Daily Archives: July 17, 2020

Jul 18th 2020

A Dominant Character: The Radical Science and Restless Politics of J.B.S. Haldane. By Samanth Subramanian. W.W. Norton; 400 pages; $40. Atlantic Books; 20.

TOWARDS THE end of his life, J.B.S. Haldane was inseparable from a pebble that had been found in the Valley of Elah in Israel, where David felled Goliath with a similar projectile. A king-size man who towered over British biology for several decades in the middle of the 20th century, Jack Haldanethe half-Danewas a more obvious Goliath, but he always took the side of the underdog.

That is the contradiction at the heart of Samanth Subramanians astute and sympathetic biography. An Eton- and Oxford-educated communist, who with a handful of others fleshed out Darwins theory of natural selection by marrying it to genetics and grounding it in maths, Haldane was born into privilege but came to identify himself with the masses. And if his unconscious sense of entitlement can sometimes be grating, it is more than offset by his humour, facility for language, intellectual generosity andthe product of all thishis giant contribution to the popularisation of science.

Science was his first and most enduring love. Aged three, studying blood trickling from a cut, he is supposed to have asked, Is it oxyhaemoglobin or carboxyhaemoglobin? Thus began a life of inquiry in which he was always either being experimented onnotably by his father, the physiologist J.S. Haldaneor experimenting on himself or others. Bertrand Russell thought that science could rarely be beautiful, but for Haldane beauty came through understanding. Until I took to scientific plant-breeding, he wrote, I did not appreciate the beauty of flowers.

Haldane wrote a great deal, in learned journals but also in the popular press and in response to letters from the scientifically curious, and on a breathtaking range of subjects. Please send me no more caterpillars, he pleaded on one of the many occasions that his mailbag threatened to overwhelm him. As he coped with his own and other peoples inquisitiveness, world events intruded. He wrote parts of a paper on genetic linkagewhereby two genes that sit close to each other on a chromosome are more likely to be inherited togetherwhile serving in the trenches during the first world war.

It was in the trenches, too, that Haldanes rejection of his birthright crystallised. As disappointed by the officer class as he was by army chaplains, he wrote to his mother that, when the revolution came, the people would strangle the last Duke in the guts of the last parson. But he was attracted to Marxism for more than just its egalitarian ideals; it struck him as practical, transparentin short, scientific. Though he kept his distance from the Communist Party of Great Britain (CPGB) until 1942, MI5 had him down as a subversive from the time of his only visit to the Soviet Union, in 1928.

Haldanes politics and his science clashed mightily in 1948, when as the CPGBs foremost intellectualand, by then, one of the most influential geneticists in the worldhe refused to publicly condemn the pseudoscience of Trofim Lysenko. Stalins favourite agronomist claimed that he could drum desirable traits into wheat by altering its environment, just as Jean-Baptiste Lamarck had once believed giraffes had stretched their necks through practice. In the Soviet Union scientists who disagreed with Lysenko vanished. One of them, Nikolai Vavilov, had hosted Haldane in Moscow. Haldanes own science contradicted Lysenkoism. Nobody who knew him could fathom his stance.

Mr Subramanian doesnt defend it either. He makes it clear that Haldane ignored overwhelming evidence of Vavilovs internment and death in the gulag. But he uses the episode to illustrate a wider truth, which is that science cannot be extricated from politics. Today many scientists describe their research as apolitical, but Haldane knew that was impossible: I began to realise that even if the professors leave politics alone, politics wont leave the professors alone.

It meant that he was prepared to change his mind. Eugenics was a mainstream theory when he entered biology, and he partially embraced it. But he also warned that genetics was too young a science to be applied successfully. His ideas evolved until they fell into line with those of the scientists now wielding genetic-engineering tools to improve humanity (though they would reject the eugenics label).

Haldane changed his mind too slowly about the Soviet Union, but having done so he found new hope in India, where he moved in 1957. Its bureaucracy maddened him and he said so loudly and oftenflashing his white male privilege like a peacocks tailbut its tropical profusion provided him with a natural laboratory, and the climate was kinder to a body damaged by decades of self-experiment. When he died there in 1964, still holding the stone from Elah, it was no surprise to anyone that he donated his body to science.

This article appeared in the Books & arts section of the print edition under the headline "Trial and error"

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The flawed brilliance of J.B.S. Haldane - The Economist

Photograph by Nathaniel St. Clair

In all the discussions of the origin of the COVID-19 pandemic, enormous scientific attention has been paid to the molecular character of the SARS-CoV-2 virus, including its novel genome sequence in comparison with its near relatives. In stark contrast, virtually no attention has been paid to the physical provenance of those nearest genetic relatives, its presumptive ancestors, which are two viral sequences named BtCoV/4991 and RaTG13.

This neglect is surprising because their provenance is more than interesting. BtCoV/4991 and RaTG13 were collected from a mineshaft in Yunnan province, China, in 2012/2013 by researchers from the lab of Zheng-li Shi at the Wuhan Institute of Virology (WIV). Very shortly before, in the spring of 2012, six miners working in the mine had contracted a mysterious illness and three of them had died (Wu et al., 2014). The specifics of this mystery disease have been virtually forgotten; however, they are described in a Chinese Masters thesis written in 2013 by a doctor who supervised their treatment.

