The Covid-19 pandemic: Failure to predict, failure to report. Part Three -- Who wants to talk about the giant furin cleavage site in the room? [Updated]

Among "SARS-like viruses," only SARS-CoV-2 has a short genetic segment, the FCS, that makes it particularly infectious to humans. How did it get there? Some want to talk about it, some don't.

Of all the SARS-like viruses known, of which this is only a sampling, only SARS-CoV-2 (here ID’d by its original name, Wuhan-Hu-1) has a furin cleavage site. (From AJ Chan and SH Zhan, Mol Biol Evol)

In early January 2020, shortly after the world became aware that a dangerous virus had emerged out of Wuhan, a team of Chinese researchers led by Yong-Zhen Zhang of Fudan University in Shanhai first unveiled a draft of its genome sequence. Less than three weeks later, the Chinese team, joined by a British scientist based in Australia, formally published the sequence in Nature, along with commentary on its features.

Shortly afterwards, a second team, led by Shi Zhengli of the Wuhan Institute of Virology, published its own sequence and description of the virus, also in Nature.

The new virus, both groups found, was closely related to SARS-CoV, a member of the subgenus Sarbecovirus and the pathogen that had caused a worldwide outbreak of SARS in 2002-4. And like that of the SARS virus, the so-called receptor binding domain of its spike protein could bind to ACE2, a receptor on human cells used by both SARS-CoV and SARS-CoV-2 to enter them.

There was one omission in the reports on the sequence, however, which soon struck some scientists as very odd. The sequence showed clearly that SARS-CoV-2 has a short genetic segment called a furin cleavage site (FCS) in its spike protein, which makes it much more infectious—and dangerous—to human cells. (For an explanation of how the FCS works and why it is important to Covid-19 pathogenesis, see this among other good explanations.) The SARS virus, SARS-CoV, does not have it, nor do any other viruses often called “SARS-like” and which can infect humans and animals. However, many other coronaviruses do have similar sites, as well as the HIV and influenza viruses.

The omission by Shi Zhengli’s team, which actually had the sequence first although it was later getting to press, was particularly puzzling, because that group was well poised scientifically to spot features like the FCS. (Indeed, some would later accuse Shi of deliberately failing to mention the FCS, although there is no direct evidence for that.)

[Note: The above paragraphs have been modified to clarify certain details]

While the Chinese teams did not mention the FCS in SARS-CoV-2 in their Nature papers, others were quick to notice it. By January-February 2020, two other teams had already published on its unusual presence and possible significance. But for the first year of the pandemic, there was very little talk—at least, nor publicly—about how the FCS actually got there. A lot of the reason for that, as I have discussed in previous posts about the Covid origins debate, is that even speculations about the possibility that the Covid virus was the result of genetic engineering combined with some kind of lab leak were branded as “conspiracy theories” and labeled “disinformation” by many social media outlets, influential scientists, and mainstream journalists (including science journalists, who had the greatest responsibility for investigating any issues about the pandemic’s origins.)

It’s hard to be sure when the FCS first came back under the public spotlight, but many date it to a long article by former New York Times science writer Nicholas Wade in The Bulletin of the Atomic Scientists. The article, published in May 2021, quoted famed biologist and Nobel laureate David Baltimore, in the context of a lengthy section about FCS and what it might mean for Covid origins. I’m going to quote that excerpt in full (the quote was added to the online version of the story after it was first published):

“When I first saw the furin cleavage site in the viral sequence, with its arginine codons, I said to my wife it was the smoking gun for the origin of the virus,” said David Baltimore, an eminent virologist and former president of CalTech. “These features make a powerful challenge to the idea of a natural origin for SARS2,” he said.

After controversy broke out over his comments, Baltimore, the following month, elaborated on his views in a longer interview for the Bulletin. In that interview, he made an error that some natural origins proponents would make quite a big deal of later (see below.) Baltimore said that SARS-CoV-2 was the only betacoronavirus that had the FCS, confusing that larger group of coronaviruses with the smaller Sarbecovirus subgenus that SARS-CoV-2 is part of. But he did modify his original statement, making clear that he no longer thought the FCS was a smoking gun, and that both of the two leading hypotheses for the origins of Covid-19 remained on the table.

