The question of which mutations to Covid drive vaccine escape sure do seem relevant to pandemic response to me! Of course in a coherently-competent world we wouldn’t need this at all (remember that Australia and NZ both eliminated Covid with a short lockdown in early 2020?), but given the world we’re actually in I’m a big fan of escape-resistant vaccines—and getting them approved and delivered faster.
80% of transgenic mice, not humans died (or got fairly ill and were euthanized) to the modified strain, compared to 100% (of transgenic mice, not humans) to the original Wuhan wild-type virus. IN MICE is one of the best-known reporting biases! There’s literally a @justsaysinmice tweet about this study!
Yeah, there’s clearly been some level of misbehavior here, and the institutional responses documented above are clownish. This is clearly in the genre of unacceptably risky work that probably created and then leaked pandemic Covid, which I wish we’d cut back on and confine to labs in the remote desert instead of dense cities.
But I don’t think we’d be discussing this specific paper at all if the 80% MORTALITY! headlines hadn’t been amplified, I don’t think they were accurate, and I would prefer that we stop undermining the credibility of the rationalist community and important arguments against unacceptably risky research by failing to check the basic details before posting alarmist headlines.
If you must, I’d strongly prefer a framing like “This is another unfortunately-common example of research I think is unacceptably risky. Note the mismanagement, the inconsistent descriptions and justifications of this project and whether it constitutes ‘gain of function’, the history of bio lab leaks, etc. While research on immune escape could be valuable, reforming vaccine approval and distribution would be much more effective and less risky.”
Strong upvote. And well, your reply certainly builds up *my* trust of the rationalist community. Zvi should aim to maintain a healthy background level of disappointed readers to build up a robust peer-review population.
Mu. Ask “how does this knowledge actually affect pandemic response”, not what I’d do. I claim personal expertise in neither case.
(If I could set policy we’d have driven R0<<1 at minimal cost (Covid was eradicable, and eliminated at several times in several countries!), had generic-coronavirus vaccine bases and pre-authorized challenge trials if that was infeasible, etc. In the world we’re actually in, my understanding is that research like this feeds in to vaccine design, however far from ideal vaccine policy and delivery might be.)
Then why do you claim knowledge about it having effects?
generic-coronavirus vaccine bases and pre-authorized challenge trials if that was infeasible, etc. In the world we’re actually in, my understanding is that research like this feeds in to vaccine design
There are already lots of different coronaviruses out there in the wild. If you create a generic-coronavirus vaccine that works for all of those in the wild, what do you expect to gain from knowing that it works for a tiny (relative to the existing pool of coronaviruses) portion of new lab-created viruses?
But I don’t think we’d be discussing this specific paper
Discussing COVID gain-of-function papers is important whether or not there are 80% MORTALITY claims. If Zvi would have heard of the paper he would have written about it in either case.
It’s unclear to me which headline you considered misleading. Which rationalist outlet said in a headline something about 80% MORTALITY without mentioning that it’s in mice?
Baseline again, I strongly support not doing any research that might collect, create, or leak pandemic pathogens. Defining this study as “not gain of function” is only defensible on technicalities that make the term almost meaningless.
It’s unclear to me which headline you considered misleading. Which rationalist outlet said in a headline something about 80% MORTALITY without mentioning that it’s in mice?
I’m not complaining about “literally failing to mention mice”, but rather “without appearing to know that the wild-type strain was 100% lethal to the same mice” - ‘in (transgenic) mice’ should be a signal that you need to read the study before using it as evidence. As an exemplar, I consider William A Eden’s tweet (the opener to this post) to be irresponsible reporting.
Zvi’s title for this post, “Covid 10/20/22: Wait, We Did WHAT?” is also more hyperbolic than I’d prefer, as is the opening: The what, in this case, was the type of thing that could cause another pandemic: … None of the other developments should scare you. I disagree that we should be scared of this particular study; and while the system of institutions and incentives that supports such work does need to be dismantled, I think the rationalist response to this paper has undermined our credibility and had the wrong marginal impact.
There’s a self-correction process at play here (and in Alyssa’s tweet above), but we shouldn’t make this kind of mistake in the first place and ought to correct it more quickly and comprehensively if we do.