We arranged to have this Masters thesis translated into English. The evidence it contains has led us to reconsider everything we thought we knew about the origins of the COVID-19 pandemic. It has also led us to theorise a plausible route by which an apparently isolated disease outbreak in a mine in 2012 led to a global pandemic in 2019.

The origin of SARS-CoV-2 that we propose below is based on the case histories of these miners and their hospital treatment. This simple theory accounts for all the key features of the novel SARS-CoV-2 virus, including ones that have puzzled virologists since the outbreak began.

The theory can account for the origin of the polybasic furin cleavage site, which is a region of the viral spike protein that makes it susceptible to cleavage by the host enzyme furin and which greatly enhances viral spread in the body. This furin site is novel to SARS-CoV-2 compared to its near relatives (Coutard, et al., 2020). The theory also explains the exceptional affinity of the virus spike protein for human receptors, which has also surprised virologists (Letko et al., 2020; Piplani et al, 2020; Wrapp et al., 2020; Walls et al., 2020). The theory further explains why the virus has barely evolved since the pandemic began, which is also a deeply puzzling aspect of a virus supposedly new to humans (Zhan et al., 2020; van Dorp et al., 2020; Chaw et al., 2020). Lastly, the theory neatly explains why SARS-CoV-2 targets the lungs, which is unusual for a coronavirus (Huang et al., 2020).

We do not propose a specifically genetically engineered or biowarfare origin for the virus but the theory does propose an essential causative role in the pandemic for scientific research carried out by the laboratory of Zheng-li Shi at the WIV; thus also explaining Wuhan as the location of the epicentre.

The apparent origin of the COVID-19 pandemic is the city of Wuhan in Hubei province, China. Wuhan is also home to the worlds leading research centre for bat coronaviruses. There are two virology labs in the city, both have either collected bat coronaviruses or researched them in the recent past. The Shi lab, which collected BtCoV/4991 and RaTG13, recently received grants to evaluate by experiment the potential for pandemic pathogenicity of the novel bat coronaviruses they collected from the wild.

To add to these suggestive data points, there is a long history of accidents, disease outbreaks, and even pandemics resulting from lab accidents with viruses (Furmanski, 2014; Weiss et al., 2015). For these and other reasons, summarised in our article The Case is Building that COVID-19 Had a Lab Origin, we (a virologist and a geneticist) and others have concluded that a lab outbreak is a credible thesis. Certainly, a lab origin has at least as much circumstantial evidence to support it as does any natural zoonotic origin theory (Piplani et al., 2020; Segreto and Deigin, 2020; Zhan et al., 2020).

The media, normally so enamoured of controversy, has largely declined even to debate the possibility of a laboratory escape. Many news sites have simply labelled it a conspiracy theory.

The principal reason for media dismissals of the lab origin possibility is a review paper in Nature Medicine (Andersen et al., 2020). Although by Jun 29 2020 this review had almost 700 citations it also has major scientific shortcomings. These flaws are worth understanding in their own right but they are also useful background for understanding the implications of the Masters thesis.

The question of the origin of the COVID-19 pandemic is, in outline, simple. There are two incontrovertible facts. One, the disease is caused by a human viral pathogen, SARS-CoV-2, first identified in Wuhan in December 2019 and whose RNA genome sequence is known. Second, all of its nearest known relatives come from bats. Beyond any reasonable doubt SARS-CoV-2 evolved from an ancestral bat virus. The task the Nature Medicine authors set for themselves was to establish the relative merits of each of the various possible routes (lab vs natural) by which a bat coronavirus might have jumped to humans and in the same process have acquired an unusual furin site and a spike protein having very high affinity for the human ACE2 receptor.

When Andersen et al. outline a natural zoonotic pathway they speculate extensively about how the leap might have occurred. In particular they elaborate on a proposed residence in intermediate animals, likely pangolins. For example, The presence in pangolins of an RBD [Receptor Binding Domain] very similar to that of SARS-CoV-2 means that we can infer that this was probably in the virus that jumped to humans. This leaves the insertion of [a] polybasic cleavage site to occur during human-to-human transmission. This viral evolution occurred in Malayan pangolins illegally imported into Guangdong province. Even with these speculations there are major gaps in this theory. For example, why is the virus so well adapted to humans? Why Wuhan, which is 1,000 Km from Guangdong? (See map).

The authors provide no such speculations in favour of the lab accident thesis, only speculation against it:

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 system. (italics added).

[Passaging is the deliberate placing of live viruses into cells or organisms to which they are NOT adapted for the purpose of making them adapted, i.e. speeding up their evolution.]

It is also noteworthy that the Andersen authors set a higher hurdle for the lab thesis than the zoonotic thesis. In their account, the lab thesis is required to explain all of the evolution of SARS-CoV-2 from its presumed bat viral ancestor, whereas under their telling of the zoonotic thesis the key step of the addition of the furin site is allowed to happen in humans and is thus effectively unexplained.

