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论文研究 - COVID-19大流行：其起源，影响和治疗.pdf

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    COVID-19 Pandemic: Its Origin, Implications and Treatments
    Abstract
    Keywords
    1. Introduction
    2. Origin of COVID-19
    3. Implications of COVID-19
    4. Treatment of COVID-19
    5. Conclusion
    Acknowledgements
    Conflicts of Interest
    References
    Open Journal of Regenerative Medicine, 2020, 9, 43-64 https://www.scirp.org/journal/ojrm ISSN Online: 2169-2521 ISSN Print: 2169-2513 COVID-19 Pandemic: Its Origin, Implications and Treatments Peter K. Law Cell Therapy Institute, Wuhan, China How to cite this paper: Law, P.K. (2020) COVID-19 Pandemic: Its Origin, Implica- tions and Treatments. Open Journal of Re- generative Medicine, 9, 43-64. https://doi.org/10.4236/ojrm.2020.92006 Received: April 8, 2020 Accepted: April 18, 2020 Published: April 21, 2020 Copyright © 2020 by author(s) and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access Abstract This is a succinct and current review of pertinent literature to guide develop- ing serum therapy as an emergent treatment to save human lives at times of natural or genetically engineered viral/bacterial pandemics. The origin of 2019-nCoV and implications of COVID-19 are discussed using direct quotes of published scientific literature to avoid misinterpretation on this very im- portant event that has caused great loss of human lives and international so- cial economy. It is the goal of this review to warn against and to correct inter- national misunderstanding created by deliberate falsification of scientific do- cumentations and events. This misunderstanding may lead to further destruc- tion of life, economy, and political relations. People should not be blind-sighted when making life decisions. Keywords 2019-nCoV, COVID-19, Serum Therapy, Pandemics, Epidemics, Convalescent Plasma, Coronavirus, Vaccine, Bacteria, Mutation, Biologic Warfare Weapons 1. Introduction Scientists are passionate with their visions, taking pride in their work, credit in their inventions, and responsibility to human society, all for the betterment of mankind. It is in this context that I present this review with the hope that bio- logical warfare will be banned, and that mankind will unite to combat natural pandemics like plague, diphtheria and malaria. My generation of baby-boomers was blessed with social/economic prosperity and no world war, the number one killer of mankind. However, what we expe- rienced with COVID-19, H1N1, SARS, H7N1, H7N9, MERS, AIDS and Ebola within the last 30 years were terrorizing events with destruction of life, economy, relationship, and communication, leaving shadows of anxiety, fear, mistrust and 43 Open Journal of Regenerative Medicine DOI: 10.4236/ojrm.2020.92006 Apr. 21, 2020
    P. K. Law DOI: 10.4236/ojrm.2020.92006 discrimination for significant years of our relatively short lives. COVID-19’s in- volvement of the livelihood of 7.7 billion people in 211 countries with an esti- mate of over 250,000 deaths before it ends is the equivalence of destruction second only to a World War. If we do not take haste to manage this human ca- tastrophe, life in a year will be beyond comprehension. As human beings, we need to establish emergency protocols to save lives, and to quickly rebuild and sustain social harmony and world economy at times of sudden pathogenic attacks. With continual competition in development of bio- logical warfare weapons, sudden outbreaks, either intentional or unintentional, will render certain countries less desirable to be inhabited, even for those who had been pre-vaccinated, believing that they might become immunotolerant of the viral antigens. We will miss beautiful cultures that we once enjoyed and che- rished. Once There was Peace Paleontology recorded that simple lives such as viruses and bacteria were original inhabitants of Earth some 3.5 billion years ago. The first mammal ap- peared 200 million years ago, and the first dinosaur, about 50 million years be- fore it [1]. These evolutionary ancestors of man (Homo Sapiens) had survived bacterial and viral pathogens for 250 million years. Through evolution, they de- veloped a highly specific and potent immune surveillance system throughout their bodies, distributed through the blood circulatory system. By the time human beings came to exist some 3 million years ago, our im- mune system had already evolved to reach and sustain an equilibrium with the natural faunas of bacteria and viruses, including those found in the 20-million- year-old flying mammalian species of bats [2]. It was not until groups of Ameri- can virologists and molecular geneticists succeeded in editing viral DNA/cDNA/ RNA/m-RNA sequence in late-1990’s that the equilibrium was broken. By 1998, a wide variety of viral delivery vehicles for genes had been tested in- cluding murine retroviruses, recombinant adenoviral vectors, adeno-associated virus, HSV, EBV, HIV vectors, and baculovirus. Fusogenic peptides in combina- tion with liposomes, or polymers, were used to enhance the release of plasmid DNA from endosomes. There were techniques to exploit the HIV-1 virus to en- gineer vectors for gene transfer, the combining of viruses with polymers or ca- tionic lipids to improve gene transfer, the attachment of nuclear localization signal peptides to oligonucleotides to direct them to nuclei, and the invention of molecular switch systems allowing genes to be turned on or off at will [3]. 