A few weeks ago a former journalist Nicholas Wade penned a long conspiracy “theory” pointing fingers at the Wuhan Institute of Virology for a possible lab leak causing the COVID-19 pandemic.

Wade quoted the Nobel-prize-winning virologist Baltimore in his piece:

“When I first saw the furin cleavage site in the viral sequence, with its arginine codons, I said to my wife it was the smoking gun for the origin of the virus,” said David Baltimore, an eminent virologist and former president of CalTech. “These features make a powerful challenge to the idea of a natural origin for SARS2,” he said.

Let’s reholster that smoking gun…

Kristian Andersen is a Ph.D. virologist who early in 2020 wrote an important Nature Letters paper showing that the SARS-CoV-2 virus was most likely a naturally derived virus and not engineered in a lab. Andersen responded to Baltimore’s smoking gun comment with some very specific tweets firmly debunking the smoke from any guns:

The furin cleavage site (FCS) / polybasic cleavage site is present in SARS-CoV-2 at the S1/S2 junction of the spike protein where it mediates the cutting (by the host protease furin, among others) of the spike, which is required for infection of cells.

This introductory tweet basically says that the FCS is like a flag within the virus’ spike protein for a human protein scissors called a furin to come and cut the spike. Cutting the spike at the location makes it much easier for the virus to then get into our cells.

Andersen provided a detailed map of that flag, shown below:

Andersen continued his scientific tweetise by explaining how the virus’ flag was made and what it does:

The FCS was created by an out-of-frame insertion of “CTCCTCGGCGGG” creating the “(P)RRAR” amino acid sequence, which constitutes a suboptimal polybasic cleavage site that is important for expanding SARS-CoV-2 host range, it’s transmission and pathogenesis, etc.

There’s a lot in that short sentence to let’s unpack that a bit.

Out-of-frame insertion…

Andersen’s comment about an out-of-frame insertion means that the DNA code CTCCTCGGCGGG is not read in the normal in-frame triplets CTC-CTC-GGC-GGG. If we consult a codon table we see that those codons translate into an amino acid sequence: L-L-G-G (or leucine-leucine-glycine-glycine). However, this short sequence was inserted into the virus genome out-of-frame so it was actually read nCT-CCT-CGG-CGG-Gnn. The first and last triplets are part of an existing codon with the letters nnn. So the middle three codons translate to: x-P-R-R-x. We have only a part of the FCS Andersen mentioned which is (P)RRAR — so where does the rest come from?

This dozen letters of genetic code was inserted within a previously existing codon, not between codons the way a scientist would engineer an insertion.

The previous amino acid was a serine. The codons for serine include: TCT, TCC, TCA, and TCG.

Since the first out-of-frame codon is nCT, we know that the original codon was TCT. The insertion happened between the first T of the serine codon, and the last two CT.

If our out-of-frame insert happens within this serine codon, we end up with the following: TCT-CCT-CGG-CGG-GCT.

Now if we translate that, we end up with the following: S-P-R-R-A.

The original amino acid next to the serine is an arginine, R. Therefore the full sequence including the original S-R becomes: S-P-R-R-A-R.

Sub-optimal cleavage site…

Next, after explaining how the FCS was encoded by an out-of-frame insertion of a dozen nucleotides (genetic letters), Andersen then calls the result a “suboptimal polybasic cleavage site”. What does he mean by this?

A furin is a protein which is evolutionarily designed to cut other proteins. Enzymes like proteases, protein scissors that cut other proteins, typically recognize very specific targets. In our case, furins recognize short amino acid sequences and cut near those targets. The sequence furins recognize are: R-X-[K/R]-R↓. We know R = arginine, K = lysine, and X = any amino acid. The arrow designates where furin cuts the target protein.

The FCS in the SARS-CoV-2 virus is R-R-A-R and differs from that simple R-X-[K/R]-R motif. Furthermore, efficient cleavage requires more than four amino acids. Optimal furin cleavage sites actually requires about 20 amino acids. The following illustrates what is known as optimal furin cleavage sites:

For example, the viral sequence contains two isoleucines in the P3′ and P4′ region which calls for small hydrophillic amino acids, whereas isoleucines are aliphatic amino acids.

It is clear that the SARS-CoV-2 site works as a furin target, but is far from optimal.

Transmission and pathogenesis…

Finally, Andersen concludes his second tweet in this series by saying: “…polybasic cleavage site …is important for expanding SARS-CoV-2 host range, it’s transmission and pathogenesis…”.

Studies of coronaviruses without the furin cleavage site showed that this short insertion is essential for infection into human cells and is key to the transmission (ability to infect new hosts) and pathogenicity (ability to grow in the host cells) of this virus.

