Report 101: Gain-of-Function Research and Origin of SARS-CoV-2, the Virus That Causes COVID-19
After years of half-truths and outright falsehoods, facts are emerging about SARS-CoV-2’s origins. The Wuhan Institute of Virology (WIV) purged important genome sequence information from its servers and was not forthcoming regarding their research, so complete details will never be known. Enough can be pieced together for objective molecular geneticists to uncover the likely process used to create the pathogen, and the preponderance of the evidence supports the lab leak hypothesis. The possibility that the pathogen evolved “naturally” from a wild host, such as a bat, is implausible based on both known viral mechanisms of evolution and sequence analysis. Public health officials and others used the “natural evolution” hypothesis to muddy the waters for a trusting public. Individuals trained in genetic engineering techniques can recreate the molecular steps used to create SARS-CoV-2, and its first appearance in the Chinese city of Wuhan points to the WIV as the likely source. How the pathogen escaped the laboratory is a completely separate issue. Why U.S. health agencies worked so hard to discredit the lab leak hypothesis remains an important question. In sum, this started public loss of trust in government, in science, and in the policies put forward to address COVID-19.
Members of Congress and the media use the phrase “gain-of-function research” as a catchphrase to describe the process by which SARS-CoV-2 was created. That may be fine for Congressional meetings, but very little effort has been made to inform the public what the phrase means or about the extensive array of biochemical manipulations available to the researcher to carry out this type of research. Thus, due to this lack of clarity, the public remains prey to continued cover-ups and lies put forth by the government to explain what happened. Creating SARS-CoV-2 required multiple complex sequence changes that could not have happened by random genetic mutation in a natural setting. It is important to understand this if we are to unravel the COVID-19 fiasco.
Gain of function mutation is a powerful, well-established research tool used by geneticists to identify which amino acids of a protein play a role in a specific function of that protein. The concept is not new, but the advent of genetic engineering technology added a new dimension to how the research is done. Imagine a protein that binds to a blue barbell molecule (Function 1) and splits it into two blue balls (Function 2). To study which amino acids are involved in each of these functions of binding and splitting the blue barbell, the genetic approach is to isolate mutations (i.e., alterations in the amino acids of the protein) that effect its ability to carry out the function. Mutations that prevent the protein from functioning are called “loss-of-function” mutations. Loss-of-function mutations could disable the protein in a variety of ways including altering its binding to the blue barbell molecule or its ability to split it into two blue balls. “Gain-of-function” mutations expand the capability of the encoded protein without affecting its ability to carry out the original function. Mutations that make the protein capable of binding both BLUE and RED barbell molecules are “gain-of-function” mutations. Gain-of-function mutations are much rarer and should only identify amino acids involved in binding the barbell molecule. Thus, they are far more informative than loss-of-function mutations. It should be noted that, in the true sense of the term, gain-of-function mutations retain their original function.
Since the 1900s, geneticists isolated mutations using different methods that introduced mutations randomly, such as chemical mutagens or X-ray radiation. Once sequencing was developed, the exact altered amino acids could be determined. Random mutagenesis required using culture techniques to identify mutant strains, determining the mutated site in the genome, isolating that gene, and, lastly, sequencing it. Genetic engineering techniques now allow researchers to target mutations to a specific site in a gene and then ask how that change altered the function of the encoded protein. Selection of targets of interest in a protein are often based on X-ray crystallography studies of the three-dimensional structure of the protein or sequence homology to other proteins of similar function.
The SARS-CoV-2 virus that was spreading worldwide was isolated and sequenced, and the sequence compared to dozens of known coronaviruses. These results were used to construct an evolutionary tree and do sequence comparisons (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166309/pdf/main.pdf). SARS-CoV-2 falls into a subgroup of coronaviruses that includes SARS-CoV-1 and coronaviruses that infect bats and pangolins. MERS-CoV and other known human coronaviruses strains lie in other subgroups. SARS-CoV-2 is most closely related to a bat coronavirus, BatCoV-RaTG13, with which it is 97% identical. Both SARS-CoV-1 and SARS-CoV-2 bind to the human ACE2 receptor protein via their Spike protein, a protein that extends from the virus particle surface. Coronavirus Spike protein is responsible for recognizing and binding to the host cell surface receptor, invading the host cell membrane, and thereby starting the infection process. Thus, the Spike protein determines which host organism(s) the specific viral strain can infect and which of the host’s organs are targeted for infection.
Despite sharing the same host cell surface receptor, the SARS-CoV-1 and SARS-CoV-2 Spike proteins are only 76% identical overall and only 64% identical in the S1 section of Spike that contains the receptor binding domain. SARS-CoV-2 and BatCoV-RaTG13 Spike protein sequences are nearly identical despite host differences — S1 and S2 sections of Spike are 96% and 100% identical, respectively. SARS-CoV-2 S1 sequence is uniquely different from other coronaviruses in its subgroup by having an insertion of three basic arginine residues that create a protease cleavage site that optimizes the infection process. Similar cleavage site sequences are present in MERS-CoV and several other human coronaviruses. These findings suggest a complex, multi-step process origin for SARS-CoV-2 not easily explained by natural processes.
