The trouble with the synthetic furin hypothesis and all this DRASTIC stuff on that grant, etc. is that all of this work would certainly be done in known viral vectors... you would never go messing around testing spike proteins in some totally random virus backbone whose in-vitro behavior hadn't been worked out before in your assay cell lines.
So, maybe I missed something, but none of the experimental designs I've seen in those grants would ever plausibly lead to the SARS-COV-2 sequence. Again, pre-pandemic there was no reason to be sneaky about this stuff if it were actually being done... I don't know why anyone would waste their time on some uncharacterized, completely markerless viral vector for these RBD and proteolysis tests.
Sigh... maybe if we -had- been doing those experiments earlier we would have discovered this new clade and been more ready for it. That grant looks spooky to some people precisely because it was so prophetic.
I don't think those grants would have led to the SARS-CoV-2 sequence either, because the base strain is different. BUT let's be real here. You don't ask for money and do the experiment. You do the experiment and then ask for continuation money. So it is a "generally accepted grantsmanship strategy" that WIV would have been working on viruses adjacent to that in the grant with the same techniques, and adjacent techniques that would lead to the natural next step. If that natural next step infected a postdoc that was careless that one time when he/she was pulling a 9-9-6 workweek... It's all so terrifyingly plausible to anyone who has been there on the front lines doing lab work.
You're really into stacking these hypotheticals. Why would anyone bother developing a pile of fiddly new vectors? cui bono? Vector development sucks, I've done it in simpler virus families. And why do it completely markerless? Remember that the other odd thing about this grant was that a lot of the genetic work was supposed to be done in the US. If it were already being done we'd probably have had those sequences in -our- databases!
My (recent) experience with viral development is that it can be done in radical multiplex. You don't make one vector at a time. You mix five together, let or encourage them to recombine, then use sequencing, screens and molecular assays to sort out the details of which of the trillions you create has your desired phenotype and why. If this group was thinking about adding a furin cleavage site, they could do so using a template homologous to the appropriate regions of diverse natural viruses, then use selection in cell culture or animal models to establish where it landed and what effects it had on infection.
It's highly unlikely that an established group would write a proposal that didn't describe their current research trajectory.
Although you have made a lot of arguments against it, I still don't know why it seems so unreasonable to you that SARS-CoV-2 might have laboratory origins. I think it's just that your prior expectations run against this. To me it's much easier to imagine than a natural spillover, given the modern urban circumstances and very unusual viral features and phenotype. Maybe my work experience is more aligned with this possibility than yours?
I specialized in high throughput synthetic biology and in applications adapting vectors and pathogenic proteins to subvert the human immune system (for immunooncology mostly). So I have all the background needed for supervillain thinking here :p Of course you can do multiplex markerless construction - but it’s a huge pain in the ass at these lengths and it still leaves open the question of what the point of such work would be.
I feel like I’m taking crazy beans - 20 years ago a satbecoronavirus from a wet market nearly started a global pandemic - hell my colleagues at the time were the ones that identified it as a coronavirus! We have epidemiological evidence this happened again. Absolutely nothing about this sequence is obviously synthetic or even unusual for coronaviruses. How is zoonosis not the null hypothesis?
No, you use money/resources from a previous grant to do exploratory work on the next grant while you are writing it. Sometimes you double-dip, so you write up a grant for one place, change parameters and personell slightly for another, etc. Have you ever actually worked in a research lab?
I wouldn't believe it if you told me COVID-19 was produced via carefully planned work. IMO, COVID-19 could only have been produced via exploratory work.
Look, fact of the matter is, I have consumed ~2M USD of resources on a seven year PhD that did not have grant money attached to it. Despite my important results, my grad school PI did not pursue further work in the direction I piloted. And as a postdoc I've steered DOE funded bioengineering project away from a strategy I knew would be unfruitful towards results that garnered three papers in as many years, but were very much not "in the proposed work of the grant" (though very much in the spirit of it). Ultimately we rewrote the grant to reflect the effect magnification I got and we were rejected for renewal, haha. Moreover, at the end, we did the experiment we were actually funded for, and found no effect.
Grants and science writ large are not the ideal spherical cow you think it to be.
So, maybe I missed something, but none of the experimental designs I've seen in those grants would ever plausibly lead to the SARS-COV-2 sequence. Again, pre-pandemic there was no reason to be sneaky about this stuff if it were actually being done... I don't know why anyone would waste their time on some uncharacterized, completely markerless viral vector for these RBD and proteolysis tests.
Sigh... maybe if we -had- been doing those experiments earlier we would have discovered this new clade and been more ready for it. That grant looks spooky to some people precisely because it was so prophetic.