Not long afterwards, various groups of scientists began to publish on the meaning of the FCS for Covid origins. Representative papers were authored by Alina Chan of the Broad Institute in Cambridge, MA (coauthor of the book “Viral”) and Shing Hei Zhan in the journal Molecular Biology and Evolution, and in the Proceedings of the National Academy of Sciences by virologist Robert Garry of Tulane University. I will refer readers to them (and there are many others) to get contrasting perspectives on whether the FCS might have been genetically engineered into a SARS-like viral backbone—say, at the Wuhan Institute of Virology WIV)—and then leaked out to cause a pandemic.

But then something happened that scientists and journalists alike should have taken serious note of, but in most cases did not. It turned out that researchers at the WIV, in collaboration with American scientists, wanted to and intended to insert furin cleavage sites into SARS-like viruses. We know that from their own words.

Drastic and the DEFUSE proposal to DARPA

On September 23, 2021, The Intercept broke the story that scientists from the WIV (including the famous “Batwoman” Shi Zhengli), the EcoHealth Alliance (led by Peter Daszak), and the lab of virologist Ralph Baric at the University of Carolina, had, three years earlier, submitted a grant proposal to the Defense Advanced Research Projects Agency (DARPA.) The big news was right in the first paragraph:

“Among the scientific tasks the group described in its proposal, which was rejected by DARPA, was the creation of full-length infectious clones of bat SARS-related coronaviruses and the insertion of a tiny part of the virus known as a “proteolytic cleavage site” into bat coronaviruses. Of particular interest was a type of cleavage site able to interact with furin, an enzyme expressed in human cells.”

The document was leaked to a dissident group of scientists and investigators known as DRASTIC, which has worked tirelessly to keep the lab origins hypothesis alive in the face of severe social and political pressure to suppress it. We will talk later about what the rejection of the grant proposal by DARPA (apparently on safety grounds) may or may not mean for the Covid origins debate, and how the news media has handled that question. But for many scientists and journalists still willing to consider a lab origin for the pandemic despite the huge pressures against taking that view, it was a game-changer. The article’s authors, Sharon Lerner and Maia Hibbett, quoted Alina Chan among others:

“Some kind of threshold has been crossed,” said Alina Chan, a Boston-based scientist and co-author of the upcoming book “Viral: The Search for the Origin of Covid-19.” Chan has been vocal about the need to thoroughly investigate the possibility that SARS-CoV-2 emerged from a lab while remaining open to both possible theories of its development. For Chan, the revelation from the proposal was the description of the insertion of a novel furin cleavage site into bat coronaviruses — something people previously speculated, but had no evidence, may have happened.

Indeed, Chan has said many times since that the DARPA proposal, funded or not, is a critical piece of the puzzle of Covid-19 origins. That’s because it shows that the key researchers involved the study of coronaviruses—especially SARS-like viruses—wanted to insert FCS’s into SARS-like backbones and actually had the intention to do it. I have said myself, many times on social media, that the day The Intercept broke this story, legacy mainstream media like the New York Times and the Washington Post should have assigned investigative teams to the Covid origins story.

But that’s not what happened. In fact, something very different happened. The mainstream news media did everything it could to avoid the story and its possible significance, and continues to do so today. An example: New York Times science writer Carl Zimmer, who has done a number of stories on Covid origins, discussed the furin cleavage site extensively in a July 15, 2022 story, focusing on its possible significance for how the virus may have jumped from animals to humans—but made no mention whatsoever of the DARPA proposal and very quickly dismissed the role the FCS plays in the lab-leak hypothesis for Covid origins. (I had to read this story twice to really believe it; you should too.)

Zimmer’s story is an example of the strong tendency, among both scientists and science journalists, towards clear bias, and in some cases blatant dishonesty, in the way the issues poised by the FCS and the DARPA proposal have been addressed. I will discuss some more egregious examples below.

Does parsimony favor a lab origin for the FCS in SARS-CoV-2?

As I have stated many times, in this newsletter and on social media, I do not personally have an opinion on which of the two leading hypotheses for Covid origins is correct. That’s simply because I do not think there is any direct evidence for either one. There is lots of circumstantial evidence, some pointing one way and some the other, but no smoking guns. Who knows if there ever will be.

But I do share the frustration of lab-leak proponents that their hypothesis is unfairly treated among both scientists and the media. There are many examples of that, but the failure to report on the DARPA proposal is a glaring one.