A further imbalance is that key information needed to judge the merits of a lab origin theory is missing from their account. As we detailed in our previous article, in their search for SARS-like viruses with zoonotic spillover potential, researchers at the WIV have passaged live bat viruses in monkey and human cells (Wang et al., 2019). They have also performed many recombinant experiments with diverse bat coronaviruses (Ge et al., 2013; Menachery et al., 2015; Hu et al., 2017). Such experiments have generated international concern over the possible creation of potential pandemic viruses (Lipsitch, 2018). As we showed too, the Shi lab had also won a grant to extend that work to whole live animals. They planned virus infection experiments across a range of cell cultures from different species and humanized mice with recombinant bat coronaviruses. Yet Andersen et al did not discuss this research at all, except to say:

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 world

This statement is fundamentally misleading about the kind of research performed at the Shi lab.

A further important oversight by the Andersen authors concerns the history of lab outbreaks of viral pathogens. They write: there are documented instances of laboratory escapes of SARS-CoV. This is a rather matter-of-fact allusion to the fact that since 2003 there have been six documented outbreaks of SARS from labs, not all in China, with some leading to fatalities (Furmanski, 2014).

Andersen et al might have also have noted that two major human pandemics are widely accepted to have been caused by lab outbreaks of viral pathogens, H1N1 in 1977 and Venezuelan Equine Encephalitis (summarised in Furmanski, 2014). Andersen could even have noted that literally hundreds of lab accidents with viruses have resulted in near-misses or very localised outbreaks (summarised by Lynn Klotz and Sam Husseini and also Weiss et al., 2015).

Also unmentioned were instances where a lab outbreak of an experimental or engineered virus has been plausibly theorised but remains uninvestigated. For example, the most coherent explanation for the H1N1 variant swine flu pandemic of 2009/10 that resulted in a death toll estimated by some as high as 200,000 (Duggal et al., 2016; Simonsen et al. 2013), is that a vaccine was improperly inactivated by its maker (Gibbs et al., 2009). If so, H1N1 emerged from a lab not once but twice.

Given that human and livestock viral outbreaks have frequently come from laboratories and that many scientists have warned of probable lab escapes (Lipsitch and Galvani, 2014), and that the WIV itself has a questionable biosafety record, the Andersen paper is not an even-handed treatment of the possible origins of the COVID-19 virus.

Yet its text expresses some strong opinions: Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus..the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used backbone.the evidence shows that SARS-CoV2 is not a purposefully manipulated virus.we do not believe that any type of laboratory-based scenario is possible. (Andersen et al., 2020).

It is hard not to conclude that what their paper mostly shows is that Drs. Andersen, Rambaut, Lipkin, Holmes and Garry much prefer the natural zoonotic transfer thesis. Their rhetoric is forthright but the evidence does not support that confidence.

Indeed, since the publication of Andersen et al., important new evidence has emerged that undermines their zoonotic origin theory. On May 26th the Chinese CDC ruled out the Huanan wet market in Wuhan as the source of the outbreak. Additionally, new research on pangolins, the favoured intermediate mammal host, suggests they are not a natural reservoir of coronaviruses (Lee et al., 2020; Chan and Zhan, 2020). Furthermore, SARS-CoV-2 was found not to replicate in bat kidney or lung cells (Rhinolophus sinicus), implying that SARS-CoV-2 is not a recently-adapted spill over Chu et al., 2020).

In our own search to resolve the COVID-19 origin question we chose to focus on the provenance of the coronavirus genome sequences BtCoV/4991 and RaTG13, since these are the most closely related sequences to SARS-CoV-2 (98.7% and 96.2% identical respectively). See FIG 1. (reproduced from P. Zhou et al., 2020).

For comparison, the next closest virus to SARS-CoV-2 is RmYN02 (not shown in Fig 1.) (H. Zhou et al., 2020). RmYN02 has an overall similarity to SARS-CoV-2 of 93.2%, making its evolutionary distance from SARS-CoV-2 almost twice as great.

BtCoV/4991 was first described in 2016. It is a 370 nucleotide virus fragment collected from the Mojiang mine in 2013 by the lab of Zeng-li Shi at the WIV (Ge et al., 2016). BtCoV/4991 is 100% identical in sequence to one segment of RaTG13. RaTG13 is a complete viral genome sequence (almost 30,000 nucleotides) that was only published in 2020, after the pandemic began (P. Zhou et al., 2020).

Despite the confusion created by their different names, in a letter obtained by us Zheng-li Shi confirmed to a virology database that BtCoV/4991 and RaTG13 are both from the same bat faecal sample and the same mine. They are thus sequences from the same virus. In the discussion below we will refer primarily to RaTG13 and specify BtCoV/4991 only as necessary.

These specifics are important because it is these samples and their provenance that we believe are ultimately key to unravelling the mystery of the origins of COVID-19.

The story begins in April 2012 when six workers in that same Mojiang mine fell ill from a mystery illness while removing bat faeces. Three of the six subsequently died.

In a March 2020 interview with Scientific American Zeng-li Shi dismissed the significance of these deaths, claiming the miners died of fungal infections. Indeed, no miners or deaths are mentioned in the paper published by the Shi lab documenting the collection of RaTG13 (Ge et al., 2016).

But Shis assessment does not tally with any other contemporaneous accounts of the miners and their illness (Rahalkar and Bahulikar, 2020). As these authors have pointed out, Sciencemagazine wrote up part of the incident in 2014 as A New Killer Virus in China?. Science was citing a different team of virologists who found a paramyxovirus in rats from the mine. These virologists told Science they found no direct relationship between human infection and their virus. This expedition was later published as the discovery of a new virus called MojV after Mojiang, the locality of the mine (Wu et al., 2014).