Importantly, the furin cleavage site may have been the key in the spread of this virus from the original bat host to humans, possibly through an intermediate species.

Where did FCS come from…

Andersen then beautifully addressed the question of where the FCS came from. I’ll just extensively quote from most of his thread here. He tweeted:

FCSs are abundant, including being highly prevalent in coronaviruses. While SARS-CoV-2 is the first example of a SARSr virus with an FCS, other betacoronaviruses (the genus for SARS-CoV-2) have FCSs, including MERS and HKU1.

He’s saying that evolution solved the “problem” of putting FCS into viral genomes many times. This is not unusual or difficult for viruses.

There is nothing mysterious about having a “first example” of a virus with an FCS. Viruses sampled to date only give us a teeny-tiny fraction of all the viruses circulating in the wild. Fragments — such as the CTCCTCGGCGGG — come and go all the time.

How did SARS-CoV-2 acquire the FCS? We don’t know, however, we know four main mechanisms often lead to insertions: (1) mutation (2) polymerase slippage (3) template switching (4) recombination All of which play key roles in coronavirus (incl. SARS-CoV-2) evolution.

While we don’t know for sure how SARS-CoV-2 acquired the FCS, template switching is a very likely explanation with a plausible mechanism: https://link.springer.com/article/10.1007%2Fs00705-020-04750-z … We also find insertions — albeit not FCSs (yet) — in highly related viruses, e.g., RmYN02:

Template switching likely also play an important role during the ongoing evolution of SARS-CoV-2: https://www.biorxiv.org/content/10.1101/2021.04.23.441209v1 …. We need to see this in the context of the decades of evolution of the SARS-CoV-2 ancestor and related viruses in bats. It’s safe to say indels come and go.

The FCS itself, (P)RRAR, is not an optimal site (for cleavage) and has never previously been used in CoV experiments to the best of my knowledge — unlike more optimal sites, which have been inserted into SARSr CoVs for basic research:

The exact same (P)RRAR FCS found in SARS-CoV-2 can be found in different viruses, including Feline coronavirus (FCoV), which is an alphacoronavirus. Note, site not present in all closely related viruses and plenty of indels around the site — like SARS-CoV-2 vs SARSr CoVs.

If we zoom in on the (P)RRAR site in SARS-CoV-2 and compare it to the one found in (some) FCoV sequences, we can see there’s a fair bit of homology outside the FCS too — including likely O-linked glycans being conserved.

The (P)RRAR FCS isn’t optimal and while it’s ‘sufficient’ for SARS-CoV-2s ‘success’ as a pandemic virus, it’s not an ideal site as defined by the canonical R‐X‐K/R‐R FCS seen in many proteins (viral and otherwise).

The “P” from the (P)RRAR insert isn’t directly part of the cleavage site itself, but, intriguingly, may regulate it via the nearby O-linked glycans. This is seen in host proteins: https://www.jbc.org/article/S0021-9258(20)32890-8/fulltext …, but also in SARS-CoV-2:

Importantly, however, in recent month we have started seeing the “P” mutating towards residues creating more optimal furin sites — P681H and, especially, P681R, which can be found in B.1.1.7 and B.1.617.x, suggesting the virus may evolve towards more efficient usage of the site.

So Baltimore’s first point — that the FCS found in SARS-CoV-2 is somehow unusual — is simply incorrect. FCSs are found in a multitude of different coronaviruses, indels come and go frequently, and the exact (P)RRAR can be found in other coronaviruses.

Now, the codons. Here, Baltimore is talking about the two codons coding for the first two arginines (R) following the P — CGG. The CGG codon is rare in viruses because it’s an example of an unmethylated “CpG” site that can be bound by TLR9, leading to immune cell activation.

Despite being rare, however, CGG codons *are* found in all coronaviruses, albeit at low frequency. Specifically, of all arginine codons, CGG is used at these frequencies in these viruses: SARS: 5% SARS2: 3% SARSr: 2% ccCoVs: 4% HKU9: 7% FCoV: 2% Nothing unusual here.

Furthermore, if we go back to the FCoV sequences and compare them to SARS-CoV-2 at the nucleotide level you’ll see that FCoV also uses CGG to code for R immediately following the P. The next R is CGA (non-CpG) in FCoV, while it’s CGG in SARS-CoV-2 — one nucleotide difference.

We see CGG multiple times in different ways — here’s an example comparing another “PR” stretch between SARS-CoV-2, RaTG13, and SARS-CoV in the N gene. Note how SARS-CoV-2 and RaTG13 both use CGG, while SARS-CoV-2 uses CGC for the first R, while later R’s are coded by CGT or AGA.

