Yves here. KLG turns to what should be getting more serious attentions than it is: bird flu and what we might do now, having not made serious interventions early. His intro:
As H5N1 spreads the scientific literature will ramp up, so we need to know what to expect. This post considers a preprint on the putative origins of the current H5N1 variant of concern. While the overall hypothesis is not out of bounds, the authors cannot be considered objective, disinterested observers. This has been common in the COVID-19 literature (now up to 426,491 entries in PubMed), with less than optimum results. So with H5N1 we need to read well and with close attention to the “priors” of those who contribute to the current literature on H5N1. This is not an easy task with so many publishers and purveyors in action in the current environment, but it must be done. Whatever we do, the mistakes made with COVID-19 must not be repeated with a spreading H5N1 avian flu.
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
Are we facing a new pandemic, less than five years after the beginning of the current one? Maybe. The H5N1 “bird flu” is causing much consternation among the medical establishment and naturally, given the disputed origin and trajectory of COVID-19, the origins of Highly Pathogenic Avian Influenza (HPAI) H5N1 are already being discussed and disputed by those who want to get ahead of the game. Unfortunately, this is the nature of the current literature of Biomedicine [1], as we have often discussed in this series for nearly the past two years. Recent updates include these from the FDA, CDC, and WHO.
Several days ago I was forwarded a copy of a preprint with the title Proximal Origin of Epidemic Highly Pathogenic Avian Influenza H5N1 Clade 2.3.4.4b and Spread by Migratory Waterfowl. This has been an interesting topic with ramifications that characterize the current scientific literature. As with virtually all preprints and peer-reviewed papers in the online databases, this paper looks quite “good.” A preprint server produces a professional product. This paper investigates:
(T)he possible laboratory origins of…HPAI H5N1…currently affecting various animal species and causing sporadic human infections…(and concludes that)…the proximal origins of HPAI H5N1 may be the USDA Southeast Poultry Research Laboratory (SEPRL) in Athens, Georgia, and the Erasmus Medical Center in Rotterdam…as the result of serial passage (of the virus) in mallard ducks at SEPRL.
The ostensible purpose of this paper is to pose a question and suggest further research:
It is (sic) possible that HPAI H%N1 clade 2.3.4.4b evolved not in nature, but as a result of serial passage of other Gain-of Function (GOF) research in a laboratory? We hope the following investigative report will serve as a starting point for further investigation by specialists in the fields of virology, molecular biology, and avian flu epidemiology.
There can be no serious objection to this on the surface. The cult of the expert has led us astray regarding COVID-19 for more than four years, without much of a resolution in sight. Their figures are well presented, but the authors are not convincing in their selective review of the literature and conclusion that this variant of H5N1 if the likely product of serial passage of the virus (or intentional mutagenesis of this variant). Nor is it obvious how one variant can have two origins, one in Rotterdam and one in Georgia.
Still, it is clear that laboratory accidents do cause infections. During my early apprenticeship in the laboratory, I read of a centrifuge service technician who contracted Rocky Mountain Spotted Tick Fever and died. Our regular service contract technician would not go near our centrifuges for routine maintenance until they were sterilized. Although we did not use any infectious agents, he was correct in his precaution. This paper does raise questions that should be answered whether it is ever published or not after peer review. [2] Similar questions regarding SARS-CoV-2 have not been answered. And therein lies much of the backstory if this very preliminary contribution to the current H5N1 literature.
But first a primer on reading the scientific literature and the use and abuse of preprints. At the beginning of my life as a scientist, a “preprint” was a paper in manuscript form that was in preparation or had already been submitted to a journal but not yet published. It was circulated confidentially among collaborators and colleagues informally so that they could be aware of where the field was going. Somewhat later preprints became the route to publication in mathematics and physics, as manuscripts were made available to the interested readers on arXiv (1991). A paper could remain in preprint form for years before appearing officially “in print.”
More recently preprint servers have become common in the biological and biomedical sciences, with bioRxiv (2013) and medRxiv (2019) as successors to arXiv. Both of these are hosted and moderated by Cold Spring Harbor Laboratory Press. CSHL Press (distributed by Oxford University Press) is a division of Cold Spring Harbor Laboratory on Long Island. With the lamentable exception of its detour into eugenics in from 1910 to 1939, CSHL has been one of the most productive biological laboratories in the world, with the institutional disinterestedness essential to the production of reliable science. This was considered here previously in an analysis of the work of Nancy Cartwright and colleagues.
