UPDATE: JUNE 1, 2021
THE LANCET COVID-19 RESOURCE CENTRE
Origin of Covid — Following the Clues
Did people or nature open Pandora’s box at Wuhan?
The Covid-19 pandemic has disrupted lives the world over for more than a year. Its death toll will soon reach three million people. Yet the origin of pandemic remains uncertain: the political agendas of governments and scientists have generated thick clouds of obfuscation, which the mainstream press seems helpless to dispel.
In what follows I will sort through the available scientific facts, which hold many clues as to what happened, and provide readers with the evidence to make their own judgments. I will then try to assess the complex issue of blame, which starts with, but extends far beyond, the government of China.
By the end of this article, you may have learned a lot about the molecular biology of viruses. I will try to keep this process as painless as possible. But the science cannot be avoided because for now, and probably for a long time hence, it offers the only sure thread through the maze.
The virus that caused the pandemic is known officially as SARS-CoV-2, but can be called SARS2 for short. As many people know, there are two main theories about its origin. One is that it jumped naturally from wildlife to people. The other is that the virus was under study in a lab, from which it escaped. It matters a great deal which is the case if we hope to prevent a second such occurrence.
I’ll describe the two theories, explain why each is plausible, and then ask which provides the better explanation of the available facts. It’s important to note that so far there is no direct evidence for either theory. Each depends on a set of reasonable conjectures but so far lacks proof. So I have only clues, not conclusions, to offer. But those clues point in a specific direction. And having inferred that direction, I’m going to delineate some of the strands in this tangled skein of disaster.
A Tale of Two Theories
After the pandemic first broke out in December 2019, Chinese authorities reported that many cases had occurred in the wet market — a place selling wild animals for meat — in Wuhan. This reminded experts of the SARS1 epidemic of 2002 in which a bat virus had spread first to civets, an animal sold in wet markets, and from civets to people. A similar bat virus caused a second epidemic, known as MERS, in 2012. This time the intermediary host animal was camels.
The decoding of the virus’s genome showed it belonged a viral family known as beta-coronaviruses, to which the SARS1 and MERS viruses also belong. The relationship supported the idea that, like them, it was a natural virus that had managed to jump from bats, via another animal host, to people. The wet market connection, the only other point of similarity with the SARS1 and MERS epidemics, was soon broken: Chinese researchers found earlier cases in Wuhan with no link to the wet market. But that seemed not to matter when so much further evidence in support of natural emergence was expected shortly.
Wuhan, however, is home of the Wuhan Institute of Virology, a leading world center for research on coronaviruses. So the possibility that the SARS2 virus had escaped from the lab could not be ruled out. Two reasonable scenarios of origin were on the table.
From early on, public and media perceptions were shaped in favor of the natural emergence scenario by strong statements from two scientific groups. These statements were not at first examined as critically as they should have been.
“We stand together to strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin,” a group of virologists and others wrote in the Lancet on February 19, 2020, when it was really far too soon for anyone to be sure what had happened. Scientists “overwhelmingly conclude that this coronavirus originated in wildlife,” they said, with a stirring rallying call for readers to stand with Chinese colleagues on the frontline of fighting the disease.
Contrary to the letter writers’ assertion, the idea that the virus might have escaped from a lab invoked accident, not conspiracy. It surely needed to be explored, not rejected out of hand. A defining mark of good scientists is that they go to great pains to distinguish between what they know and what they don’t know. By this criterion, the signatories of the Lancet letter were behaving as poor scientists: they were assuring the public of facts they could not know for sure were true.
It later turned out that the Lancet letter had been organized and drafted by Peter Daszak, president of the EcoHealth Alliance of New York. Dr. Daszak’s organization funded coronavirus research at the Wuhan Institute of Virology. If the SARS2 virus had indeed escaped from research he funded, Dr. Daszak would be potentially culpable. This acute conflict of interest was not declared to the Lancet’s readers. To the contrary, the letter concluded, “We declare no competing interests.”
Peter Daszak, president of the EcoHealth Alliance
Virologists like Dr. Daszak had much at stake in the assigning of blame for the pandemic. For 20 years, mostly beneath the public’s attention, they had been playing a dangerous game. In their laboratories they routinely created viruses more dangerous than those that exist in nature. They argued they could do so safely, and that by getting ahead of nature they could predict and prevent natural “spillovers,” the cross-over of viruses from an animal host to people. If SARS2 had indeed escaped from such a laboratory experiment, a savage blowback could be expected, and the storm of public indignation would affect virologists everywhere, not just in China. “It would shatter the scientific edifice top to bottom,” an MIT Technology Review editor, Antonio Regalado, said in March 2020. A second statement which had enormous influence in shaping public attitudes was a letter (in other words an opinion piece, not a scientific article) published on 17 March 2020 in the journal Nature Medicine. Its authors were a group of virologists led by Kristian G. Andersen of the Scripps Research Institute. “Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus,” the five virologists declared in the second paragraph of their letter.