That’s because there is nothing outlandish, “fringe,” or “conspiratorial” about the lab-leak hypothesis. In my view, all attempts to brand it that way are patently dishonest. Moreover, all statements that the natural origins hypothesis carries the greatest weight of the evidence are unsupported by actual facts, as I argued in a recent two-part post. We know for a fact that the Wuhan institute was genetically engineering SARS-like viruses, inserting new genetic segments into them, testing them on mice “humanized” with virus receptors normally found in people, and so forth. And they had been doing it for many years. We also know that the Wuhan lab and its collaborators WANTED to insert FCS’s into SARS-like viruses to study their properties. More on that in a moment. Finally, we know that there have been many lab accidents (SARS escaped from Chinese labs and caused outbreaks a number of times in the 2000s) over the years, and that they are not really rare events as much as we might hope they would be.

Alex Washburne, a scientist who was featured in the posts linked to above, published an excellent essay on the origins debate recently on his Substack newsletter, entitled “The Totality of the Circumstances surrounding SARS-CoV-2 emergence.” I highly recommend it because Alex has penned a persuasive and elegant argument for why he thinks the lab-leak hypothesis is not only more likely, but makes more sense in terms of the classic scientific principle of parsimony (also known as Occam’s Razor)—the simplest explanation, with the fewest complications and moving parts, is the best.

Of course, we can’t apply that principle too strictly, as some try to do, because obviously the more complicated, convoluted explanation sometimes ends up being the right one. For that reason, parsimony is not proof, nor is it a final argument. But let me quote two passages concerning the DARPA proposal and the furin cleavage site:

The motives and intentions to create such a virus did not die with the rejection of DEFUSE. While not funded by DARPA, similar research proposals were funded by NIAID and others prior to and during the emergence of SARS-CoV-2, and may easily have provided enough discretionary funding to support the inexpensive research proposed in DEFUSE. The DEFUSE grant is the letter proposing the crime: catch wild bat coronaviruses, send them to Wuhan, assemble infectious clones in vitro with a specific method, swap Spike genes and add Furin cleavage sites, all to find an extremely human-infectious coronavirus against which we could produce vaccines.

and

In the context of the DEFUSE grant and a Wuhan emergence lacking the geographic fingerprint of an animal trade outbreak, the human-specific FCS of SARS-CoV-2 is not an independent piece of evidence with an unquantifiable probability of occurring in nature. To call the first ever FCS in a sarbecovirus an independent piece of evidence would be like calling a silver bullet independent of both the gun and the letter proposing to use a silver bullet in that exact gun. Under a zoonotic origin theory, the FCS is an astonishingly low-probability event that is independent of the Wuhan origin and independent of the DEFUSE grant. Under the most compelling lab origin theory, these pieces of evidence are all dependent by being so clearly linked to a well-defined research program.

In my view, this explains why scientists and science journalists have such problems with the FCS and the solid evidence for plans to genetically engineer it into a SARS-like virus. To even admit that this was going on is to give so much ammunition to the lab-leak side that they might just walk away with the argument. To some extent, they are: Polls consistently show the majority of Americans think the pandemic started in a lab in China.

What is the obligation of scientists and science journalists to be intellectually honest?

First let’s look at the behavior of some scientists when faced with the DARPA proposal. Last year, not long after the DARPA proposal was revealed, the editor of Science, H. Holden Thorp, published an editoral in which he cited it as an example of how scientists sometimes engage in “Self-inflicted wounds.”

Holden wrote:

How the furin cleavage site wound up in the virus is a focus of debate over the origins of the pandemic. Never mind that the experiments, which hardly posed a threat, were not conducted and were proposed by UNC scientists.

As I pointed out in my own commentary on his editorial, Holden gave no evidence for his statement that the experiments had not been done, nor has he done so despite myself and other asking him repeatedly to provide that evidence. Nor, of course, could he really know, especially if the FCS insertions were done in China. Indeed, the Wuhan Institute of Virology recently lost its NIH funding precisely because they refuse to tell the agency what they did with the money they were given through a sub-grant with Peter Daszak’s EcoHealth Alliance. (Amazingly and disgracefully, virtually all mainstream media have ignored this very big story, which bears directly on how forthright the WIV and Chinese officials have been about what went on in their labs.)

So, is Holden lying about what he knows, bullshitting us and pretending that he knows, thinks he knows, gaslighting us into thinking he knows—dear reader, take your choice.