What this episode suggests though is that these researchers were looking for a potentially lethal virus and not a lethal fungus. Also searching the Mojiang mine for a virus at around the same time was Canping Huang, the author of a PhD thesis carried out under the supervision of George Gao, the head of the Chinese CDC.

All of this begs the question of why the Shi lab, which has no interest in fungi but a great interest in SARS-like bat coronaviruses, also searched the Mojiang mine for bat viruses on four separate occasions between August 2012 and July 2013, even though the mine is a 1,000 Km from Wuhan (Ge et al., 2016). These collecting trips began while some of the miners were still hospitalised.

Fortunately, a detailed account of the miners diagnoses and treatments exists. It is found in a Masters thesis written in Chinese in May 2013. Its suggestive English title is The Analysis of 6 Patients with Severe Pneumonia Caused by Unknown viruses.

The original English version of the abstractimplicates a SARS-like coronavirus as the probable causative agent and that the mine had a lot of bats and bats feces.

The six ill miners were admitted to the No. 1. School of Clinical Medicine, Kunming Medical University, in short succession in late April and early May 2012. Kunming is the capital of Yunnan province and 250 Km from Mojiang.

Of the descriptions of the miners and their treatments, which include radiographs and numerous CAT scans, several features stand out:

1) From their admission to the hospital their doctors informed the medical office of a potential outburst of disease i.e. a potential epidemic outbreak. Thus, the miners were treated for infections and not as if they had inhaled noxious gases or other toxins.

2) The symptoms (on admission) of the six miners were: a) dry cough, b) sputum, c) high fevers, especially shortly before death d) difficulty breathing, e) myalgia (sore limbs). Some patients had hiccoughs and headaches. (See Table 1).

3) Clinical work established that patients 1-4 had low blood oxygen for sure it was ARDS (Acute Respiratory Distress Syndrome) and immune damage considered indicative of viral infection. Additionally, a tendency for thrombosis was noted in patients 2 and 4. Symptom severity and mortality were age-related (though from a sample of 6 this must be considered anecdotal).

4) Potential common and rare causes of their symptoms were tested for and mostly eliminated. For patients 3 and 4 these included tests for HIV, Cytomegalovirus, Epstein-Barr Virus (EBV), Japanese encephalitis, haemorrhagic fever, Dengue, Hepatitis B, SARS, and influenza. Of these, only patient 2 tested positive for Hepatitis and EBV.

5) Treatment of the six patients included ventilation (patients 2-4), steroids (all patients), antivirals (all except patient 5), and blood thinners (patients 2 and 4). Antibiotics and antifungal medications were administered to counter what were considered secondary (but significant) co-infections.

6) A small number of remote meetings were held with researchers at other universities. One was with Zhong Nanshan at Sun Yat-Sen University, Guangdong. Zhong is the Chinese hero of the SARS epidemic, a virologist, and arguably the most famous scientist in China.

7) Samples from the miners were later sent to the WIV in Wuhan and to Zhong Nanshan, further confirming that viral disease was strongly suspected. Some miners did test positive for coronavirus (the thesis is unclear on how many).

8) The source of infection was concluded to be Rhinolophus sinicus, a horseshoe bat and the ultimate conclusion of the thesis reads the unknown virus lead to severe pneumonia could be: The SARS-like-CoV from the Chinese rufous horseshoe bat. Thus the miners had a coronavirus but it apparently was not SARS itself.

These findings of the thesis are significant in several ways.

First, in the light of the current coronavirus pandemic it is evident the miners symptoms very closely resemble those of COVID-19 (Huang et al, 2020; Tay et al., 2020; M. Zhou et al., 2020). Anyone presenting with them today would immediately be assumed to have COVID-19. Likewise, many of the treatments given to the miners have become standard for COVID-19 (Tay et al., 2020).

Second, the remote meeting with Zhong Nanshan is significant. It implies that the illnesses of the six miners were of high concern and, second, that a SARS-like coronavirus was considered a likely cause.

Third, the abstract, the conclusions, and the general inferences to be made from the Masters thesis contradict Zheng-li Shis assertion that the miners died from a fungal infection. Fungal infection as a potential primary cause was raised but largely discarded.

Fourth, if a SARS-like coronavirus was the source of their illness the implication is that it could directly infect human cells. This would be unusual for a bat coronavirus (Ge et al., 2013). People do sometimes get ill from bat faeces but the standard explanation is histoplasmosis, a fungal infection and not a virus (McKinsey and McKinsey, 2011; Pan et al., 2013).

Fifth, the sampling by the Shi lab found that bat coronaviruses were unusually abundant in the mine (Ge at al., 2016). Among their findings were two betacoronaviruses, one of which was RaTG13 (then known as BtCoV/4991). In the coronavirus world betacoronaviruses are special in that both SARS and MERS, the most deadly of all coronaviruses, are both betacoronaviruses. Thus they are considered to have special pandemic potential, as the concluding sentence of the Shi lab publication which found RaTG13 implied: special attention should particularly be paid to these lineages of coronaviruses (Ge at al., 2016). In fact, the Shi and other labs have for years been predicting that bat betacoronaviruses like RaTG13 would go pandemic; so to find RaTG13 where the miners fell ill was a scenario in perfect alignment with their expectations.