Kristian G. Andersen, Scripps Research
Unfortunately this was another case of poor science, in the sense defined above. True, some older methods of cutting and pasting viral genomes retain tell-tale signs of manipulation. But newer methods, called “no-see-um” or “seamless” approaches, leave no defining marks. Nor do other methods for manipulating viruses such as serial passage, the repeated transfer of viruses from one culture of cells to another. If a virus has been manipulated, whether with a seamless method or by serial passage, there is no way of knowing that this is the case. Dr. Andersen and his colleagues were assuring their readers of something they could not know.
The discussion part their letter begins, “It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus”. But wait, didn’t the lead say the virus had clearly not been manipulated? The authors’ degree of certainty seemed to slip several notches when it came to laying out their reasoning.
The reason for the slippage is clear once the technical language has been penetrated. The two reasons the authors give for supposing manipulation to be improbable are decidedly inconclusive.
First, they say that the spike protein of SARS2 binds very well to its target, the human ACE2 receptor, but does so in a different way from that which physical calculations suggest would be the best fit. Therefore the virus must have arisen by natural selection, not manipulation.
If this argument seems hard to grasp, it’s because it’s so strained. The authors’ basic assumption, not spelt out, is that anyone trying to make a bat virus bind to human cells could do so in only one way. First they would calculate the strongest possible fit between the human ACE2 receptor and the spike protein with which the virus latches onto it. They would then design the spike protein accordingly (by selecting the right string of amino acid units that compose it). But since the SARS2 spike protein is not of this calculated best design, the Andersen paper says, therefore it can’t have been manipulated.
But this ignores the way that virologists do in fact get spike proteins to bind to chosen targets, which is not by calculation but by splicing in spike protein genes from other viruses or by serial passage. With serial passage, each time the virus’s progeny are transferred to new cell cultures or animals, the more successful are selected until one emerges that makes a really tight bind to human cells. Natural selection has done all the heavy lifting. The Andersen paper’s speculation about designing a viral spike protein through calculation has no bearing on whether or not the virus was manipulated by one of the other two methods.
The authors’ second argument against manipulation is even more contrived. Although most living things use DNA as their hereditary material, a number of viruses use RNA, DNA’s close chemical cousin. But RNA is difficult to manipulate, so researchers working on coronaviruses, which are RNA-based, will first convert the RNA genome to DNA. They manipulate the DNA version, whether by adding or altering genes, and then arrange for the manipulated DNA genome to be converted back into infectious RNA.
Only a certain number of these DNA backbones have been described in the scientific literature. Anyone manipulating the SARS2 virus “would probably” have used one of these known backbones, the Andersen group writes, and since SARS2 is not derived from any of them, therefore it was not manipulated. But the argument is conspicuously inconclusive. DNA backbones are quite easy to make, so it’s obviously possible that SARS2 was manipulated using an unpublished DNA backbone.
And that’s it. These are the two arguments made by the Andersen group in support of their declaration that the SARS2 virus was clearly not manipulated. And this conclusion, grounded in nothing but two inconclusive speculations, convinced the world’s press that SARS2 could not have escaped from a lab. A technical critique of the Andersen letter takes it down in harsher words.
Science is supposedly a self-correcting community of experts who constantly check each other’s work. So why didn’t other virologists point out that the Andersen group’s argument was full of absurdly large holes? Perhaps because in today’s universities speech can be very costly. Careers can be destroyed for stepping out of line. Any virologist who challenges the community’s declared view risks having his next grant application turned down by the panel of fellow virologists that advises the government grant distribution agency.
The Daszak and Andersen letters were really political, not scientific statements, yet were amazingly effective. Articles in the mainstream press repeatedly stated that a consensus of experts had ruled lab escape out of the question or extremely unlikely. Their authors relied for the most part on the Daszak and Andersen letters, failing to understand the yawning gaps in their arguments. Mainstream newspapers all have science journalists on their staff, as do the major networks, and these specialist reporters are supposed to be able to question scientists and check their assertions. But the Daszak and Andersen assertions went largely unchallenged.
