A proximal witch hunt
Anti-science activism rears its ugly head in the US
(This post was first published in 2023 after the “proximal origins” authors Prof. Kristian Andersen and Prof. Robert Garry were called before the GOP-led Select Subcommittee, and later smeared by them)
Background:
Science has come under pressure in the information age.
I wished that I did not need to write this, but today was another sad milestone on a trajectory towards a new dark age of myth, manipulation and magical thinking. The shameless, unethical lies told today by a GOP led witch hunt to smear scientists for publishing a scientific paper in a peer-reviewed journal is unconscionably unethical. It was a calculated media stunt to keep a false political narrative and conspiracy myth alive. It represents a silencing of inconvenient voices, voices of reason in a world seemingly gone mad.
Some say the true origins of Covid-19 will never be solved. I disagree. Having lived in that story for the last three years, I can say with certainty that none of these ‘man-made’ theories are supported by scientific evidence. Often, they are in direct contradiction to established scientific knowledge and in stark contrast to the emerging scientific consensus on a zoonotic origin of SARS-CoV-2.
Media manipulators including political anti-science activists have often fabricated false uncertainty out of whole cloth, but they can not hide that science pronounced the ‘man-made’ emperor naked. (And so did the recent intelligence community assessment). Instead of talking about science, evidence or facts, politicians now seek to discredit scientists who dare speak up against their fictions.
What we have witnessed today is however not only anti-science, it is also anti-democratic. Guilty until proven innocent is how autocratic nations treat their designated scapegoats, and how fanatics burn witches.
What I found specifically appalling is the false portrayal by politicians that those who change their minds when new evidence arises are to be treated with scorn and suspicion, rather than celebrated. It shows a fundamental decline not only in scientific literacy, but spits on and punishes what we should strive for in our shared humanity.
So what what it is worth; here is what I gathered from my interviews with various scientists with primary knowledge.
The real story of how the proximal origins paper came about.
The origins of a scientific study
“Eddie, can I discuss something with you? I think I have seen something… I need to talk it through… to pull me back from the edge”
This is how Eddie Holmes would summarize the time when his friend Kristian Andersen approached him on January 31th, 2020. And when Kristian calls, Eddie would listen.
Kristian Andersen is a renowned evolutionary virologist at the Scripps institute in California. By 2023, our paths had intersected a few times over the last months, but this time I did not want to talk science, but history, with him. While at a conference in Switzerland, he submitted himself to my friendly interrogation, certainly friendlier than the witch hunt the US Congress had in store for him. He still managed to carry the weary strain of repetition with patience, even three years in. When it comes to emerging disease outbreaks, he knew what he was talking about. His voice, however, bore the echo of fatigue; an audible testament to the countless recollections of his early work he’d been compelled to retell.
Like many, Kristian had first heard about the new outbreak via the proMED mail. When the first genome sequences became available to researchers, many emerging disease experts started paying a closer look, including him. Kristian had been working on emerging diseases like Ebola and Lassa fever in West Africa, or Zika in South America previously so when he heard about the outbreak in Wuhan, he and his colleagues immediately started with the basics of their craft. They tried to place 2019-nCoV among the wider viral family tree by comparing it to previously found viruses, including SARS, WIV1 — a SARS-related virus published by the Wuhan institute of virology — and of course the 2018 bat viruses from Zhoushan. “We basically took all available sequences from GenBank” Kristian explained. When a few more samples of 2019-nCoV trickled in, he spent some time cleaning up the sequencing data for possible errors and contaminations — a necessary step when trying to do some precision work later — before he created a phylogenetic tree of the outbreak. It would allow him to date back the timing of the outbreak, of course under many assumptions he ballparked by taking SARS as proxy. “That [dating] was the first focus. This is what I have done a lot”, he’d explained to me the timeline once again. Dating is crucial to get a feeling of how quickly the numbers grow and when the outbreak started, which could be weeks, months or even years in some cases. The records of his early thinking are still available online, on a website called “virological”, a mixture of message board, discussion forum and preprint server for virologists. I double checked his early entries. Coincidentally, he had put his timing estimate for the first human infections to around November 2019, a date that would hold up until today.
It was good science and all pretty standard for his line of work, by no means controversial.
