“We can’t exclude the possibility that this came from a laboratory experiment rather than from an animal” – Prof Nikolai Petrovsky
The possibility that SARS-CoV-2 is a human-manipulated virus that escaped from a lab has been flagged up by a whole series of scientists, such as Prof Richard Ebright, Prof Stuart Newman, Dr Michael Antoniou, Dr Jonathan Latham, Yuri Deigin, Dr Billy Zhang, and Prof Jonathan J. Couey.
Now it is gaining further scientific support in the form of two papers, recently posted on academically established pre-peer review websites. Although these studies have not yet been peer-reviewed, they are being taken seriously by the scientific community, which has opened up a lively discussion on social media.
The first study, led by Dr Alina Chan at the Broad Institute, MIT (USA), strongly challenges the much promoted narrative that the virus jumped from animals to humans at the Huanan seafood and wildlife market in Wuhan, China.
The researchers compared SARS-CoV-2 to the earlier SARS virus, SARS-CoV, which caused a human epidemic in 2003. They found that by the time SARS-CoV-2 was first officially announced and its genetic sequence reported in late 2019, it was already pre-adapted to human transmission, to an extent similar to late epidemic SARS-CoV. This is very different from how SARS-CoV first emerged. That virus was initially far less well adapted to infecting humans and had to acquire many mutations gained though many rounds of infectious cycles to reach peak infectivity. This type of progressive adaptation (mutation and selection) is exactly what is expected and known to happen in animal to human virus disease transmission. But SARS-CoV-2, even at very early stages of its detection in humans, was already highly adapted for human infectivity. In other words, no sufficiently similar natural “parent” animal virus or, in the researchers’ words, “branches of evolution stemming from a less well-adapted human SARS-CoV-2-like virus” have been found.
Casting further doubt on the “zoonosis” (jump from animal to human) theory of the virus’s origin is that samples taken from the Huanan market in Wuhan were found to contain viruses that were genetically identical to human SARS-CoV-2. According to Dr Chan, “This makes it unlikely for the Huanan market isolates to have come from an intermediate animal host; likely from SARS2-infected humans who visited the market.”
Interestingly, just in the last few days Chinese scientists have themselves thrown cold water on the “wet market” theory. According to the Wall Street Journal, "China’s top epidemiologist said Tuesday that testing of samples from...[the wet market]...failed to show links between animals being sold there and the pathogen." As all pandemic-related communications from scientists in China are now centrally vetted, we can conclude that the Huanan market theory is being walked back at an official level because of the lack of supporting evidence.
Indeed, on 27 May the Chinese government came up with another theory for the virus’s emergence. The Huanan market is now described as “more of a victim rather than the origin” of SARS-CoV-2 and the the virus is now claimed to have “multiple origins” – a suitably vague term that says nothing about laboratory escapes.
Lab escape theory “should be considered”
Alina Chan and colleagues say, "The sudden appearance of a highly infectious SARS-CoV-2 presents a major cause for concern that should motivate stronger international efforts to identify the source and prevent near future re-emergence." In this context they conclude that the possibility of a lab escape “should be considered regardless of how likely or unlikely”.
In GMWatch’s view, Dr Chan’s research suggests one of three potential origin scenarios:
1) SARS-CoV-2 has a natural origin in animals. If this is the case, it must have been circulating in humans in Wuhan long before the Chinese government alerted the international authorities to the COVID-19 epidemic, thus giving the animal virus the time needed to adapt to humans, as was seen with SARS-CoV in the 2003 epidemic.
2) SARS-CoV-2 is a natural animal-derived virus that has been studied in a laboratory for human infectivity for a considerable period of time, during which it acquired mutations that make it highly infectious to humans. The human-adapted virus then escaped from the lab that was studying it, with the Wuhan Institute of Virology (WIV) being a prime candidate.
3) SARS-CoV-2 is a genetically engineered virus that escaped from a lab that constructed it, such as the WIV.
Interestingly, however, the researchers pre-emptively close off the third option. They define the potential lab-origin virus as “non-genetically engineered”, even though their paper presents no evidence that such a virus could not have been genetically engineered. Given the long history of genetic engineering of coronaviruses at the WIV, this is an unwarranted assumption.
GMWatch pointed out to Alina Chan on Twitter that based on her research, the virus could be GM, or not. Dr Chan conceded that this was the case – “That’s right” – adding that “there is no direct evidence for any particular origin scenario”. Her latter comment is correct, but her admission that the virus could be GM shows that her claim in the paper that it is non-genetically engineered is inaccurate and requires correction in any final published paper.
Another Twitter commentator responded to our tweet by citing data from biotech entrepreneur Yuri Deigin’s blog post, which lays out strong evidence in support of the virus being genetically engineered.
