Nicholas Wade is the Andrew Wakefield of molecular virology


For the past month or so, my inbox has been inundated with letters insisting that they have proof of the lab leak hypothesis for the origin of SARS-CoV-2. Their insistent missives are full of jargon, like arginine codons and furin cleavage sites, and insistence that the particular sequence found in the virus could not possibly have arisen naturally. I am not an expert in viral genomics by any means, so my usually reply is a shrug that I don’t know the details, but I find their claim that the viral sequence could not have appeared by natural causes to be naive and unlikely, and that their probability argument is not a clincher. I’ve usually refrained from pointing out that they sound exactly like a few generations of creationists I’ve had to put up with.

A lot of that jargon and argument can be traced back to an article by Nicholas Wade in which he made those very same claims. I tend to veer away from anything by Wade — his embarrassingly bad book that advocated for “race realism” convinced me he’s not a trustworthy source — so I didn’t dig deeply into it. He seems to have persuaded some people, including David Baltimore(!), who has since retracted his endorsement of Wade’s “smoking gun”.

A science writer I trust far more, Thomas Levenson, explains what’s wrong with Wade’s claim.

Wade asserted that a particular arrangement of a specific sequence in the viral genome, called a codon, was unlikely to have gotten there naturally. There are actually six different codons for arginine, and the one found in a particular region of the SARS-CoV-2 genome called the furin cleavage site does occur less frequently in viruses than it does in the human genome. An even more telling detail to Wade is that this uncommon arginine codon shows up twice in that small segment of the virus’s genome. For that to occur naturally, Wade wrote, “a chain of events has to happen, each of which is quite unlikely.”

That’s what Baltimore assented to. But scientists say Wade misdescribed critical links in his chain. Scripps Research virologist Kristian Andersen led an early inquiry into the possible role of a lab escape in the origin of the virus, which concluded that it “is not a laboratory construct,” a finding that Wade termed “poor science” in his article. After Baltimore’s quote became public, Andersen re-entered the argument, and became one of a number of researchers to challenge many of the details Wade relied on. Andersen told Nature that Wade’s claim that steps in the emergence of the virus were too improbable to have occurred is not true. Rather, the pandemic virus uses that codon about 3 percent of the time that its genome calls for arginine—not common, but not impossibly scarce either—and, importantly, that other coronaviruses make use of it too, at similar or greater frequency.

Columbia University virologist Vincent Racaniello says the unusual pairing of a particular codon that Wade saw as decisive actually points away from laboratory manipulation. “We have some idea why this codon is rare in RNA viruses,” Racaniello says. Selection pressures have been identified that would discourage its use in viral genomes. But, he says, “We don’t know why it’s not zero. The fact that it is conserved in many viruses means that it’s beneficial in some way we don’t understand.” This is the kind of mystery that evolution throws at researchers all the time. Racaniello adds that if a lab researcher was trying to modify a virus to measure its effect, the researcher wouldn’t use the codon pairing identified by Wade because its effect would be too unpredictable.

I’d had an uncomfortable feeling with any argument that claims a low probability makes something impossible, because improbable things happen all the time. But 3%! That’s not low, especially not when you’ve got a virus with a population of trillions.

Comments

  1. chrislawson says

    Reading the genome like this for patterns indicating a lab leak is nothing more than numerology for xenophobes who don’t give a shit about editorial standards or basic human decency.

  2. Matt G says

    A truck full of seeds explodes in a Walmart parking lot. Two seeds fall through the cracks in the pavement and grow into flowers. One flower says to the other: “Look! We are perfectly adapted to living in this parking lot.”

  3. raven says

    But, he says, “We don’t know why it’s (the unusual arginine codon) not zero. The fact that it is conserved in many viruses means that it’s beneficial in some way we don’t understand.”

    There are a lot of possible reasons why an uncommon arginine codon could occur.