The study and the reaction to it by the NHI are evidence that the system is malfunctioning. Researchers are still engaging in the type of research that can produce pandemics even if the chance of a single study doing so is likely less than 1%. The fact that this kind of research is done is scary.
I’m not complaining about “literally failing to mention mice”, but rather “without appearing to know that the wild-type strain was 100% lethal to the same mice”
The fact that the wild-type strain was 100% doesn’t really matter for the danger posed by the strain leaking. Sometimes there’s a tradeoff between lethality and infectiousness for viruses.
If the headline would instead be “Researchers choose a virus with 100% lethality in mice and thought it was a good idea to add the Omicron spike protein to it that likely makes it more infectious to humans” I don’t know why that would scare us any less.
The culture that produces this kind of apologism for dangerous research along with claims that speaking this way about dangerous research damages the credibility of the rationalist community is exactly where the problem is.
Status-based claims of “you should not take about X because you might lose credibility ” are what people did when we talked about masks early in the pandemic and at all sorts of points where rationalists differed from the orthodox wisdom.
It’s a necessary pre-condition to make any progress on sane progress of pandemic prevention to fight that kind of apologism.
Zvi didn’t even mention that the researchers thought it was a good idea not to do the experiment under biosafety level 4.
It seems like you misunderstood something here: the “virus with 100% lethality in mice” was the original wild-type (“Wuhan”) sars-cov-2 virus. It was the mice that were engineered for their susceptibility to it. That’s why the 80% headline number is meaningless and alarmist to report in isolation: The new strain is 80% fatal in mice which were genetically engineered to be susceptible to original-flavor COVID, which is 100% fatal to them.
Are you somehow asserting that the original sars-cov-2 virus is not in the reference class of “very dangerous virus” and that I fail to understand that the original sars-cov-2 is not dangerous?
I just responded to Zac’s assertion that we should look at the fact that it reduces lethality from 100% to 80%. He made the argument that this commission is a problem and I said why it doesn’t.
You can also make an argument that it’s important to talk about the fact that we are talking about the original strain but that’s not an argument that Zac made.
But let’s think about whether “it was the original COVID strain” should make us think that this wasn’t a risky idea and see what their paper has to say about that.
We generated chimeric recombinant SARS-CoV-2 encoding the S45 gene of Omicron in the backbone of an ancestral SARS-CoV-2 isolate and compared this virus with the naturally circulating Omicron variant. The Omicron S-bearing virus robustly escapes vaccine-induced humoral immunity, mainly due to mutations in the receptor-48 binding motif (RBM), yet unlike naturally occurring Omicron, efficiently replicates in cell lines and primary-like distal lung cells. In K18-hACE2 mice, while Omicron causes mild, non-fatal infection, the Omicron S-carrying virus inflicts severe disease with a mortality rate of 80%. This indicates that while the vaccine escape of Omicron is defined by mutations in S, major determinants of viral pathogenicity reside outside of S.
The virus they created is more lethal than Omicron (in the mouse model) and more potentially more transmissible than the original COVID strain.
Here, we characterized the K18-hACE2 mouse model expressing human (h)ACE2 in mice, controlled by the human keratin 18 (K18) promoter, in the epithelia, including airway epithelial cells where SARS-CoV-2 infections typically start.
Given that those mice are more like humans than normal mice, I do think that a virus that’s more lethal to them than Omicron also has a good chance of being more harmful to humans than Omicron.
While I think that you could excuse researchers who produce a modified virus with lower lethality and lower transmissible than an already existing virus, the idea that you don’t want to do a virus that’s either more lethal or more transmissible than existing viruses is a bad idea. Especially, the idea that not do those experiments under the best conditions for safety that’s possible which would be biosafety level 4.
I read a lot of Derek Lowe early in the pandemic and regard him highly, but in this case I think he’s wrong. Going through the comments of Lowe’s post, I came across a link to this essay by a distinguished biologist, Stephen Salzberg, at Johns Hopkins agreeing with Zvi’s perspective.
Salzberg is a computational biologist, not a virologist, but he’s a distinguished professor at a prestigious school and does not seem to be on the fringe politically as far as I can tell If anybody knows more about him, please let me know.
