by Jonathan Latham PhD and Allison Wilson, PhD
On July 23rd Senator Rand Paul (chair of the Senate’s Committee on Homeland Security and Government affairs, HSGAC) belatedly released the transcript of a Slack messaging group comprising four of the five leading virologists who wrote the now notorious paper ‘The Proximal Origin of SARS-CoV-2’ (Andersen et al., 2020). The four Slack authors are Kristian Andersen (Scripps), Eddie Holmes (University of Sydney), Bob Garry (Tulane University), and Andrew Rambaut (University of Edinburgh). The 1,123 page Slack text, spanning over two years worth of correspondence, can very profitably be read (and has been written up) for several reasons: one being to witness the shameless chicanery and conniving of these four virologists that other scientists, the intelligence community, and politicians chose to rely on, even as the four virologists manipulated them and the scientific peer review system. The transcript can also be read as an unprofessional spectacle of sub-adolescent name calling and profanity. The word F**k is used 180 times; Sh*t is on 241 pages; Prominent scientists, even ones who were agnostic about the lab leak, get referred to by insulting nick-names: ‘Bloomshit’, ‘e-dim’ or ‘E-dumb’, ‘Frankie Bollocks’; while the Paris group of researchers are ‘Parisites’.
But to a virologist, and to anyone determined to solve the COVID-19 origin puzzle itself, it is their secret doubts, the sins against science, against conventional virology, and against logic, of the Slack group–who are experts after all–that reveal what we really needed to know. More than that, as an unexpected bonus, the Slack messages also expose the internal mechanics of their lab leak defense.
Sure enough, the Slack virologists created a self-righteous bubble, contemptuous rather than respectful of different scientific viewpoints and contradictory evidence. A classic example is this pair of quotes (p491):
And then Bob Garry two months later (p713):
Let us quickly therefore, as a reminder to ourselves, “break it down” for them to illustrate that bubble.
First, an epicentre in Wuhan is several points combined. China has many cities and tens of thousands of live animal markets, but only Wuhan hosts a globally unique coronavirus collecting and research laboratory (the WIV) with a special interest in SARS-related coronaviruses. This laboratory was known even to its own staff for its poor biosecurity (Zhiming, 2019). The city is also nearly 1,000 miles from where the bat coronaviruses closely related to SARS-CoV-2 have been found. Besides the improbability of Wuhan as an epicentre there is the apparently perfect human adaptedness of the SARS-CoV-2 outbreak strain (more on this below). There is also the single phylogenetic origin of the outbreak, a classic hallmarks of lab escapes, and which the Slack authors and others strove hard but unconvincingly to make disappear (Pekar et al., 2022; Bloom, 2023; Cowan, 2025). There are also suspiciously positioned restriction enzyme sites in the SARS-CoV-2 genome (Bruttel et al., (2021), as Kristian Andersen privately noted in early February 2020. Then there are other slightly lesser red flags of a lab origin, such as the inability to find infected intermediate hosts or even susceptible animals being that sold at Wuhan markets.
It is important to highlight the partisan, unbalanced, and frankly anti-scientific thinking pervading the Slack. But the real value in the Slack transcript requires a laser focus on the specific scientific issues that troubled its authors most. And, surprisingly perhaps, the biggest elephant in their bubble was the question of the human adaptedness of the SARS-CoV-2 origin strain.
The Slack authors devoted disproportionate effort to discussing to what extent SARS-CoV-2 was human adapted and comparing this with the adaptation of SARS-CoV-2 strains when inserted in other species; which is another way of determining its adaptedness to humans. The human adaptedness problem became a sticking point for them because it resisted reconciliation with a market origin, and especially it could not be resolved with a market origin in December 2019. For these reasons it eventually became critical to them to dispose of the adaptedness issue. And they did this with an outlandish and unique virological argument, that SARS-CoV-2 was a “generalist virus”. As will be shown, this claim didn’t fit the evidence at all and, furthermore, it would have made SARS-CoV-2 unlike any other coronavirus and arguably any virus.
What thinking lay behind this striking decision?
The troublesome “human adaptedness” question
The word “adapt” appears on 69 Slack pages. Most of these instances refer to viral adaptation, either to humans, or to other hosts by way of comparison.
