[alevskaya]

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!

[inciampati]

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?

[alevskaya]

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?