Human intervention possible
The other paper pointing to a possible lab escape is more forthright about the possibility of human intervention. The paper is authored by a team led by Nikolai Petrovsky, a vaccine developer and a professor at the College of Medicine and Public Health at Flinders University in Adelaide, Australia. Using cutting edge computer molecular modelling tools, the researchers conclude that SARS-CoV-2 contains unique properties that mean it could have been cultured and selected in the laboratory to increase human infectivity.
Prof Petrovsky said his team considers that human manipulation is plausible because of the unmatched ability of the virus’s protruding spike protein to infect human cells. The virus’s ability to bind to human cells “far exceeds” its ability to infect other animals, he said. He added, “This, plus the fact that no corresponding virus has been found to exist in nature, leads to the possibility that COVID-19 is a human-created virus. It is therefore entirely plausible that the virus was created in the biosecurity facility in Wuhan [WIV] by selection on cells expressing human ACE2 [receptor], a laboratory that was known to be cultivating exotic bat coronaviruses at the time.”
Prof Petrovsky told Sky News that he also doesn’t exclude the natural origin theory: “The two possibilities which I think are both still open is that it was a chance transmission of a virus from an as yet unidentified animal to human. The other possibility is that it was an accidental release of the virus from a laboratory. Certainly we can’t exclude the possibility that this came from a laboratory experiment rather than from an animal. They are both open possibilities.”
Genetic engineering the quicker way to human infectivity
Commenting on Prof Petrovsky’s conclusion that SARS-CoV-2 could have originated from culture of a wild virus and selection in human cells, the London-based molecular geneticist Dr Michael Antoniou agreed that this scenario was plausible: “You can certainly develop a human-infective virus like SARS-CoV-2 by repeatedly passing a wild bat virus through human cells, in the way that Prof Petrovsky describes. You culture human cells with the virus, allowing the virus to replicate, and harvest the resulting viruses. This selects for the most human-infective viruses, which you use to re-infect more cells. By going through successive rounds of this process, you are gradually selecting for viruses that have acquired mutations leading to enhancement of human infectivity. Eventually you end up with a virus that is optimized for human infectivity.”
However, Dr Antoniou added that there are far quicker and more efficient ways to achieve this aim.
For example, if you start with little information about what your human-infective virus looks like, you can genetically engineer a large number of SARS-CoV spike protein variants within phages. Phages are viruses that can infect bacteria. Phages can be genetically engineered to express on their exterior coat the CoV spike protein with a different variant of the receptor binding domain (RBD) – the part of the spike protein that allows the virus to bind to the ACE2 protein on human cell surfaces and thus enables infection to take place. This collection of phage variants with different RBDs is called a “phage display library”. The “library” of variants is then cultured with human cells in order to select for those phages with spike protein variants that bind to the ACE2 receptor.
Then the DNA is extracted from the phage with the best-binding spike protein and sequenced. Based on the sequence, a whole virus optimized for human infectivity can be synthesized.
Alternatively, Dr Antoniou explained, if you start with some information, as is likely with a group of researchers experienced in coronavirus gain-of-function research, there is an even quicker way to create a human-infective virus. Given that past research indicates that the nature of the spike protein alone doesn’t determine infectivity, it seems sensible to generate a library of spike mutant proteins directly within a whole coronavirus, which would also contain any other components necessary for infectivity.
In this case, you would take a DNA clone of a coronavirus that you know to be close to human infectivity, based on the sequence of its RBD. (Manipulation of DNA clones of coronaviruses is the standard procedure used to generate mutant viruses, including chimeras, in gain-of-function experiments, such as those carried out by scientists at the University of North Carolina and the Wuhan Institute of Virology.) You would then use the genetic engineering technique of DNA synthesis to generate a large number of randomly mutated versions of the spike protein RBD. The RBD mutations that you engineer could be more narrowly targeted by focusing on those regions encoding the amino acids whose nature and positions you know to be most critical for docking onto the human ACE2 receptor. The mutant versions of the RBD would then be selected for strong binding to the ACE2 receptor and consequently high infectivity of human cells.
Both methods described above would not leave any “signature” of genetic engineering. That’s an important consideration, given that Prof Petrovsky believes that genetic engineering was not involved in the development of SARS-CoV-2 due to the absence of such a signature.
Genetic engineering likely
In GMWatch’s view, to bypass the efficient genetic engineering-based methods described by Dr Antoniou in favour of the more laborious culture and selection-only method suggested by Prof Petrovsky would seem a curious decision for any laboratory committed to investigating coronavirus gain-of-function, such as the WIV.
The conclusions that we draw from these two new papers and Dr Antoniou’s input are that the “zoonosis” theory of SARS-CoV-2’s origin looks increasingly open to question, that the lab escape theory appears to be a solidly based scenario and, if that is what happened, genetic engineering is highly likely to have played a part in the development of the virus.
Report by Claire Robinson