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Here’s another guest blog by Dr. Marissa Carter. Sit down before you read it. You may want to pass this on!
–Caroline

COVID-19 Virus: The Origin Story

The accepted origins story is that this virus crossed from some animal to a human at a wet market, and this human then started human-to-human transmission of the virus to create the current pandemic. Given the impact of the pandemic, you might think there would be a lot of interest in understanding exactly how this came about. However, I am struck by the ferocity with which theories about the origin of the COVID-19 virus are shot down if they cross the lines of the “accepted” story. The problem is that the accepted story doesn’t explain:

  • Which animal it came from: Bats? Pangolins? Goldfish? We don’t know.
  • Why a third of the patients in the initial cluster didn’t have any links to the market.
  • The symptom onset date of the first patient identified was Dec 1, 2019. None of the male patient’s family members developed fever or any respiratory symptoms. No epidemiological link was found between the first patient and later cases.
  • How exactly the mutations that caused the virus to utilize the furin cleavage site might have occurred. (This was the massive gain-of-function in viral entry we talked about in the previous blog.). The accepted story is that two different viruses combined in some animal and that this “natural” chimera was the viral progenitor source.
  • Why the 4 putative HIV-1 RNA sequences in the COVID-19 genome first reported by Indian scientists are just random mutations that have nothing to do with anything or are found in lots of other living things.
  • Why the pandemic started in a city that is also host to the only level 4 BSL level lab in China that had been studying coronaviruses for a very long time.
  • And why France emphatically denies that China’s level 4 BSL lab was not involved in the outbreak.

The Cast and Characters of “Pandemic” (which is NOT a movie)

Let’s begin by going over a little history and meeting some of the players.

The Wuhan National Biosafety Laboratory of the Chinese Academy of Sciences (which we will call the Wuhan P4), was certified for BSL level 4 operations and has an interesting history. France helped the Chinese build the lab and it was modelled on the P4 Jean Mérieux-Inserm Laboratory in Lyon, where the Ebola virus from the African outbreak was first confirmed and characterised in 2014. It has collaborated with several US scientists, including James Le Duc, director of the Galveston National Laboratory at the University of Texas, one of the largest active biocontainment facilities on a US campus. The NIH (yes, that’s the USA’s NIH) funded the Wuhan Virology Institute to the tune of $3.7 million, and that was only the most recently funded project in the last decade. The project’s goal was to experiment on bats from caves in Yunnan province and guess what they found? Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus. This was published in late 2017. The head of the NIH at the time we funded the Chinese virology program with U.S. tax dollars was Dr Anthony Fauci. Other US researchers collaborating with P4 include individuals from the University of Alabama, the University of North Texas, Harvard University, and the National Wildlife Federation.

By 2017, a number of researchers were becoming concerned about the operation at P4; there had been a number of accidents and the risk of a dangerous virus getting loose accidentally was seriously discussed. Experts also speculated that it was already being used for biowarfare programs. The issue came to head in an article published in Nature. Since that time, concern over the biosecurity of P4 has continued with officials from the U.S. State Department, who visited the complex writing cables to Washington listing a litany of complaints about the establishment. Ultimately these warnings fell on deaf ears.

The individual who has run the coronavirus program at P4, Dr Shi Zhengli, who goes by the unofficial moniker of “China’s Bat Lady,” has never publicly expressed worry about security at P4, and has repeatedly stated that there was no breach of virus integrity at the lab complex that could have caused the initial outbreak in the city of Wuhan, is an interesting character. She is the scientists who discovered that bats were the repository population for the SARS-like coronaviruses, and is the key author of a number of coronavirus studies coming from P4 that have been published in the open literature.

Read this profile of Dr. Zhengli from Wikipedia:

“She led a research team that studied how SARS-coronaviruses from bats could infect the human ACE2 receptor, where she gained this function via combining novel SARS-CoV viruses from bats with human immunodeficiency virus-based (HIV) pseudovirus systems to facilitate hACE2 as a receptor for cell entry and subsequent infection. (Translation: Dr. Zhengli created a virus in the lab that was a combination of bat coronavirus and HIV genes which is what enabled the bat virus to infect humans.)

In 2014, Shi Zhengli continued her work in bat coronavirus gain-of-function experiments led by Ralph S. Baric of University of North Carolina, finding that SARS had the potential to re-emerge from coronaviruses circulating in bat populations in the wild. That same year (2014), the US National Institutes of Health placed a moratorium on gain-of-function studies, which increase transmissibility and virulence of pathogens, with influenza, MERS and SARS viruses due to concerns over the risks vs. benefits of performing such research. The NIH lifted this moratorium in 2017.”