When geneticists looked carefully at the SARS-CoV-2 Spike protein sequence, they found it to still carry the sequence hallmarks of its laboratory creation. This information was withheld from the public. NIH-funded researchers who spoke out in emails about this were told that their grants were in jeopardy, and so the public was left in the dark. The so-called natural host reservoir species from which it supposedly evolved was never identified despite extensive searching. Bats, pangolins, and other species for sale in the Wuhan Wet Market were ruled out as possible natural host reservoirs of SARS-CoV-2. These facts alone rule out the “natural” origin theory from the Wuhan Wet Market. The significance of this simple fact was never publicly elaborated upon. In the absence of a host reservoir with the potential of close human interaction, the natural origin theory becomes highly unlikely. Moreover, the mechanism by which the SARS-CoV-2 sequence could been produced in a natural host cannot be explained by known mechanisms of chimera formation and sequence exchange, thereby making the “natural” origin hypothesis highly unlikely.
Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID) for over 40 years, has long claimed that the NIAID never funded gain-of-function research. National Institutes of Health (NIH) Principal Deputy Director Lawrence Tabak expanded this subject in his May 2024 meeting with Congress by saying that “the generic term [gain-of-function] is research that goes on in many, many labs around the country.” (https://oversight.house.gov/release/hearing-wrap-up-nih-repeatedly-refutes-ecohealth-alliance-president-dr-peter-daszaks-testimony-tabak-testimony-reveals-federal-grant-procedures-in-need-of-serious-reform/) Dr. Francis Collins, former head of the NIH, elaborated on these statements in previous testimony to Congress saying there “is a generic description of gain-of-function which is utilized in scientific and public conversation, but [it] is not appropriate to apply that to a circumstance where we’re talking about a potential pathogen.” (https://nypost.com/2024/05/16/us-news/nih-director-admits-taxpayers-funded-gain-of-function-research-in-wuhan-four-years-after-covid-pandemic-began/) Since the ability to infect a reservoir host is not retained, the research to create SARS-CoV-2 is not gain-of-function research in the true sense of the term but, rather, “replacement of a functional domain.” The above discussion explains how these somewhat contradictory statements can be considered truthful. Nonetheless, these NIH leaders are using semantics and obfuscation to deflect responsibility for their actions.
Director Tabak for the first time publicly reported at his May 2024 Congressional meeting that U.S. tax funds indirectly supported gain-of-function research carried out in the WIV in the years prior to the COVID-19 pandemic. The full details can be read in a collection of articles that appeared on The Intercept based on NIH documents obtained by a Freedom of Information Act (FOIA) request (https://theintercept.com/collections/origins-of-covid/) . The WIV research funding came via an NIH grant to Peter Daszak’s EcoHealth Alliance, which used it to fund research in the WIV. The grant was to carry out limited studies to determine whether bat coronavirus Spike protein could bind to the human ACE2 receptor and, thereby, infect humans, which it could not. Instead, WIV used this funding to modify a bat coronavirus Spike protein gene to sequences from the human SARS and MERS coronaviruses, thereby creating a coronavirus capable of infecting humans. It would appear that EcoHealth was aware of this misuse of the funds, a clear violation of the terms of the NIH grant. Worse than that, EcoHealth did not report it to the NIH which is responsible for grant activity oversight. This negligence was allowed to continue. Both EcoHealth and the NIH oversight committee should be held responsible. (https://theintercept.com/2021/10/01/nih-bat-coronavirus-grant-ecohealth-alliance/)
There is a long history of NIH directly funding this type of work. Dr. Shi Zhengli, the leading bat coronavirus researcher at the WIV, trained with Dr. Ralph Baric at the University of North Carolina – Chapel Hill. While in the Baric lab, she studied gain-of-function research techniques with coronavirus, and the research was supported by NIH grants (https://www.nature.com/articles/nm.3985). Dr. Baric’s studies had been criticized as “potentially dangerous” by scientists as early as 2015 (https://www.nature.com/articles/nature.2015.18787). In 2018, President Barack Obama banned U.S. funding of gain-of-function research with pathogens. (https://www.science.org/content/article/us-halts-funding-new-risky-virus-studies-calls-voluntary-moratorium) A regulatory panel was established to monitor grants for potential hazardous pathogen research. (https://obamawhitehouse.archives.gov/blog/2014/10/17/doing-diligence-assess-risks-and-benefits-life-sciences-gain-function-research) The EcoHealth grant appears to have bypassed the oversight of this regulatory panel. Standard progress reports are required for annual renewal of funding. The only available progress report was submitted two years late, which begs the question of EcoHealth’s transparency with the NIH and NIH oversight. (https://theintercept.com/2021/11/03/coronavirus-research-ecohealth-nih-emails/)
It is not clear where to go from here. U.S. bans on such research are ineffective. Research on pathogens is not expensive, and the techniques are widely known. Bad actors interested in creating ever more deadly pathogens are everywhere. A repeat of the highly flawed and destructive COVID-19 policy responses is unthinkable. But what has changed? A complete overhaul of our health agencies, especially the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC), and changes in federal laws, like the Public Readiness and Emergency Preparedness (PREP) Act, will be required. Never again!
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Corinne Michels, PhD, is an internationally recognized molecular geneticist studying the regulation of gene expression in the model eukaryote Saccharomyces cerevisiae, baker’s and brewer’s yeast. Her research was consistently funded by grants from the US National Institutes of Health and the National Science Foundation. She authored of over 75 research journal articles, review articles, and book chapters in scientific publications. Dr. Michels’ textbook, Genetic Techniques for Biological Research: A Case Study Approach (John Wiley & Sons), is widely used in both the classroom and research laboratory.