Talk:The science

Laboratory derived

New Study By Dr. Steven Quay Concludes 99.8% likely that SARS-CoV-2 Came from a Laboratory

The final conclusion after systematically examining twenty-six different, independent facts and evidence is that it is a 99.8% probability SARS-CoV-2 came from a laboratory and only a 0.2% likelihood it came from nature.

A paper published by Dr. Steven Quay, M.D., PhD. in the last days of January 2921 entitled, "A Bayesian analysis concludes beyond a reasonable doubt that SARS-CoV-2 is not a natural zoonosis but instead is laboratory derived."

Dr. Steven Quay stated "Like many others, I am concerned about what appear to be significant conflicts of interest between members of the WHO team and scientists and doctors in China and how much this will impede an unbiased examination of the origin of SARS-CoV-2."

The good doctor went on to state, "By taking only publicly available, scientific evidence about SARS-CoV-2 and using highly conservative estimates in my analysis, I nonetheless conclude that it is beyond a reasonable doubt that SARS-CoV-2 escaped from a laboratory. The additional evidence of what appears to be adenovirus vaccine genetic sequences in specimens from five patients from December 2019 and sequenced by the Wuhan Institute of Virology requires an explanation. You would see this kind of data in a vaccine challenge trial, for example. Hopefully the WHO team can get answers to these questions." for its activation (Figure 2).

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Figure 2. Biological functions of ACE2. In physiological situations, ACE2 functions as a carboxypeptidase enzyme that catalyzes the hydrolysis of angiotensin II (Ang II) into Ang(1–7) by cleaving off a phenylalanine (Phe). In the presence of the spike protein, this enzyme becomes a membrane receptor for cell signaling that uses the spike protein as a ligand for its activation. Kuba et al. [28] showed that the injection of mice with recombinant SARS-CoV-1 spike protein reduced the ACE2 expression and worsened the acid-induced lung injury. In mice with an acid-induced lung injury, the recombinant SARS-CoV-1 spike protein dramatically increased angiotensin II, and the angiotensin receptor inhibitor losartan attenuated the spike protein-induced enhancement of lung injury [28]. Thus, these in vivo studies demonstrated that the spike protein of SARS-CoV-1 (without the rest of the virus) reduces the ACE2 expression, increases the level of angiotensin II, and exacerbates the lung injury.

The SARS-CoV-2 spike protein without the rest of the viral components has also been shown to activate cell signaling by Patra et al. [29]. The authors reported that the full-length SARS-CoV-2 spike protein expressed by the means of transient transfection, either in the human lung alveolar epithelial cell line A549 or in the human liver epithelial cell line Huh7.5, activated NF-κB and AP-1 transcription factors as well as p38 and ERK mitogen-activated protein kinases, releasing interleukin-6. This cell signaling cascade was found to be triggered by the SARS-CoV-2 spike protein downregulating the ACE2 protein expression, subsequently activating the angiotensin II type 1 receptor [29]. These experiments using transient transfection may reflect the intracellular effects of the spike protein that could be triggered by the RNA- and viral vector-based vaccines.

These results collectively reinforce the idea that human cells are sensitively affected by the extracellular and/or intracellular spike proteins though the activation of cell signal transduction.

4. Pulmonary Hypertension

PAH is a serious disease without a cure that can affect males and females of any age including children. The increased pulmonary vascular resistance in PAH results in right heart failure and subsequently death. Patients diagnosed with PAH only live for 2–3 years from the time of diagnosis on average if untreated [30,31]. Even with currently available therapies, only 60–70% of PAH patients survive for three years [32,33,34,35]. PAH is hard to detect because its symptoms (e.g., shortness of breath, fatigue, and dizziness) are similar to those of other common non-life threatening conditions, and the official diagnosis for PAH must be made through invasive right heart catheterization [36]. Endothelial dysfunction is a common feature of patients with PAH and COVID-19 [37,38].

PAH “outbreaks” have occurred in association with exposure to certain drugs or toxins [39]. A major outbreak of PAH occurred in 1965 and was associated with aminorex, a weight-loss stimulating drug [39,40]. Approximately 0.2% of people who took this drug developed PAH [40]. An epidemic was observed two years after the introduction of aminorex, and half of the patients died 10 years after the epidemic [39].

We studied pulmonary vessels of COVID-19 patients and those of H1N1 influenza-infected patients who died of ARDS [21]. The pulmonary arteries of postmortem COVID-19 patient lungs consistently exhibited histological characteristics of vascular wall thickening, mainly due to the hypertrophy of the tunica media. Detailed pathological analysis revealed that the boundaries between the vessels and the surrounding lung parenchyma have lost clarity, the SMCs of the middle lining of the arteries have enlarged, the nuclei of SMCs have swollen, and vacuoles have been generated in the cytoplasm of SMCs [21]. A morphometric analysis determined that the median pulmonary vascular wall thickness values were 15.4 μm for the COVID-19 patients and 6.7 μm for the influenza patients, and these values were significantly different from each other [21].

