similar manuscript at the nominally leading Journal of Biological Chemistry (JBC) would cost as much or more than $2,000 in page charges and other surcharges. A close colleague who was an Associate Editor at JBC asked me if I would pay a $100 submission fee to JBC. I replied, of course, thinking it would be in lieu of the other charges. But no. The $100 would be in addition to the other fees. I asked him if it made more sense to spend the $2,000+ on lab supplies for research or to massage my vanity with a marginally higher “impact factor.” No good answer was forthcoming.
[4] Jeffrey Beall, who was an academic librarian and the University of Colorado-Denver, first identified “predatory publishers” in his eponymous Beall’s List as titles that skirted peer review and published papers that were barely reviewed. Beall’s List was disappeared, but a mirror site is maintained anonymously. There is much open-access money to be made at $1,000+ for each manuscript accepted, converted to pdf and posted on a website, and for a long time no one had really noticed what was going on. Beall here and here, for example. Jeffrey Beall is now retired. Nevertheless, many academic libraries maintain a list of suspect “journals.”
[5] One of the most prominent individuals to realize the profit in scientific publishing was none other than Robert Maxwell, proprietor of Pergamon Press and father of Ghislaine.
[6] Frontiers accused Jeffrey Beall of scientific misconduct; an investigation by the University of Colorado returned no findings or actions against Mr. Beall.
[7] Which it may have been, but the notion that the virus was “created” in the laboratory, even as a result of gain-of-function research, is barely credible but highly believable among many.
[8] There is some evidence the drug that dare not be named interferes with viral RNA synthesis. Thalidomide has uses in the treatment of leprosy and multiple myeloma.
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There appears to be an archived (and semi-maintained?)copy of Beall’s list available at Beall’s List of Potential Predatory Journals and Publishers
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Dorthey Bishop has a couple of recent blog posts on the state of academic publishing people might find interesting. BishopBlog
How many people are suffering COVID-19 and being told that it’s not COVID-19? It’s not COVID-19 unless we stick a swab up your nose and find SARS-CoV-2. What if SARS-CoV-2 is wreaking havoc in every organ of the body except the nose? People are coming into emergency rooms with all sorts of weird symptoms. But it couldn’t be COVID-19 because they didn’t test positive for COVID-19.
KLG: The Lancet, which is one of the very best biomedical journals, has led the way on many COVID-19 issues. It also loosed Andrew Wakefield upon the world.
They also continued to stand behind (last time I checked) the discredited PACE study that claimed CBT and Graded Exercise Therapy were effective treatments for ME/CFS. And that single, unreplicated study was enough to set the treatment protocol for NICE (UK) and CDC (US) and in the Netherlands. It took a long time for NICE and the CDC to withdraw those protocols (and they did so very quietly) and a lot of damage was done.
For other non-medical people like me:
ME/CFS is myalgic encephalomyelitis/chronic fatigue syndrome
The symptoms and etiology of ME/CFS are very much like those of Long Covid. As one who has had ME/CFS since experiencing a serious respiratory infection in 2006, I am hopeful that the increased incidence of post-acute sequelae will generate more money for research and treatment of this condition. Ever the giddy optimist, me.
I am a well published neuroscientist, and I have to say the take on open access publishing is too broad brush. We need to get the paywalls out of science publishing… period. It has always been a scourge to scientists to deal with hundreds of paywalls at various journals. Any good scientist knows which journals can be trusted, and which ones can’t. You spend gobs of time going through literature searches, sometimes every day, so it’s not like you are a babe in the woods. If you have a problem with open access publishing, then fix it by standardizing peer review criteria at all journals. Some of the most cited and most misleading articles in science in recent years (I’m thinking about Alzheimer disease) have been published at the big journals with paywalls. The data turned out to be fabricated. So this is a problem in science in general, not a problem with open access publishing.
Yes, the fact that PUBLIC funded research is not freely available is insane.
“Any good scientist knows which journals can be trusted, and which ones can’t. You spend gobs of time going through literature searches, sometimes every day, so it’s not like you are a babe in the woods. If you have a problem with open access publishing, then fix it by standardizing peer review criteria at all journals.”
True. The problem doesn’t begin with “any good scientist,” though, who has a natural allergic reaction to poor papers from marginal sources. The problem begins with “anyone” citing so-called peer-reviewed research that gives spam a bad name. Spam is recognizable to all except the very young and very old and the terminally credulous. The problem is that a pdf from a spam journal is outwardly indistinguishable, to a non-scientist citizen, from a pdf from the Proceedings of the Royal Society (a descendant of Philosophical Transactions of the Royal Society, 1665), IIRC the first scientific journal. But I have also noticed that “many good scientists” are publishing in “journals” produced by open-access purveyors who were on Beall’s List but have now laundered themselves into respectability. Are are these scientists oblivious, just playing the game, or mendacious in the pursuit of a reward of some kind? All three, maybe? I recently looked up a former colleague who has been on what he believes is an upward trajectory for nearly 40 years. He has >450 entries in PubMed, or about 10 per month. Several of his most recent have been from those original Beall’s List miscreants. This, from a scientist who actually laughed at a presentation of mine because it was based on a paper in Experimental Cell Research. Archival, yes. A good journal, also yes, published at the time by Academic Press. Did the work hold up to scrutiny, yes. Open-access fee is currently $2910, hmm. Any cell biologist will recognize members of the Editorial Board. I have yet to recognize a single member of the Editorial Board of a spam journal, but I confess to not looking very hard. My former colleague with the fine pedigree and sharper ambition is still not in the National Academy of Sciences, which has been his professed goal since I met him in 1983. His postdoctoral mentor is, however.