All changed when on January 30ths, Kristian Andersen received an email from his department head, Prof. Dennis Burton. It read: “Is there anything in the sequences you have done that could definitively rule out gain-of-function studies that have been carried out in labs as a source of 2019-nCoV? I won’t quote you, I am just interested” The circulating rumors certainly had not passed him. But the two had and still have a very good relationship, so Kristian replied a bit tongue-in-cheek: “You are a tinfoil hat, but sure, I’ll take a look”. He further inquired if there was a specific reason to look deeper. Dennis Burton replied: “As usual, the conspiracy theories […] are going over the top on nCoV. It would be good to just focus on the science to see where it leads”. Kristian was in a good position to do so, he had already set up alignments — sequence matched comparisons — of closely related virus genomes to figure out what genetic elements might make 2019-nCoV so unusual. Trying to understand new viruses is often in relation to already known ones. After his exchange with Dennis, he decided to go through with a fine-tooth comb at all the genomic oddities he could find that might point towards laboratory manipulation or unexplained genetic elements given related viruses.
He noticed multiple differences, for example a comparison with SARS and MERS showed that 2019-nCoV had acquired a furin cleavage site at the S1/S2 position — where the spike protein gets cleaved — but that short amino acid motif was not included in RaTG13, the closest bat relative. He also noticed that there was a high rate of mutations at amino acid residues — specific positions within the larger spike protein — that would lie within the receptor-binding domain of the protein. This was the part that allowed the viral protein to target the human ACE2 receptor and enter our cells. These mutations could be a sign of selection pressure in a human host, of an adaptation to our biology. He even discovered an amino acid residue in 2019-nCoV receptor-binding domain that was similar to SARS, but not RaTG13, which could be a natural reversion but also a possibly purposeful introduction. Maybe somebody wanted to make the receptor-binding domain more SARS-like, because SARS is known to infect humans whereas many bat viruses are not. Lastly, he found a common restriction site — a sequence motif that molecular biologists sometimes introduce to shuffle genetic elements in and out of larger sequences — at the end of the spike protein sequence, followed by a drop in overall sequence diversity. Something like this might indicate that the upstream diversity in the spike protein was spliced in artificially. None of these oddities was a smoking gun, but on that day, it was enough to get Kristian worried. He had been roughly aware about the work conducted at the WIV, and at which biosafety level they operated with bat viruses. He would frantically rush through all their publications to get up to speed on their research and by the evening, he reached out to Eddie Holmes. “Can I discuss something with you? I think I have seen something… I need to talk it through… to pull me back from the edge”.
Unbeknownst to Kristian, Eddie Holmes was already primed for suspicion. He had chatted just before with his longtime friend Jeremy Farrar, then head of the UK Wellcome Trust, a powerful funding organization. He was independently wondering if this virus could have escaped from a lab, given the conspiracy theories and chatter online and the fact that Zheng-Li Shi had just released RaTG13, the closest known cousin of this new virus. Nobody could escape the news cycle. At his behest, Eddie had looked at Shi’s publication yet did not find anything suspicious, but when Kristian called and showed him all the oddities he obtained from his sequence comparisons, including the acquisition of a furin cleavage site that looked like it was inserted, Eddie became agitated. “Call me now”, he wrote to his friend Jeremy Farrar. For Jeremy, it was late, and he replied “What? Now?”… Eddie: “NOW”.
So he called, and when he explained what Kristian had told him, Jeremy would ”go from 0 to 100 in like two seconds”, Eddie recalled their exchange.
Everything just seemed to be coalescing. The closest viral relative from the WIV lab, the explosive growth in cases in Wuhan requiring a city-wide lockdown, Kristian Andersen reaching out with some odd features that look potentially engineered and a possible furin cleavage site insertion not found in RaTG13.