    One is simply the pathway that produced it. If it was a mutation from another codon for another amino acid, it could have been the only arginine codon possible by changing one base in one step, a single base point mutation.

    IIRC, the furin cleavage site that Wade is looking at is an indel compared to other coronavirus sequences. Indel meaning insertion or deletion of bases mutations. (NIH: A mutation named with the blend of the words insertion and deletion. It refers to a length difference between two ALLELES where it is unknowable if the difference was originally caused by a SEQUENCE INSERTION or by a SEQUENCE DELETION.)
    Insertion mutations are a common type of mutation in eukaryotes.
    They are also a common type of mutation known to occur in Coronaviruses.

    As to why an uncommon arginine codon might be favored, who knows. RNA folds up in various ways with a lot of intramolecular base pairing structures. It could be that this arginine codon keeps the folding structure more open and easier to translate.

  4. Matt G says

    @3 raven- there is a blog post by Science Duuude who discusses the 12-base, out-of-frame insertion which gave rise to the (non-ideal) polybasic cleavage site used by furin.

  5. raven says

    @4 Matt I just saw it

    SCIENCE DUUUDE’S COLUMN
    Debunking Nicholas Wade’s Origin of COVID Conspiracy Theory
    May 29, 2021

    The novel furin cleavage site in the Covid-19 virus is a 12 base insertion mutation. An indel. Wade says it is impossible and shows that the Covid-19 virus is a human made construct.
    He is flat out wrong here.

    The tl;dr version. Indels are quite common in Coronaviruses in general and Covid-19 virus in particular.
    We see them all the time as we sequence various clinical samples.
    “Using sequences from the GISAID database, we catalogue over 100 insertions and deletions in the SARS-CoV-2 consensus sequences.”

    Published: 20 March 2021
    Indels in SARS-CoV-2 occur at template-switching hotspots
    Brianna Sierra Chrisman, Kelley Paskov, Nate. Stockham, Kevin Tabatabaei, Jae-Yoon Jung, Peter Washington, Maya Varma, Min Woo Sun, Sepideh Maleki & Dennis P. Wall
    BioData Mining volume 14, Article number: 20 (2021) Cite this article

    Abstract
    The evolutionary dynamics of SARS-CoV-2 have been carefully monitored since the COVID-19 pandemic began in December 2019. However, analysis has focused primarily on single nucleotide polymorphisms and largely ignored the role of insertions and deletions (indels) as well as recombination in SARS-CoV-2 evolution.

    Using sequences from the GISAID database, we catalogue over 100 insertions and deletions in the SARS-CoV-2 consensus sequences.
    We hypothesize that these indels are artifacts of recombination events between SARS-CoV-2 replicates whereby RNA-dependent RNA polymerase (RdRp) re-associates with a homologous template at a different loci (“imperfect homologous recombination”). We provide several independent pieces of evidence that suggest this. (1) The indels from the GISAID consensus sequences are clustered at specific regions of the genome. (2) These regions are also enriched for 5’ and 3’ breakpoints in the transcription regulatory site (TRS) independent transcriptome, presumably sites of RNA-dependent RNA polymerase (RdRp) template-switching. (3) Within raw reads, these indel hotspots have cases of both high intra-host heterogeneity and intra-host homogeneity, suggesting that these indels are both consequences of de novo recombination events within a host and artifacts of previous recombination.

    We briefly analyze the indels in the context of RNA secondary structure, noting that indels preferentially occur in “arms” and loop structures of the predicted folded RNA, suggesting that secondary structure may be a mechanism for TRS-independent template-switching in SARS-CoV-2 or other coronaviruses. These insights into the relationship between structural variation and recombination in SARS-CoV-2 can improve our reconstructions of the SARS-CoV-2 evolutionary history as well as our understanding of the process of RdRp template-switching in RNA viruses.