2. Origin of COVID-19 2019-nCoV genomics indicated that it was a recombinant virus of SARS-CoV and HIV origins. The two species of viruses had distinct and distance pedigrees, and because of the different space and time of their existence, their recombinant had never appeared in a natural setting [4]. Therefore, 2019-nCoV could not be a product of nature, but rather a product of human genetic engineering. 44 Open Journal of Regenerative Medicine
    P. K. Law To uncover the scientific origin of the 2019-nCoV, it is necessary to under- stand certain pertinent scientific reports of gene therapy. Gene therapy encom- passes interventions that involve deliberate alteration of the genetic material of living cells to prevent or to treat diseases [5]. This FDA definition places two major technologies into the field of gene therapy: 1) Conducted in February and published in The Lancet on July 14, 1990 by my team, myoblast transfer therapy is the world’s first human gene therapy and so- matic cell therapy [6]. Through natural cell fusion, which is inherent in myoge- nesis and muscle regeneration, genetically normal myoblasts inserted their nuc- lei with full complements of normal genes into hereditary DMD dystrophic muscle cells to produce dystrophin, a structural protein that was not produced in DMD muscles due to the genetic defect. The transfer of genetic material and information occurred in vivo, with the myoblasts serving as the source and the vehicle of gene transfer. Gina Kolata reported on the front page of the New York Times on Sunday June 3, 1990 that “Cell Transplant Found Effective in Muscle Disease: Muscular Dystrophy Patient Showed Strength Increase in First Human Test.” William French Anderson [7], then the Director of Virology of the National Institutes of Health (NIH), said that if the finding was confirmed, “This would be a land- mark.” [8] Dr. Francis Collins, then a gene therapy researcher at the University of Michigan in Ann Arbor said the research “is a promising lead….” [8]. He recognized that, “there are some real possibilities here…” and both were right with the myoblast technology [9]. Peter Gorner reported on the front page of the Chicago Tribune on April 6, 1992 that “Tests confirm promise of genetic treat- ment for dystrophy.” 2) Single gene transduction In September 1990, Anderson transferred the adenosine deaminase (ADA) gene into the T cells of a 4-year-old girl with severe combined immunodeficien- cy (SCID) using a retroviral vector [10]. Although the integrated vector and ADA gene expression persisted, the subject had to take regular medication throughout the two years of gene treatment. The authors concluded that this single gene therapy was safe and effective to treating patients with this very rare form of disease [11]. On that basis, NIH’s Anderson claimed to be the first per- son ever to succeed in gene therapy [12] and became widely acclaimed by Americans as the “Father of Gene Therapy” [11] [12]. Central to this technology is the use of viruses as vectors to deliver normal copies of the faulty or missing gene into a particular cell type of a patient, hoping that the therapeutic gene will be expressed to produce a structural or regulatory protein, thereby alleviating the disease symptom(s) [13] [14]. However, viral vector gene transfer technology has not saved as many lives as once expected, but has killed many as I foretold. The viral related death of Jesse Gelsinger and participants of other trials in 1999 [15] compelled the FDA to re-evaluate gene therapy regulations, thus setting back the development of all 45 Open Journal of Regenerative Medicine DOI: 10.4236/ojrm.2020.92006