One final point about the CGG codons in the FCS — if they were somehow “unnatural”, we’d see SARS-CoV-2 evolve away from “CGG” during the ongoing pandemic. We have more than a million genomes to analyze, so what do we find if we look at synonymous mutations at the “CGG_CGG” site?

Remarkably stable. Specifically, CGG is 99.87% conserved in the first codon and 99.84% conserved in the second. This is *very* strong evidence that SARS-CoV-2 ‘prefers’ CGG in these positions.

R is coded by six different codons, yet the simple single transition “CGA” is only observed in ~0.02% of sequences. The second most ‘popular’ codon at these sites is “CGT” (a transversion) at 0.11% frequency. In other words — there is nothing unusual about the codons either.

So Baltimore’s second point is also false, invalidating his hypothesis that the “FCS […] with its arginine codons […] was the smoking gun for the origin of the virus”. Baltimore does not provide any evidence to support his hypothesis and the data support a natural origin.

Does this disprove a lab leak? No. However, it disproves there being a “smoking gun” in the FCS and lends further evidence to natural emergence — but it also does not *prove* that scenario. To this day, we have yet to see any scientific evidence supporting a lab leak.

Baltimore backs down…

In an interview with Nature and the Los Angeles Times, David Baltimore conceded that he went too far with his smoking gun comment. In an email to the LAT, Baltimore said that he

“should have softened the phrase ‘smoking gun’ because I don’t believe that it proves the origin of the furin cleavage site but it does sound that way. I believe that the question of whether the sequence was put in naturally or by molecular manipulation is very hard to determine but I wouldn’t rule out either origin.”

Where does that leave us…

Let’s get back to quoting Andersen who has been the most reliable and expert voice so far in all of these back-and-forth comments. Andersen emailed the LAT:

“We cannot prove that SARS-CoV-2 has a natural origin and we cannot prove that its emergence was not the result of a lab leak.

However, while both scenarios are possible, they are not equally likely,” Andersen wrote. “Precedence, data and other evidence strongly favor natural emergence as a highly likely scientific theory for the emergence of SARS-CoV-2, while the lab leak remains a speculative incomplete hypothesis with no credible evidence.”

The post Nobel-Winning Virologist David Baltimore Eats Wuhan Crow appeared first on Medika Life.

Nicholas Wade is wrong

The Wall Street Journal, meanwhile, has been busy pushing an “undisclosed U.S. intelligence report” suggesting that three Chinese researchers at the now-famous Wuhan Institute of Virology were hospitalized in November 2019. These workers had “symptoms consistent with both Covid-19 and common seasonal illness”.

Conspiracy theories of the COVID-19 virus SARS-CoV-2 originating in an accidental lab release being peddled by Trump’s former FDA commissioner and the WSJ are not surprising. Supporters of Trump clearly have no love of truth as witnessed by how the GOP is treating long-time uber-conservative party leader Liz Cheney.

The most recent salvo of dubious theories comes from Nicholas Wade, a former science writer for Nature and Science and the New York Times. Despite Wade’s journalistic pedigree, close reading of his latest essay on the origins of COVID-19 reveals a poor adherence to reporting standards, investigatory lapses and major biases, and insistent mis-representation or outright falsehoods, leading to erroneous and unsupportable conclusions.

Unfortunately, Wade’s conspiracy theory has already gotten significant press, and is notable mostly for his highly personal attacks on those with divergent views: Drs. Anthony Fauci and Francis Collins and Kristian Anderson and Peter Daszak are among his most prominent targets.

Wade promises to guide you through the molecular biology of viruses, but his promise is shallow. Wade’s essay shows that his biology knowledge is ankle-deep and packed with major and minor errors and misrepresentations. He has a bachelor’s degree in biology so he is not completely uneducated.

However, Wade proves the classic trope that a little knowledge is a dangerous thing. His essay is exactly that — a dangerous thing.

Let’s see why.

More personal than molecular biology…

Wade spends much of his essay doling out personal takedowns of some key coronavirus researchers who have communicated scientific observations contrary to his opinions. The first of many victims is Dr. Peter Daszak, and the second is Dr. Kristian Anderson, followed by others.

Let’s focus on Wade’s attacks on Dr. Anderson since Wade presses several buttons here. First, Dr. Anderson and his team published a Nature letters article early during the pandemic explaining why an engineered origin of the virus was unlikely.

In the first step of Wade’s assault, he characterizes Anderson’s Nature letter as “…an opinion piece, not a scientific article…”. Wade’s Wikipedia page says that he was an editor at prestigious scientific journals Nature and Science, and therefore clearly knows better. Wade’s claim that a Nature letter like Anderson’s is only opinion and not a scientific article is not a small error, but an intentional assault on facts and truth.