Doubts about natural emergence
Natural emergence was the media’s preferred theory until around February 2021 and the visit by a World Health Organization commission to China. The commission’s composition and access were heavily controlled by the Chinese authorities. Its members, who included the ubiquitous Dr. Daszak, kept asserting before, during and after their visit that lab escape was extremely unlikely. But this was not quite the propaganda victory the Chinese authorities may have been hoping for. What became clear was that the Chinese had no evidence to offer the commission in support of the natural emergence theory.
This was surprising because both the SARS1 and MERS viruses had left copious traces in the environment. The intermediary host species of SARS1 was identified within four months of the epidemic’s outbreak, and the host of MERS within nine months. Yet some 15 months after the SARS2 pandemic began, and a presumably intensive search, Chinese researchers had failed to find either the original bat population, or the intermediate species to which SARS2 might have jumped, or any serological evidence that any Chinese population, including that of Wuhan, had ever been exposed to the virus prior to December 2019. Natural emergence remained a conjecture which, however plausible to begin with, had gained not a shred of supporting evidence in over a year.
And as long as that remains the case, it’s logical to pay serious attention to the alternative conjecture, that SARS2 escaped from a lab.
Why would anyone want to create a novel virus capable of causing a pandemic? Ever since virologists gained the tools for manipulating a virus’s genes, they have argued they could get ahead of a potential pandemic by exploring how close a given animal virus might be to making the jump to humans. And that justified lab experiments in enhancing the ability of dangerous animal viruses to infect people, virologists asserted.
With this rationale, they have recreated the 1918 flu virus, shown how the almost extinct polio virus can be synthesized from its published DNA sequence, and introduced a smallpox gene into a related virus.
These enhancements of viral capabilities are known blandly as gain-of-function experiments. With coronaviruses, there was particular interest in the spike proteins, which jut out all around the spherical surface of the virus and pretty much determine which species of animal it will target. In 2000 Dutch researchers, for instance, earned the gratitude of rodents everywhere by genetically engineering the spike protein of a mouse coronavirus so that it would attack only cats.
The spike proteins on the coronavirus’s surface determine which animal it can infect. CDC.gov
Virologists started studying bat coronaviruses in earnest after these turned out to be the source of both the SARS1 and MERS epidemics. In particular, researchers wanted to understand what changes needed to occur in a bat virus’s spike proteins before it could infect people.
Researchers at the Wuhan Institute of Virology, led by China’s leading expert on bat viruses, Dr. Shi Zheng-li or “Bat Lady”, mounted frequent expeditions to the bat-infested caves of Yunnan in southern China and collected around a hundred different bat coronaviruses.
Dr. Shi then teamed up with Ralph S. Baric, an eminent coronavirus researcher at the University of North Carolina. Their work focused on enhancing the ability of bat viruses to attack humans so as to “examine the emergence potential (that is, the potential to infect humans) of circulating bat CoVs [coronaviruses].” In pursuit of this aim, in November 2015 they created a novel virus by taking the backbone of the SARS1 virus and replacing its spike protein with one from a bat virus (known as SHC014-CoV). This manufactured virus was able to infect the cells of the human airway, at least when tested against a lab culture of such cells.
The SHC014-CoV/SARS1 virus is known as a chimera because its genome contains genetic material from two strains of virus. If the SARS2 virus were to have been cooked up in Dr. Shi’s lab, then its direct prototype would have been the SHC014-CoV/SARS1 chimera, the potential danger of which concerned many observers and prompted intense discussion.
“If the virus escaped, nobody could predict the trajectory,” said Simon Wain-Hobson, a virologist at the Pasteur Institute in Paris.
Dr. Baric and Dr. Shi referred to the obvious risks in their paper but argued they should be weighed against the benefit of foreshadowing future spillovers. Scientific review panels, they wrote, “may deem similar studies building chimeric viruses based on circulating strains too risky to pursue.” Given various restrictions being placed on gain-of function (GOF) research, matters had arrived in their view at “a crossroads of GOF research concerns; the potential to prepare for and mitigate future outbreaks must be weighed against the risk of creating more dangerous pathogens. In developing policies moving forward, it is important to consider the value of the data generated by these studies and whether these types of chimeric virus studies warrant further investigation versus the inherent risks involved.”
That statement was made in 2015. From the hindsight of 2021, one can say that the value of gain-of-function studies in preventing the SARS2 epidemic was zero. The risk was catastrophic, if indeed the SARS2 virus was generated in a gain-of-function experiment.
Inside the Wuhan Institute of Virology
Dr. Baric had developed, and taught Dr. Shi, a general method for engineering bat coronaviruses to attack other species. The specific targets were human cells grown in cultures and humanized mice. These laboratory mice, a cheap and ethical stand-in for human subjects, are genetically engineered to carry the human version of a protein called ACE2 that studs the surface of cells that line the airways.
