SARS-CoV-2 injects people with rna that induces viral fragment production in human cells. It was always a tradeoff between a small non-reproducing set of viral proteins, a full-blown self-reproducing infection of the entire virus that spreads to others, or an endless series of lockdowns (there apparently isn't a possible world where all the countries coordinate to exterminate covid directly).
Or maybe it was in humans a bit before it took off. I see Daszak's kind of changed his tune a bit these days to not mention anything like that lab stuff.
The paper I cited above is a specific example of a team constructing a virus from a RNA sequence that they bought commercially, and then using it to infect human cells in vitro. The virus they constructed is a coronavirus very similar to sars-cov-2. Note that the spike sequence was provided by the Wuhan lab, and it's the spike sequence that makes sars-cov-2 so infectious.
The paper has been cited 121 times. You will find more examples there:
There's nothing in that list that argues against SARS-CoV-2—and its spike protein and furin cleavage site in particular—being produced by serial passage through any of a variety of cell lines expressing human ACE-2.
It does seem unlikely that the SARS-CoV-2 genome, or spike protein, or even just a small segment including the furin cleavage site, was synthesized. Although without knowing what protein folding modeling capabilities and synthesis capabilities the WIV had, who knows for sure?
Sigh. As I've said in other posts, if any experiment of this sort were the source of sars-cov-2, it would be -blindingly- obvious. The synthetic metagenomic experiments looking into spike, etc. leave completely obvious traces, number one being the use of known, characterized viral vectors. Using some random isolates as experimental vectors is not only methodologically pointless and counterproductive, it's vastly more difficult to do.
Here's the Cliff Notes version of the argument in this paper:
1. SARS-CoV-2 has a number of unique and unusual genetic features, when compared to close relatives, many of which explain its high virulence and infectivity among humans.
2. A series of research papers published by a group of virologists, dating back a little over a decade, demonstrate (1) a progressively increasing understanding of viral features which make coronaviruses more infectious and virulent in humans, and (2) laboratory capabilities for successfully creating chimeric viruses (e.g. moving one specific protein sequence from a bat SARS-like virus to human SARS virus) to test their hypotheses.
3. Each of the unique and unusual features of SARS-CoV-2 appears somewhere in this line of research.
4. Researchers from the Wuhan Institute of Virology, located in the city where the outbreak began, were intimately involved this line of research.
Taken together, the publicly-available evidence indicates that a select group of virologists had the domain knowledge and laboratory capabilities to create chimeric viruses which possess each of the unusual features of SARS-CoV-2, and that select group of virologists was concentrated at the Wuhan Institute of Virology located at ground zero for the pandemic.
The authors feel that, in light of this preponderance of circumstantial evidence, the hypothesis that the biogenesis of SARS-CoV-2 involved human intervention should be seen as the leading (i.e. most likely) explanation.
They do not make any statement about how the virus first infected a live human and spread into a pandemic, but conditioned on their biogenesis hypothesis being true, one would then assume an accidental lab release from WIV as the most likely explanation.
It doesn’t actually matter. The things SARS-CoV-2 can do already existed inside the world of bat viruses and bat immunology. What happened is that it found an “adapter” to fit to human cells. It could have been a lab leak, it could have been pure chance in a biologically risk-pressurized environment, and it doesn’t matter.
It messes us up. It is a threat to the health and wellbeing of people. It’s surprisingly easy to stop transmission, and surprisingly difficult to work with after infection. There’s a lot of clear scientific knowledge on actions we can take. The academic papers on this mostly lay unread. There is a waiting time from clear scientific results in molecular biology to medical and engineering applications, and this waiting time is far, far too long. Not as in “move fast and break things”, but rather “doctors should read”.
> “We will conduct in vitro pseudovirus binding assays, using established techniques2, and live virus binding assays (at WIV to prevent delays and unnecessary dissemination of viral cultures) for isolated strains.” (D1, p.12)
> “We will validate results from chimeric viruses by re-characterizing full-length genome versions, testing whether backbone genome sequence alters full length SARSr-CoV spillover potential. QS for full-genome characterization will be selected to reflect strain differences in antigenicity, receptor usage, growth in human cells and pathogenesis.”(D1, p.13)
> “We will test growth in primary HAE cultures and in vivo in hACE2 transgenic mice. We anticipate recovering ~3-5 full length genome viruses/year.”(D1, p.13)
> “We will analyze all SARSr-CoV S gene sequences for appropriately conserved proteolytic cleavage sites in S2 and for the presence of potential Furin cleavage sites74,75.