The underlying explanation for this focus is that the complex lifecycle of viruses requires them to carefully balance multiple competing interests. They typically have to match entry and exit from different cell types with evasion of multiple different forms of host immunity, transmission between hosts, and numerous other parameters that affect their long and short term prospects. Just as we humans must balance our work and home lives, finances, etc., if any significant viral life history factor is removed or altered then the balance between all of them will change. Thus the great fear of virologists who isolate a novel virus is that during amplification in its first petri dish, where the constraints normally imposed by acquired immunity and innate immune cells are absent, the novel virus becomes a non-representative culture-adapted virus, as many older viruses are (Kaul et al., 2007; Shirato et al., 2018). This responsiveness to prevailing conditions comprises a fundamental principle of virology (Simmonds et al., 2019). Because the degree of adaptedness of a virus to its a host is understood to be a highly sensitive indicator of its history, if an unknown virus fails to adapt in a specific host or environment this is as good as a proof that it came from that host and that environment.
Thus Bob Garry wrote in the first Proximal Origin Slack (p45), when the adaptedness question first arose, that evidence of early adaptation or lack of it by SARS-CoV-2 is:
“VERY important. even decisive.”[sic]
In March 2020 the Slack participants plus Ian Lipkin published their Proximal Origins of SARS-CoV-2 in Nature Medicine. It highlighted high infectiousness and high transmissibility as features of the novel virus from Wuhan. It was suggested that this impressive human adaptedness would likely be explained by cryptic circulation. This is the idea that imperfectly adapted precursors of SARS-CoV-2 circulated undetected in humans prior to the detection of known cases, giving them the opportunity to evolve into the better-adapted SARS-CoV-2 that is considered to be the origin strain.
Subsequent research has confirmed the initial adaptedness of SARS-CoV-2 up until the emergence of the Alpha variant, by which date viruses were becoming selected for immune escape (Markov et al., 2023). These assessments used statistical genetics to compare the relative frequencies of synonymous (i.e. silent) mutations (dS) against the frequency of nonsynonymous mutations (dN). The basis of this well-established method is to assume that synonymous mutations are selectively neutral whereas nonsynonymous mutations are more likely to represent adaptations, therefore the relative frequency of the two mutation types provides an estimate of virus maladaptiveness. A poorly adapted virus will generate a high proportion of nonsynonymous mutations as selection pressure forces it to become better adapted. This method (often referred to as dS/dN) is considered uncontroversial and reliable and accordingly multiple research groups concluded that SARS-CoV-2 (in this nine month period) was barely evolving or not evolving at all (Shan et al., 2020; Cagliani et al., 2020; Chaw et al., 2020; Chiara et al., 2021; MacLean et al., 2021; Tai et al., 2022). So whereas according to the zoonosis theory SARS-CoV-2 should be adapted either to the former host (i.e. bats or to an intermediate host) it was, instead, adapted to humans from the moment it was first detected.
Initially, the Slack authors accepted this interpretation. Thus here is Kristian Andersen (p72):
But, in February 2021, Eddie Holmes alerted them to a preprint (later published in Cell) that apparently changed their minds (Kang et al., 2021). Kang et al. suggested (using a novel statistical genetic approach) that the SARS-CoV-2 genome had evolved in humans prior to its first detection and so was not preadapted after all. Simultaneously, (also on pps536-537, which pages are worth reading in full) the Slack authors rejected the accepted dS/dN method. This was for no clear reason and despite having previously made extensive use of it themselves as the first Proximal Origin Slack shows. They reached both of these conclusions by assuming that a novel amino acid in SARS-CoV-2 (A372 in the spike protein, which differs from ancestral bat coronaviruses which feature T at position 372), and first identified by Kang et al., had appeared after the pandemic started. A372 appeared to them proof that the virus had adapted in humans via cryptic circulation.
This reasoning, as Kristian Andersen pointed out to them, wasn’t very solid. It required assuming A372 wasn’t already present in the first SARS-CoV-2 to jump from its previous host (p536):
And since genomes with T372 were never found in humans this suggestion of Andersen’s is more consistent with the evidence. But, without offering reasons, the others ignored him.
That wasn’t the end of the Slack preadaptation story. Accepting the Kang result absolutely requires a belief in undetected precirculation. But, in mid 2022 the Slack virologists published two major papers (Pekar et al., 2022 and Worobey et al., 2022) asserting that SARS-CoV-2 originated at the Huanan Seafood Market in December 2019. Exactly when these papers were conceived is not clear from the Slack. But a December 2019 spillover leaves no opportunity for cryptic circulation at all.