  6. garnetstar says

    I was quite persuaded by the Anderson et al article in Nature, March 2020, which Wade shamelessly and ignorantly trashes as just “opinion” (no, it is a peer-reviewed research paper, and Wade knows that very well. He’s lying). I’m no expert in viral genomics either, and know a lot less about it than many of the commenters above. But, even I could understand the paper.

    I wish to point out that the reason that Anderson and team began that study is that the virus’ genome had features that they thought pointed to human engineering. So, they did not start with some bias against that! And, upon close study and the acquisition of data, their preliminary hypothesis was proven wrong, and they ended up with proof that the virus “is not a laboratory construct”. It’s rare that a research paper has such definitive data that such an unqualified statement (not the usual “highly unlikely”) can be made.

    But, that’s a peer-reviewed published study by experts, and can only be challenged by another peer-reviewed published study that presents reliable data that contradicts the Anderson paper’s conclusions. No such study has been published. So, as of now, the final word from science is that COVID was not human-engineered. Nothing that is not a peer-reviewed published study can even question that.

    And, until Wade produces such a study, his ignorant, biased blatherings, or anyone else’s hysterical speculations, are meaningless.

  7. raven says

    Speaking of human made pandemics, there are still outbreaks occurring in parts of the USA. The fundie xian/Red states of course.
    This is while we are now throwing out thousands of doses of outdated vaccines that we literally can’t give away, since the vaccines are free.
    At this point, 99% of all Covid-19 virus infections are in the unvaccinated.

    Unvaccinated Missourians fuel COVID-19: ‘We will be the canary’
    By HEATHER HOLLINGSWORTH Published: Jun. 23, 2021 waff. com edited for length

    KANSAS CITY, Mo. (AP) — As the U.S. emerges from the COVID-19 crisis, Missouri is becoming a cautionary tale for the rest of the country: It is seeing an alarming rise in cases because of a combination of the fast-spreading delta variant and stubborn resistance among many people to getting vaccinated.

    Intensive care beds are filling up with surprisingly young, unvaccinated patients, and staff members are getting burned out fighting a battle that was supposed to be in its final throes.

    The state now leads the nation with the highest rate of new COVID-19 infections, and the surge is happening largely in a politically conservative farming region in the northern part of the state and in the southwestern corner, which includes Springfield and Branson, the country music mecca in the Ozark Mountains where big crowds are gathering again at the city’s theaters and other attractions.

    While over 53% of all Americans have received at least one shot, according to the Centers for Disease Control and Prevention, most southern and northern Missouri counties are well short of 40%. One county is at just 13%.

  8. says

    The core of it seems to stretch back to a fellow named Stephen Quay, a vitamin salesman who coauthored an article in the WSJ on this. Wade cites Quay as well on it. And it is an absolutely staggering piece of pure quackpottery – Bayesian extrapolation that would make Josh McDowell proud, his strategy for peer review being not to submit to a peer review journal but just emailing actual scientists and whinging (in his paper) that they haven’t gotten back to him on his timetable. And that seems to be the root of so much of this stuff.

    https://zenodo.org/record/4642956#.YMH_GGZOm9e

  9. robro says

    I’m very ignorant about all this stuff, although I have a friend who spent 35 years studying HIV. He has pointed me to a couple of reports that convinced me that there’s no there there. However, I’m sure this will fuel the “debate”…or is that hoo-ha: Deleted Wuhan COVID Sequence Found on Google Cloud. Jesse Bloom, the guy who dug up the deleted information posted this as a preprint paper on BioRxiv (too long and way over my head): Recovery of deleted deep sequencing data sheds more light on the early Wuhan SARS-CoV-2 epidemic. I don’t think Bloom is claiming anything about a lab leak or engineered virus, or that there was something unethical about NIH deleting the information, just that he found it…but I haven’t read too deeply on the matter.