SARSr-CoV S with mismatches in proteolytic cleavage sites can be activated by exogenous Trypsin or Cathepsin L.
Where clear mismatches occur, we will introduce appropriate human-specific cleavage sites and evaluate growth potential in Vero cells and HAE cultures.”
> “We will also review deep sequence data for low abundant high risk SARSr-CoV that encode functional proteolytic cleavage sites, and if so, introduce these changes into the appropriate high abundant, low risk parental strain.” (D1, p.13)
This strange furin cleave site allows the virus to bind to human ACE2 receptors. An interesting scientific reading on this, which does not rule out genetic manipulation in a lab:
That article is reporting on the letter by Andersen et al [1] that Nicolas Wade addresses in his article in the Bulletin of the Atomic Scientists [2] that was published a few weeks back, right around the time the lab hypothesis started gaining steam; it's still probably the strongest case that's been made for it. I think it dispatches the Andersen letter quite handily, but YMMV:
> A second statement that had enormous influence in shaping public attitudes was a letter (in other words an opinion piece, not a scientific article) published on 17 March 2020 in the journal Nature Medicine. Its authors were a group of virologists led by Kristian G. Andersen of the Scripps Research Institute. “Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus,” the five virologists declared in the second paragraph of their letter.
> [...] True, some older methods of cutting and pasting viral genomes retain tell-tale signs of manipulation. But newer methods, called “no-see-um” or “seamless” approaches, leave no defining marks. Nor do other methods for manipulating viruses such as serial passage, the repeated transfer of viruses from one culture of cells to another. If a virus has been manipulated, whether with a seamless method or by serial passage, there is no way of knowing that this is the case. Andersen and his colleagues were assuring their readers of something they could not know.
> [...] The two reasons the authors give for supposing manipulation to be improbable are decidedly inconclusive.
> First, they say that the spike protein of SARS2 binds very well to its target, the human ACE2 receptor, but does so in a different way from that which physical calculations suggest would be the best fit. Therefore the virus must have arisen by natural selection, not manipulation.
> If this argument seems hard to grasp, it’s because it’s so strained. The authors’ basic assumption, not spelt out, is that anyone trying to make a bat virus bind to human cells could do so in only one way. First they would calculate the strongest possible fit between the human ACE2 receptor and the spike protein with which the virus latches onto it. They would then design the spike protein accordingly (by selecting the right string of amino acid units that compose it). Since the SARS2 spike protein is not of this calculated best design, the Andersen paper says, therefore it can’t have been manipulated.
> But this ignores the way that virologists do in fact get spike proteins to bind to chosen targets, which is not by calculation but by splicing in spike protein genes from other viruses or by serial passage. With serial passage, each time the virus’s progeny are transferred to new cell cultures or animals, the more successful are selected until one emerges that makes a really tight bind to human cells. Natural selection has done all the heavy lifting. The Andersen paper’s speculation about designing a viral spike protein through calculation has no bearing on whether or not the virus was manipulated by one of the other two methods.
> The authors’ second argument against manipulation is even more contrived. Although most living things use DNA as their hereditary material, a number of viruses use RNA, DNA’s close chemical cousin. But RNA is difficult to manipulate, so researchers working on coronaviruses, which are RNA-based, will first convert the RNA genome to DNA. They manipulate the DNA version, whether by adding or altering genes, and then arrange for the manipulated DNA genome to be converted back into infectious RNA.
> Only a certain number of these DNA backbones have been described in the scientific literature. Anyone manipulating the SARS2 virus “would probably” have used one of these known backbones, the Andersen group writes, and since SARS2 is not derived from any of them, therefore it was not manipulated. But the argument is conspicuously inconclusive. DNA backbones are quite easy to make, so it’s obviously possible that SARS2 was manipulated using an unpublished DNA backbone.
> And that’s it. These are the two arguments made by the Andersen group in support of their declaration that the SARS2 virus was clearly not manipulated. And this conclusion, grounded in nothing but two inconclusive speculations, convinced the world’s press that SARS2 could not have escaped from a lab.
Section 2.3 of the reddit post [0] (titled: "And if it were created in a lab, SARS-CoV-2 would have been engineered by an idiot") mentions covid having a polybasic cleavage site, which is suboptimal for humans (the "ford focus" of cleavage sites), but binds to many other species (ferrets, cats, chimps, etc), along with a promiscuous and somewhat unstable spike protein to bind to those diverse ace2 receptors, meaning this was most likely made by nature, jumping through animal populations.
The article you linked seemed to mention furin cleavage sites in a hypothetical context, unless I'm missing something.