To thread this needle, their chosen solution was to reject human adaptedness completely and propose that SARS-CoV-2 was a “generalist virus” with a wide host range, or “pantropic” as Bob Garry called it. The “generalist” virus idea, in contrast to highly human adapted, came from MacLean and colleagues and was enthusiastically adopted (MacLean et al., 2021):
“doubtless SC2 is very pantropic [generalist]” wrote Bob Garry (p602); and a gleeful Eddie Holmes messaged (p715):
Followed by Holmes: “It’s a true generalist” (p781).
And for the remainder of the Slack dialogue, preadaptation to humans (or perfect human adaptation) of the origin strain becomes not just a doubtful proposition but “mind numbingly dumb” (p637), “misinformation” (p695), “nonsense” (p747). In another reversal, their former orthodoxy had become a heresy.
This generalist thesis is important and deserves careful attention. First, by erasing the human adaptedness of the origin strain it removes a formerly immovable obstacle to the market theory. But, second, it is not supportable for two major reasons:
a) The first problem is that the preadaptation idea refers specifically to the origin strain. It is the surprising human adaptedness of the putative outbreak virus that the Slack authors sought to explain. However, the outbreaks they count as evidence for generalism mostly include later strains and novel variants of SARS-CoV-2. Since these later types acquired infectivity towards different mammalian species, such as mice, rats, and white-tailed deer, they are not relevant to the question of whether SARS-CoV-2 emerged as a generalist; in fact they argue against it (Oude Munninck et al., 2021; Shuai et al. 2021; McBride et al., 2023; Schlottau et al., 2020). Similarly, MacLean et al. (originators of the generalist hypothesis) claim infection of pangolins as key evidence of generalism, even though no SARS-CoV-2 infection of a pangolin has ever been reported (MacLean et al., 2021).
In fact, origin or near-origin strains of SARS-CoV-2 infect only a small number of species under experimental settings and transmit between even fewer (Jahid et al., 2024). Those infected outside of labs are almost all mustelids (ferrets/mink or otters) or felines (lions, tigers, panthers, snow leopards, and domestic cats) on farms or in zoos, that is under unnatural and crowded conditions.
b) The second major problem for the generalist hypothesis is that in laboratory experiments with mink and mice, characteristic host-specific mutations immediately appear in the spike and other viral proteins (Leist et al., 2020; Tai et al., 2022; Pulit-Penaloza et al., 2022; Huang et al., 2021). Similarly, outside of labs, e.g. on mink farms and also in wild deer and big cat COVID19 outbreaks, species-specific mutations also appear and for each species are often the same mutations as appear in laboratories. These mutations are adaptations to the new host, thereby demonstrating that in non-human species the initially infecting virus is not perfectly adapted (Tai et al., 2022; Markov et al., 2023; McBride et al., 2023; Iglesias-Caballero, 2024; Bashor et al., 2025).
Thus the contrasting behaviour of SARS-CoV-2 in humans, where adaptations accumulated very slowly, compared to mink, mice, deer, cats, and other hosts where adaptation begins instantaneously, cannot be accounted for by inventing the concept of a generalist virus. Nevertheless, if we continue to consider the medium term, i.e. the first nine months as SARS-CoV-2 spread across the world, a small number of adaptive amino acid mutations did arise. What do they tell us?
What really happened with adaptation?
Fortunately, in 2026, no one need any more depend on statistical genetic estimates to gauge early SARS-CoV-2 adaptation. This is because it is now known which were the key earliest SARS-CoV-2 mutations after emergence in Wuhan and, approximately at least, their functions. And the spoiler is that virologists are hesitant to discuss them in much detail (or it seems fund research on most of them) because none of those identified so far are human-specific adaptations. Rather, they are either transmission mutations or putative transmission mutations. These mutations thus confirm and extend the statistical genetic findings: the SARS-CoV-2 origin strain was indeed fully human adapted and the virologists who dismissed them were wrong to.
In the following analysis we define four mutations as keys to the adaptiveness question. The first was the nucleotide change A23403G. This created the famous Spike protein change referred to as D614G (this notation indicates an amino acid substitution in which G, glycine, replaced D, aspartate, at Spike position 614). the second is C14408U (which gave the substitution nsp12: P323L in which L, leucine, replaced P, proline at position 323 in the nsp12 protein). These first two are non-synonymous changes. In addition to these are the two mutations C241U and C3037U. These are nucleotide changes only and they don’t affect the amino acid sequence of any viral protein (Colson et al., 2024).
