by dscheim
Legacy coronavirus biochemistry was overlooked that governs spike protein toxicity, key morbidities, risk factors and therapeutic responses
David E. Scheim 1, Thomas J. Borody 2, Robert Clancy 3
1US Public Health Service, Commissioned Corps, Inactive Reserve, Blacksburg, VA 24060, USA, dscheim@alum.mit.edu
2Centre for Digestive Diseases, Five Dock, NSW 2046, Australia, thomas.borody@cdd.com.au
3University of Newcastle School of Medicine, Newcastle, NE1 7RU, Australia, robert.clancy181@gmail.com
In a paper published today in Viruses (Basel) [1], an international team of researchers, including two fellows of their nations’ academies of sciences (Colleen Aldous, senior author Wendy Hoy) and others who participated in Nobel prize-honored research (Thomas Borody, Morimasa Yagisawa), has revealed how coronavirus biochemistry well-established over past decades governs the morbidities of COVID-19, risk factors and therapeutic approaches. TrialSite News is pleased to feature this important research.
The glycan monomer sialic acid, ubiquitous on eukaryotic cell surfaces, serves as the initial attachment point to host cells for the COVID-19 virus—SARS-CoV-2—as well as for other coronaviruses. The virus can then slide over to ACE2 for cell entry. SARS-CoV-2 spike protein attaches particularly tightly to the dense sialic acid coatings on the trillions of red blood cells (RBCs), platelets and endothelial cells in the human adult. These interlaced attachments trigger the RBC aggregation, microvascular occlusion and vascular damage underlying the oxygen deficits, blood clotting and related morbidities of severe COVID-19.
In the genetics-centric research environment of recent decades, however, most COVID-19 research ignored this older, well-established biochemistry, focusing instead on SARS-CoV-2 replication and its replication receptor, ACE2. Yet the typical human cell is coated with at most a few hundred ACE2 molecules vs. millions of virally-binding sialic acid molecules. This misdirected focus led to oversights of significant consequence, as detailed in the Viruses paper.
More broadly, disregard for the active physiological role of RBCs yields unreliable or erroneous reporting of pharmacokinetic parameters as routinely obtained for most drugs and other bioactive agents using detection in plasma, with whole blood levels being up to 30-fold higher.
Substantiation of the importance of this glycan biochemistry for COVID-19:
- RBC aggregation as experimentally induced in several animal species using an injected polysaccharide caused most of the same morbidities of severe COVID-19.
- Three major risk factors for COVID-19 mortality—older age, diabetes and obesity—are each associated with significantly increased RBC aggregation and microvascular occlusion.
- Three generic drugs that gleaned the most interest as COVID-19 therapeutics each reduce blood cell aggregation—one of these, ivermectin, disaggregated virally induced RBC clumps in vitro within 30 minutes.
- For mammalian species, clinical susceptibility to COVID-19 correlates to RBC aggregability, with statistical significance (p=0.03).
- The two human betacoronaviruses that express a sialic acid-cleaving enzyme, hemagglutinin esterase, are benign, while the other three—SARS, SARS-CoV-2, and MERS—are virulent.
As detailed in the newly published paper and summarized below, this glycan biochemistry is also key to disentangling controversies that have arisen over the efficacy of certain generic COVID?19 treatment agents, one of which, ivermectin, competitively binds to several sites on SARS?CoV?2 spike protein, and the safety of spike protein-based COVID?19 vaccines.
COVID-19 therapeutics
One key fallacy arising from the disregard of well-established coronavirus biochemistry was the assumption that since SARS-CoV-2 spike protein (SP) cannot replicate, it must be harmless, a belief that underlay the choice of SP as the immunogen for most COVID-19 vaccines. Yet once SP gains entry into the bloodstream, it becomes dangerous. Adding SARS-CoV-2 SP to human RBCs caused them to aggregate [2]. SP injected into Zebrafish embryos caused RBC clumping and vascular occlusion within minutes [3]. RBC clumps were found in the blood of most severe COVID-19 patients in several studies [4].
The toxic character of SARS-CoV-2 SP, despite its inability to replicate, is of more than theoretical concern. The newly published biochemistry paper reviews clinical studies that tracked markers of microvascular occlusion, including retinal vascular density and myocardial FDG uptake, with significant abnormalities persisting months after COVID-19 vaccinations. It also references a study of the health records of 99 million COVID-vaccinated individuals conducted by an international collaboration of 24 institutions, which found significantly increased incidences of myocarditis, pericarditis and other serious conditions [5]. Serious adverse effects were observed as well in a Yale study of 241 post-COVID vaccine syndrome patients [6].
On the other hand, the three generic drugs that gleaned the most attention as therapeutics for COVID-19 had a sound biochemical basis for efficacy, each significantly reducing RBC aggregation. The most distinct clinical benefits were observed for ivermectin, which neutralizes the virulence of SARS-CoV-2 SP by strongly binding to several sites on its N-terminal domain, competitively inhibiting its attachments to host cell glycans. In vitro, ivermectin not only blocked the SP-induced formation of RBC clumps, but it disaggregated such SP-induced RBC clumps within 30 minutes [2].
This blood cell disaggregation effect was manifested clinically by rapid resolution of oxygen deficits in severe COVID-19 patients, typically within 1-2 days after ivermectin treatment, sometimes within hours. This dramatic and readily observable clinical benefit sparked interest in and mass use of ivermectin by doctors to treat their critically ill COVID-19 patients in 25 countries by early 2021 [7]. Three clinical studies demonstrated this rapid normalization of peripheral oxygen saturation (SpO2) in severe COVID-19 patients within 1-2 days after treatment with ivermectin, as reviewed in the newly published COVID-19 biochemistry paper and shown in the figure below, from that paper.
Compounding the confusion about the biochemical mechanism of ivermectin, as the paper also notes, was the vulnerability of medical science to commodification, a subject that has engaged the contributions of some of science’s most distinguished scholars. Richard Horton, editor-in-chief of The Lancet, for example, wrote in 2015 that plagued by “flagrant conflicts of interest,” “much of the scientific literature, perhaps half, may simply be untrue” [8].
Financially driven biases against genetic drugs and crude fabrications of ivermectin poisonings
Such financially driven biases present obstacles to the use of generic drugs in competition with patented offerings. One example is the triple-therapy generic treatment for H. pylori (peptic ulcers), a previously intractable condition, developed four decades ago in Australia. It was shown to be 96% curative in a clinical trial conducted in 1990 by Thomas Borody, a coauthor of this COVID-19 biochemistry paper and also a coinvestigator of one of the studies for ivermectin shown in the figure above (Hazan et al., 2021). That triple-therapy cure for peptic ulcers was rapidly deployed in Australia, saving thousands of lives, but was not widely used in the rest of the world until almost a decade later, after the patents for two best-selling palliative drugs for that condition expired. The related discovery of the bacterial cause of peptic ulcers (H. pylori) was honored with the Nobel Prize for Medicine in 2005.
The rapidly expanding use of ivermectin to treat COVID-19 worldwide faced two streams of pushback by early 2021. One was a flurry of fabricated reports of ivermectin poisonings in the US reported in the major media worldwide, debunked and retracted, as exposed by the Washington Post [9] and other sources [10,11]. In one of the more imaginative of these fabrications, “gunshot victims” who were “left waiting as horse dewormer overdoses overwhelm[ed] Oklahoma hospitals” were shown waiting in line wearing winter coats, when temperatures that summer day ranged between 80° and 95° F.