After Jeremy talked to Kristian as well, he and Eddie were thunderstruck and wondering what to do. They wanted to assemble a group of people who could discuss this clearly and started spitballing names. Experts like Ron Fouchier, Christian Drosten, Marion Koopmans came to mind. They did not invite Ralph Baric because he was too close to the Wuhan institute of virology. “Let me tell you now, Ralph did nothing wrong. But we wanted to make this a proper investigation and felt he was too close to the work”, Eddie explained their reasoning. Jeremy contacted Anthony Fauci, he also told Eddie that he would need to reach out to the Australian intelligence services, as would he for the British and Kristian for the American officials. Within three hours, Eddie was on the phone with the head of the agency. “How the hell did you manage that?”, I asked him. His idea was to reach out to the then Chief Medical Officer of the Government, Brendan Murphy, via a colleague at the University of Sidney who knew him. “I told them it was urgent, and Brendan called me within the hour, which is impressive for Saturday morning”. After they hung up, it would not take another hour and his phone rang again. It was Nick Warner, then head of the Office of National Intelligence. They went over the possibilities as well.
It had been a nerve-wracking Saturday for Eddie, but he felt that he had told “everyone that needs to know within a few hours of finding out”
His friend Jeremy Farrar from the UK’s Wellcome Trust — who had been in meetings all week with the American CDC under Redfield, NIH/NIAID under Anthony Fauci and the WHO to hear updates from George Gao on the situation in Wuhan — had at the same time reached out to Anthony Fauci. “Tony… I would really like to speak with you this evening. It is 10 pm now UK. Can you phone me?” Soon after, they two would talk and Jeremy advised Anthony to also reach out to Kristian as well. Exhausted, Jeremy went to bed. Not long after, on his Saturday, he would find another email from Anthony in his mail:
“Jeremy: I just got off the phone with Kristian Anderson and he related to me his concern about the Furine site mutation in the spike protein of the currently circulating 2019-nCoV. I told him that as soon as possible he and Eddie Holmes should get a group of evolutionary biologists together to examine carefully the data to determine if his concerns are validated. He should do this very quickly and if everyone agrees with this concern, they should report it to the appropriate authorities. I would imagine that in the USA this would be the FBI and in the UK it would be MIS. It would be important to quickly get confirmation of the cause of his concern by experts in the field of coronaviruses and evolutionary biology. In the meantime, I will alert my US. Government official colleagues of my conversation with you and Kristian and determine what further investigation they recommend. Let us stay in touch.“
Jeremy following the recommendation of Eddie and Kristian then set up the invitations for the first conference call, including Christian Drosten, a renowned corona virologist and SARS-1 veteran from Germany, Mike Ferguson from Wellcome Centre for Anti-Infectives Research in the UK, the Dutch virologist and gain-of-function expert Ron Fouchier, the emergent disease veterinarian and MERS veteran Marion Koopmans, evolutionary virologist and phylogenetics expert Andrew Rambaut, as well as virologist Bob Garry from Tulane university, Stefan Pohlmann, a virologist at the German Primate Centre in Gottingen and a range of institutional leaders such as Tony Fauci from NIAID, Francis Collins from NIH, Paul Schreier and Josie Golding from the Welcome Trust in the UK. By 2 pm Washington time, the group would convene.
The content of this teleconference on the 1st of February in 2020 has subsequently become a staple in the ‘manmade’ mythology as the ‘place where it happened’, so to speak. An international cover-up with high-ranking public officials and key virologists, if one were to believe the fictions told today.
I guess experts discussing important topics in small circles are known to invite the imagination of the public.
How come that Kristian Andersen and other scientists, once so alarmed, came to change their mind? Why did he, together with Eddie Holmes, Andrew Rambaut, Bob Garry and another author publish a paper a few weeks later stating “…we do not believe that any type of laboratory-based scenario is plausible”? Was there foul play? Did grant money change hands?
By all indications, what happened in reality was much more mundane. We know this inside story quite well today because all their communications have since been leaked, released or made public via FOIA — freedom of information act — request, and having heard about the event multiple times from different scientists, seeing their communication and emails at the time, there was no big mystery what happened.
They had some technical troubles trying to get everybody connected. Jeremy would give an introduction about the meeting, Kristian would prepare a powerpoint presentation showing the oddities he had found, and then they would discuss what they thought of it. The coronavirus experts were more skeptical about Kristian’s suggestion, having seen very similar things in other viruses. Anthony Fauci and Francis Collins were mostly silent and let the experts raise points. The supposed HIV-like insert analysis that an Indian preprint has laid out were also discussed and discarded as flawed rather quickly.