    P. K. Law DOI: 10.4236/ojrm.2020.92006 gene therapy programs including mine using no virus but human somatic cells called myoblasts. There were numerous deficiencies associated with the use of the single gene transduction technology [9]. Much of the hurdles that were 18 years ago [16] [17] remain unresolved today. Grandstands over the Human Genome Project (HGP) [18]-[23] and somatic gene therapies [10] [11] [16] [24] [25] [26] in the last three decades fueled en- thusiasm that most human diseases would eventually be cured with molecular medicine [27] [28]. In his position as the Director of the National Institutes of Health (NIH), and in his “Language of God” [23], Collins not only did not pro- vide any genetic treatment for COVID-19, he presented “evidence of make- be- liefs” and misled the world with the natural origin of 2019-nCoV [29]. Amidst all the “if’s”, “but’s”, “possibly”, and “almost certainly”, Collins rec- orded, “So, what is the natural origin of the novel coronavirus responsible for the COVID-19 pandemic? The researchers [30] don’t yet have a precise answer.” People in Collins’ position were often put in ugly situations of having to give up their scientific aptitude and choosing, because of political pressure from their immediate employer, the US Congress. I was once at the receiving end, or rather, non-receiving end of such malice [31]. Collins continued, “Existing computer models predicted that the new corona- virus would not bind to angiotensin converting enzyme II (ACE2) as well as the SARS virus. However, to their surprise, the researchers found that the spike pro- tein of the new coronavirus actually bound far better than computer predic- tions.” After presenting two scenarios of circumstantial evidence of genomic modeling, Collins concluded, “Either way, this study leaves little room to refute a natural origin for COVID-19.” [29] Collins continued, “The researchers [30] went on to analyze genomic data re- lated to the overall molecular structure, or backbone, of the new coronavirus. Their analysis showed that the backbone of the new coronavirus’s genome most closely resembles that of a bat coronavirus discovered after the COVID-19 pan- demic began. However, the region that binds ACE2 resembles a novel virus found in pangolins, a strange-looking animal sometimes called a scaly anteater. This provides additional evidence that the coronavirus that causes COVID-19 almost certainly originated in nature. If the new coronavirus had been manu- factured in a lab, scientists most likely would have used the backbones of coro- naviruses already known to cause serious diseases in humans.” Was Collins talking about biological weapon in this last sentence? What kind of scientists were Collins referring to who would intentionally cause serious dis- eases in humans? In his tax-payers’ entrusted position of NIH Director, Collins cited a non-committal reference [30] and presented a deliberate falsification of published scientific literature of studies described below that were supported by at least three Institutes of NIH, to mislead the world that COVID-19 originated from a natural course of viral evolution of the Hubei bats. I hereby present below the direct, unequivocal evidence that 2019-nCoV is a 46 Open Journal of Regenerative Medicine
    P. K. Law biological warfare weapon originally produced in the USA, and that COVID-19 is a pre-meditated event designed for the USA to consolidate and to sustain po- litical and economic supremacy internationally. In 2008, a group of SARS-like CoVs (SL-CoVs) isolated from horseshoe bats had their N terminus of the spike protein (S) combined with a human immunodeficiency virus (HIV)-based pseudovirus system, together with cell lines expressing the angiotensin-converting enzyme 2 (ACE2) molecules of hu- man, civet, or horseshoe bat. Ren et al. reported, “in addition to full-length S of SL-CoV and SARS-CoV, a series of S chimeras was constructed by inserting dif- ferent sequences of the SARS-CoV S into the SL-CoV S backbone.” This was a Guided Natural Selection, a process designed to select a lethal, transmissible virus by serially infecting cells of an animal model that had ACE2 receptors similar to human. The chimeric S (spike) covering the receptor-binding domain (RBD) gained its ability to enter cells via human ACE2 receptor sites. The Chinese authors demonstrated that “after replacement of a small segment (aa 310 to 518) of Rp3-S by the cognate sequence of BJ01-S, the chimeric spike protein mimics the function of BJ01-S in regard to receptor usage in the HIV pseudovirus assay system.” That was sufficient to convert the SL-CoV S from non-ACE2 binding to human ACE2 binding, indicating that the SL-CoV S is largely compatible with SARS-CoV S protein both in structure and in function [32]. The CoV spike glycoproteins were responsible for cellular receptor recog- nition [32] [33], cell tropism [34] [35], and host specificity [36]. Ren et al. also reported failure of SARS-CoV S protein to use bat RpACE2 as a receptor, suggesting that despite the presence of a diverse group of SL-CoVs in horseshoe bats, they were unlikely to be the natural reservoir of the immediate progenitor virus for SARS-CoV [32]. That was a non-committal way of saying that SARS-CoV did not have a natural origin. Hou et al. (2010) [37] extended the above study to ACE2 molecules from sev- en additional bat species and tested their interactions with human