How does the Masters thesis inform the search for a plausible origin of the pandemic?

In our previous article we briefly discussed how the pandemic might have been caused either by a virus collection accident, or through viral passaging, or through genetic engineering and a subsequent lab escape. The genetic engineering possibility deserves attention and is extensively assessed in an important preprint (Segreto and Deigin, 2020).

We do not definitively rule out these possibilities. Indeed it now seems that the Shi lab at the WIV did not forget about RaTG13 but were sequencing its genome in 2017 and 2018. However, we believe that the Masters thesis indicates a much simpler explanation.

We suggest, first, that inside the miners RaTG13 (or a very similar virus) evolved into SARS-CoV-2, an unusually pathogenic coronavirus highly adapted to humans. Second, that the Shi lab used medical samples taken from the miners and sent to them by Kunming University Hospital for their research. It was this human-adapted virus, now known as SARS-CoV-2, that escaped from the WIV in 2019.

We refer to this COVID-19 origin hypothesis as the Mojiang Miners Passage (MMP) hypothesis.

Passaging is a standard virological technique for adapting viruses to new species, tissues, or cell types. It is normally done by deliberately infecting a new host species or a new host cell type with a high dose of virus. This initial viral infection would ordinarily die out because the hosts immune system vanquishes the ill-adapted virus. But, in passaging, before it does die out a sample is extracted and transferred to a new identical tissue, where viral infection restarts. Done iteratively, this technique (called serial passaging or just passaging) intensively selects for viruses adapted to the new host or cell type (Herfst et al., 2012).

At first glance RaTG13 is unlikely to have evolved into SARS-CoV-2 since RaTG13 is approximately 1,200 nucleotides (3.8%) different from SARS-CoV-2. Although RaTG13 is the most closely related virus to SARS-CoV-2, this sequence difference still represents a considerable gap. In a media statement evolutionary virologist Edward Holmes has suggested this gap represents 20-50 years of evolution and others have suggested similar figures.

We agree that ordinary rates of evolution would not allow RaTG13 to evolve into SARS-CoV-2 but we also believe that conditions inside the lungs of the miners were far from ordinary. Five major factors specific to the hospitalised miners favoured a very high rate of evolution inside them.

i) When viruses infect new species they typically undergo a period of very rapid evolution because the selection pressure on the invading pathogen is high. The phenomenon of rapid evolution in new hosts is well attested among corona- and other viruses (Makino et al., 1986; Baric et al., 1997; Dudas and Rambaut 2016; Forni et al., 2017).

ii) Judging by their clinical symptoms such as the CT scans, all the miners infections were primarily of the lungs. This localisation likely occurred initially because the miners were exerting themselves and therefore inhaling the disturbed bat guano deeply. As miners, they may already have had damaged lung tissues (patient 3 had suspected pneumoconiosis) and/or particulate matter was present that irritated the tissues and may have facilitated initial viral entry.

In contrast, standard coronavirus infections are confined to the throat and upper respiratory tract. They do not normally reach the lungs (Perlman and Netland, 2009). Lungs are far larger tissues by weight (kilos vs grammes) than the upper respiratory tract. There was therefore likely a much larger quantity of virus inside the miners than would be the case in an ordinary coronavirus infection.

Comparing a typical coronavirus respiratory tract infection with the extent of infected lungs in the miners from a purely mathematical point of view indicates the potential scale of this quantitative difference. The human aerodigestive tract is approximately 20cm in length and 5cm in circumference, i.e. approximately 100 cm2 in surface area. The surface area of a human lung ranges from 260,000-680,000 cm2 (Hasleton, 1972). The amount of potentially infected tissue in an average lung is therefore approximately 4500-fold greater than that available to a normal coronavirus infection. The amount of virus present in the infected miners, sufficient to hospitalise all of them and kill half of them, was thus proportionately very large.

Evolutionary change is in large part a function of the population size. The lungs of the miners, we suggest, supported a very high viral load leading to proportionately rapid viral evolution.

Furthermore, according to the Masters thesis, the immune systems of the miners were compromised and remained so even for those discharged. This weakness on the part of the miners may also have encouraged evolution of the virus.

iii) The length of infection experienced by the miners (especially patients 2, 3 and 4) far exceeded that of an ordinary coronavirus infection. From first becoming too sick to work in the mine, patient 2 survived 57 days until he died. Patient 3 survived 120 days after stopping work. Patient 4 survived 117 days and then was discharged as cured. Each had been exposed in the mine for 14 days prior to the onset of severe symptoms; thus each presumably had nascent infections for some time before calling in sick (See Table 2 of the thesis).

In contrast, in ordinary coronavirus infections the viral infection is cleared within about ten to fourteen days after being acquired (Tay et al., 2020). Thus, unlike most sufferers from coronavirus infection, the hospitalised miners had very long-term bouts of disease characterised by a continuous high load of virus. In the cases of patients 3 and 4 their illnesses lasted over 4 months.

iv) Coronaviruses are well known to recombine at very high rates: 10% of all progeny in a cell can be recombinants (Makino et al., 1986; Banner and Lai, 1991; Dudas and Rambaut, 2016). In normal virus evolution the mutation rate and the selection pressure are the main foci of attention. But in the case of a coronavirus adapting to a new host where many mutations distributed all over the genome are required to fully adapt to the new host, the recombination rate is likely to be highly influential in determining the overall speed of adaptation by the virus population (Baric et al., 1997).

