A COVID viruswash
"On reading," by Simon Wain-Hobson, is a weekly discussion of scientific papers and news articles around gain of function research in virology.
Since January 2024, Dr. Wain-Hobson has written weekly essays for Biosafety Now discussing risky research in virology. You can read his entire series here.
On reading A genomic perspective on the origin and emergence of SARS-CoV-2 by Yong-Zhen Zhang and Edward Holmes, Cell 2020; 181:223-227.
And a little more.
Some people simply can’t stop writing. Shakespeare comes to mind exploring all sorts of genres, with rarely a dull moment.
Specialist science papers are accompanied by review articles that try to sum up a whole rather than a hole, bringing sense to a field. Eons ago, they were long, dense pieces for the initiated. They still exist, but today they tend to be short, to the point and accessible to a more general readership. They go by the names of commentaries, news & views, perspectives and other creative formulas.
Unlike papers and staid reviews, they are, by and large, not subject to peer review. The journal considers its editorial staff more than capable of sizing them up. As we saw, when topicality is the order of the day, standards plummet, yet such opinions are even more important to the journals. The result is Phil Space. This is why On reading is not sure journal editors handle topicality at all well (Cowards die many times).
Here we explore a trilogy from Eddie Holmes of the University of Sydney. He’s been analyzing viral genomes for ages and is a key author of the infamous Proximal origin paper dismissing out of hand the COVID virus lab-leak hypothesis.
#1 is entitled, We shouldn’t worry when a virus mutates during disease outbreaks, was published on February 18, 2020 in the high-profile journal Nature Microbiology. The main thesis, that the COVID virus wouldn’t significantly mutate into new forms with altered pathology, they got wrong - bigly. We’ve been there, done that (What we should worry about).
#2, The proximal origin of SARS-CoV-2 was published in Nature Medicine dated March 17, 2020, even though an earlier version was available February. It’s been dissected by many and should have been retracted. A scientific analysis was proffered in the essay Distal truths.
#3 came out in the top journal Cell dated April 16, 2020. That’s compact. Bear in mind that first SARS2 genome sequences were available by January 11, that lab leak fears surfaced by late January, that good writing takes time; that’s more like a sonic boom.
By the second paragraph of #3 we read Given that SARS-CoV-2 undoubtedly has a zoonotic origin, the link to such a ‘‘wet’’ market should come as no surprise. However, as not all of the early cases were market associated, it is possible that the emergence story is more complicated than first suspected.
The first part is clear although undoubtedly is an odd word to use given there was not enough data around in the first quarter of 2020. However, the latter sentence immediately throws into doubt their affirmations. With such a qualifier nobody can come off the fence. However, given the performance in #1 & #2 this should come as no surprise. #3 is full of contradictions. Importantly, although many of the early COVID-19 cases were linked to this market, its role in the initial emergence of SARS-CoV-2 remains uncertain. Yet not so uncertain that the link to such a ‘‘wet’’ market should come as no surprise. Go figure.
We learn that the bat viruses most closely related to SARS-CoV-2 were sampled from animals in Yunnan province, over 1,500 km from Wuhan. There are relatively few bat coronaviruses from Hubei province, and those that have been sequenced are relatively distant to SARS-CoV-2 in phylogenetic trees. The simple inference from this is that our sampling of bat viruses is strongly biased toward some geographical locations.
An inference, certainly. But do go on, flesh out competing hypotheses like a good scientist. For example, animals being shipped from farms to the Huanan wet market. Or bat samples being shipped to the Wuhan Institute of Virology (WIV), some of which had SARS2 like viruses in them, RaTG13 to name but one, published by the WIV.
They go on to say that It is therefore almost a certainty that more sampling will identify additional bat viruses that are even closer relatives of SARS-CoV-2. A key issue is whether these viruses, or those from any other animal species, contain the key RBD [receptor binding domain] mutations and the same furin-like cleavage site insertion as found in SARS-CoV-2. That’s exactly what On reading thought back in early 2020. Six years on, SARS2 like bat coronaviruses are less numerous in genome databases today than SARS1 like bat coronaviruses. This is stunning given the impact of the two: 782 dead from SARS1, greater than 25 million dead from SARS2 …and nobody is asking questions?