Overall, experts seem to be split on this matter. Which is strong enough evidence for me that the research should have been disallowed or at least regulated to the highest security level. The risks are just too great relative to what was learned from the research.
I have written a letter to my representative in the House encouraging her to legislate more restrictions on gain of function research and referencing the article linked above.
Re: that mouse study… I’m disappointed to feel I can’t trust rationalist headlines without also personally checking for inconvenient details in the preprint and expert commentary (here’s Derek Lowe in Science, or Helen Branswell in Stat.) For example:
The chimeric mix(es) in the study (wild-type plus Omicron spike protein) have previously been observed in the wild, in humans, and were outcompeted by other circulating strains. Seems important to me!
The question of which mutations to Covid drive vaccine escape sure do seem relevant to pandemic response to me! Of course in a coherently-competent world we wouldn’t need this at all (remember that Australia and NZ both eliminated Covid with a short lockdown in early 2020?), but given the world we’re actually in I’m a big fan of escape-resistant vaccines—and getting them approved and delivered faster.
80% of transgenic mice, not humans died (or got fairly ill and were euthanized) to the modified strain, compared to 100% (of transgenic mice, not humans) to the original Wuhan wild-type virus. IN MICE is one of the best-known reporting biases! There’s literally a @justsaysinmice tweet about this study!
Yeah, there’s clearly been some level of misbehavior here, and the institutional responses documented above are clownish. This is clearly in the genre of unacceptably risky work that probably created and then leaked pandemic Covid, which I wish we’d cut back on and confine to labs in the remote desert instead of dense cities.
But I don’t think we’d be discussing this specific paper at all if the 80% MORTALITY! headlines hadn’t been amplified, I don’t think they were accurate, and I would prefer that we stop undermining the credibility of the rationalist community and important arguments against unacceptably risky research by failing to check the basic details before posting alarmist headlines.
If you must, I’d strongly prefer a framing like “This is another unfortunately-common example of research I think is unacceptably risky. Note the mismanagement, the inconsistent descriptions and justifications of this project and whether it constitutes ‘gain of function’, the history of bio lab leaks, etc. While research on immune escape could be valuable, reforming vaccine approval and distribution would be much more effective and less risky.”
Strong upvote. And well, your reply certainly builds up *my* trust of the rationalist community. Zvi should aim to maintain a healthy background level of disappointed readers to build up a robust peer-review population.
Yeah, I strongly downvoted this due to the clickbaity nature of it’s and would encourage others to strong downvote it too.
What would you do differently in regards to pandemic response if you have that knowledge?
Mu. Ask “how does this knowledge actually affect pandemic response”, not what I’d do. I claim personal expertise in neither case.
(If I could set policy we’d have driven R0<<1 at minimal cost (Covid was eradicable, and eliminated at several times in several countries!), had generic-coronavirus vaccine bases and pre-authorized challenge trials if that was infeasible, etc. In the world we’re actually in, my understanding is that research like this feeds in to vaccine design, however far from ideal vaccine policy and delivery might be.)
Then why do you claim knowledge about it having effects?
There are already lots of different coronaviruses out there in the wild. If you create a generic-coronavirus vaccine that works for all of those in the wild, what do you expect to gain from knowing that it works for a tiny (relative to the existing pool of coronaviruses) portion of new lab-created viruses?
Discussing COVID gain-of-function papers is important whether or not there are 80% MORTALITY claims. If Zvi would have heard of the paper he would have written about it in either case.
It’s unclear to me which headline you considered misleading. Which rationalist outlet said in a headline something about 80% MORTALITY without mentioning that it’s in mice?
Baseline again, I strongly support not doing any research that might collect, create, or leak pandemic pathogens. Defining this study as “not gain of function” is only defensible on technicalities that make the term almost meaningless.
I’m not complaining about “literally failing to mention mice”, but rather “without appearing to know that the wild-type strain was 100% lethal to the same mice” - ‘in (transgenic) mice’ should be a signal that you need to read the study before using it as evidence. As an exemplar, I consider William A Eden’s tweet (the opener to this post) to be irresponsible reporting.
