Cancel Virology
"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.
These essays don’t take a position on Covid origins simply because there is insufficient data. Inevitably the essays cover virus evolution or simply address things virological. As virology is the Queen of the biological sciences it’s worth the effort (The Queen). On reading will focus on just two points from this review.
One. Figure 1 in the paper presents what is called a phylogenic tree made of 236 of bat coronaviruses akin to human SARS-CoV-1 and 2. This is akin to a human family tree although it is made from coronaviral genome codes. There are clearly two distinct groups, one for each of these viruses. But look closely at the numbers of complete genomes involved: 188 for the former, 48 of the latter. So?
SARS1 circa 2003. How many deaths? 774.
Global macroeconomic impact? $30-100Bn.
SARS-CoV-2 2020-present. Probably between 20-28 million dead and an economic impact way over the tens of trillions of dollars. Sovereign debt exploded. The virus is still circulating, will do so for years and will pry relentlessly on the poor and elderly.
So how come we have fewer SARS2-like bat sequences from China and SE Asia than for SARS1? The technical firepower needed to generate them is everywhere - we have around 16 million for the COVID-19 virus from humans which is unprecedented, excessive even! Yet virologists can’t generate even a hundred bat SARS2 look alike genomes in four and a half years?
It’s not that such viruses are lacking: with huge numbers of Rhinolophus bats, suggests that additional bat viruses… exist in nature. And there is strong evidence that humans are exposed to these viruses on a regular basis. In Myanmar, for example, serological tests of persons engaged in hunting, logging, and collecting forest products, or who hunted bats, revealed relatively high exposure to sarbecoviruses. This comes from a group of Chinese authors including Linfa Wang who is a well-known proponent of the natural origin of the COVID-19 virus. The dearth of bat SARS-CoV-2 like viruses and genomes makes no sense. One deduction is that this information, obtainable by straightforward field work, is not desired.
Two. The section on the timescale of emergence needs attention. Calculations on how fast the virus evolved suggest that the genetic radiation of SARS2 coronaviruses started between August to December 2019. Apparently, these dates are concordant with the available epidemiological data from Wuhan, with analyses of serological data providing no evidence for any SARS-CoV-2 in the city prior to December 2019. Yet there are a few months between the calculations and the serology. Perhaps tweaking a parameter value and recalculating could square the difference. Or perhaps the calculations are right and early serum samples are simply lacking.
Are there other data that can help resolve this small difference?
…it has been suggested that SARS-CoV-2 was present in other geographic localities, including Brazil, France, and Italy, prior to its first detection in Wuhan… The most persistent of these claims is that COVID-19 cases were present in Italy, dating back to at least September 2019. Holmes refers to nine studies, which If true, …would radically alter our understanding of virus origins and evolution.
In reality, however, these early cases almost certainly reflect some form of contamination, such as the use of nested PCR in laboratories that were actively working on COVID-19 following major outbreaks. What is nested PCR? Most readers will have had a nasal swab tested by Polymerase Chain Reaction (PCR) on some street corner during the COVID pandemic. PCR is a wonderful technique that allows billion-fold amplification of genetic material. It discombobulated biology and we’re incomparably better for it. Not surprisingly it quickly reaped the Nobel Prize for Chemistry in 1993.
It is so powerful it can pick up infinitesimal traces of genetic material lying on the surfaces of a lab bench. In the early days of the technique, circa 1988-92, many labs were plagued by contaminating DNA. On reading’s lab had multiple examples, but fortunately prevented a contamination getting into a scientific paper. It was such an issue that we told newcomers to PCR that it meant Probably a Contaminated Reaction. Over time scientists found ways to get around it.
Even today if there’s a moment’s sloppiness, bingo, you can have a contaminated reaction. And nowhere more likely than when performing nested PCR. This involves using PCR to re-amplify DNA from an initial amplification. It is called nested PCR for a technical reason we don’t need to get into here. Yet with care, nested PCR is reliably doable, and the researcher can avoid headaches and heartaches.
However, Holmes dismisses nine studies as they almost certainly reflect some form of contamination. Contamination such as the use of nested PCR in laboratories that were actively working on COVID-19. You only have to read the papers to realize that they took great care to avoid PCR contamination. The negative controls were negative. And by the way, not all of the papers used PCR. As it happens, a few of these studies used serological analyses – something totally different, but Holmes apparently misses this.
The only ‘evidence’ proffered for a contamination is Strikingly, these sequences [actually those samples taken in October 2019 from one study in Lombardy, Italy] displayed a D614G mutation in the spike protein that appeared later in the epidemic. For the enthusiasts, D614G indicates a change from aspartic acid (D) to glycine (G) at position 614 in the Spike protein sequence.