These four are critical because they (and only they) share the following characteristics–each arose early in the pandemic (in or before January 2020); each became rapidly fixed (i.e. dominant) in the viral population; and each has been retained through the whole pandemic. For D614G and P323L these unique attributes (earliness, fixation, and retention) can be seen in the figure below, from Flores-Alanis et al. (2024), and they independently corroborate that each mutation strongly boosted viral fitness.
The key question to ask about each is whether they were adaptations specifically to humans or whether they were adaptations to some other selective force operating during the pandemic (with other obvious candidates being epidemic conditions or evasion of the acquired immunity due to prior infection and vaccination building up in the population).
Spike D614G
The most famous of these by far is D614G. This spike mutation has been the subject of hundreds of papers based on early fears that it might evade immunity or be more harmful. These fears went unrealised and, instead, the primary effect of D614G, and why it seems to have been selected, is that viruses with D614G transmit faster and better. Since its effects are always the same, no matter what species is tested, D614G is not a human-specific adaptation (Hou et al., 2020a; Schlottau et al., 2020).
The virological reason why such mutants transmit better was for a while mysterious but is worth knowing since it affirms its role in transmission. D614G has complex effects on the function of the spike protein. These led to the initial expectation it would infect all cells better; but, in keeping with its lack of effect on lung titres, these effects seem to be inconsequential in most tissues, except in the cells of the upper respiratory tract where D614G mutants are more abundant (Hou et al., 2020a; Plante et al., 2021). This advantage explains better transmission and infection; but the mechanistic reason why it grows better only in the upper airways only became clear quite recently. It is that D614G mutants are superior at evading innate immunity, and innate immunity, unsurprisingly, is particularly active in the upper respiratory tract (Mesner et al., 2023). Thus improved resistance to innate immunity leads to better infection in the upper respiratory tract which leads to better person-to-person transmission. This explains why D614 variants were replaced by G614.
P323L
The story of P323L is similar but also different. P323L is a mutation of the viral polymerase. Viruses with L at position 323 replicate faster (but probably with more errors) under standard conditions (Goldswain et al., 2023). The secret to understanding P323L, however, is that it replicates better than P323 at 330C, which is the normal temperature of the nose (Kim et al., 2023). Thus P323L adapts SARS-CoV-2 to the nose, which is the critical organ for transmission and infection. Thus, just like D614G, P323L is a transmission mutation and, just like D614G, it transmits better in all species tested. Thus both P323L and D614G have been tested in hamsters and ferrets and P323L also in macaques (Kim et al., 2023). The bottom line again is that P323L is also not an adaptation specific to humans, but rather an adaptation specific to transmission.
Nose adaptation in an airborne epidemic is critical since most viruses enter a new host by infecting nose cells and equally are exhaled from nose cells; the virus may in fact never reach the lung, or, if the virus does reach the lung, the lung is not the originating site from which transmission occurs (Hou et al., 2020b). Thus, probably contrary to most lay understanding, SARS-CoV-2 goes from nose (person 1) to nose (person 2) to nose (person 3), or, alternatively, from nose to lung to nose (person 1) and to nose to lung to nose (person 2), etc. Whichever pathway is followed, and it may be a mix, adaptation to the tissues of the nasopharynx is a critical requirement for effective transmission. (This leads to an interesting question for the market origin theory; since these mutations are highly beneficial for transmission regardless of species, why they did not arise in the intermediate host?)
C3037U and C241U
Surprisingly perhaps, no credible research has been done on C3037U and only a little is known about C241U. C241U, however, is a mutation of the SL5a hexaloop which is very close to the beginning of the SARS-CoV-2 genome (which is a single stranded RNA). The SL5 region forms a complex structure of folded RNA that is thought to control production of viral proteins and also to control viral packaging. SL5 may act as a switch between these two alternative functions, which are prioritised depending on the stage of infection. Interestingly, C241U partially destabilises the specific loop it is in. By analogy with P323L it is tempting to speculate that this instability enhances functionality at lower temperatures, i.e. in the nose. The bottom line however, is that it is currently not possible to say if C241U or C3037U are human specific adaptations, except to say that they may well not be.