Dr. Shi returned to her lab at the Wuhan Institute of Virology and resumed the work she had started on genetically engineering coronaviruses to attack human cells.
Dr. Zheng-li Shi in a high safety (level BSL4) lab. Her coronavirus research was done in the much lower safety levels of BSL2 and BSL3 labs.
How can we be so sure?
Because, by a strange twist in the story, her work was funded by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the U.S. National Institutes of Health (NIH). And grant proposals that funded her work, which are a matter of public record, specify exactly what she planned to do with the money.
The grants were assigned to the prime contractor, Dr. Daszak of the EcoHealth Alliance, who subcontracted them to Dr. Shi. Here are extracts from the grants for fiscal years 2018 and 2019. “CoV” stands for coronavirus and “S protein” refers to the virus’s spike protein.
“Test predictions of CoV inter-species transmission. Predictive models of host range (i.e. emergence potential) will be tested experimentally using reverse genetics, pseudovirus and receptor binding assays, and virus infection experiments across a range of cell cultures from different species and humanized mice.”
“We will use S protein sequence data, infectious clone technology, in vitro and in vivo infection experiments and analysis of receptor binding to test the hypothesis that % divergence thresholds in S protein sequences predict spillover potential.”
What this means, in non-technical language, is that Dr. Shi set out to create novel coronaviruses with the highest possible infectivity for human cells. Her plan was to take genes that coded for spike proteins possessing a variety of measured affinities for human cells, ranging from high to low. She would insert these spike genes one by one into the backbone of a number of viral genomes (“reverse genetics” and “infectious clone technology”), creating a series of chimeric viruses. These chimeric viruses would then be tested for their ability to attack human cell cultures (“in vitro”) and humanized mice (“in vivo”). And this information would help predict the likelihood of “spillover,” the jump of a coronavirus from bats to people.
The methodical approach was designed to find the best combination of coronavirus backbone and spike protein for infecting human cells. The approach could have generated SARS2-like viruses, and indeed may have created the SARS2 virus itself with the right combination of virus backbone and spike protein.
It cannot yet be stated that Dr. Shi did or did not generate SARS2 in her lab because her records have been sealed, but it seems she was certainly on the right track to have done so. “It is clear that the Wuhan Institute of Virology was systematically constructing novel chimeric coronaviruses and was assessing their ability to infect human cells and human-ACE2-expressing mice,” says Richard H. Ebright, a molecular biologist at Rutgers University and leading expert on biosafety.
“It is also clear,” Dr. Ebright said, “that, depending on the constant genomic contexts chosen for analysis, this work could have produced SARS-CoV-2 or a proximal progenitor of SARS-CoV-2.” “Genomic context” refers to the particular viral backbone used as the testbed for the spike protein.
The lab escape scenario for the origin of the SARS2 virus, as should by now be evident, is not mere hand-waving in the direction of the Wuhan Institute of Virology. It is a detailed proposal, based on the specific project being funded there by the NIAID.
Even if the grant required the work plan described above, how can we be sure that the plan was in fact carried out? For that we can rely on the word of Dr. Daszak, who has been much protesting for the last 15 months that lab escape was a ludicrous conspiracy theory invented by China-bashers.
On 9 December 2019, before the outbreak of the pandemic became generally known, Dr. Daszak gave an interview in which he talked in glowing terms of how researchers at the Wuhan Institute of Virology had been reprogramming the spike protein and generating chimeric coronaviruses capable of infecting humanized mice.
“And we have now found, you know, after 6 or 7 years of doing this, over 100 new sars-related coronaviruses, very close to SARS,” Dr. Daszak says around minute 28 of the interview. “Some of them get into human cells in the lab, some of them can cause SARS disease in humanized mice models and are untreatable with therapeutic monoclonals and you can’t vaccinate against them with a vaccine. So, these are a clear and present danger….
“Interviewer: You say these are diverse coronaviruses and you can’t vaccinate against them, and no anti-virals — so what do we do?
“Daszak: Well I think…coronaviruses — you can manipulate them in the lab pretty easily. Spike protein drives a lot of what happen with coronavirus, in zoonotic risk. So you can get the sequence, you can build the protein, and we work a lot with Ralph Baric at UNC to do this. Insert into the backbone of another virus and do some work in the lab. So you can get more predictive when you find a sequence. You’ve got this diversity. Now the logical progression for vaccines is, if you are going to develop a vaccine for SARS, people are going to use pandemic SARS, but let’s insert some of these other things and get a better vaccine.” The insertions he referred to perhaps included an element called the furin cleavage site, discussed below, which greatly increases viral infectivity for human cells.