Nature or Nurture?

Over and over we’ve been told that COVID-19 is a virus that evolved naturally by scientists who cannot seem to stomach other possibilities. I’ll concede that it might have happened, and if it did, most likely in some cave in Yunnan. Two coronaviruses infected a particular species of bat and they exchanged RNA to make a chimera.

Maybe it’s a natural “chimera” or maybe it isn’t. it seems that back in 2007, even before The Wuhan P4 had been built, researchers at the Wuhan Institute of Virology published a paper in the Journal of Virology. More details can be read in a paper authored by a group of anonymous researchers, but I’ll abstract the key points of the 2007 Wuhan Institute here:

  • “First, the SL-CoV S was unable to use any of the three ACE2 molecules as its receptor.” (Translation: “We found a SARS-like virus that couldn’t infect human cells.”)
  • “We investigated the receptor usage of the SL-CoV S by combining a human immunodeficiency virus-based pseudovirus system with cell lines expressing the ACE2 molecules of human, civet, or horseshoe bat.” (Translation: “We combined the SARS-like virus with HIV genes in a specific attempt to make it infectious to humans.”)
  • “Third, the chimeric S covering the previously defined receptor-binding domain gained its ability to enter cells via human ACE2” (Translation: “Thanks to our engineering, the new virus (“chimeric S”) can infect human cells.”)

Eight years later, another paper came out of the newly functional Wuhan P4 lab. Here’s a portion of the abstract:

“Here we examine the disease potential of a SARS-like virus, SHC014-CoV, which is currently circulating in Chinese horseshoe bat populations. Using the SARS-CoV reverse genetics system, we generated and characterized a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone. The results indicate that group 2b viruses encoding the SHC014 spike in a wild-type backbone can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs using the novel spike protein. On the basis of these findings, we synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo. Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.” (Translation: We found another SARS-like virus in bats and created a chimera that could infect humans and replicate A LOT in the human lung, and we also found that the current SARS vaccines and treatments didn’t work against it. And that point we decided to create an entirely synthetic version of this new virus.)

Right here is the possible COVID-19 progenitor. In fact, this was THE paper that caused the controversy to be aired in Nature.

In late November of 2019, the P4 group published another key paper. Here’s a portion of the abstract:

“Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development, and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on the host cell surface and then fusing viral and host membranes. In this study, we investigated how a neutralizing monoclonal antibody (MAb), which targets the receptor-binding domain (RBD) of Middle East respiratory syndrome (MERS) coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays.” (Translation: We found out how antibodies that your immune system generates create a Trojan horse for the virus to get into your cells.)

And these gems from the Discussion:

“Moreover, a SARS-CoV RBD-specific neutralizing MAb mediates ADE of SARS-CoV pseudovirus entry. These results demonstrated that ADE of coronaviruses is mediated by neutralizing MAbs that target the RBD of coronavirus spikes. In addition, the same coronavirus strains that led to the production of fully neutralizing MAbs can be mediated to go through ADE by these neutralizing MAbs.” (Translation: We proved to our satisfaction the mechanism by which the antibodies generated by your own immune system actually create a Trojan horse for the virus to hide in, so we’re done with our research!)

Move Along, There’s Nothing to See Here

MERS? That’s interesting… In 2013 an unknown coronavirus (now known as MERS-CoV) ended up in a level 4 BSL lab at Canada’s National Microbiology Laboratory (NML). Along with many other nasty viruses, it was studied for several years by a research team headed by the Chinese-born Dr Xiangguo Qiu, head of the Vaccine Development and Antiviral Therapies Section in the Special Pathogens Program at NML. In March 2019, a shipment of these exceptionally virulent viruses from NML ended up in China. This event caused a major row, with experts questioning why Canada was sending lethal viruses to China. Dr Qiu apparently made at least five trips over the school year 2017-18 to the Wuhan P4. (Interesting sidebar: the investigation by Canadian government security services is still ongoing at NML, and factcheck.org now says that everything I have just said is pure fiction. Oh Really?)