We learn that The first major adaptive mutation in human SARS-CoV-2 was spike D614G... Although D614G was initially thought to have appeared in Italy in late February 2020… it was present in patients from Wuhan sampled in early January 2020. So finding this mutation a few months earlier in Italy is consistent. The identification of the D614G mutation early in Wuhan was never published, Holmes being the source of this new piece of information. Such a remark is very frustrating for scientists to handle as they need to see the data and discuss. Not accepting such an off the cuff remark is a habit scientists have acquired over the years.
Holmes attempts to cancel a series of studies without proof by making the claim of contaminated PCR even though some studies involve serology. Only a non-experimentalist could propose such an explanation.
Everyone agrees that the epicenter of the pandemic was Wuhan. But that doesn’t prevent the virus having crossed over to humans and transmitted at a low levels before the pandemic erupted. What made it go pandemic in Wuhan is an important question. Readers have no doubt heard of super-spreader events. The point to remember is that a pandemic epicenter does not necessarily equate with the place where the first human infection occurred.
An example? The epicenter for the HIV/AIDS pandemic is the Rift Valley region of Africa in the early 1980s. Yet the first recorded HIV sequence comes from a serum sample taken in Kinshasa, the capital of the Republic of the Congo circa 1959.
This is not a lone example. After extensive screening of human tissue specimens collected for pathology diagnostics in Kinshasa, a near complete genome was recovered from a sample dated 1966. Analyses of this and other HIV genomes suggested the genetic radiation of HIV genomes started sometime between 1881 to 1918. Indeed, there is a consensus that the pandemic lineage of HIV crossed over to humans way before the pandemic started. Clearly being transmitted at levels under the radar and going pandemic are distinct. A pandemic requires something extra.
There is even another example. HIV entered Norway in the 1960s yet, as we all know, didn’t set off a pandemic there.
Holmes and others are mixing up viruses spilling over to humans, low-level transmission, and the emergence of the pandemic.
Ralph Baric, a US coronavirologist of considerable standing said in testimony to the US Congress that that he disagrees with the most widely promulgated spillover argument: that the virus leapt from infected animals to people at the Huanan Seafood Wholesale Market, where it first burst into public view in December 2019. The argument does not hold up, he said, because genomic evidence suggests that COVID-19 was already circulating in the human population by mid-to-late October. “Clearly, the market was a conduit for expansion,” he testified. “Is that where it started? I don’t think so.”
David Morens, US epidemiologist who had worked with the CDC and former advisor to Antony Fauci also testified to Congress. He gives his take on the COVID pandemic given his long experience with infectious diseases. A number of his remarks are given below as bullet points:
• it’s true than when an epidemic begins, you don’t ever recognize the earliest cases because they’re buried under a lot of other things. There aren’t that many of them and even if they die in a city like Wuhan with tens of millions of people, an increase in deaths from an unknown disease would never be detected. It would take a long time.
• I don’t believe the market was the source of it.
• We never see where the virus comes from, we see where it’s amplified.
• The virus had been spreading for many months or a year and they got amplified by big cities in all these countries. I think that's what happened here.
Testimonies from a coronavirologist and an epidemiologist trounce the speculations of a computer analyst.
SARS-CoV-2 was circulating within and outside of China before the pandemic erupted in Wuhan. This does radically alter our understanding of virus origins.
Aside 1
By assuming that the nine papers reflect DNA contamination because of the use of nested PCR Holmes logically casts an aspersion on all scientific papers using this technique which must number in the thousands. On reading has published many papers using nested PCR, notably one in Nature where HIV DNA was recovered from single cells. It is fine to make hypotheses, but it is incumbent on those who make them to try and break them. Otherwise, it’s cherry picking. Holmes could have written to the authors asking if he could have a go at amplifying SARS2 RNA from any remaining sample material. That would have been constructive.
Aside 2
For those interested in the molecular details of the pre-pandemic viruses see
https://pubmed.ncbi.nlm.nih.gov/33292923/
https://academic.oup.com/mbe/article/38/8/3046/6257226
Aside 3
The Director General of the World Health Organization said in a tweet dated September 4, 2024: As I have said many times, including to senior Chinese leaders, China’s cooperation is absolutely critical to that process. That includes information on the Huanan Seafood Market, the earliest known and suspected cases of COVID-19, and the work done at laboratories in Wuhan. Without this information, none of us are able to rule any hypothesis out. Until or unless China shares this data, the origins of COVID-19 will largely remain unknown.
He names China and states the obvious. Yet Dr. Holmes and his colleagues continue to insist, many times a year, that they know the natural zoonosis hypothesis is the right one. The latest efforts are published in the prestigious journal Cell as well as the Journal of Virology.
Aside 4
The lady doth protest too much, methinks. Bill (Shakespeare that is) invariably conjures up an elegant formula.