SARS-CoV spike protein using both HIV-based pseudotype and live SARS-CoV infection assays. Live SARS-CoV infection was carried out with help from Gary Crameri and Jennifer Barr, under BioDefense Level 4 (BSL4) conditions at the Australian Animal Health Laboratory (AAHL) [38] [39]. The results, as reported by a group of Chinese scientists funded by the Chinese government, showed that “ACE2 of Myotis daubentoni and Rhinolophus sinicus from Hubei province supported viral entry mediated by the SARS-CoV S protein, albeit with different efficiency in comparison to that of the human ACE2.” Further, “the alteration of several key residues either decreased or enhanced bat ACE2 receptor efficiency” [39]. How effective was this genetically engineered construct that was capable of transmission cross-species from bat to human, and within the same species from human to human? Gain of function (GOF) by which the efficiency of viral spreading in human population was engineered and tested in an international collaborative study in 2015 as reported by Menachery et al. Using the SARS-CoV 47 Open Journal of Regenerative Medicine DOI: 10.4236/ojrm.2020.92006
    P. K. Law DOI: 10.4236/ojrm.2020.92006 reverse genetics system [40], a chimeric virus was generated and characterized expressing the spike of bat coronavirus SHC014 [41] in a mouse-adapted SARS-CoV backbone. The University of North Carolina (UNC) collaborative study indicated that viruses encoding the SHC014 spike in a wild-type backbone could efficiently use multiple orthologs of the SARS receptor human ACE2, rep- licate efficiently in primary human airway cells and achieve in vitro titers equiv- alent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrated replication of the chimeric virus in mouse lung with notable pathogenesis [41]. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor ef- ficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs using the novel spike protein. An infec- tious full-length SHC014 recombinant virus was synthetically re-derived and it demonstrated robust viral replication both in vitro and in vivo. 3. Implications of COVID-19 Menachery et al.’s 2015 [41] publication deserved every attention because it de- scribed the success of an international collaboration to genetically engineered a prototype of 2019-nCoV, confirmed its epidemic destructive capacity, demon- strated no effective medicament, vaccine, or any therapeutic or prophylactic modality, and predicted that COVID-19 would be preeminent. It described, “In addition to offering preparation against future emerging viruses, this approach must be considered in the context of the US government–mandated pause on gain-of-function (GOF) studies.” A moratorium was called to end risky virology studies at 14 American institutions, but such effort was in vain [42]. Human ingenuity had advanced viral and bat evolution by a million years, providing them with the new ability to kill mankind. The combined use of virus recombination [32] [33], host switching [32] [33] [34] [35] and GOF [41] were achieved. SARS-coronavirus was known for its wide-spread efficiency in popu- lating the upper respiratory tracks, and genuine HIV plasmid could devastate the infected individual’s immune system; and in this case, the target of viral entry is ACE2 receptors of human beings. The combined use of the virus recombination technology and the host switching technology was already research in the wrong direction, upsetting the million-year-old natural equilibrium between human, bats and viruses. It was the GOF, a DNA engineering technology that propelled the efficiency of transmission among the human population of this monstrous chimaera (Figure 1) of SARS-CoV and HIV recombinant to the epidemic and pandemic level. From the 1998 viral P-shuttle SN Vector to the present clustered regularly in- terspaced short palindromic repeats (CRISPR) gene editing technology, SHC014CoV, the prototype of 2019-nCoV, was the prime of viral genetic engi- neering, and a deadly one. It was biological weapon at its best. It was scientifi- cally carried out with vision and passion, and the inventors given due credits in 48 Open Journal of Regenerative Medicine