A blog by Nature lays out the difference between these two formats quite clearly:

Articles are original reports whose conclusions represent a substantial advance in understanding of an important problem and have immediate, far-reaching implications.

Letters are short reports of original research focused on an outstanding finding whose importance means that it will be of interest to scientists in other fields.

Nature letters are NOT merely opinions. This has been a long-standing feature of Nature. As a prime example, the biggest biological discovery in the 20th century may be Watson and Crick’s discovery of the double-helical and complementary nature of DNA’s structure — published in a Nature letter. Clearly not just an opinion piece.

Any science writer knows that a couple of the most important science journals are called Physics Letters A and Physics Letters B.

These Nature letters represent important scientific reports. Clearly Wade found it necessary to jettison his editorial knowledge from working at that very journal in order to diminish and dismiss Anderson’s data, discussions, and conclusions.

Furthermore, when Wade tries to tackle Anderson’s data, he remains firmly in personal attack mode with comments like:

…Unfortunately this [Anderson’s article] was another case of poor science…

Wade liberally sprinkles much more of these snide and passive aggressive attacks throughout his essay. A journalist passing judgement on a scientist’s science, suggesting himself as more knowledgeable than the scientist, and co-opting a position as a science educator while peddling obvious errors and alternative facts as science.

A poor attempt at molecular biology…

When Wade finally argued Anderson’s data and discussions, we immediately saw how out of his depth and off target he was — and therefore why he spent so much time trying to damage those with opposing views. Wade clearly found that damaging reputations was much easier than arguing the points of a field in which he was unqualified.

The first argument Wade made with Anderson was about seamless methods of cloning or DNA manipulation. Wade referred to early methods of molecular cloning that left easily detected remnants or scars in the DNA sequence. The trouble with this is that Anderson never invoked genomic scars in his paper.

Perhaps Wade was familiar with seamless cloning technology — if your only tool is a hammer, everything is a nail. One such technology was called “No see’m” and was developed and used by coronavirus researchers. Aside from Wade’s error in calling it “No-see-um” which is a type of incredibly irritating biting gnat, his bigger error is that his argument was irrelevant.

Anderson’s article said nothing about seamless technology, and instead said the following:

…Furthermore, if genetic manipulation had been performed, one of the several reverse-genetic systems available for betacoronaviruses would probably have been used19. However, the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone20.…

Anderson was referring to a characteristic set of restriction sites, natural or engineered, necessary to work with each of the reverse genetic systems — nothing to do with seamless cloning.

Reverse genetics covers a broad range of scientific methods, but common among all is the idea of changing the DNA sequence (what biologists call the genotype) and then looking for changes in the organism (its features, behaviors, chemistry, etc., all lumped under a typically obtuse scientific term, phenotype). When applied to viruses, often the goal is to see when a non-human virus becomes capable of infecting human cells.

Then Wade tried to falsely characterize one of Anderson’s arguments:

…they [Anderson et al] 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…

This is a major misrepresentation and oversimplification of Anderson’s argument. The S protein shows strong binding affinity for the human ACE2 protein, but ALSO to ACE2 proteins from other species. The viral S protein evolved in a way that bound well, but not optimally to human ACE2. Any synthetic S protein would have been engineered specific to human ACE2, and the binding would have been much more “tailored”.

What Anderson actually said was:

…SARS-CoV-2 …binds with high affinity to ACE2 from humans, ferrets, cats and other species with high receptor homology… SARS-CoV-2 may bind human ACE2 with high affinity, computational analyses predict that the interaction is not ideal7 and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding7,11. Thus, the high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2 that permits another optimal binding solution to arise. This is strong evidence that SARS-CoV-2 is not the product of purposeful manipulation…

What Anderson meant was that computational calculations show that the binding between the viral S (spike) protein and the human ACE2 protein are not “ideal” — ideal being what we expect from an engineered S protein. An engineered SARS virus might have used one of two routes:

• Insert into the viral genome a known S protein with strong binding to human ACE2 protein.
• Passage through cells and use only human ACE2 as the target.

Either route would have resulted in a much better, more customized fit of S protein to human ACE2.

Anderson argued that there were multiple ACE2 protein targets including those from human and other animals, which strongly suggests a natural origin.

The fact that Wade did not understand this basic biological concept shows how lacking his technical background is, and emphasizes his lack of qualification to pass judgement on the scientists or science being discussed.

The irony is that Wade tried hard to imply that it was Anderson, the Ph.D. virologist, who lacked technical understanding of virology. Wade says of Anderson:

…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). But since the SARS2 spike protein is not of this calculated best design, the Andersen paper says, therefore it can’t have been manipulated…

Note how Wade tries to tell us what Anderson’s assumption is? He tells us that 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.” That is emphatically NOT Anderson’s basic assumption.