It’s been said here more than once, this dearth indicates ongoing resistance to getting to the bottom of COVID origins. It’s to avoid digging up evidence that could help others apportion blame. That overrides ‘pandemic preparation’. So much for public health and the much touted One Health.
The paper moves on to a pet theme of Holmes, that of zoonosis in the Huanan wet market. Although bats are likely the reservoir hosts for this virus, their general ecological separation from humans makes it probable that other mammalian species act as ‘‘intermediate’’ or ‘‘amplifying’’ hosts, within which SARS-CoV-2 was able to acquire some or all of the mutations needed for efficient human transmission.
To an urban reader that may make sense but where’s the data? Peter Daszak’s group published a paper in 2021 that addressed this issue. They looked for antibodies to bat coronaviruses in people from SE Asia. They estimated that a median of 66,280 people are infected with SARSr-CoVs annually in Southeast Asia.
The first rider is that there are not enough studies of this sort. They could have easily missed a few hotspots. Second, while a small number compared to the population in this region, these are all spillover infections, like those of avian flu viruses, where the virus multiplies enough to induce antibodies. The big fear is efficient human to human transmission which has been attained only once – dixit COVID-19. And as readers know, once can be harrowing. Third, in China and SE Asia primarily fruit bats, but also insectivorous bats, are hunted for food, perceived medical value, for hide or teeth, or for sport. Indeed, bats are most vulnerable to overhunting in Indonesia, the Philippines, Malaysia, and islands of Oceania and the Indian Ocean.
Conclusion: humans are interacting directly with bats in a big way in some parts of SE Asia. It took less than 30 seconds of browsing to get to this Wikipedia page. As always, check, check, check again.
In short, the need for an intermediate host is wanting, although that does not make it false. That said, they bang on, it is imperative to perform a far wider sampling of animals from wet markets or that live close to human populations and on: While our past experience with coronaviruses suggests that evolution in animal hosts, both reservoirs and intermediates, is needed to explain the emergence of SARS-CoV-2 in humans… Remember, this paper was published in April 2020. There was no data either way to have any opinion as to the origins of the COVID virus nor make the deduction emphasized in bold font.
Within its entrails there are some interesting sentences, notably it cannot be excluded that the virus acquired some of its key mutations during a period of ‘‘cryptic’’ spread in humans prior to its first detection in December 2019. Specifically, it is possible that the virus emerged earlier in human populations than envisaged (perhaps not even in Wuhan) but was not detected because asymptomatic infections, those with mild respiratory symptoms, and even sporadic cases of pneumonia were not visible to the standard systems used for surveillance and pathogen identification. During this period of cryptic transmission, the virus could have gradually acquired the key mutations, perhaps including the RBD and furin cleavage site insertions, that enabled it to adapt fully to humans.
Exactly. Both Drs. Morens and Baric said this in their testimonies to Congress. It occurred for HIV/AIDS. We know that the Andes hantavirus is capable of setting up small chains of human-to-human transmission although it has not yet gone bigtime. And while not settled law, it should be on the table, a hypothesis to be addressed with data rather than rhetoric.
The piece ends with some more urban platitudes not requiring expertise in virology; …arguably the simplest and most cost-effective way to reduce the risk of future outbreaks is to limit our exposure to animal pathogens as much as possible. …stronger action against the illegal wildlife trade and removing all mammalian (and perhaps avian) wildlife from wet markets will provide an important buffer.
They must know that China is the largest consumer of chicken in the world with demand steadily increasing. Major bird flyways crisscross China, the US and Brazil, the three largest consumers of chicken. Bird flu viruses are endlessly falling to earth in guano (Skyfall). Bat coronaviruses too.
Can we have vets and those with detailed knowledge of these animals to advise us how we can live with them, exploit them more humanely – once a highly pathogenic flu virus gets into a broiler house every bird is gone in days – with the inherent dangers of the viruses they carry? Snapping photos in wet markets without supplying any data on the frequency of spillovers to humans is not the sort of thing we expect from the top journal Cell.
Holmes is the lead author in another paper in Cell a little more than a year later - The origins of SARS-CoV-2: A critical review. The author lineup includes three other Proximal origin authors.