But lots of aspects and features of SARS-CoV2 point to it being a natural virus with a human specific furin cleavage site inserted into it. In fact it looks almost exactly what you would expect from the type of experiments outlines in the DEFUSE Proposal https://www.documentcloud.org/documents/21066966-defuse-prop...
The fact that the location happens to be in the exact location proposed in experiments and commonly used in virology, and the fact that SARS-CoV2 binds to Human ACE2 more efficiently than any other species really stands out:
> Spike protein exhibited the highest binding to human (h)ACE2 of all the species tested. . .
> These findings show that the earliest known SARS-CoV-2 isolates were surprisingly well adapted to bind strongly to human ACE2, helping explain its efficient human to human respiratory transmission
> Our observations suggest that by the time SARS-CoV-2 was first detected in late 2019, it was already pre-adapted to human transmission to an extent similar to late epidemic SARS-CoV. However, no precursors or branches of evolution stemming from a less human-adapted SARS-CoV-2-like virus have been detected
Not to mention that it's absurd to think that such an infectious virus would have been circulating in Raccoon Dogs or Civets and just simply disappear after the first human was infected with zero traces to be found. Like when humans passed covid to white tailed deer that did not stop the virus from circulating in humans.
Are we supposed to just accept SARS-CoV2 spillover was the result of an "Immaculate Infection">?
To be clear, I would guess that if SARS-CoV-2 was created in a lab in Wuhan, it was created with good intentions, and escaped from the lab by mistake. And rather than figuring out where to point fingers, we can work together to prevent future pandemics by preventing research that creates deadly diseases.
My (recent) experience with viral development is that it can be done in radical multiplex. You don't make one vector at a time. You mix five together, let or encourage them to recombine, then use sequencing, screens and molecular assays to sort out the details of which of the trillions you create has your desired phenotype and why. If this group was thinking about adding a furin cleavage site, they could do so using a template homologous to the appropriate regions of diverse natural viruses, then use selection in cell culture or animal models to establish where it landed and what effects it had on infection.
It's highly unlikely that an established group would write a proposal that didn't describe their current research trajectory.
Although you have made a lot of arguments against it, I still don't know why it seems so unreasonable to you that SARS-CoV-2 might have laboratory origins. I think it's just that your prior expectations run against this. To me it's much easier to imagine than a natural spillover, given the modern urban circumstances and very unusual viral features and phenotype. Maybe my work experience is more aligned with this possibility than yours?
You are neglecting a third possibility in that it was accidentally generated in lab conditions. The furin cleavage site is a large insert relative to its closest aligning viral genome and is consistent with adaptation to cell culture conditions. The situation would look like someone infecting cells in a dish with some starter virus and continually passaging the supernatant to cells in new dishes, to examine the evolutionary adaptations. This person could have accidentally synthesized SARS-COV-2, and using improper safety protocols, got it on themselves and then went out and infected someone else.
They put 8 natural spike proteins on a well-known backbone, WIV-1. SARS-CoV-2 is not made up of any known viral backbone. It's an entirely novel virus, which differs from all previously known viruses throughout its entire genome. This is very much not what you would get from these sorts of infectivity studies.
No it's not possible. The thing that makes Sars-Cov-2 unique is its binding site in the human body. Sars-Cov-2 binds to the ACE2 receptor, which is found in just about every organ in your body. Unlike many other viruses which target receptors more localized to e.g. your throat/airway, Sars-Cov-2 can infect cells in your nasal cavity, stomach, lungs, heart, olfactory neurons, you name it. And every cell it infects will be destroyed; either by bursting to release the viral replicas, or by an immune system response.
In the Washington Post an American virologist finally published a detailed analysis of the "spike protein research" theory:
Some people have wondered whether these types of experiments could have produced SARS-CoV-2. The answer is, in this case, not really. In theory, if you had the right viruses in your catalogue, sure. But there are no indications that anyone had ever seen this virus nor any viruses similar enough to serve as its genetic building blocks before SARS-CoV-2 emerged in the population. The Wuhan institute’s most recent chimeric virus used a very different coronavirus as its genetic backbone. Looking at the body of research produced there, it’s clear that scientists were laser-focused on the bat viruses related to SARS-CoV, which spurred research on coronaviruses worldwide after it emerged in 2003 because of its pandemic potential. There’s just no trace of SARS-CoV-2 in the lab, and if the SARS-CoV-2 progenitor or its building blocks weren’t in the lab before the pandemic, the pandemic could not have started there — even accidentally.
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