Anderson et al are virologists and they know (far better than Wade) how scientists design viral proteins. Wade packed false assumptions into Anderson’s head and article, concepts which are clearly wrong.

Wade worked hard to tell us that a Nature-published virologist made incorrect assumptions about how virologists design and make viral proteins — and then wants to tell us how virologists really do this work?

Read what Wade goes on to say:

…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…

Anderson’s comment on computation had nothing to do with engineering the virus — Wade mischaracterized and twisted Anderson’s intent. Anderson only discussed the after-the-fact computation of protein binding.

By the way, Wade also erred by saying that virologists don’t use calculations to design protein binding. Here is only one example of many articles showing how virologists DO indeed use computation to design protein-protein binding interactions.

Wade was wrong TWICE in one argument — Wade was wrong because virologists do indeed use calculations and computation to design protein-binding interactions — and Wade was also wrong because Anderson’s article never discussed that kind of computation.

Wade then tried to argue further:

…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…

Wade clearly doesn’t understand the field and assumes that any DNA backbone will work. That is not true and is why the few backbones developed took so long, and are still used. They work.

Development of mouse hepatitis virus and SARS-CoV infectious cDNA constructs – PubMed: The genomes of transmissible gastroenteritis virus (TGEV) and mouse hepatitis virus (MHV) have been generated with a…pubmed.ncbi.nlm.nih.gov

Here are some comments from a real virologist that directly refute what Wade says is “quite easy to make”:

… To reiterate, most of SARS-CoV-2 comes from a bat coronavirus closely related to RaTG13. This virus is not known to cause disease in humans. If we were virus engineers (and this actually happens to be my job in the Benhur Lee Lab) we would need to:

Make a virus backbone from a never-before-seen virus that looks like, but isn’t, RaTG13 without having any reason to believe it would be a better starting place than a previously characterized virus (like the original SARS-CoV)

Spend months to years building a system that is easy to engineer (reverse-genetics system) when there are other virus backbones readily available.

Choose the RBD region from an unknown pangolin coronavirus even though all computer models show it should be suboptimal at binding ACE2, and show that it binds well in spite of the models (paper 1, paper 2, paper 3, paper 4)

All of these steps sound like bad ideas from a scientist’s perspective: there were easier ways to engineer a coronavirus, and no one would have rationally chosen either the bat virus backbone or the pangolin portion of the spike protein. Therefore, SARS-CoV-2 is unlikely to be man-made from pieces of other viruses — we have zero evidence that any person or lab has attempted even one part of this process.…

Then Wade minimized Anderson’s paper as follows:

…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. A technical critique of the Andersen letter takes it down in harsher words…

Wade clearly didn’t understand that Anderson discussed several other important points including something called a polybasic cleavage site. This is a short sequence of amino acids which is a target for protein scissors called proteases. Proteases clip proteins at specific cleavage sites defined by a short amino acid sequence. Anderson et al discuss how a cleavage site can be acquired by the influenza hemagglutinin protein by repeated passage in cell culture or animals. Anderson also talks about its absence in most viruses closest to SARS2, that the RaTG13 is 96% identical but differs significantly in the RBD, but the pangolin CoV are similar to SARS2 especially the 6 key resides in the RBD. Anderson also says:

…a hypothetical generation of SARS-CoV-2 by cell culture or animal passage would have required prior isolation of a progenitor virus with very high genetic similarity, which has not been described. Subsequent generation of a polybasic cleavage site would have then required repeated passage in cell culture or animals with ACE2 receptors similar to those of humans, but such work has also not previously been described. Finally, the generation of the predicted O-linked glycans is also unlikely to have occurred due to cell-culture passage, as such features suggest the involvement of an immune system18…

Now that we are aware of how shallow Wade’s understanding of biology is, it is no surprise that he completely missed the point about O-linked glycans, and that they only form when the virus is exposed to an immune system.O-linked glycans on viruses are thought to shield them from their host’s immune system. Therefore, the presence of these sugars (and the amino acids which host them), strongly point to the virus’s evolution in an adaptive immune system such as ours.

Trying to cast doubts on natural emergence of SARS-CoV-2…

Wade next tried to cast doubts on natural emergence of SARS-CoV-2. He pointed to the WHO’s visit to China and that “the Chinese had no evidence to offer the commission in support of the natural emergence theory”. What Wade failed to mention is that the US harangued China during the Trump administration, and the Chinese probably and understandably felt no inclination to openly share data with the US or the rest of the world. We would do the same even though that is not responsible or the right thing to do. But most of us are unlikely to do the responsible and right thing when we have just been admonished and insulted on the world stage.