They start with the evidence for a zoonosis. Fine. However, as what really matters is how they handle competing hypotheses, we’ll home in on the section Could SARS-CoV-2 have escaped from a laboratory.
The 1977 A/H1N1 influenza pandemic, that most likely originated from a large-scale vaccine challenge trial, is the only documented example of a human epidemic or pandemic resulting from research activity. No epidemic has been caused by the escape of a novel virus, and there is no data to suggest that the WIV—or any other laboratory—was working on SARS-CoV-2, or any virus close enough to be the progenitor, prior to the COVID-19 pandemic. All scenarios are anchored on past examples, while the last part just means the authors, like everybody else, had no access to what is unpublished.
The WHO has said many times that China has not been forthcoming with information (WHO wordplay on COVID origins) which is unfortunate. Furthermore, we know there were biosafety issues at the WIV in 2019. Arguments that the WIV were not working on a virus close enough to be the progenitor is such a lame argument and one we’ve handled a number of times, if only in the last essay (Cowards die many times). Once again, way below the level Cell should be tolerating.
Under the rubric Evidence from genome structure and ongoing evolution of SARS-CoV-2 we read those Recurring mutations in the receptor binding domain of the spike protein… similarly enhance viral infectivity, refuting claims that the SARS-CoV-2 spike protein was optimized for binding to human ACE2 upon its emergence. This is glorious for in Proximal origin we were told that SARS-CoV-2 appears to be optimized for binding to the human receptor ACE2 (Distal truths). This illustrates the dangers of inventing conclusions to fit the hypothesis – they need walking back as data comes in. Of course, this is neatly solved by coming up with a new COVID origin paper every year or two. Lol.
Combined, these findings show that no specific human ‘‘pre’’ adaptation was required for the emergence or early spread of SARS-CoV-2, and the claim that the virus was already highly adapted to the human host, or somehow optimized for binding to human ACE2, is without validity. Preadaptation is an allusion to the virus having been grown on human cells in the lab. The reference is to a preprint of Alina Chan who went on to write a book about the lab leak hypothesis.
They mention the polybasic furin cleavage site, although there is nothing new. The sequence alignments in Figure 1b are shoddy and reveal the hand of man, much like on a previous occasion, back in 1985, where there was an overriding need to show sequence homology between the AIDS virus and human T cell leukemia viruses. Things didn’t pan out this way.
Let’s stop for you get the message; anything but critical.
Conclusions
• More science fiction that has zero impact on the virus origins issue.
• Words matter hugely in science. If you tolerate ambiguity, move out.
• Top scientific journals publish this stuff to align with the funders of science, their benefactors, espousing the credo that COVID-19 was/is just another zoonosis. It’s still open. In doing so, they align with learned societies who say the same to ‘protect’ science.
• Funding organizations the world over pay journals to publish work they have funded yet don’t insist on reason when it comes to discussing controversy.
• Who oversees the journals? Nobody. And when they go rogue, then what? Funding organizations and learned societies should come down on them like a ton of bricks. You see the problem.
• The best lack all conviction.
• A boycott would change things fast.
Aside 1
Some quickies about writing gleaned over the years.
• The essence of writing is rewriting. Aka it needs time, something scientists no longer devote to writing.
• Easy reading is hard writing while hard reading is easy writing. An International Herald Tribune editor eons ago.
• If you copy from one it’s called plagiarism, if you copy from two it’s called research.
• When a scientist boasts they wrote a paper in an afternoon, it shows.
• Publish it which mustn’t be confused with publishit.
Aside 2
Couldn’t resist borrowing …and nobody is asking questions? from John Le Carré’s Tinker, Tailor, Soldier, Spy.
Aside 3
Let’s break for the summer. Rendez-vous September. Bonnes vacances.
please answer Eddie's question: why did Shi publish RaTG13 since “that would only help point the finger at them? Makes no sense.”
https://jimhaslam.substack.com/p/6-if-you-believe-the-wiv-engineered
If overconfidence is disqualifying, then the lab-leak narrative has a much bigger credibility problem. For years, it has repeatedly mistaken suspicion for evidence and possibility for proof.