SCIENCE DUUUDE'S COLUMN

Debunking Nicholas Wade’s Origin of COVID Conspiracy Theory

Shoveling the never-ending horse-pucky out of the stables of truth…

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Former FDA head Scott Gottlieb was quoted by CNBC on Monday May 24, suggesting there is growing “circumstantial evidence supporting the theory that the virus could have escaped from a lab”.

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.

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 1paper 2paper 3paper 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.

Illustration of copy-choice recombination which may drive RNA virus mutations (from Figure 1 of Chrisman et al, 2021).

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

Different methods of RNA virus recombination (from Figure 1 of Simone-Loriere and Holmes., 2011).

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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Science Duuudehttps://scienceduuude.medium.com/
Husband, dad, scientist, loves to share sciency stuff and goofiness. Follow me on Twitter

24 COMMENTS

  1. Thank you for taking the time to write this excellent rebuttal. I only wish it got as much exposure as the wade piece.

  2. Hi Kun Sai,

    Thanks for reading and commenting – much appreciated!

    On your comments, let me add a couple things.

    First, where you say: “The article authored by Dr. Andersen et al. is not related to the topic of “lab leaking”. The article claims that the SARS-CoV-2 is unlikely to be man-made.”

    Andersen’s paper is specifically about the likely origins of the virus, whether it is natural or, as you say, man-made. But…

    But here is a quote directly from the Andersen paper:

    “…Basic research involving passage of bat SARS-CoV-like coronaviruses in cell culture and/or animal models has been ongoing for many years in biosafety level 2 laboratories across the world27, and there are documented instances of laboratory escapes of SARS-CoV28. We must therefore examine the possibility of an inadvertent laboratory release of SARS-CoV-2…”

    Here is the link to Andersen’s article:
    https://www.nature.com/articles/s41591-020-0820-9

    Your comment about “Natural virus can escape” is curious. A natural virus which has gained the ability to infect humans has evolved out in the world. It enters the lab, presumably through the publicized cave collection expeditions. And then it “escapes” the lab. But it is already out in the world. So I am somewhat confused by this comment.

    In any case, read the Andersen paper and let me know if your comments and opinions remain the same.

    Second, you home in on Wade’s claim “newer methods leave no defining marks”. I said it was irrelevant because Andersen does not argue about seamless cloning technology. Furthermore, there ARE defining marks from the most common methods used, which Wade is not familiar with. These are things I specifically pointed out and discussed.

    I hope I answered your questions but if not, please let me know what I’ve left unclear and I’ll try to fill in the gaps.

    SD

  3. Hi Joe (Emersberger),

    Sorry for the delay in getting back to you.

    I’m a biologist, but not a virologist (and welcome any comments and corrections from virus folks), but most of this is basic biology and is pretty straightforward.

    For your question about gain of function (GoF):
    “…why the following passage from the grant proposal would not necessarily count as gain-of-function research as apparently the NIH has claimed: “”We will use S protein sequence data, infectious clone technology, in vitro and in vivo infection experiments and analysis of receptor binding to test the hypothesis that % divergence thresholds in S protein sequences predict spillover potential. “…”

    …let’s take that quote item by item to see if we can get some insight into the grant proposal.

    First, using protein sequence data is purely a computational approach to biology. You can determine evolutionary relationships between and within a species, so this is a very powerful approach. This is not GoF research – though it can inform how to plan and execute GoF work.

    Second, infectious clone technology is basic molecular biology as applied to viruses with a key step being the reverse transcription of RNA virus genome into DNA, where the DNA can then be inserted into a bacterial plasmid. That plasmid can then be used in a wide variety of ways including GoF. But infectious cloning is not GoF.

    Third, in vitro and in vivo infection experiments are using cells from an animal in a cell culture dish and infecting just those cells with the virus of interest. In vivo means infecting the animal itself. These are not GoF by themselves, but can certainly be part of GoF experiments.

    Fourth, analysis of receptor binding can be done by biochemical methods such as gel shift assays and other methods which look at just the proteins from the virus and the target protein from the host. This is not GoF, but the data from these experiments can be used to plan and execute GoF experiments.