So now we come to the preprint under discussion, which is hosted by Preprints.org, a division of MDPI, whose open-access article processing charges (as of January 2023) are listed here. The disclaimer, which is broadly applicable to all preprints, at the top of the pdf but not original link reads:
Disclaimer/Publisher’s Note: The statements, opinions, and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions, or products referred to in the content.
This is the first thing the general reader must keep in mind when reading the scientific literature, which is increasingly first publicized from preprints. The second thing is to examine the interests and motives of the authors, and that includes all of the biomedical literature, preprints and published alike.
What about the present authors, who are affiliated with the McCullough Foundation of Dallas, Texas? Nicolas Hulscher is a Fellow of the McCullough Foundation who produced this video (3:16) on the McCullough Foundation and “will be concerned with will provide insightful analysis across the four core pillars of the Foundation: Investigative Scholarship, Education, Justice, and Public Policy”. John Leake studied with the late Sir Roger Scruton [3] and wrote The Courage to Face COVID-19 with Peter A. McCullough, who is the namesake of the McCullough Foundation and a well-known COVID contrarian (not that there is anything wrong with that in principle). From the mission statement of the McCullough Foundation:
McCullough Foundation is dedicated to the proposition that a government of the people, by the people, for the people, can only exist if the people are educated about health, disease, and public health policies. As James Madison, author of the U.S. Constitution remarked: “Knowledge will forever govern ignorance, and a people who mean to be their own governors must arm themselves with the power knowledge gives.”
As we learned during the COVID-19 pandemic, our deep-seated fear of deadly infectious disease makes us very susceptible to manipulation by public health officials (often in league with undeclared commercial interests) who invoke emergency power with the purported objective of protecting us. Thus, our fear of infectious disease can be exploited by unscrupulous public officials in the same way our fear of foreign invaders has been used by dictators and tyrants throughout history. Again, to quote James Madison: “The means of defense against foreign danger have been always the instruments of tyranny at home.”
This is standard libertarian discourse, such as it is. This also finds its echo on the liberal side of the divide, for example in a significant selection of the catalog of Chelsea Green, one of my favorite publishers. This did not arise ex nihilo. Dr. McCullough is an advocate of what can only be called libertarian medicine and has recently been the Chief Scientific Officer of The Wellness Company, which among other things offered “free medical care” to the residents of East Palestine, Ohio after the horrific Norfolk Southern derailment in February 2023.
The question for us is “Where does libertarian medicine come from?” Libertarian medicine should be a category mistake. The practice of medicine has always been as much art as science, but in our infatuation with the idea of progress (here, for example) we have forgotten this. Medicine has become (very) big business during my lifetime, with care of the people somewhere under the bottom line. Consequently, the clinical judgment of primary care physicians, whose life’s purpose is to care for their patients as people and not conditions defined by algorithms, has been devalued. The backlash has been severe among those who are the victims of our misguided healthcare system. This includes those who deliver healthcare and those who need the help of their doctors and nurses.
From the beginning of COVID-19 all parts of the politico-healthcare establishment – NIH, CDC, WHO, FDA – have frequently been tone deaf in their pronouncements of “Trust the science” and “I represent science (with the corollary that those advocating unconventional approaches are quacks and cranks by my definition).” Aside from immediate identification of SARS-CoV-2 as the agent of the COVID-19, very little true science informed the early responses. to the pandemic. This includes pronouncements from Dr. McCullough and his like-minded contrarians that “children are not at risk” and that “those who are infected with SARS-CoV-2 have permanent immunity.” The first statement is outrageous. The second statement was known to be untrue soon after the identification of respiratory disease caused by coronaviruses in the 1950s.
The response to COVID-19 by Dr. McCullough and his coworkers is not unlike that of the American Institute for Economic Research (AEIR) in their wonderfully named Great Barrington Declaration. How could something with that name not be true? Given that the AIER is a libertarian thinktank dating to Great Depression the text of the GBD could probably have been written by ChatGPT with the proper prompts. But it is not true. [4] But neither were the primary strategies promoted by the politico-healthcare establishment, which accelerated straight to mRNA vaccines and not much further. And they had no excuse in not knowing that lasting immunity to coronaviruses is a chimera. Thus, these vaccines prevent neither infection nor transmission. But widespread and sustained use of effective masks would have worked to contain the pandemic, along with improvements in ventilation and air filtration. During this time antivirals could have been developed, such as those that made AIDS a manageable disease for the vast majority of those who can afford the drugs. That everyone who needs those drugs cannot get them is another matter altogether.