They then tackled Kristian’s oddities one by one. Andrew Rambaut compared the level of mutations between SARS-1 and its closest bat relative as well as SARS-CoV-2 with RaTG13; they had been in the same range, ergo the diversity was certainly possible to come about by natural processes. He was however unsure about the furin-cleavage site. Ron Fouchier noted that bat coronaviruses generally do not have furin cleavage sites, but human coronaviruses do. And these have entered human populations decades, if not centuries ago, so certainly were not engineered or tinkered with. So natural evolution can not be ruled out. Ron also noted that the single amino acid substitution in the receptor binding domain, a likely reversion from RaTG13 but identical to SARS-1, is generally absent in bats and could be a sign of adaptation to a host, for example mice. But for lab experiments, it would not make much sense, as one would work with a characterized virus to test these adaptations, not an unknown bat virus.
Christian Drosten was more dismissive, seeing the oddities as some cherry-picked coincidences that are not inconsistent with anything he knew about coronaviruses. Kristian and Eddie maintained that 5 out of 6 amino acids — shown critical in SARS-1 to bind to humans — in the receptor binding domain were altered between bat virus RaTG13 and SARS-CoV-2. This apparent adaptation to bind human ACE2 needed to be explained. Additionally, the insertion of a furin cleavage site still looked very suspicious to them and others agreed. They were also not satisfied with the corona virologists dismissing the predicted O-linked glycosylation — sometimes, specific amino acids in proteins have exposed sites where complex sugar molecules can get attached to by the cellular machinery — surrounding the furin cleavage site, because they believed it might be significant. Glycosylation on virus particles can contribute to various things, from immune system evasion to facilitated cell entry, and it sure seemed like the inserted furin cleavage site was opening up the protein for glycosylation in three nearby places. Isn’t that relevant?
Kristian became a bit obsessed, he confided in me. He was quite convinced and he thought if he would just have to go through old publications, he would certainly find proof.
“All I needed to do is basically find pieces of this virus before the pandemic”
He has also discussed this topic with his fellow Scripps professor Mike Farzan, who put a flea in his ear that serial passage — the consecutive infection of cells or animal models with the virus to study how it mutates and adapts to a host — of viruses can select for furin cleavage sites. This is because passaging in cell culture requires the use of trypsin, a protease similar to furin that allows the infected cells to be harvested from the dish by breaking away their connection to the culture dish. Maybe using trypsin facilitates selection for such cleavage sites in viruses? Kristian could laugh about it today. Turns out, that whole thing was not true. Maybe he misunderstood, he wasted days looking for papers to report on this phenomenon, but it was not supported by any evidence he could find.
Rummaging through their old emails, I did have to smile a little bit. Clearly, Kristian, Eddie and Jeremy could not unsee the figments they thought they had recognized. Even Bob Garry could not explain how the furin cleavage site came about by natural processes. Our brains are good at connecting the dots, sometimes too good. We see things that are not there. Especially when the data is just too limited and the need to understand dire, our expectations shape our perceptions. The corona virologists Ron and Christian, coming from different backgrounds with different expectations, would be more of the ‘looks like another mirage to me’ persuasion.
“Everything that seems counterintuitive with CoVs is actually logical when you work with them a few times”,
Jasnah Kholin’s, a corona virologist based in Hong Kong, words rang in my ear. She had been amused by the false shadows Kristian had been chasing, but this was of course with the power of hindsight.
At a hastily arranged teleconference, our perceptions and intuitions can mislead us, and in the fever of the situation, who would turn out correct was not a given. “I am honestly 50:50 on this”, Jeremy Farrar would write after the conference. “And Eddie is like 60:40 for a lab origin”. While the overall feeling from all experts was that deliberate engineering can likely be ruled out, the idea that serial passage in a lab could bring forth such strong adaptation to human ACE2 was compelling. Even Tony Fauci asked about serial passage in hACE2 mice — lab animals where the mouse gene encoding the ACE2 receptor had been exchanged for its human version — could have been what was done? Adaptations during serial passage are likely indistinguishable from natural selection. Without more time for science to sort out the kinks, and especially more data coming from an increasingly reluctant China, this would be the best they could do.