    So I hope this answered your question – the research items specified in the paragraph you quoted are all standard and classical methods of doing basic biology and virology. None are specific for GoF work, but all can be used to plan or be used within GoF work.

    Let me know if I can clarify anything else.

    SD

  4. Another comment I left didn’t seem to get posted. Apologies if you see this question twice.

    I have no bio background, so could you please explain why the following passage from the grant proposal would not necessarily count as gain-of-function research as apparently the NIH has claimed: “”We will use S protein sequence data, infectious clone technology, in vitro and in vivo infection experiments and analysis of receptor binding to test the hypothesis that % divergence thresholds in S protein sequences predict spillover potential. “

  5. 1, The article authored by Dr. Andersen et al. is not related to the topic of “lab leaking”. The article claims that the SARS-CoV-2 is unlikely to be man-made. Natural virus can escape.

    2, It seems to me that Mr. Wade claims that “newer methods leave no defining marks”. That is, manipulation cannot be detected. Is this true? Your article does not address this issue. You say that “his argument was irrelevant”, but I think it is relevant.

  6. Considering what we are now learning from Dr. Fauci’s emails, what is your current opinion of possibility of a lab leak? Dr. Collins admitted this week that although NIH had funded the Wuhan lab, they had “no control over what else they were doing with those funds”. Also, the National Institutes of Health hosted Wuhan Institute of Virology researchers at a 2011 conference focusing on scientific research that could pose a “significant threat” to human health – including manipulation of bat coronaviruses. At the event, the Wuhan Institute of Virology’s Deputy Director repeatedly asserted that his controversial lab had “no regulation” on this form of risky research.

  7. I also would like to add that I have yet to see a SINGLE piece of evidence that the Wuhan lab conducted Gain of Function research. That claim is a major premise in Wade’s argument as well as that of other lab escape truthers’. Wade said he has evidence of this and cited a quote in his article but the quote suggested no such thing. In fact, Wade in this interview (@ 31:18) says explicitly (backtracks?) that he has seen no specific evidence they did carry out such research.

    https://www.youtube.com/watch?v=qVVE6MD7tRw&t=1878s

    The only study he cited and others cite to suggest WIV did such research was actually conducted at the Uni. of North Carolina at Chapel Hill in 2014/15. It says that very clearly in that study.

  8. I found this article (but also the Wade article) to be COMPLETELY unpersuasive. The arguments for a Wuhan lab escape and counter arguments are totally fallacious and both sides have strawmanned the heck out of each other.

    Ultimately I do not think that the virus leaked from the Wuhan lab. Why? Primary reason is that for such a virus to be housed there, it would have had to be top secret. The Wuhan lab had published many previous reports on findings of new viruses. One of which is the closest known relative of Sars2. Why wouldn’t they publish Sars2 if they had it in their lab? If you say it was a top secret virus, why would they keep a top secret virus in a institute that had foreign scientists from all over the world visiting and was indeed built by the French and US (google it)? And why would they have published data on RaTG13 (the closest relative of Sars2) if they wanted to keep it a secret when that would only throw suspicions? Wouldn’t they keep BOTH virus data under top secret? If they wanted to keep a virus top secret, they would need to do so at a top secret lab far away from prying eyes (likely military lab).

    I think all options need to be on the table. There is a 3rd option no one talks about but to me is just as likely if not more so. The intentional release hypothesis. So we have three potential hypothesis (1. natural spillover. 2. accidental lab leak (not necessarily from Wuhan) and 3. intentional release from lab as a kind of bioweapon). I have yet to see one single argument conclusively affirming or rejecting ANY of these three hypothesis.

  9. Dear SD,

    Thank you for your detailed reply to my comments. Here are my thoughts:

    1) Politicians, for all their shortcomings, are answerable to the public. Perhaps the single most important thing for a politician is getting re-elected. Because of this, even if they indulge in war-mongering, they won’t cross certain lines. The cloistered and secure (thanks to the tenure system) professional life of a scientist puts the profession in an almost unique category. This has its advantages but isn’t it evident that one should involve the public-at-large when extremely dangerous research is carried out ?

    2) Let us assume that GoF research has its benefits for public medicine (I am not convinced that the benefits outweigh the risks, considering that the most expensive and time-consuming part of vaccine development is human trials, which have to be carried out by pharma companies).

