Might SARS‐CoV‐2 Have Arisen via Serial Passage through an Animal Host or Cell Culture?

In their new article, Might SARS‐CoV‐2 Have Arisen via Serial Passage through an Animal Host or Cell Culture?, published with free access in August, K&D Sirotkin explore the suggestion that the COVID 19 virus was accidentally released from a laboratory in Wuhan. The journal is BioEssays, published by Wiley online. The comments below are fully referenced in the article.

The article suggests the novel coronavirus could have come from dual‐use gain‐of‐function research, as the process of viral serial passage mimics a natural zoonotic jump, and offers explanations for SARS‐CoV‐2’s distinctive features, raising ethical questions about the risks of this area of research.

Noting that this virus acts like no microbe humanity has ever seen, the authors contend that the natural origin hypothesis fails to account for its unique genomic characteristics, and ignores the long history of serial passage as a method to manipulate viral genomes by forcing zoonosis between species, with the same signature but shorter time frame compared to natural viral mutation.

The dual‐use gain‐of‐function research tool of serial passage was first applied to an influenza virus in 1977. Then in 1979, a Soviet lab leaked weaponized anthrax through an improperly maintained exhaust filter, but Soviet authorities blamed the deaths on contaminated local meat. This cover-up, with the same reason provided as in Wuhan, withstood inquiries until 1992, when analysis of genetic distance proved the weapons lab was to blame.

In 2011, serial passage between ferrets created viruses that were transmissible by aerosol. One highly virulent strain was said to “make the deadly 1918 pandemic look like a pesky cold.” Since then, gain‐of‐function serial passage through ferrets has increased viral virulence and transmission.

One virulence feature of COVID 19 is a furin cleavage site. In influenza, these come from serial passage in laboratories or farms. They are absent from coronaviruses more than 60% similarity to COVID 19. The artificial generations added by forced serial passage create the artificial appearance of evolutionary distance, as found with SARS‐CoV‐2, which is distant enough from any other virus that it has been placed in its own clade.

Acquisition of the furin cleavage site was one of the key adaptations that enable SARS‐CoV‐2 to efficiently spread. This could have been spliced directly into the novel coronavirus’s backbone in a laboratory using classic recombinant DNA technology, with use of serial passage to remove any sign of direct genetic manipulation. A furin cleavage site introduced to a coronavirus via recombination appeared to increase lethality while also damaging respiratory and urinary systems, paralleling SARS‐CoV‐2 systemic multi-organ symptoms for lungs, the cardiovascular and nervous systems and kidneys.

The University of North Carolina and Wuhan institutions such as the Institute of Virology have researched gain‐of‐function in bat‐borne coronaviruses since 2013, when a coronavirus that targets the ACE2 receptor like SARS‐CoV‐2 was isolated from a wild bat. Another gain‐of‐function experiment reconstructed the SARS coronavirus to impart affinity for ACE2 by isolating a civet progenitor and serially passing it through cell lines. Then a chimeric bat‐borne coronavirus directly manipulated a spike‐protein gene to produce a virulent strain which produced a dire warning from the Pasteur Institute about its trajectory if it escaped.

A private repository has over 1500 strains of largely undisclosed viruses to draw from for experiments. Published work to manipulate bat coronavirus genomes is consistent with the wet‐work that would be needed to engineer this novel coronavirus in a laboratory. The Wuhan Institute of Virology has refused to release the lab notebooks of its researchers, which are expected to be meticulously detailed given the sensitive and delicate work that takes place in such laboratories. These notebooks would likely be enough to exonerate the lab from having any role in the creation of SARS‐CoV‐2.

The SARS‐CoV‐2 could not be intentionally engineered, but it could well be selected for after serial passage through ferrets or cell cultures in a lab, considering that it spreads readily among ferrets and among minks, a closely related subspecies. A viable pathway for its emergence could be infected bats defecating on commercial mink farms in Hubei.

The novel coronavirus appears to be far more adapted to human ACE2 receptors than those found in bats, which is unexpected given that bats are the virus’s assumed source. Surprisingly, the virus was perfectly adapted to infect humans since its first contact with us. It had no apparent need for any adaptive evolution at all, an unexpected finding since viruses are expected to mutate substantially as they acclimate to a new species.

A study of people who live near bat caves found minimal exposure to bat coronaviruses, and no antibodies in Wuhan, casting doubt that SARS‐CoV‐2 was circulating in humans prior to the outbreak, and making a zoonotic jump more unlikely. Natural jumps leave wide serological footprints due to the evolutionary ‘trial‐and‐error’ that must occur before mutations that allow adaptation to a new host species are selected.

Examination of all past gain‐of‐function serial passage research by the scientific community at large could determine what other definitive genomic signatures serial passage leaves besides the creation of furin cleavage sites, in case more of those can be found in this novel coronavirus. For example, SARS‐CoV‐2 appears to cloak the novel coronavirus from white blood cells, as does HIV, and it has a genomic region like bacteria, which may contribute to cytokine storms in adults.

The Sirotkin paper concludes that gain‐of‐function research is troubling, with potential conflict with the Nuremberg Code ban on experiments that could endanger human life unless potential humanitarian benefits significantly outweigh the risks. The Center for Arms Control and Non‐Proliferation has calculated that the odds that any given potential pandemic pathogen might leak from a lab could be better than one in four. The creation of virulent Bird Flu strains using serial passage contributed to the NIH imposing a moratorium on dual‐use gain‐of‐function research from 2014 until 2017, after which it was relaxed to allow study of influenza and coronaviruses. This moratorium was meant to limit “the potential to create, transfer, or use an enhanced potential pandemic pathogen.” The increased pace of research into coronaviruses would have increased the risk of a lab leak. These viruses were pinpointed in 2006 as a viable vector for an HIV vaccine, and research into a pan‐coronavirus vaccine has been ongoing for decades. The fact that gain‐of‐function research creates opportunities for pandemic viruses to leak out of labs calls for a re‐examination of the moratorium against this practice.

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