In disjointed style, Dr. Daszak is referring to the fact that once you have generated a novel coronavirus that can attack human cells, you can take the spike protein and make it the basis for a vaccine.
One can only imagine Dr. Daszak’s reaction when he heard of the outbreak of the epidemic in Wuhan a few days later. He would have known better than anyone the Wuhan Institute’s goal of making bat coronaviruses infectious to humans, as well as the weaknesses in the institute’s defense against their own researchers becoming infected. But instead of providing public health authorities with the plentiful information at his disposal, he immediately launched a public relations campaign to persuade the world that the epidemic couldn’t possibly have been caused by one of the institute’s souped-up viruses. “The idea that this virus escaped from a lab is just pure baloney. It’s simply not true,” he declared in an April 2020 interview.
The Safety Arrangements at the Wuhan Institute of Virology
Dr. Daszak was possibly unaware of, or perhaps he knew all too well, the long history of viruses escaping from even the best run laboratories. The smallpox virus escaped three times from labs in England in the 1960’s and 1970’s, causing 80 cases and 3 deaths. Dangerous viruses have leaked out of labs almost every year since. Coming to more recent times, the SARS1 virus has proved a true escape artist, leaking from laboratories in Singapore, Taiwan, and no less than four times from the Chinese National Institute of Virology in Beijing.
One reason for SARS1 being so hard to handle is that there were no vaccines available to protect laboratory workers. As Dr. Daszak mentioned in his December 19 interview quoted above, the Wuhan researchers too had been unable to develop vaccines against the coronaviruses they had designed to infect human cells. They would have been as defenseless against the SARS2 virus, if it were generated in their lab, as their Beijing colleagues were against SARS1.
The status of the COVID19 pandemic is changing rapidly due to the global response to control of the virus. In the following paragraphs, and figures are listed the significant changes which have taken place in the last 30 days.
GLOBAL DEATHS/GLOBAL CASES/CASE FATALITY RATES
Globally there are now 114 million cases reported, and 2.5 million deaths. Listed below are the top five countries in cases reported, and deaths.
US: 28.5 million cases, 510,900 deaths, 156.5/100K, CFR=1.8%
Brazil: 10.5 million cases, 254,492 deaths, 121.7/100K, CFR=2.4%
Mexico: 2 million cases, 185,715 deaths, 147.2/100K, CFR=8.9%
India: 11.1 million cases, 157,157 deaths, 11.6/100K, CFR=1.4%
UK: 4.1 million cases, 122,849 deaths, 4.1/100K, CFR=2.9%
Italy: 2.9 million cases, 97,699 deaths, 161/100K, CFR= 3.3
In the US cases, and deaths have been stable or falling since the end of February. The initiation of the US vaccination campaign has coincided with a significant reduction in COVID19 cases, deaths, and hospitalizations.
US VACCINATION PROGRAM & NEW J&J/JANSEN VACCINE
The J&J experimental vaccine received FDA Emergency Use Authorization (EUA) this past weekend. Four million doses were shipped out last week with an additional 16 million doses available by the end of March. The new vaccine uses technology J&J employed with its FDA-approved EBOLA vaccine, and similar technology is used in their Zika, RSV, and HIV vaccination programs.
Briefly, their approach uses a harmless human Adenovirus to shuttle into human cells the DNA necessary to have the cells make the COVID19 spike protein. Hence, like the Pfizer, and Moderna vaccines, the S protein is again used to stimulate the production of immunizing antibodies.
The new vaccine has two key advantages over the other two experimental vaccines. First, it requires a single dose, and second it is much easier to store. Since it is less fragile than the mRNA vaccines, it can be stored at 36-46 F (2-8 C). However, its effectiveness was only 70%, but it reduced severe COVID by 85%, and was 100% effective in preventing death. In addition, it prevented moderate to severe disease by 64% with the South African COVID19 mutant.
Currently the US is doing approximately 1.5 million vaccinations per day with 96 million doses delivered, and 76.8 million doses administered. The US now has 51million people vaccinated or 15.5% of the population vaccinated. Our best estimates for reaching herd immunity are between 70-90% of the population vaccinated. Some experts believe 55% of our population has natural immunity to COVID19, and if that is true herd immunity could be reached by the end of April. Unfortunately, Dr. No It All (aka Dr. Fauci) says it will take the entire summer.
In summary, in the last thirty days we have seen many encouraging trends, and with a third experimental receiving EUA-approval by FDA there is every reason to believe these trends will continue or even accelerate.
P.S. Next month the COVID19 mutants will be explored ! Stay tuned