    But it seems insane to carry out this research in “normal” labs in universities inside big cities, even with appropriate biosafety levels. Considering the risks, such labs should exist in remote, sparsely populated parts of a country.
    This might act as a dampener for potential researchers, but again it is a question of risks vs benefits.

    It is also astonishing that there appears to be no international regulatory body monitoring GoF research around the world. I dread the scenario of such labs cropping up in developing countries like India, where enforcement of safety standards by the local government is extremely lax.

    3) Labs routinely deal with other dangerous substances such as radioactive materials and highly poisonous chemicals. However, as the past year has shown, a deadly virus can have a far more devastating impact than any of these.

    4) Regarding GoF at Wuhan, I would like to know your thoughts about this snippet from an article by scientists working there:

    “In this study, we confirmed the use of human ACE2 as receptor of two novel SARSr-CoVs by using chimeric viruses with the WIV1 backbone replaced with the S gene of the newly identified SARSr-CoVs. Rs7327’s S protein varied from that of WIV1 and WIV16 at three aa residues in the receptor-binding motif, including one contact residue (aa 484) with human ACE2. This difference did not seem to affect its entry and replication efficiency in human ACE2-expressing cells.”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708621/

    Thanks.

  10. I read Wade’s article, but I don’t have a Biology background to know if all his details, or lack there of were correct or misleading as you appear to state with your rebuttal. However, “Where is the intermediate animal species” that helped with the jump from Bats to people for the Covid-19 virus? How is it the host was found so easily for SARS1 and MERS viruses and had left traces in the environment. Yet no host found for Covid-19? And Covid-19 does not translate back to bats with infections?
    And if you do acknowledge that Wuhan Institute of Virology (WIF) was indeed performing gain of function experiments on Coronavirus (with our without U.S. Tax dollars, which is severe point of contention because most Americas would NOT want to put the world through this kind of risk again), then why do you try to dismiss Wade’s main goal, which is that there is a possibility that this lab accidently leaked the virus?

    If the three sick workers from the WIF lab from November 2019 prove to have had Covid-19, would they not represent infected patients 1, 2, and 3? What does that possibility do to all your logic, all your research, and all your academia that you have provided in your article, in your focused efforts to debunk Wade?
    All Wade has done with his article is to “wake up” Americans that we were lied to – for 15 months, and that a lab leak was possible at WIF, and repeat the MOST obvious fact, WIF is very close proximity to the Wuhan wet market which has been the official story from Communist China for 16 months from which this virus came from.

    And if a lab leak has killed 3.7M people WW and climbing, infected 173M WW and climbing, and caused untold economic, physical, and psychological damage to the entire world for the past 18 months, shouldn’t the United States and the world try to confirm or deny this possibility, and ensure this never happens again? Or is your whole point is that you are better at biology and logic than Wade, and therefore one must discard all the logic and information Wade has provided, much like the Mass Media did back in May 2020. What is your conclusive proof that this virus came exclusively from nature? If you don’t have it, then you too have an opinion based on science and logic, nothing more.

    • Hello Juan.
      I am certain the author will respond in due course. Your comments include a few errors, first of all, that the SARS1 path from animal to human was rapidly tracked down. It in fact took years and I speak under correction, but it’s still not been established beyond absolute doubt. With regards to this article, the point is as follows. Wade has made a number of statements that are simply just wrong. We won’t get into his motivation for that, but they are irrefutably incorrect. Stating a few facts doesn’t change the basis of the argument.
      Any argument offered, such as Wade’s, relies on established fact. You cannot acknowledge that his argument contains errors and still claim it to be sound. It simply isn’t.
      Can the laboratory origin theory be proven or disproven? Is the virus of natural origin? Scientists whose actual day jobs entail working with these viruses are telling us it looks natural rather than manufactured.
      We don’t have reason to doubt them unless we can prove, they, like Wade, are telling whoppers. That appears unlikely, given their numbers and critical views.

  11. Hi Jason,

    Thanks for reading and your comments. Much appreciated!

    Your comment on serial passage suggests you might not know how or why that type of work is done. Wikipedia has a good article on serial passage, here:
    https://en.wikipedia.org/wiki/Serial_passage

    I hope this answers your questions – if not let me know and I’ll try to answer more directly.