Inside the miners a large tissue was simultaneously infected by a population of poorly-adapted viruses, with each therefore under pressure to adapt. Even if the starting population of virus lacked any diversity, many individual viruses would have acquired mutations independently but only recombination would have allowed these mutations to unite in the same genome. To recombine, viruses must be present in the same cell. In such a situation the particularities of lung tissues become potentially important because the existence of airways (bronchial tubes, etc.) allows partially-adapted viruses from independent viral populations to travel to distal parts of the lung (or even the other lung) and encounter other such partially-adapted viruses and populations. This movement around the lungs would likely have resulted in what amounted to a passaging effect without the need for a researcher to infect new tissues. Indeed, in the Masters thesis the observation is several times made that areas of the lungs of a specific patient would appear to heal even while other parts of the lungs would become infected.

v) There were also a number of unusual things about the bat coronaviruses in the mine. They were abnormally abundant but also there were many different kinds, often causing co-infections of the bats (Ge et al., 2016). Viral co-infections are often more infectious or more pathogenic (Latham and Wilson, 2007).

As the WIV researchers remarked about the bats in the mine:

we observed a high rate of co-infection with two coronavirus species and interspecies infection with the same coronavirus species within or across bat families. These phenomena may be owing to the diversity and high density of bat populations in the same cave, facilitating coronavirus intra- and interspecies transmissions, which may result in recombination and acceleration of coronavirus evolution. (Ge et al., 2016).

The diversity of coronaviruses in the mine suggests that the miners were similarly exposed and that their illness may potentially have begun as co-infections.

Combining these observations, we propose that the miners lungs offered an unprecedented opportunity for accelerated evolution of a highly bat-adapted coronavirus into a highly human-adapted coronavirus and that decades of ordinary coronavirus evolution could easily have been condensed into months. However, we acknowledge that these conditions were unique. They and their scale have no exact scientific precedent we can refer to and they would be hard to replicate in a lab; thus it is important to emphasize that our proposal is fully consistent with the underlying principles of viral evolution as understood today.

In support of the MMP theory we also know something about the samples taken from the miners. According to the Masters thesis, samples were taken from patients for scientific research and blood samples (at least) were sent to the WIV.

In the later stage we worked with Dr. Zhong Nan Shan and did some sampling. The patient* tested positive for serum IgM by the WuHan Institute of Virology. It suggested the existence of virus infection (p62 in the section Comprehensive Analysis.)

(*The original does not specify the number of patients tested.)

The Masters thesis also states its regret that no samples for research were taken from patients 1 and 2, implying that samples were taken from all the others.

We further know that, on June 27th, 2012, the doctors performed an unexplained thymectomy on patient 4. The thymus is an immune organ that can potentially be removed without greatly harming the patient and it could have contained large quantities of virus. Beyond this the Masters thesis is unfortunately unclear on the specifics of what sampling was done, for what purpose, and where each particular sample went.

Given the interests of the Shi lab in zoonotic origins of human disease, once such a sample was sent to them, it would have been obvious and straightforward for them to investigate how a virus from bats had managed to infect these miners. Any viruses recoverable from the miners would likely have been viewed by them as a unique natural experiment in human passaging offering unprecedented and otherwise-impossible-to-obtain insights into how bat coronaviruses can adapt to humans.

The logical course of such research would be to sequence viral RNA extracted directly from unfrozen tissue or blood samples and/or to generate live infectious clones for which it would be useful (if not imperative) to amplify the virus by placing it in human cell culture. Either technique could have led to accidental infection of a lab researcher.

Our supposition as to why there was a time lag between sample collection (in 2012/2013) and the COVID-19 outbreak is that the researchers were awaiting BSL-4 lab construction and certification, which was underway in 2013 but delayed until 2018.

We propose that, when frozen samples derived from the miners were eventually opened in the Wuhan lab they were already highly adapted to humans to an extent possibly not anticipated by the researchers. One small mistake or mechanical breakdown could have led directly to the first human infection in late 2019.

Thus, one of the miners, most likely patient 3, or patient 4 (whose thymus was removed), was effectively patient zero of the COVID-19 epidemic. In this scenario, COVID-19 is not an engineered virus; but, equally, if it had not been taken to Wuhan and no further molecular research had been performed or planned for it then the virus would have died out from natural causes, rather than escaped to initiate the COVID-19 pandemic.

Our proposal is consistent with all the principal undisputed facts concerning SARS-CoV-2 and its origin. The MMP proposal has the additional benefit of reconciling many observations concerning SARS-CoV-2 that have proven difficult to reconcile with any natural zoonotic hypothesis.

For instance, using different approaches, numerous researchers have concluded that the SARS-CoV-2 spike protein has a very high affinity for the human ACE2 receptor (Walls et al., 2020; Piplani et al., 2020; Shang and Ye et al., 2020; Wrapp et al., 2020). Such exceptional affinities, ten to twenty times as great as that of the original SARS virus, do not arise at random, making it very hard to explain in any other way than for the virus to have been strongly selected in the presence of a human ACE2 receptor (Piplani et al., 2020).