We clearly need China to be a good global citizen and to be open and honest about what they have found, to share their data as well as processes and procedures within their research institutes that may have in any way contributed to the pandemic (or not). In order for China to act like a good global citizen, we need to treat them as such, the way we would want to be treated.

Lacking China’s data, we are missing valuable information needed to refute or prove the lab escape thesis. We don’t know what we don’t know. Nonetheless, the existing biological data rests strongly on the side of natural emergence.

Wade claimed that the lack of evidence from China supports a lab-release of SARS-CoV-2 and against natural emergence. When in fact it merely emphasizes the Chinese government’s troublesome policy of secrecy.

Wade says, “… Natural emergence remained a conjecture which, however plausible to begin with, had gained not a shred of supporting evidence in over a year”. In fact, the evidence more powerfully supports natural emergence as Anderson’s Nature paper indicated.

Wade further showed his confusion about science by making it seem fast and easy to track down viral hosts and the evolution of previous coronavirus pandemics, saying:

…This was surprising because both the SARS1 and MERS viruses had left copious traces in the environment. The intermediary host species of SARS1 was identified within four months of the epidemic’s outbreak, and the host of MERS within nine months. Yet some 15 months after the SARS2 pandemic began, and a presumably intensive search, Chinese researchers had failed to find either the original bat population, or the intermediate species to which SARS2 might have jumped, or any serological evidence that any Chinese population, including that of Wuhan, had ever been exposed to the virus prior to December 2019…

When in fact, tracing down these viruses is a huge amount of work and actually took over a decade, not months. The finds virologists made for SARS1 and MERS were a combination of massive epidemiological efforts and huge luck.

It took 15 years after SARS1 to identify the animal origin of that pandemic. Finding the civet intermediary for SARS1 was a lucky strike which was not replicated for the original source of the virus.

Wade repeatedly pushed this idea that we should have found evidence already:

…Natural emergence remained a conjecture which, however plausible to begin with, had gained not a shred of supporting evidence in over a year…

And we see why he is so anxious for this exploration to have yielded conclusive results, because he says:

…as long as that remains the case, it’s logical to pay serious attention to the alternative conjecture, that SARS2 escaped from a lab…

The logic is quite the reverse. The evolutionary pedigree of the virus is an important part but only part of the tapestry of data which builds the case for natural emergence. The lack of host species is merely that — a lack that will eventually be filled in. The lack of this data does not automatically make lab escape a more plausible hypothesis. The genomic and genetic data that Anderson and others have established continue to be best explained by natural emergence.

The pot calling the Chinese kettle black…

Wade also tried to set the stage of the Chinese virus research and show how terrible their efforts were. He quoted from two research grants:

RePORTER: Grant Link

Federal RePORTER: Grant Link

Wade then selectively quoted two technical aims of the proposal and then interpreted them in a way to give them a most sinister mad scientist purpose:

… What this means, in non-technical language, is that Dr. Shi set out to create novel coronaviruses with the highest possible infectivity for human cells. …

No. That is not the correct way to interpret those aims. First, let’s provide the overall goal of this project to establish context — always an important journalistic principle:

…This project seeks to understand what factors allow animal Coronaviruses to evolve and jump into the human population by studying virus diversity in a critical group of animals (bats), a sites of high risk for emergence (wildlife markets) in an emerging disease hotspot (China)…

And one of the specific aims to meet that goal was to:

… to test the hypothesis that % divergence thresholds in S protein sequences predict spillover potential…

Threshold is the key term. You cannot make a predictive model of infection by creating something that has, as Wade says, “the highest possible infectivity for human cells”.

Instead, the goal is to sneak up on the smallest amount of genetic change, the threshold, at which a non-human virus becomes a human virus. Making the virus maximally infective tells you nothing other than it makes people sick, that it can infect humans.

Scientists are more subtle than what Wade communicated or understood. Finding the threshold, or minimum genetic change to trigger human infections, gives scientists tremendous predictive power. Finding a maximally infective virus does nothing other than bestow dubious bragging rights.

Again, when Wade offered to explain to you the reader what the technical meaning of something in a scientific document, I hope you have learned not to trust his claim or promise.

Wade also spent considerable effort discussing laboratory safety levels such as here:

… There are four degrees of safety, designated BSL1 to BSL4, with BSL4 being the most restrictive and designed for deadly pathogens like the Ebola virus.…

And then he made sure to take a quote out of context, trying to maximize the impression that the Chinese work was substandard by saying:

…Much of Dr. Shi’s work on gain-of-function in coronaviruses was performed at the BSL2 safety level, as is stated in her publications and other documents. She has said in an interview with Science magazine that “The coronavirus research in our laboratory is conducted in BSL-2 or BSL-3 laboratories.” …

Although Wade provided the link to the Science interview, he knows that most people do not take the effort to click the link and read. It is worth your time if you have read that far in his (and my) article.