    Best,

    SD

  12. Hi Jeff (redvegan),

    Thanks for reading and your comments. Much appreciated!

    One of the Nature journal editors does not have a Ph.D., but to your point the vast majority do, unlike the News and Features editors.

    But if the Wikipedia page is accurate and Wade was a Nature editor on either the publications side or the News and Features side, he knew that Nature Letters are every bit a prestigious academic/research accomplishment as a Nature Article.

    Even as a mere science writer for a Main Street media property he would be well aware of that.

    The point is Wade’s clear manipulation of the facts, making Andersen’s paper seem to most of the uninformed public that a Nature Letter was merely opinion – that shows the depths of deceit Wade is willing to stoop to in order to push his agenda and bias against the Chinese.

    His more recently published book on genes and race emphasizes the innate racism in his world-view.

    This racism is what drives his opinions and writing, not science.

    Best,

    SD

  13. Hi Akhila,

    Thanks for reading and your thoughtful comments. Much appreciated!

    First, my deepest condolences. I also have seen here in the US the horrors of this virus, amplified by a prior government and a minority of the citizens who resist public health measures designed for the greater good, instead insisting on small personal freedoms.

    I agree fully that scientists are humans – but I disagree with your statement that a typical scientist’s main desire is to publish – that is an unintended effect of the career path and the short-sighted criteria set by institutional managements for positions and advancement. Most scientists I know are motivated to make useful discoveries – most are smart enough to excel in any of the much easier career paths but choose the harder and less-compensated sciences – only to find their path blocked by inane publishing requirements.

    The purpose of GoF research is to understand what genetic changes are required for new capabilities – in viruses and pathogens that new capability we need to understand is the ability to infect humans. Don’t you think that this pandemic is exactly the reason WHY we need this type of research? I imagine that this pandemic shows why we do NOT want to keep our head buried in the sand just because the research does have some risks.

    India is one of the countries along with the US and several others who possess nuclear weapons, weapons which can easily destroy all life on earth as we know it. Human politicians who make many more errors than scientists because many refuse to follow facts, logic, science… but we give them power over the rest of us through control of nuclear weapons… Don’t you think that is a more important power to defuse than the power to discover the genetics of organisms which can potentially kill millions?

    On your questions of what the Chinese did or did not do, I’m sorry but I cannot admit to any knowledge that has not been released.

    I linked to what I thought were relevant documents through my article – one of those was a grant application which suggested the direction of research. However, we all know that research takes turns and directions often different from what an application specifies. So did WIV do GoF research? Like any of the hundreds of virology labs around the world, possibly, but I don’t know.

    The point about biosafety levels is that much work does not require BSL4. Most of the work is molecular biology, manipulating the DNA to create changes in the code. It is not until you are creating infectious particles that the work must move to higher biosafety facilities. My point was noting the journal Science and how they acknowledged that most virology work around the world occurs in BSL2 and 3.

    It is like if you are working on your custom-made super-car, some work you can do in your living room (designing or ordering parts), some work might happen in your garage, some might happen outside in your driveway (perhaps if you are working with dangerous solvents), and then perhaps some work might be on special race tracks (high-speed testing). It is exactly the same in biological work. Each stage happens in different facilities as the risks dictate…. Not all virology work requires BSL4.

    I hope this answers your questions.

    Best,

    SD

    • I get your point that Nicolas Wade badly distorted this passage (below) from grant proposal by ignoring the significance of the word “threshold”, but can you explain why this is not necessarily gain-of-function research? I have barely any background in biology so please forgive me if this is a dumb question for somebody at your level.

      “We will use S protein sequence data, infectious clone technology, in vitro and in vivo infection experiments and analysis of receptor binding to test the hypothesis that % divergence thresholds in S protein sequences predict spillover potential.”

  14. If the serial passage was done in vivo would it not have been exposed to an immune system thereby countering your claim that certain features couldn’t be produced by serial passage?