In addition to this, a recent report found that the spike of RaTG13 binds the human ACE2 receptor (Shang and Ye et al., 2020). We proposed above that the virus in the mine directly infected humans lung cells. The main determinant of cell infection and species specificity of coronaviruses is initial receptor binding (Perlman and Netland, 2009). Thus RaTG13, unlike most bat coronaviruses, probably can enter and infect human cells, providing biological plausibility to the idea that the miners became infected with a coronavirus resembling RaTG13.

Moreover, the receptor binding domain (RBD) of SARS-CoV-2, which is the region of the spike that physically contacts the human ACE2 receptor, has recently been crystallised to reveal its spatial structure (Shang and Ye et al., 2020). These authors found close structural similarities between the spikes of SARS-CoV-2 and RaTG13 in how they bound the human ACE2 receptor:

Second, as with SARS-CoV-2, bat RaTG13 RBM [a region of the RBD] contains a similar four-residue motif in the ACE2 binding ridge, supporting the notion that SARS-CoV-2 may have evolved from RaTG13 or a RaTG13-related bat coronavirus (Extended Data Table 3 and Extended Data Fig. 7). Third, the L486F, Y493Q and D501N residue changes from RaTG13 to SARS CoV-2 enhance ACE2 recognition and may have facilitated the bat-to-human transmission of SARS-CoV-2 (Extended Data Table 3 and Extended Data Fig. 7). A lysine-to-asparagine mutation at the 479 position in the SARS-CoV-2 RBD (corresponding to the 493 position in the SARS-CoV-2 RBD) enabled SARS-CoV to infect humans. Fourth, Leu455 contributes favourably to ACE2 recognition, and it is conserved between RaTG13 and SARS CoV-2; its presence in the SARS CoV-2 RBM may be important for the bat-to-human transmission of SARS-CoV-2 (Shang and Ye et al., 2020). (italics added)

The significance of this molecular similarity is very great. Coronaviruses have evolved a diverse set of molecular solutions to solve the problem of binding ACE2 (Perlman and Netland, 2009; Forni et al., 2017). The fact that RaTG13 and SARS CoV-2 share the same solution makes RaTG13 a highly likely direct ancestor of Sars-CoV-2.

A further widely noted feature of SARS-CoV-2 is its furin site (Coutard et al., 2020). This site is absent from RaTG13 and other closely related coronaviruses. The most closely related virus with such a site is the highly lethal MERS (which broke out in 2012). Possession of a furin site enables SARS-CoV-2 (like MERS) to infect lungs and many other body tissues (such as the gastrointestinal tract and neurons), explaining much of its lethality (Hoffman et al., 2020; Lamers et al., 2020). However, no convincing explanation for how SARS-CoV-2 acquired this site has yet been offered. Our suggestion is that it arose due to the high selection pressure which existed in the miners lungs and which in general worked to ensure that the virus became highly adapted to the lungs. This explanation, which encompasses how SARS-CoV-2 came to target lung tissues in general, is an important aspect of our proposal.

The implication is therefore that the furin site was not acquired by recombination with another coronavirus and simply represents convergent evolution (as suggested by Andersen et al., 2020).

An intriguing alternative possibility is that SARS-CoV-2 acquired its furin site directly from the miners lungs. Humans possess an epithelial sodium channel protein called ENaC-a whose furin cleavage site is identical over eight amino acids to SARS-CoV-2 (Anand et al., 2020). ENaC-a protein is present in the same airway epithelial and lung tissues infected by SARS-CoV-2. It is known from plants that positive-stranded RNA viruses recombine readily with host mRNAs (Greene and Allison, 1994; Greene and Allison, 1996; Lommel and Xiong, 1991; Borja et al., 2007). The same evidence base is not available for positive-stranded animal RNA viruses, (though see Gorbalenya, 1992) but if plant viruses are a guide then acquisition of its furin site via recombination with the mRNA which encodes ENaC-a by SARS-CoV-2 is a strong possibility.

A further feature of SARS-CoV-2 has been the very limited adaptive evolution of its genome since the pandemic began (Zhan et al., 2020; van Dorp et al., 2020; Starr et al., 2020). It is a well-established principle that viruses that jump species undergo accelerated evolutionary change in their new host (e.g. Baric et al., 1997). Thus, SARS and MERS (both coronaviruses) underwent rapid and readily detectable adaptation to their new human hosts (Forni et al., 2017; Dudas and Rambaut, 2016). Such an adaptation period has not been observed for SARS-CoV-2 even though it has now infected many more individuals than SARS or MERS did. This has even led to suggestions that the SARS-CoV-2 virus had a period of cryptic circulation in humans infections that predated the pandemic (Chaw et al., 2020). The sole mutation consistently observed to accumulate across multiple studies is a D614G substitution in the spike protein (e.g. Korber et al., 2020). The numerically largest analysis of SARS-CoV-2 genomes, however, found no evidence at all for adaptive evolution, even for D614G (van Dorp et al., 2020).