    P. K. Law Figure 1. Modelled homo-trimer spike glycoprotein of 2019-nCoV. The inserts from HIV envelop protein are shown with colored beads, present at the binding site of the protein, from [47]. funding and publications for their inventions. However, this invention was to benefit no human beings or bats; it would kill them by the millions if left uncon- trolled. It revolutionized military warfare, killing enemies without deploying troops, without demarcating boundary, without war declaration, and usually without knowledge or evidence of attack. This invention enabled its owner to kill any mammals having human ACE2 receptors. The 2015 publication of Menachery et al. alerted a potential pandemic if un- curbed [41]. In the title of the original article published in Nature Medicine, it used the phrase of “pose threat to human emergence”. That was five years before COVID-19, in the land of technologic totalism of USA, where two Chinese scientists shared their academic advances and were given the middle and the second-last placement in the long 15-author list. It was for the American tech- nology of GOF that they collaborated with UNC. The latter was close to Fort Detrick, a key BioDefense Laboratory of the 4th level (BSL4) for biologic weapon production and testing. The GOF “turbo-charged” the SARS-CoV/HIV recom- binant and, for the first time, transformed it to become the world’s most power biological weapon of pandemic caliber. This is the origin of the 2019-nCoV. Author Contribution of Menarchery et al. recorded, “V.D.M. designed, coor- dinated and performed experiments, completed analysis and wrote the manu- script. B.L.Y. designed the infectious clone and recovered chimeric virus- es…..R.S.B. designed experiments and wrote manuscript.” These were the origi- nal responsible scientific designers of the biological bomb that left 1,852,021 di- agnostically infected with COVID-19, and 114,090 dead in 211 countries on April 13, 2020, and these numbers are on an exponential up-swing. As for “preparation against future emerging viruses” since Menarchery et al’s publication five years ago, only one publication has appeared six days ago on April 6, 2020 from the same UNC laboratory of Prof. Ralph S. Baric where 49 Open Journal of Regenerative Medicine DOI: 10.4236/ojrm.2020.92006
    P. K. Law DOI: 10.4236/ojrm.2020.92006 2019-nCoV prototype was engineered and tested. It documented a vaccine which was tested on mice might be a potential treatment for COVID-19. Other- wise, there has been no documentation of any of the 2019-nCoV transmitting bats, if any, were killed to protect human lives. There has not been publication of studies documenting inoculation of bats with 2019-nCoV to study if bat-virus relationship is symbiotic or parasitic, and how well do the bats immune-tolerate these natural or foreign antigens. To a business mind, why spent the money to make a man-killing chimeric virus, and found a vaccine against it, unless the vaccine could be sold at a good profit. However, it is extremely hard if not impossible to develop such vaccine, even by the UNC team itself [43]. Due to the tremendous random recombination of the chimeric viral RNA with different DNA repertoires from different patients by nature, no vaccine can be completely effective in principle, not even manufac- tured by Baric’s team from UNC for Americans [43]. The only scientifically valid vaccine can only be derived from pooled antisera of rehabilitated patients of the same blood type [44] [45]. Immediately available therapy for the critically-ill and dying patients could only be from serum therapy as previously described [44] [45]. One’s own immune system is the number one protection. Failing that, pas- sive immunogens [44] [45] have to be implemented immediately to save lives. The study of Menachery et al. was heavily funded. Its Acknowledgement cited, “Research in this manuscript was supported by grants from the National Insti- tute of Allergy & Infectious Disease and the National Institute of Aging of the US National Institutes of Health (NIH) under awards U19AI109761 (R.S.B.), U19AI107810 (R.S.B.), AI085524 (W.A.M.), F32AI102561 (V.D.M.) and K99AG049092 (V.D.M.), and by the National Natural Science Foundation of China awards 81290341 (Z.-L.S.) and 31470260 (X.-Y.G.), and by USAID-EPT- PREDICT funding from EcoHealth Alliance (Z.-L.S.). Human airway epithelial cultures were supported by the National Institute of Diabetes and Digestive and Kidney Disease of the NIH under award NIH DK065988 (S.H.R.). We also thank M.T. Ferris (Dept. of Genetics, University of North Carolina) for the reviewing of statistical approaches and C.T. Tseng (Dept. of Microbiology and Immunolo- gy, University of Texas Medical Branch) for providing Calu-3 cells.” A very unusual and unique statement appeared at the end of the Acknowled- gement, “Experiments with the full-length and chimeric SHC014 recombinant viruses were initiated and performed before the GOF research funding pause and have since been reviewed and approved for continued study by the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.” These last two sentences constituted a NIH disclaimer. What had the sponsors have in mind when they funded this project? No scientist would believe that the project was for the benefit of man, bat, or virus. Coutarda et al. identified a furin-like cleavage site present in 2019-nCoV, SARS CoV and in MERS-CoV but absent in CoV of the same clade. “This furin- 50 Open Journal of Regenerative Medicine
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