So, where do we go from here? I honestly do not know, so let the discussion begin. But while reading Everything is Predictable: How Bayesian Statistics Explain Our World by Tom Chivers, for a better understanding of the Reverend Bayes in my work, I found the kernel of an answer but not the solution in this quote:
We appear to be Bayesian machines (italics in original). That’s true at a fairly high level: humans are rubbish at working out Bayes’ theorem formally, but the decisions we make in everyday life are pretty comparable to those that an ideal Bayesian reasoner would make. Which, unfortunately doesn’t mean we all end up agreeing – if my prior beliefs are very different from yours, then the same evidence can lead us to entirely different conclusions, but sincere disagreements on apparently well-evidenced questions about the climate, or vaccines, or any number of other questions.
And we’re Bayesian at a deeper level, too. Our brains, our perception, seem to work by predicting the world – prior probabilities – and updating those predictions with information from our senses: new data. Our conscious experience of the world can be best described as our priors. I predict, therefore I am.
Yes, we are Bayesian in our approach to the world around us. Our problems lie in “sincere” disagreements that are not and “well-evidenced” questions for which the evidence is not disinterested. Does the notional libertarian have a sincere disagreement with mask mandates on scientific and epidemiological grounds, or is he just irritated that his negative liberty is infringed upon when masks, which do work, are recommended? Does the expressive leftist really believe the solution to urban blight in its many forms is to defund the police or is this idea simply performative nonsense? In each of these examples the causes are much deeper than the reactions.
Regarding “well-evidenced” questions, the scientific support for the efficacy of COVID-19 mRNA vaccines was very thin from the beginning. Whether they have been effective is a matter of definition, but they have not stopped transmission or infection, which is the general expectation of a vaccine. The data showing that the current H5N1 virus is the result of laboratory “experiments” is likewise thin and the paper under discussion is tendentious in my view. But what we can and must do is keep our wits about us and remain sincere and persuadable only by good, disinterested evidence, which is the only kind of scientific evidence. SARS-CoV-2 was an unknown of sorts in November 2019, although it should not have been after the previous SARS and MERS outbreaks. That we dropped them as a pressing scientific problem is unfortunate, not to mention ridiculous. Influenza viruses are a known quantity. What we must not do is forget that which we already know about them. And remember what Maimonides said a thousand years ago, “You must accept the truth from whatever source it comes,” so long as the source does not have an axe to grind.
Even though Proximal Origin of Epidemic Highly Pathogenic Avian Influenza H5N1 Clade 2.3.4.4b and Spread by Migratory Waterfowl clearly has an agenda, it is not impossible that serial passage of H5N1 has selected for mutations that make this variant more virulent. A mechanism for how this variant could have origins on two continents requires “imagination,” but evolution can converge. Still, preprints are just that, preliminary, in addition to being provisional, as are all scientific hypotheses. One other tip when reading this literature: If the primary author is described as a Fellow (scroll down to lower left of page) of the organization taking responsibility for the paper but the sole contact information is his gmail address, that can be taken as a waving red flag.
Acknowledgment
Thanks to LS for suggesting this topic. I take full responsibility for any and all deficiencies in the argument.
Notes
[1] I view Biomedicine as the often-corrupt offshoot of Biomedical Science, largely purveyed by Big Pharma, Big Ag, and Big Science, plus their marketing divisions, along with their antagonists on the Right and the Left.
[2] We have covered problems with peer review here, but the goal is to improve peer review, not discard it. Sisyphus comes to mind.
[3] Some of whose work I have read. Scruton was a conservative, apparently with a lowercase “c”, which means he was a Liberal with an uppercase “L”, who wrote in an interesting voice about modern philosophy. His book on caring for the environment locally identifies where the individual should begin, even if it offers no general solution to the coming inconvenient apocalypse. Sir Roger was also on the take for Big Tobacco.
[4] Note to the indispensable Matt Taibbi from a current subscriber and a reader since before the takedown of the Vampire Squid: One of the three primary authors of the Great Barrington Declaration, Jay Bhattacharya, MD-PhD, is not a scientist and he was never a physician. His MD from Stanford means little other than adornment of his CV, because he never qualified to be a physician through residency and board certification. Instead, he went from medical school directly to his PhD in the Stanford Department of Economics. As I understand it, if he identifies himself as a physician or implies he is that kind of “doctor,” he is breaking the law in many states.