The general observation is therefore that Sars-CoV-2 has remained functionally unchanged or virtually so (except for inconsequential genetic changes) since the pandemic began. This is a very important observation. It implies that SARS-CoV-2 is highly adapted across its whole set of component proteins and not just at the spike (Zhan et al., 2020). That is to say, its evolutionary leap to humans was completed before the 2019 pandemic began.

It is hard to imagine an explanation for this high adaptiveness other than some kind of passaging in a human body (Zhan et al., 2020). Not even passaging in human cells could have achieved such an outcome.

More:
A Proposed Origin for SARS-CoV-2 and the COVID-19 Pandemic - CounterPunch

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Global CRISPR-Based Therapeutics Market 2020 Segmented by Product, Application, Key Players and Regional Analysis to 2025 - Cole of Duty

Nobody knows when the Covid-19 pandemic will come into an end. This unprecedented era surely brings a new world order in every aspect of life. Like other countries, Bangladesh is also facing the harsh attack of the coronavirus. From the richer country to the poorest counterpart, the health management system couldnt work smoothly and our country is also not an exception. Despite limited resources, our front-line Covid-19 fighters e.g. doctors, nurses, medical staff, civil administrations, law enforcement personnel, and others are trying to manage the pandemic. We should give our heartfelt gratitude towards these heroes. Besides this, we would like to point out another pool of front-liners who have worked very silently in Covid-19 situation and they are none but biotechnologists.

Test, Trace, Isolate and Support is the public health intervention in entire Covid-19 management throughout the world. The test increased in the last couple of months enormously comparable to the first two months of the onset of the virus in this country, though test frequency towards one million people is still insignificant. Besides this, the World Health Organization (WHO) recommended Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) Techniques is one of the most sophisticated molecular biology tools where skilled personnel are a must.

Any limitations in the procedure of the test could result in a false positive or negative outcome, which would be very unfortunate for the suspect cases. Containment level of laboratory Covid-19 test includes following issues like the biosafety level of the laboratory, standard sample collection, sample preparation, and analysis of the results as well as troubleshooting in any stage of the procedures. A graduate of the biotechnology discipline with having a master's degree could easily be a great option to tackle the challenge as PCR is routine work in their lab courses and research.

Profound theoretical knowledge with hands-on training turns biotech personnel into a capable workforce for performing the test and leads the managing of the laboratories soundly. A very recent press release from Bangladesh Association of Biotechnology Graduates (BABG) has represented that more than sixty young biotechnology graduates from different universities are working as a voluntary manner as a corona fighter in different testing laboratories. Some of them are directly incorporated in establishing Covid-19 laboratories while some of them are integrated into performing and troubleshooting the tests. Additionally, a pool of expert young biotech graduates is moving throughout the country to train medical staff as well.

Young biotech graduates have accelerated the pace of work of establishing Covid-19 laboratories in their departments in some public universities i.e. Shahjalal University of Science and Technology, University of Chittagong and performing the Covid-19 test very smoothly while they also put tremendous contribution to the other laboratories of the different universities, medical colleges and so on. It should be pointed out that all of them are working in a completely unpaid manner without health insurance or any other incentive guarantee. Some scientific officers who belong to the biotech community are also come forward to contribute to these pandemic situations.

National Institute of Biotechnology (NIB), Bangladesh Council of Scientific and Industrial Research (BCSIR), and some other institutions reveal the genome sequence of SARS-CoV-2, where biotech graduates play a pivotal role in scientific work. Besides this, faculty members of genetic engineering and biotechnology along with young researchers are engaging themselves in research regarding the dynamics of the coronavirus in our country as well as epitope-based vaccine design through in silico approaches. Their research result has been published in a different peer-reviewed journal which also presents the scientific face of Bangladesh. Some others also participated in stay home awareness campaign during this pandemic as well as some others are writing articles for the mass people that could get rid of misinformation.

Though biotech graduates are working from the very beginning of this pandemic, they are not considered as a temporary molecular biologist post in a recent circular which is undoubtedly frustrating. Moreover, genetic engineering and biotechnology graduates are excluded from the list of trained laboratory personnel in a recent press release for the private medical college Covid-19 laboratory containment list. Along with other graduates from life sciences like biochemistry and molecular biology, microbiology, and other subjects, biotechnology graduates are as competent as others.

They have proved their credentials for the last three months. So, biotech graduates should be integrated into the laboratory trained personnel for Covid-19 tests as well as any future appointment in molecular biology or medical biotechnologist post in the recent future. Each year, the country has produced almost eight hundred biotech graduates who could play an essential role in Covid-19 testing as well as management of the pandemic.

BABG has made a volunteer list of biotech graduates who want to put their contribution in Covid-19 testing facilities as other sectors if needed. Besides this, they have made an expert pool of graduates who could be able to train the medical staff and establish biosafety level containment in the laboratories. Covid-19 is a situation that opens all of our eyes to fact that except the combinatorial effect of a multidisciplinary approach, there is no escape. This is not only the issue for the doctors or medical staff but also the trained personnel like biotechnologists, microbiologists and biochemists, and others. An integrated approach could bring a light of hope in coronavirus management in our country.

The writer is Assistant Professor, Department of Genetic Engineering and Biotechnology, Jagannath University. Email: mmhasansohag@geb.jnu.ac.bd

Original post:
Biotech graduates in the time of Covid-19 - theindependentbd.com