  10. says

    I recently read a very interesting article with Christian Drosten, one of the world’s leading scientists on SARS, who developed the first PCR test for Sars Cov 2 and his reasoning on why he doesn’t think it was lab made or a failed and escaped experiment was quite simple (paraphrasing from memory here):
    For such an experiment, you need a functioning clone of the virus. To build such a clone takes about 2 years. The clone to Sars Cov 1 exists. If a lab experiment escaped and went wrong, it would be based on that, not on a completely new virus.
    Occam’s Razor at its best.

  11. nomadiq says

    I’ve been called upon by non-biology trained members of my family to explain much of what is in the Wade article. The questions are all of the same mold… ‘how is it this virus is so perfect to infect humans? … it must be deliberate’. I respond along the lines of, ‘how many viruses do you think there are that are poorly spread amongst humans and/or don’t present much danger? …. crickets … well there are millions. You would be right to think that these viruses don’t have genetic code that (is suspicious) works extremely well at infecting and killing people. But we don’t talk about those viruses because we don’t care about them. We care about the one virus that spreads and kills quite effectively. So of course THAT virus contains genetic code that is very good at infecting/killing people. It has to. It has been selected for us to notice how odd it HAS TO BE compared to other coronaviruses in the first place.’ This is how evolution works. It’s like being amazed that there are giraffes in an ecosystem where a lot of the food is located in tall trees – you can be a Lamarckian and still understand this. It’s not remarkable at all that if there are animals there then they are tall. If not tall, no animals. Same with viruses. Oh, is there a massive viral load globally amongst humans? And you’re surprised this virus is perfect for infecting humans? What kind of virus, not well adapted to infecting humans, ends up being a global pandemic? That’s not even possible. To believe otherwise is to believe smallpox was engineered before humans even knew what viruses are.

    None of this proves COVID-19 was definitely not engineered. But what proof is there that it was? We would need the notebooks of the researcher/group who designed it, otherwise there just is no proof! And any argument about the CCP covering things up is speculation and not proof. I don’t trust the CCP either, but we have no proof COVID-19 was designed.

  12. unclefrogy says

    But 3%! That’s not low, especially not when you’ve got a virus with a population of trillions.

    I am in no way qualified to answer specific questions in virology but as someone with an interest in science and the processes of nature that right there seems to be an example of where all of these I have to say ignoramuses with an ax to grind miss the boat. They just can not seem to get it in their heads that the number is not 1 to a dozen or 2 and when you add in time into your calculations ,nature is if anything patient, rare things happen all the f’n time
    uncle frogy

  13. wzrd1 says

    Robro touched on one tidbit that was recently reported upon. Several strains of coronavirus genomes were deleted by contributor request, due to their not circulating as part of the pandemic. They were detected in Wuhan at the initial onset of the initial Wuhan outbreak and swiftly vanished as many outbreaks frequently do, being outcompeted by the pandemic strain.
    That literally shouts that multiple coronavirus strains were present in proximity to the human population and SARS-nCoV-2 adapting better and spread well enough to become an epidemic and eventually pandemic. A spillover from a lab would tend to be only one specific strain alone.

  14. garnetstar says

    Yes, to the above, and also to viruses almost always circulating in humans, eventually evolving to get better at infecting/casusing illness, before they cause a noticeable outbreak.

    An example I recall: I’ve read that the first person who was known to have had HIV (whatever version of it was around then) died in 1959. He was British and had been a sailor, traveling around to lots of countries, eating food from street vendors, etc. His final illness was odd, so they kept some of his tissue samples frozen. And, when tested in the 1980’s or 1990’s, the tissues had HIV in them.

    And it took decades after the 1950’s for HIV to finally be able to go pandemic. No reason that a smiliar path may not have happened with these coronaviruses.

  15. garnetstar says

    Also, if anyone thinks that Ebola appeared suddenly out of nowhere in the 1976 first outbreak, newly-born but perfectly adapted to infect and kill humans like Athena springing fully-formed out of Zeus’ head, they are mistaken.

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