Great post, thanks. As an idiot layman it is hard be as critical as one would like with the journal articles one sees. Furthemore, for those who have made their mind up to some extent (in my case: Covid is and will continue to be really bad, and we should try – or in Australia’s case resume – containment) confirmation bias is always a risk, especially when a SARS virus has been so idiotically politicised from day one. And confirmation bias isn’t just a risk for laymen of course but also the twitter scientist tribalism scene – which can be quick to promote preprints etc., (although having said that, Leonardi’s hypotheses vis à vis T-cells have been published in Frontiers, and they appear to be holding up rather well) as well as disingenuous and misleading criticisms of studies which certain people may disagree with (Prasad denigrating various mask studies on inane grounds as a distraction from their obvious utility, and his “I demand RCTs for interventions I don’t like” fetishism come to mind). So, yes, information gathering has been a daunting process after starting from nothing for the past few years, although NC has been a very helpful starting point, and most readers are better apprised of the long term risks and potential collective, societal consequences for letting this disease spread unchecked than most.
Finally, with a view to your next piece:
Not only that, but it was complete revisionism too: as GM has pointed out, the clinical endpoint was originally >50% efficacy, which the vaccines (not the updated one which I don’t know enough about, although I gather that its 25mg WT, 25mg BA.5 formulation is something of a joke) have fallen well short of for some time, and CureVac was rejected EUA for failing to meet this endpoint. Another revisionist canard that has taken hold is that the vaccines only started losing efficacy with Omicron, even though it was apparent that this was happening long before Omicron’s emergence, with Delta.
I do have a question (by no means expecting a definitive answer) with the bit that I emphasised though: it seems to be the case that Omicron has traded pathogenicity for transmissibility. If that is so, then how do we disentangle that characteristic with the vaccines’ putative impact on reduction of symptom severity for Omicron? Is it an open question how Omicron would be affecting an immune-naïve population?
Definitely not an “idiot layman” BP! But that is how most members of the PMC view all of us who are not down with their innate superiority.
Someone else will have to answer your immunology question!
> disentangle
It’s a very fine question which can’t be answered well, given path-dependence. Even a twins study would have too-sparse data for the older cohort. And the question accepts a dangerous assumption, that only short-term symptoms count.
Very true, I only ask it as such because that is the overwhelming assumption of the general public, and defines their approach to and opinions of the crisis, but of course it is only one part of the problem. It’s an open question which I think more people would do well to be aware of.
It’s always difficult for the layman to parse meaning from the vocabulary of any specialized discipline but I think I understand most of what you have written.
I was pleased to see your footnote #8 regarding the drug that shall not be named… and since it pertains to the topic of animal medicine, I’m curious as to your insights on fomatidine, which was prescribed by my vet for my cat to address a clinical diagnosis of pancreatitis. It seemed to do the trick and Zelda responded quickly.
The only symptom of illness I have encountered during the covid pandemic was gastrointestinal – pain in the upper abdomen, most acutely after eating, accompanied by GERD/heartburn and the discomfort of excessive stomach gas only partly relieved through relentless burping. Given its primary use in humans for exactly those symptoms, fomatidine – unsurprisingly – relieved them with great, indeed almost immediate, efficiency. It also eliminated the sensation of “shortness of breath” which I assumed resulted from the gas build-up directly effecting a certain inflexibility in my lungs ( as an opera singer, anything that keeps air “trapped” in the lungs is hard not to notice).
I understand this may have nothing to do with being an effective treatment for covid. But pancreatitis is usually listed as a possible complication of the virus, yes?
Famotidine might have some use. Evidence is equivocal, however. TMI, but the list is here. Some of these journals are quite good. Others? YMMV. But the problem is that an inexperienced parser of the biomedical literature cannot know without too much effort.
PubMed has long been my go-to site.
Should I be taking articles (especially the tsunami of those originating from China), with a grain of (since familial hypertension runs in the family) KCl?
Caveat emptor! This applies across the board. And to a large extent it always has. Scientists can be blinkered and they certainly make mistakes. One of my best papers (in my opinion) has an absolute howler in it. I used very old, junior high biology-level taxonomic term as a temporary placeholder in a figure. I neglected to change it and it became permanent, for all to see my dumbassery. Oops! Confirmation bias is real. Some scientists have objectives other than the expansion of knowledge and understanding of the natural world in mind, for social, economic, political and personal reasons. But I would not call them scientists. Marketers, crooks, spammers…yes. But on the author line, they are identified as scientists. Always.
And keep after Hayek!
As a Ph.D. researcher and postdoc my opinion of the serious white papers with their smart looking charts and typography changed as I evolved into an expert in my field. What at first seemed like an amazing world where the smart people had important conversations about esoterica later revealed itself to be mostly a) practically useless or b) venal self interest of the researcher or their sponsor.
The more money on the line on any given topic the more the skepticism that showed to any paper, especially when they can’t replicate.
Thank you, KLG, for your insights. I work in a scientific field far removed from medicine and with much lower stakes. It’s disheartening to learn that the foibles and petty status-seeking I see in my publish-or-perish milieu apply to medicine as well. Though I don’t know why I expected it to be any different.