this is a bit of conspiracy theory for you:
QUOTE from that paper:
"To engineer and create a human-targeting coronavirus, they would have to pick a bat coronavirus as the template/backbone. This can be conveniently done because many research labs have been actively collecting bat coronaviruses over the past two decades32,33,70,72,81-85. However, this template virus ideally should not be one from Dr. Zhengli Shi’s collections, considering that she is widely known to have been engaged in gain-of-function studies on coronaviruses [her work was paid for by American government]. Therefore, ZC45 and/or ZXC21, novel bat coronaviruses discovered and owned by [Chinese] military laboratories33, would be suitable as the template/backbone. It is also possible that these military laboratories had discovered other closely related viruses from the same location and kept some unpublished. Therefore, the actual template could be ZC45, or ZXC21, or a close relative of them.
The postulated pathway described below would be the same regardless of which one of the three was the actual template. Once they have chosen a template virus, they would first need to engineer, through molecular cloning, the Spike protein so that it can bind hACE2.
The concept and cloning techniques involved in this manipulation have been well-documented in the literature44-46,84,86. With almost no risk of failing, the template bat virus could then be converted to a coronavirus that can bind hACE2 and infect humans44-46.
Second, they would use molecular cloning to introduce a furin-cleavage site at the S1/S2 junction of Spike. This manipulation, based on known knowledge60,61,65, would likely produce a strain of coronavirus that is a more infectious and pathogenic.
Third, they would produce an ORF1b gene construct. The ORF1b gene encodes the polyprotein Orf1b, which is processed post-translationally to produce individual viral proteins: RNA-dependent RNA polymerase (RdRp), helicase, guanidine-N7 methyltransferase, uridylate-specific endoribonuclease, and 2’-O-methyltransferase.
All of these proteins are parts of the replication machinery of the virus. Among them, the RdRp protein is the most crucial one and is highly conserved among coronaviruses. Importantly, Dr. Zhengli Shi’s laboratory uses a PCR protocol, which amplifies a particular fragment of the RdRp gene, as their primary method to detect the presence of coronaviruses in raw samples (bat fecal swap, feces, etc). As a result of this practice, the Shi group has documented the sequence information of this short segment of RdRp for all coronaviruses that they have successfully detected and/or collected. Here, the genetic manipulation is less demanding or complicated because Orf1b is conserved and likely Orf1b from any β coronavirus would be competent enough to do the work. However, we believe that they would want to introduce a particular Orf1b into the virus for one of the two possible reasons:
1. Since many phylogenetic analyses categorize coronaviruses based on the sequence similarity of the RdRp gene only18,31,35,83,87, having a different RdRp in the genome therefore could ensure that SARS-CoV-2 and ZC45/ZXC21 are separated into different groups/sub-lineages in phylogenetic studies. Choosing an RdRp gene, however, is convenient because the short RdRp segment sequence has been recorded for all coronaviruses ever collected/detected. Their final choice was the RdRp sequence from bat coronavirus RaBtCoV/4991, which was discovered in 2013. For RaBtCoV/4991, the only information ever published wasthe sequence of its short RdRp segment83, while neither its full genomic sequence nor virus isolation were ever reported. After amplifying the RdRp segment (or the whole ORF1b gene) of RaBatCoV/4991, they would have then used it for subsequent assembly and creation of the genome of SARS-CoV-2. Small changes in the RdRp 17 sequence could either be introduced at the beginning (through DNA synthesis) or be generated via passages later on. On a separate track, when they were engaged in the fabrication of the RaTG13 sequence, they could have started with the short RdRp segment of RaBtCoV/4991 without introducing any changes to its sequence, resulting in a 100% nucleotide sequence identity between the two viruses on this short RdRp segment83. This RaTG13 virus could then be claimed to have been discovered back in 2013.
2. The RdRp protein from RaBatCoV/4991 is unique in that it is superior than RdRp from any other β coronavirus for developing antiviral drugs.
RdRp has no homologs in human cells, which makes this essential viral enzyme a highly desirable target for antiviral development.
As an example, Remedesivir, which is currently undergoing clinical trials, targets RdRp. When creating a novel and human-targeting virus, they would be interested in developing the antidote as well. Even though drug discovery like this may not be easily achieved, it is reasonable for them to intentionally incorporate a RdRp that is more amenable for antiviral drug development.
Fourth, they would use reverse genetics to assemble the gene fragments of spike, ORF1b, and the rest of the template ZC45 into a cDNA version of the viral genome. They would then carry out in vitro transcription to obtain the viral RNA genome. Transfection of the RNA genome into cells would allow the recovery of live and infectious viruses with the desired artificial genome.
Fifth, they would carry out characterization and optimization of the virus strain(s) to improve the fitness, infectivity, and overall adaptation using serial passage in vivo. One or several viral strains that meet certain criteria would then be obtained as the final product(s). "