Pulmonary vascular wall thickening in COVID-19 patients was also observed on the computed tomography scan of the chest [41,42]. Thus, these results together indicated that COVID-19 is associated with pulmonary vascular wall thickening. Investigations on whether this pulmonary vascular wall thickening is related to clinically significant PAH and the role of the spike protein in the pathogenesis of PAH are warranted.

RBD-only

5. RBD Only-Containing SARS-CoV-2 Spike Protein Does Not Elicit Cell Signaling in Human Cells

In contrast to the full-length spike protein [26,29] or the full-length SARS-CoV-2 spike protein S1 subunit [21], we found that the RBD only-containing protein (Figure 1) did not promote cell signaling. Our Western blotting results monitoring the MEK activation showed that the mean ± SEM phosphorylated MEK to MEK protein ratio values were 0.05 ± 0.003 (untreated), 1.9 ± 0.07 (treated with the full-length S1 protein), and 0.05 ± 0.003 (treated with the RBD only-containing protein) for human pulmonary artery SMCs; and 0.09 ± 0.006 (untreated), 0.90 ± 0.06 (treated with the full-length S1 protein), and 0.10 ± 0.003 (treated with the RBD only-containing protein) for human pulmonary artery endothelial cells [21].

The different effects of the full-length S1 and RBD only-containing proteins may be important considering that BNT162b2 and many other COVID-19 vaccines express the full-length spike protein, while the BNT162b1 vaccine encodes only the RBD region [9,10,11,12,13,14,15,16,17,18,19,20]. There are some other RBD-based COVID-19 vaccines being developed as well [43]. It is possible that the RBD-based vaccines are less immunogenic, but may not affect the host cells. Thus, they may be less risky considering potential long-term adverse effects. However, in the in vivo study of the SARS-CoV-1 spike protein described above [28], a deletion mutant that only contained the RBD also worsened the acid-induced lung failure, like the full-length spike protein. Thus, further work is needed to understand effects of the full-length spike protein and the RBD-only containing protein in various biological processes.

pathogenesis

6. Discussion

It is generally thought that the sole function of viral membrane fusion proteins is to allow the viruses to bind to the host cells for the purpose of viral entry into the cells, so that the genetic materials can be released and the viral replication and amplification can take place. However, recent observations suggest that the SARS-CoV-2 spike protein can by itself trigger cell signaling that can lead to various biological processes. It is reasonable to assume that such events, in some cases, result in the pathogenesis of certain diseases.

Our laboratory only tested the effects of the SARS-CoV-2 spike protein in lung vascular cells and those implicated in the development of PAH. However, this protein may also affect the cells of systemic and coronary vasculatures, eliciting other cardiovascular diseases such as coronary artery disease, systemic hypertension, and stroke. In addition to cardiovascular cells, other cells that express ACE2 have the potential to be affected by the SARS-CoV-2 spike protein, which may cause adverse pathological events. Thus, it is important to consider the possibility that the SARS-CoV-2 spike protein produced by the new COVID-19 vaccines triggers cell signaling events that promote PAH, other cardiovascular complications, and/or complications in other tissues/organs in certain individuals (Figure 3). We will need to monitor carefully the long-term consequences of COVID-19 vaccines that introduce the spike protein into the human body. Furthermore, while human data on the possible long-term consequences of spike protein-based COVID-19 vaccines will not be available soon, it is imperative that appropriate experimental animal models are employed as soon as possible to ensure that the SARS-CoV-2 spike protein does not elicit any signs of the pathogenesis of PAH or any other chronic pathological conditions.

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Figure 3. Possible actions of the SARS-CoV-2 spike protein. The SARS-CoV-2 spike protein of the intact virus targets ACE2 of the host cells to facilitate the membrane fusion and the viral entry. The SARS-CoV-2 spike protein also elicits cell signaling in human cells [21,29]. COVID-19 vaccines introduce the spike protein into the human body. In addition to eliciting an immune response that suppresses the viral entry, the spike protein produced by the COVID-19 vaccines may also affect the host cells, possibly triggering adverse events. Further investigations addressing this possibility are warranted.

7. Conclusions

In conclusion, the recent advancement in the SARS-CoV-2 spike protein-based COVID-19 vaccine development is exciting and has shed light on how to end the current pandemic. These vaccines should benefit elderly people with underlying conditions if they do not exhibit any acute adverse events. However, we need to consider their long-term consequences carefully, especially when they are administered to otherwise healthy individuals as well as young adults and children. In addition to evaluating data that will become available from SARS-CoV-2 infected individuals as well as those who received the spike protein-based vaccines, further investigations of the effects of the SARS-CoV-2 spike protein in human cells and appropriate animal models are warranted.

Author Contributions

Conceptualization, Y.J.S.; validation, Y.J.S. and S.G.G.; investigation, Y.J.S. and S.G.G.; resources, Y.J.S. and S.G.G.; writing—original draft preparation, Y.J.S.; writing—review and editing, Y.J.S. and S.G.G.; visualization, Y.J.S.; supervision, Y.J.S.; project administration, Y.J.S.; funding acquisition, Y.J.S. Both of the authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Institutes of Health (NIH), grant numbers R21AI142649, R03AG059554, and R03AA026516, with funding awarded to Y.J.S. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

https://www.mdpi.com/2076-393X/9/1/36/htm

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