A single line often inverts meaning once you see what it
answers, so neighbouring messages are always shown.
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No. No.
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So there was no suggestion that you should remain silent or not?
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No. Again, I was silent because I had sort of felt that maybe I caused the whole meeting to occur because I had talked about it earlier. And I wanted to hear what independent people thought. Otherwise, I could drive the whole direction of the meeting, and that was not right. At least that was my -- if it's flawed thinking, then I apologize. But I don't think it was flawed thinking.
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And back to the DARPA proposal, had you done any of the work that you were proposing to do under that proposal prior to the application?
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2026-04-10 09:00
Ralph S. Baric
No. We've never dropped a furin cleavage site into a coronavirus like that.
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Were you aware of any of the other applicants having done the work prior to?
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Yeah, I think maybe we should take a second and review the furin cleavage site, because you seem to think it is the critical event that drove SARS-2 to be pathogenic. So in the coronavirus literature, furin cleavage sites have a mixed history. So in feline enteric coronavirus, if that virus has a furin cleavage site it's DC.Scheduling@LexitasLegal.com asymptomatic. It's an enteric disease. It's when you lose the furin cleavage site that it becomes a fulminant, deadly disease that is 100 percent fatal in cats. So loss-offunction of that furin cleavage site kills you dead, the cat. In mouse hepatitis virus, a couple of researchers had removed the furin cleavage site and said what happens to the pathogenesis? There was no change. Another group, taking pseudoviruses, had introduced furin sites into the SARS-coronavirus 2003 strain, and the only thing they found was slightly increased infectivity. Nothing big. Nothing that said "eureka." So now let's compare SARS from 2003 and SARS-2, and let's ask the question, what experiments were done to prove that the furin cleavage site drove severe disease in SAR-2 pathogenesis. What they did was a loss-of-function experiment. They deleted those four residues that were introduced by whatever means, and they asked what happened to the virus. It was less pathogenic, and it was less transmissible. Eureka. Furin cleavage site causes that phenotype. Except when you look at the other figures in the paper, where it shows that it also knocked down the ability of other proteases to cleave at that S1/S2 boundary. So it wasn't a furin cleavage site-specific knockout. DC.Scheduling@LexitasLegal.com It was a global protease knockout. And that's what a lossof-function experiment does. The only way to really prove it is to take a virus that doesn't have a furin cleavage site and stick it in. That's gain-of-function. It's causality. You know for a fact. I can make the argument in this room, and I can argue it in front of scientists, that the introduction of the furin cleavage site in SARS-2 attenuated its pathogenesis and increased its transmissibility, and that was to its benefit. And that's not what you hear. I've looked at a bunch of these different protease studies that people did, where they knocked out the sequence. They were making global proteolytic cleavage knockouts on the spike. And if you don't cleave S1/S2 efficiently, you knock down replication and pathogenesis. I also say that SARS-coronavirus-2 had the same R rate that SARS coronavirus 2003 had, early in the pandemic. They both transmitted efficiently. The difference was one transmitted very late only, after severe disease occurred - - that was 2003 -- and in 2019, that strain transmitted before you got disease. And that's why it's a pandemic and the other one was not. Sorry, I know that went long. You're probably mad at me.
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No, I'm mad at him. DC.Scheduling@LexitasLegal.com
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But I think it was important to say in this meeting that be careful what you read in an abstract, or even what you hear from the scientific community, because they're not always right. There is uncertainty in a lot of things, and this particular issue has uncertainty around it.