Again, let’s provide a little context. The question by Science Magazine was as follows:

…Given that coronavirus research in most places is done in BSL-2 or BSL-3 labs — and indeed, you WIV didn’t even have an operational BSL-4 until recently — why would you do any coronavirus experiments under BSL-4 conditions? …

Notice that? Most places do coronavirus research in BSL-2 or BSL-3 labs, so there is nothing unusual in Chinese labs doing the same.

Dr. Shi’s response was:

… The coronavirus research in our laboratory is conducted in BSL-2 or BSL-3 laboratories.

After the BSL-4 laboratory in our institute has been put into operation, in accordance with the management regulations of BSL-4 laboratory, we have trained the scientific researchers in the BSL-4 laboratory using the low- pathogenic coronaviruses as model viruses, which aims to prepare for conducting the experimental activities of highly pathogenic microorganisms.

After the COVID-19 outbreak, our country has stipulated that the cultivation and the animal infection experiments of SARS-CoV-2 should be carried out in BSL-3 laboratory or above. Since the BSL-3 laboratories in our institute do not have the hardware conditions to conduct experiments on non- human primates, and in order to carry out the mentioned research, our institute had applied to the governmental authorities and obtained the qualification to conduct experiments on SARS-CoV-2 for Wuhan P4 laboratory, in which the rhesus monkey animal model, etc. have been carried out.

The experimental activities are supervised by our institute’s biosafety committee and complied with the biosafety regulations.…

Going batty…

Wade then tried to teach us about bat biology:

…The two closest known relatives of the SARS2 virus were collected from bats living in caves in Yunnan, a province of southern China. If the SARS2 virus had first infected people living around the Yunnan caves, that would strongly support the idea that the virus had spilled over to people naturally. But this isn’t what happened. The pandemic broke out 1,500 kilometers away, in Wuhan…

Spillover of the virus from bats to people directly is only one possible way SARS-CoV-2 evolved. However, even if that happened, spillover probably did not happen near the first discovery site of the virus. We should ask what is the range of the carrier (NOT to put a pin in a map where the virus was first discovered and limit our assumptions about where spillover happened).

Wade then continued:

…Beta-coronaviruses, the family of bat viruses to which SARS2 belongs, infect the horseshoe bat Rhinolophus affinis, which ranges across southern China. The bats’ range is 50 kilometers, so it’s unlikely that any made it to Wuhan. In any case, the first cases of the Covid-19 pandemic probably occurred in September, when temperatures in Hubei province are already cold enough to send bats into hibernation…

An individual animal’s range is not a hard limit like a car’s. Animals often far exceed the normal range, so a journalist claiming “so it’s unlikely” is far from the reality. Furthermore, hibernation is not a period of complete inactivity in bats. Bats show significant activity during hibernation even in the depths of winter when torpor is highest. September in Hubei, the temperature ranges from 4–15C, so hibernation is neither required nor absolute during such a mild month.

Wade then tries to make the chain of virus infections seem like an exercise in improbabilities by saying certain conditions “must” occur on his say-so:

…What if the bat viruses infected some intermediate host first? You would need a longstanding population of bats in frequent proximity with an intermediate host, which in turn must often cross paths with people. All these exchanges of virus must take place somewhere outside Wuhan, a busy metropolis which so far as is known is not a natural habitat of Rhinolophusbat colonies. The infected person (or animal) carrying this highly transmissible virus must have traveled to Wuhan without infecting anyone else. No one in his or her family got sick. If the person jumped on a train to Wuhan, no fellow passengers fell ill…

Wade concocted a story of false improbabilities — he arbitrarily states conditions: “What if the bat viruses infected some intermediate host first? You would need a longstanding population of bats in frequent proximity with an intermediate host…”. No. Are there well-established conditions for spillover of virus from bats into other species? Where does Wade get the condition that a longstanding population of bats must be in frequent proximity with the host? Is that a known requirement? Says who? Must there be frequent proximity? Must the infected intermediate host often cross paths with humans? Who says? Wade?

Why MUST these virus exchanges in an intermediate host be outside Wuhan? The first SARS began in a city — Foshan in Guangdong province, originated in bats, and through a civet intermediate before spreading in humans with high mortality (10%).

It took 15 years after SARS1 to identify the animal origin of that pandemic. The lack of clear evidence of a natural origin for SARS2 is NOT a strike against that hypothesis — lack of data is only that — a lack of data.