Zvi’s title for this post, “Covid 10/20/22: Wait, We Did WHAT?” is also more hyperbolic than I’d prefer, as is the opening: The what, in this case, was the type of thing that could cause another pandemic: … None of the other developments should scare you. I disagree that we should be scared of this particular study; and while the system of institutions and incentives that supports such work does need to be dismantled, I think the rationalist response to this paper has undermined our credibility and had the wrong marginal impact.
There’s a self-correction process at play here (and in Alyssa’s tweet above), but we shouldn’t make this kind of mistake in the first place and ought to correct it more quickly and comprehensively if we do.
The study and the reaction to it by the NHI are evidence that the system is malfunctioning. Researchers are still engaging in the type of research that can produce pandemics even if the chance of a single study doing so is likely less than 1%. The fact that this kind of research is done is scary.
The fact that the wild-type strain was 100% doesn’t really matter for the danger posed by the strain leaking. Sometimes there’s a tradeoff between lethality and infectiousness for viruses.
If the headline would instead be “Researchers choose a virus with 100% lethality in mice and thought it was a good idea to add the Omicron spike protein to it that likely makes it more infectious to humans” I don’t know why that would scare us any less.
The culture that produces this kind of apologism for dangerous research along with claims that speaking this way about dangerous research damages the credibility of the rationalist community is exactly where the problem is.
Status-based claims of “you should not take about X because you might lose credibility ” are what people did when we talked about masks early in the pandemic and at all sorts of points where rationalists differed from the orthodox wisdom.
It’s a necessary pre-condition to make any progress on sane progress of pandemic prevention to fight that kind of apologism.
Zvi didn’t even mention that the researchers thought it was a good idea not to do the experiment under biosafety level 4.
It seems like you misunderstood something here: the “virus with 100% lethality in mice” was the original wild-type (“Wuhan”) sars-cov-2 virus. It was the mice that were engineered for their susceptibility to it. That’s why the 80% headline number is meaningless and alarmist to report in isolation: The new strain is 80% fatal in mice which were genetically engineered to be susceptible to original-flavor COVID, which is 100% fatal to them.
Are you somehow asserting that the original sars-cov-2 virus is not in the reference class of “very dangerous virus” and that I fail to understand that the original sars-cov-2 is not dangerous?
I just responded to Zac’s assertion that we should look at the fact that it reduces lethality from 100% to 80%. He made the argument that this commission is a problem and I said why it doesn’t.
You can also make an argument that it’s important to talk about the fact that we are talking about the original strain but that’s not an argument that Zac made.
But let’s think about whether “it was the original COVID strain” should make us think that this wasn’t a risky idea and see what their paper has to say about that.
From the actual paper:
The virus they created is more lethal than Omicron (in the mouse model) and more potentially more transmissible than the original COVID strain.
The mouse model in question is described in The K18-Human ACE2 Transgenic Mouse Model Recapitulates Non-severe and Severe COVID-19 in Response to an Infectious Dose of the SARS-CoV-2 Virus:
Given that those mice are more like humans than normal mice, I do think that a virus that’s more lethal to them than Omicron also has a good chance of being more harmful to humans than Omicron.
While I think that you could excuse researchers who produce a modified virus with lower lethality and lower transmissible than an already existing virus, the idea that you don’t want to do a virus that’s either more lethal or more transmissible than existing viruses is a bad idea. Especially, the idea that not do those experiments under the best conditions for safety that’s possible which would be biosafety level 4.
I read a lot of Derek Lowe early in the pandemic and regard him highly, but in this case I think he’s wrong. Going through the comments of Lowe’s post, I came across a link to this essay by a distinguished biologist, Stephen Salzberg, at Johns Hopkins agreeing with Zvi’s perspective.
http://genome.fieldofscience.com/2022/10/gain-of-function-experiments-at-boston.html
Salzberg is a computational biologist, not a virologist, but he’s a distinguished professor at a prestigious school and does not seem to be on the fringe politically as far as I can tell If anybody knows more about him, please let me know.
Overall, experts seem to be split on this matter. Which is strong enough evidence for me that the research should have been disallowed or at least regulated to the highest security level. The risks are just too great relative to what was learned from the research.
I have written a letter to my representative in the House encouraging her to legislate more restrictions on gain of function research and referencing the article linked above.