Conclusions
What we learn from analysing how the Slack virologists dealt with the human adaptedness question are two things of critical and enduring importance.
The first is that that the Slack authors, though highly motivated, could find no valid grounds in either logic or virology for dismissing the human adaptedness of the outbreak strain. Rather, their dismissal of human adaptedness was based on pure necessity. The pressure they felt was obscured by the bluster, but the market zoonosis hypothesis rested from the beginning on very slender threads. The strongest evidence linking the outbreak with an animal origin were that (1) multiple December COVID-19 patients had a link to the Huanan Market and (2) some SARS-CoV-2 genomes were found there in surface swab samples. These were facts but their actual import was uncertain. The samples and patients may merely have been representative of Wuhan in December 2019; or they may have resulted entirely from ascertainment bias since China’s CDC initially seemed to assume a market origin. To avoid them being irrelevant the outbreak date had to be pinned to that month. Hence any other finding that threatened a December origin, such as earlier patients or samples, had to be confronted or denied. Obviously, precirculation contradicts a December origin and without precirculation there is no explanation for human adaptedness compatible with a zoonosis. Hence human adaptedness had to go too. Thus the Slack messages reveal at last the strategic rationale underlying the zoonotic defence in the West. This explains the panic (that close followers of the origin story may recall) when on February 25th 2022 the leaders of China’s CDC published a preprint proposing that the Huanan Market in Wuhan was indeed just an ordinary market and SARS-CoV-2 was already widespread by the time it was sampled. (This CCDC manuscript was eventually published as Liu et al., 2023).
The second revelation is the decisiveness of human adaptedness for the origin question. No one, including the Slack virologists, has ever scientifically contradicted the human adaptedness of SARS-CoV-2 as it first appeared in Wuhan. What Kristian Andersen presciently wrote on February 10th, 2020 remains fundamentally accurate today (p24):
“Let’s not forget that what we’ve observed is completely unprecedented as far as I know. Never before has a zoonotic virus jumped into humans and spread through the population like wildfire with this kind of speed. This in itself would require further inquiry.”
“Nothing in biology”, wrote geneticist Theodosius Dobzhansky, “makes sense except in the light of evolution”. And because viruses evolve so rapidly, this axiom applies especially to them: nothing refutes a zoonotic hypothesis like adaptation by SARS-CoV-2 in all animals except humans. With no refutation of it in sight, we are compelled to face as fact that every nucleotide (and not just the spike region) of a genome 30,000 nucleotides in length was unprecedentedly adapted to a supposedly ‘new’ host. And with zero evidence for precirculation in humans one must therefore accept as a fact also that, prior to emergence, SARS-CoV-2 underwent some form of human preadaptation process.
The reasons this hasn’t long been clear are, in part, that the definitive facts have taken time to emerge. But the other part is that senior virologists like the Slack group knew all along that adaptedness could be decisive if the chips didn’t fall their way. And, decisively, they have not — and so the research literature, though rich in evidence, is alternately, coy, silent, or actively misleading about the import of mutations like D614G for the origin question. A classic case is Pulit-Penaloza et al., who infected multiple ferrets with SARS-CoV-2 and deep sequenced the viruses that emerged (2022). Without counting the spike these authors found 18 nonsynonymous mutations that arose multiple times independently and that thereby verify rapid adaptation to the new host; but they failed to note, discuss, or even count them and consigned the entire data set to the supplementary section.
If the scientific case is still not clear the private thoughts and admissions of Bob Garry, Kristian Andersen, Andrew Rambaut, and Eddie Holmes now are. As of today only unreasonable doubt can deny the overwhelming likelihood that a virus leaked from a lab is what the human population of Wuhan was exposed to in 2019. No WIV whistleblower or paper trail, just a close look at the available scientific data, is needed to accept this as overwhelmingly the likeliest cause.
Applying ordinary scientific standards to both the zoonosis hypothesis and the lab leak hypothesis we thus arrive at the real question. It is not whether SARS-CoV-2 was a zoonosis but:
What combination of research, sampling or other processes leads a bat coronavirus to become a fully adapted human respiratory virus?
Here is not the place to propose an answer; but two obvious though very divergent choices are immediately available. There is one that opinion writers in mainstream media or authors with publishing contracts invariably mention when permitted to discuss the origin of SARS-CoV-2; and there is another possibility that they ignore.
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