By February 1st, on the other side of the world, the Chinese leadership had found itself increasingly under pressure. Not only did it fail to control the narrative, they had to publicly resort to dramatic lockdown measures. Tens of thousands of people were infected and started dying in increasing numbers. Even worse for the autocratic party, their foreign adversaries and other anti-CCP forces all around the world would use the outbreak for political attacks. The rightwing anti-communist party newspaper Epoch Times published a lengthy fabrication about how senior political leaders had planned to use bioweapons based on MERS as part of their military strategy. US senator Tom Cotton would openly implicate the Wuhan Institute of Virology and get in a public spat with the Chinese ambassador. Indian newspapers would report excessively about “HIV” similarities, the press in Israel would quote dubious Israeli and US intelligence experts about supposed bio warfare. And social media would be a zoo at this point. Every amateur sleuth, every wannabe scientist, every crank, contrarian and conspiracy theorist would write long twitter threads, facebook posts or medium blogs reporting about the connections they have ‘unearthed’ — usually via google search or google translate — to a hungry and willing audience. For many trained, and even more untrained eyes, everything seemed to coalesce on a common theme: Something was not natural about this new virus.
That is our brain at work in the information age. The more we search for suspicious connections, the more spurious connections the search engines will deliver to us. By the end of January, conspiracy myths had rune wild, and a chimera of various overlapping ideas — from weak biosafety and secret military ambitions for coronavirus research to bat researchers at the WIV making hybrid viruses with HIV — would eventually rise out of the sensemaking wetware we call our pattern-recognizing brains. Once we believe we have spotted a worrisome pattern, it becomes difficult to unsee. For most of human history, missing a pattern could’ve cost our life. Seeing a pattern where there is none? Not so much. Under threat, we are especially sensitive to trade accuracy for speed, and there was a virus exploding like nothing we have ever witnessed before. Is it really surprising we feared manmade malice behind the ravaging beast?
Without further data, we were likely to wade in the dark for a long time.
Yet to provide some illumination in times of darkness is, in essence, the role of the scientific process. Most of the time however, it is too slow to be of immediate relevance. But not always.
Eddie Holmes had mentored a lot of great students over his career, and one of them had just reached out on his most stressful weekend.
“Hey Eddie, I got some wildlife samples that seem to be really cool for SARS-CoV-2… they are from a coronavirus in pangolins… Can we have a chat about this?”
…the message would read, coming from Tommy Lam, a bioinformatician and computational virologist at the University of Hong Kong. His specialty has been developing new tools for sequence databases to allow better genomic analysis, and these tools found some intriguing sequencing samples with high similarity to parts of the SARS-CoV-2 genome. They originated from the Guangdong Wildlife Rescue Center, which had received 21 live Malayan pangolins — protected animals resembling walking pine cones with hard scales often used in Chinese medicine — from the Anti-smuggling Customs Bureau. Most were in very poor health, and their bodies were covered with skin eruptions. 16 died even after extensive rescue efforts by caretakers, their lungs swollen with a frothy liquid. Researchers from the Guangdong Key Laboratory of Animal Conservation had taken samples for metagenomic sequencing and published a paper finding an infection with an unspecified coronavirus. Tommy Lam had written to the data repository SRA archive to make those sequences public, and after checking them out, he found they resembled in part 2019-nCoV. He immediately reached out to his former mentor Eddie so they could have a look together. Independently, a bioinformatician in the US named Matt Wong had also found them and put a quick post about them on the website virological. After the hectic weekend of the teleconference, when Eddie finally found time to look at the virological post and talk to Tommy about those pangolin sequences, he almost fell out of his chair. The pangolin coronavirus had a receptor binding domain that was almost identical to the one of SARS-CoV-2. And those mysteriously adapted amino acids so relevant for human ACE2 binding? The pangolin virus had all six of them, while the closest bat relative RaTG13 did not. How the hell did a divergent, not at all similar pangolin coronavirus come up with an almost perfectly matched genetic puzzle piece shared by SARS-CoV-2?
Kristian had been obsessed with finding any genetic piece of SARS-CoV-2 used by any lab to prove that the virus might have escaped from one. Suddenly, one of those pieces appeared not in a lab but in the most smuggled animals on the entire planet.