  15. There’s always a cost-benefit ratio to “risky” research. What horrors are we leaving humanity defenceless against by not mastering GoF research? I have zero faith that research driven by the profit motive of pharmaceutical companies has humanity at its heart, but I also know the egos of scientists are restrained by those of other scientists – cheating is career suicide in a pool of watchful competitors. One little reported fact is that there were lines of research posited by the Wuhan Lab that the resposible authorities said no to because the staff and the facilities were not yet up to the required international standard. The idea that Beijing is a rogue actor chasing bioweapons is sheer nonsensenfor political effect. Zhongnanhai are actually very conservative bureaucrats.

  16. Hi,
    I just wanted to note that it seems highly improbably that Nicholas Wade was ever an editor at Nature. Maybe a “Features Editor”? Because all the editors (with no qualifying adjectives) listed at Nature have PhD’s.
    Best,
    Jeff Melton

  17. Hi,

    I am from India. Having witnessed the horrors of this pandemic, I have strong objections to some of your statements, especially this one: “we are capable of doing risky research and minimizing the impacts, and have shown the ability to be proactive and practical in our control of these experiments.” Scientists are human beings – a typical scientist’s main desires are to publish good papers and earn the recognition of his/her peers. They are not any wiser or more thoughtful than businessmen trying to maximize their profits. And yes, some of them are juvenile enough to care about “bragging rights” for having created viruses with infectivity beyond threshold levels. Even if the lab-leak theory turns out to be false, it is the height of arrogance to demand that the general public support Gain-of-Function research because
    “we are capable of doing risky research”.

    I gather that you do admit that

    (1) Gain-of-Function research on coronaviruses was being done in the Wuhan lab and

    (2) The biosafety levels required for this kind of research were not enforced.

    (As for (2), I was taken aback by your remark “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.” Notwithstanding your “capable of doing risky research” boast, this just indicates that there are several potential pandemics waiting to happen).

    Hubris always leads to misery – please think of the millions of innocent people around the world whose lives have been shattered before putting up a defense of misguided research. Gain-of-Function exists because some scientists want to produce more papers – please don’t sugar-coat this with altruistic reasons. This is the case irrespective of the truth of the lab-leak theory.

  18. Hi SD,
    Thanks for your response, please forgive my fuzzy logic, I have no conclusion regarding the question of natural vs manmade virus, both are possible. I am not a scientist and do not believe that we are capable of doing risky research and minimizing the impacts in every case. Having lived most of my life under the treat of a nuclear holocaust, I tend to be skeptical of that opinion. Everything has a potential for good or evil and some of us will sometimes confuse the two.

  19. Hi Jo,

    Thanks for reading and commenting. Much appreciated!

    Good question about isolating the virus.

    The answer is, yes. Many times last year, immediately after the new virus was identified, scientists from various countries including here in the US were able to isolate and confirm the SARS-CoV-2 virus. Here are just a sampling of a few papers and other reports of this work:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036342/

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239045/

    https://www.sciencedirect.com/science/article/pii/S0031302520309399

    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238614

    https://www.cdc.gov/coronavirus/2019-ncov/lab/grows-virus-cell-culture.html

    I hope I answered your question.

    Best,

    SD

  20. Hi Joe,

    Thanks for reading and commenting. Much appreciated!

    You ask a good question about risks of gain of function experiments. Every scientific and technical discipline has tremendous risks potentially affecting health and life. This is particularly acute in the biological sciences where we now have the ability to modify the code of life.

    The moment biologists gained the ability to modify the genetics of an organism at the “machine code” level by modifying single nucleotides of DNA, the risks of our research amplified. There are internationally sanctioned protocols in place to try and control the risks of our genetic modifications of various organisms:
    https://www.loc.gov/law/help/restrictions-on-gmos/international-protocols.php

    The Asilomar Conference was an early attempt to self-regulate genetic engineering, and was held within a couple years of the first report of Recombinant DNA:
    https://en.wikipedia.org/wiki/Asilomar_Conference_on_Recombinant_DNA

    So I think we are capable of doing risky research and minimizing the impacts, and have shown the ability to be proactive and practical in our control of these experiments.

    From the wording of your question it seems you are making an erroneous and extreme conclusion, presumably based on something I wrote… unfortunately I can’t see anything I wrote that could lead to your conclusion that “there is nothing to fear from” GoF experiments.

    Can you point me to your logic and the starting point in my writing that leads you there?

    Regardless, I hope I answered your question.

    Best,

    SD

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