The SARS1 pandemic was in 2002–3, and Shi was unable to identify the bats from which it originated, and passed through civets to humans, until 2013. And it wasn’t until 2017 that scientists identified the single population of bats from which the first SARS virus originated.

So, pointing to the knowledge of SARS1 now, and the lack of similar knowledge for SARS2 is highly deceptive and misleading.

Furin cleavage site…

Wade continues his assault on facts and biology on an important part of the SARS-CoV-2’s spike protein:

…The furin cleavage site is a minute part of the virus’s anatomy but one that exerts great influence on its infectivity. It sits in the middle of the SARS2 spike protein. It also lies at the heart of the puzzle of where the virus came from… of all known SARS-related beta-coronaviruses, only SARS2 possesses a furin cleavage site. All the other viruses have their S2 unit cleaved at a different site and by a different mechanism…

Wade purposely exaggerates the rareness of SARS-CoV-2 possessing a furin cleavage site. There are only four SARS-related betacoronaviruses — SARS-CoV-1 and -2, RaTG13, ad SL-CoV-WIV1. And indeed SARS-CoV-2 is the only betacoronavirus with a furin cleavage site. ONLY one of four!

What Wade conveniently neglects is that Furin cleavage sites are common in coronaviruses, and is present in a virus which is evolutionarily close to SARS-CoV-1 and -2. A Hibecovirus, close relative to the sarbecovirus (the family to which SARS-CoV-1 and -2 belong) and which infects the Hipposideros bat, has a furin cleavage site at the same location in the S protein. Wade is not correct to wave away the lack of furin cleavage sites in this virus family.

Again, Wade fails in his promise to teach you some molecular biology of viruses when he claims:

…How then did SARS2 acquire its furin cleavage site? …Two ways viruses evolve are by mutation and by recombination… Beta-coronaviruses will only combine with other beta-coronaviruses but can acquire, by recombination, almost any genetic element present in the collective genomic pool. What they cannot acquire is an element the pool does not possess. And no known SARS-related beta-coronavirus, the class to which SARS2 belongs, possesses a furin cleavage site…

There are more than two ways for RNA viruses to obtain mutations. A very important mechanism which Wade is ignorant of is something called copy-choice recombination or template switching, where the RNA-dependent RNA-polymerase changes template in the middle of making copies of the viral RNA.

More broadly, template switching allows RNA viruses to recombine with unrelated viruses:

Wade insists that this acquisition of a furin cleavage site is a rare or impossible event, and it is not.

Wade further confuses the molecular biology of viruses by claiming that human codons, the three-letter code which translates the genetic code into amino acids, were used in the furin cleavage site, and that is highly suscpicious evidence of human interference in virus evolution, of tampering with the genetic code. No.

These viruses evolved to replicate and use the human host’s machinery — which included the human host’s codon usage. There is absolutely nothing unusual in seeing a mix of codon usage especially in a virus which has recently switched hosts from one species to another (with possibly some intermediates in between).

Wade goes on to use the creationist language of improbability to argue against very natural evolutionary steps:

…a chain of events has to happen, each of which is quite unlikely for the reasons given above. A long chain with several improbable steps is unlikely to ever be completed….

This is exactly the argument creationists use to say why the eye could not have been evolved, or a human for that matter… nonsense. The POWER of evolution is exactly that — despite your fear that the argument can go too far… we have evolved using such rare sets of events.

Wade further argued that scientists are ignorant of codon usage frequencies:

…For the lab escape scenario, the double CGG codon is no surprise. The human-preferred codon is routinely used in labs. So anyone who wanted to insert a furin cleavage site into the virus’s genome would synthesize the PRRA-making sequence in the lab and would be likely to use CGG codons to do so….

If it was important for a particular codon to be used, virologists are very cognizant of which set, human or viral, should be used. Human-preferred codons are NOT blindly used, nor are they just routinely used in all labs. Codon usage is a conscious and important matter in molecular biology. Indeed, it may very well be that bacterial codon usage is actually the single most widely used preferred codon-set.

Then Wade tries to use a quote from a virologist to support his claims:

…“When I first saw the furin cleavage site in the viral sequence, with its arginine codons, I said to my wife it was the smoking gun for the origin of the virus,” said David Baltimore, an eminent virologist and former president of CalTech. “These features make a powerful challenge to the idea of a natural origin for SARS2,” he said….

NO — Baltimore is incorrect — there is no smoking gun!

If you’d like to read my thoughts on Biden’s newly announced 90-day investigation into the Origin of Covid in China, please click here.

Nicholas Wade, images are all used in accordance with Title 17 U.S.C. Section 107, commonly known as “fair use law”. This material is distributed without profit with the intent to provide commentary, review, education, and increase public health knowledge.

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