More recently, the same stunt was pulled by two scientists closely identified with the natural origins hypothesis, Michael Worobey and Angela Rasmussen, both of whom have figured in these posts and my social media output. In a September 2022 piece in Foreign Policy, the pair briefly discuss the DARPA proposal as follows:

Despite having no scientific expertise on the matter, [Jeffrey] Sachs authored an opinion piece in the Proceedings of the National Academy of Sciences, making the unsupported claim that this part of the viral genome, called the furin cleavage site, was “a deliberate introduction,” citing an unfunded grant proposal from researchers at EcoHealth Alliance, the University of North Carolina at Chapel Hill, and WIV, describing work that was likely never performed. Furin cleavage sites have evolved naturally in multiple coronaviruses, including two that cause the common cold.

“…Describing work that was likely never performed.” Not only is that statement unsupported in this piece, but Worobey has failed to respond to numerous public and private requests from me to provide the evidence for it. Again, deliberate lying, stretching the truth, putting it out there and hoping for the best? In my view, and I think many others will agree, this is unacceptable.

It’s especially unacceptable because there are reasons to think that Shi Zhengli herself may be lying about whether the FCS work was done. In a Twitter exchange with Science reporter Jon Cohen, an old colleague from my own days at the journal, Jon said this:

Here Jon is quoting Shi Zhengli from an interview he had done with her. She denies the FCS experiments, but goes on to make a statement—that such work was not within her “expertise,” and thus presumably not within the expertise of the WIV—that many scientists have told me cannot possibly be true. In fact, Shi’s own published record demonstrates that her lab was fully capable of doing the kind of genetic engineering of viruses necessary to insert an FCS. I have even been told that any virology lab worth its salt can do this; the WIV is the leading bat coronavirus lab in the world.

(One might think that Jon Cohen would have done his own investigation into whether Shi Zhengli was telling the truth, and what her possible lying might imply, but there are no signs yet that he has.)

Another journalist who has done extensive interviews with Shi Zhengli is Jane Qiu, a Beijing based journalist who has profiled her twice, once in Scientific American and more recently in Technology Review. After Jane published the second story, I criticized her for not asking Shi about the burning question of the FCS and what her lab had done. Here are the highlights of our exchange (Alina Chan was also in the conversation):

So I was hopeful that Jane, if she had asked the right questions, would let us know what Shi had said about this. But here is what we got instead:

Several others also asked Jane about what Shi had said, but Jane has never told us. Instead the question was deemed “not important.”

In case anyone thinks I am picking on Jane (we do need journalists in China to help get to the bottom of the origins debate), let me close with another remarkable example of journalistic malfeasance on this story.

Last month, Jane wrote a piece for the Pulitzer Center entitled “Journalistic Objectivity and the origins of Covid-19: A dispatch from the front lines.” The first half of the article is a pretty good exploration of the struggles modern journalism is having with notions of “objectivity,” fairness, and balance. Then Jane suddenly switches and gives an example of how journalism can go wrong, that of David Baltimore in Nicholas Wade’s piece in the Bulletin. I think it best to quote the entire excerpt:

The article, for instance, included a sensational quote from David Baltimore—an expert on viruses that can cause cancer for which he won the Nobel Prize for Physiology or Medicine in 1975—saying that a seemingly peculiar genetic feature of SARS-CoV-2, known as the furin cleavage site, was “the smoking gun” that makes “a powerful challenge” to the natural-origins theory. This, as Wade insinuated, is evidence that the virus was engineered in the Wuhan lab.

Baltimore, however, was wrong. Many contagious pathogens—including some coronaviruses and influenza viruses—have naturally evolved this type of genetic feature because it gives them an evolutionary advantage by making them more infectious. The episode offers a good example of how journalism can go wrong—when journalists do not critically evaluate what’s said but pay more attention to who said it.

We’ve already discussed Baltimore’s error, and how it does not necessarily detract from his main point. But does Jane tell readers about the DARPA proposal, which was revealed six months after Wade’s story, to provide us with necessary context for understanding the debate over the FCS and why it is so important?

She does not. I’ve been a journalist for 44 years, and I can tell you this is one of the worst pieces of journalistic dishonesty and malpractice I have ever seen. Jane knew full well the importance of the FCS in the origins debate and had discussed it with others (including me of course) directly, not that long before her Pulitzer piece. But it was an inconvenient fact, one that interfered with her narrative, so she left it out.

We need to get to the bottom of the pandemic’s origins, so we can prevent future ones. Everyone agrees on that in principle. But to do that takes honesty and integrity from both scientists and science journalists, who are responsible for making sure the public is properly informed. If I am accusing some colleagues of dishonesty, which I obviously am, let them come forward and explain themselves.

Meanwhile, the search for the truth behind this murderous pandemic goes on.