It dramatically changed the opinion of scientists, and a week later by February 8th, Eddie Holmes and most others had already come to see a natural origin much more likely given these developments. Kristian needed a few more days because he still wanted to search more in the literature, try a few ideas and follow up on the weird glycans surrounding the furin cleavage site. In the weeks after the teleconference, Kristian, Eddie, Bob, Andrew and Ian Lipkin — an emergent disease immunologists and SARS and MERS veteran — kept working on the viral genome and origin question. Eventually, Kristian, the last lab origin hold-out, could not justify to himself to keep his suspicions alive given that the scientific evidence told a very different story.
And that is a good thing.
In times of existential threat or uncertainty, our brains tend to overfit patterns to speed up our sensemaking. It becomes hard to unsee something we think we have recognized, and once our beliefs harden, we rarely ever revisit them but rather opt to justify and defend what we hold true. The scientific method is antithetical to this aspect of our human nature, it prompts us to constantly seek to overcome the pitfalls of our intuitions, the fervor of our beliefs, the unholy pull of our fears, or the sweet biases of our wishful thinking.
The newly discovered pangolin sequences were an opportunity to challenge one’s intuitions, and as a trained scientist, Kristian overcame seeing the false figments he once believed true. So did Eddie Holmes and the others. Shared deliberation, varied expertises and backgrounds, time to work on a problem and opportunity to go on wild goose chases are all part of that process. Science is not about having the perfect evidence to answer every question, it is about using evidence to better approximate the boundaries of our knowledge and dispel the myths of our preconceived notions.
There rarely is perfect certainty or evidence. How the hell these pangolin viruses came to share a hitherto unseen key genetic element with SARS-CoV-2 is still not solved to this day. But just as these genetic pieces would have been a smoking gun for a lab origin had they appeared in some previous coronavirus work, their appearance in trafficked pangolins meant that there was a much larger laboratory somewhere out there in the wild that we all know much too little about.
Conclusion
There really is no great mystery behind the conception of this scientific paper, it started with testing different hypotheses pertaining to possible origins of the virus based on its genomic sequences, features, behavior and relationship to other known viruses. Kristian Andersen and many other emergent disease experts are very knowledgeable at what they do, but nobody knows everything.
Having some false assumptions initially about the details within a very specific viral family outside their expertise is not unusual. In fact, it was an opportunity to learn more about the depths of coronavirus biology and they quickly absorped the knowledge from other domain experts, as well as the available scientific literature. Add to this some powerful pieces of emerging evidence, and their updated beliefs became not an oddity to be investigated, but a necessity for any evidenc-focused scientists worth his salt.
So I guess if there is one thing you should ask yourself:
Who would you rather trust on scientific issues; the conniving, lying politicians who would sell their grandmother for your vote, or the humble scientists who just want you to have the facts, not matter how politically inconvenient?
This is a question you will have to ask yourself for the next years to come, because the witch hunt is not over.
Unfortunately, it has barely begun.
Sources & References:
MUST READ/WATCH:
Andersen et al., the proximal origins of SARS-CoV-2
ODNI intelligence agency assessment
Holmes et al., The origins of SARS-CoV-2: A critical review
Jiang & Wang, Science, 2022 (Perspective)
References:
Worobey M. et al., Science, 2022
Pekar J. et al., Science, 2022
Further reading and resources:
Blog: The case for a zoonotic origin of SARS-CoV-2
Blog: Lableak myth influencers & their fear-based communication tactics
Blog: How algorithmic curation empowers controversies
Blog: How our information architecture favors conspiracy myths over science
Video: Long-form discussion with SAGO member Dr. Carlos Morel (SAGO is the WHO’s scientific advisory group on the origins of pandemics)
Video: Long-form discussion with bat ecologist Dr. Alice C. Hughes and the risk of SARS-CoV-3
Video: Long-form discussion about lab leak uncertainties with virologist Dr. Stuart Neil
Update 26/07/2023: The post was updated to include the contribution of bioinformatician Matt Wong, who independently found those pangolin-CoV similarities and posted them on virological on Janurary 31st.
"Jasnah Kholin’s, a corona virologist based in Hong Kong, words rang in my ear. She had been amused by the false shadows Kristian had been chasing, but this was of course with the power of hindsight."
Is this a pseudonym?
Dear Philipp,
Great article. It would be good if you and Sam, or you and TWIV, made a video on this scientific process undertaken in the early days of the investigation.
The attacks on the authors are disgraceful and the narrative against them is out of control.
Thanks,
Ricardo