We have also been told over and over again this virus doesn’t mutate that much. We have only the S and L strains to worry about. Then this nice little study was recently published by two South Korean researchers:

“The research team analyzed all ribonucleic acid (RNA) transcripts produced by the SARS-CoV-2 in host cells by using next-generation sequencing, nanopore and nano ball sequencing. The exact location of the viral gene was found in the study while confirming the RNAs that were not found with existing methods. The team also confirmed at least 41 chemical mutations were made to the viral RNA. By finding the location, the research team identified how the viral transcripts were constructed, and they could pinpoint where the viral genes were located in the genome. According to the research, SARS-CoV-2 is in RNA form, and the virus infiltrates into the host cell and replicates while producing various subgenomic RNAs based on the genomic RNA. This subgenome synthesizes several proteins, such as spikes and shells, which make up the structure, and form a virus in the host cell with the cloned gene. After the replication is done, the virus exits the cell and infects other cells. The sum of RNA produced in the host cell is known as the Transcriptome. Previously, 10 subgenomic RNAs were known to exist, but the team’s study unboxed that only nine sub-genome RNAs actually existed. Besides, the research team discovered dozens of more RNAs produced in the hosting cell. Chemical modifications such as methylation in viral RNA were observed as well. Various biochemical changes that occur at the RNA level after transcription is called epitranscriptomes, just as those happening at the DNA-level such as DNA methylation are known as epigenomes.” (Translation: By doing a much more detailed analysis of the genome we’ve actually mapped these large numbers of mutations to the actual part of the genome that translates for specific viral proteins. And this is a virus that LOVES to mutate.)

“It is necessary to check whether the newly discovered RNAs behave as proteins that regulate viral replication and the host’s immune response,” Director Kim said. “The chemical modification of RNA seems to have relations with virus survival and immune responses.” Their general approach has also been confirmed by other Chinese researchers. (Translation: It really doesn’t matter what “strain” you were infected with; the course of the disease will depend on what mutations occur and how those mutations affect the production of sgRNAs. And there are LOT of mutations.)

This brings us to the paper published by several Indian researchers as a preprint, meaning it was not peer-reviewed. Rather than leading to a serious discussion of the merits of their findings (4 separate HIV-like RNA sequences) in the COVID-19 genome, the majority of the scientific community very quickly squashed the entire premise resulting in its retraction on medical websites. (My 2 cents worth is that this approach could have led us to some deeper insight on a few small key sequences but that no-one’s going to do that again.) Indeed, shortly thereafter, many papers came out claiming “irrefutable proof” that the virus was natural in origins. Let’s look at one of them published in Nature Medicine:

  1. “Furthermore, if genetic manipulation had been performed, one of the several reverse-genetic systems available for betacoronaviruses would probably have been used.”The reference is actually one of P4’s studies authored by the usual players and peer-reviewed by some of their cheerleaders. But, the point is just because a lab published one approach to reverse-genetic systems, and you’re in the business of doing a massive amount of very serious viral research, some of which most definitely isn’t published, doesn’t mean that you would use that system to build a COVID-19 progenitor or chimera. Also, P4 could have used an existing bat coronavirus they got from the Yunnan caves and conducted a little GOF research on it. In other words, the authors of the Nature Medicine article are pretty clueless as to how COVID-19 might have been synthesized from scratch).
  2. “However, the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone.”Well duh! The reference is to an old paper (2014) and I’m quite sure the Wuhan P4 folks have moved on since then to new backbones!

These types of papers remind me of the shoot-from-the-hip kind of approach when you want to tear someone down because you absolutely don’t like what someone says and you have buddies at the journal who will always publish you—aka the old boy network. This is not well-reasoned science at all.

Where Does That Leave Us?

  • We will likely never know the origin of the virus. The Chinese have done a stellar job of covering up the evidence that might have provided more clues.
  • My inclination is that given the pandemonium at the start of the outbreak, the pattern of early cases, and the Chinese response, this was probably a lab accident with a coronavirus they were working on.
  • We have no idea of what its potential is right now and that’s not good.
  • The very recent New York COVID-19 antibody survey data suggest that in the current wave perhaps tens of millions might already have had the virus—way more than the prediction I made a couple of weeks ago when I suggested the USA had a million cases.
  • However, that means that the mortality rate is lower than we thought. And if there are no further surprises, we can plug that data into our SEIR models.
  • Unfortunately, given the surprising pathology of the disease that keeps turning up, I’m not sure we are out of the woods regarding further surprises.
  • And it’s definitely time to rethink allowing the NIH to support Chinese virology research with US tax dollars.

That said, I’ll leave you with the immortal words of Louis Pasteur: “Chance favours the prepared mind.” (And, based on the data that’s currently public, this virus did not happen by chance.)


Marissa J Carter MA PhD MAPWCA
President
Strategic Solutions, Inc.
37 Voyager Lane, Bozeman, MT 59718, USA
Website: http://www.strategic-solutions-inc.com


Dr. Fife sees patients at the CHI St. Luke's Hospital Wound Clinic in The Woodlands, Texas. For an appointment call (936) 266-2150.



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