> Once the virus has bound to ACE2, it must complete a final step: fusing its outer membrane with the membrane of our cells. This throws the door open to infection. Using a novel live-cell imaging platform, Alex Kreutzberger, HMS instructor in pediatrics at Boston Children’s, and Tomas Kirchhausen, professor of cell biology in the Blavatnik Institute at HMS and professor of pediatrics at Boston Children’s, showed that SP1-77 blocks this step.

> “SP1-77 binds the spike protein at a site that so far has not been mutated in any variant, and it neutralizes these variants by a novel mechanism,” noted Kirchhausen. “These properties may contribute to its broad and potent activity.”

Questions:

* If mutations at this site are possible, how would this be an evolutionary deadens in a way that the current evolutionary dynamics of the virus are not?

* Surely a lack of mutations at this site, on their face, imply only that there is no evolutionary pressure on the site and its phenotypes, and, that mutations at this site are as viable as anywhere else?

* Or, is it possible that the lack of mutations (presuming that this is very accurate) indicates an evolutionary pressure to maintain functionality that is sensitive to failure due to even minor mutations or deviations in functionality?

* Surely a lack of mutations at this site, on their face, imply only that there is no evolutionary pressure on the site and its phenotypes, and, that mutations at this site are as viable as anywhere else?

* Or, is it possible that the lack of mutations (presuming that this is very accurate) indicates an evolutionary pressure to maintain functionality that is sensitive to failure due to even minor mutations or deviations in functionality?*

the answer is that something that is so highly conserved across so many variations is mission critical. Mutations occur through replication everywhere, randomly. Highly conserved means that a change is a breaking change, severely impacting fitness, if no mutations have been observed elsewhere. Ie to extend the analogy, that point is the 'mountain' SARS-CoV-2 has decided to scale.

I wonder because targeting such a site seems to me like the premise of this kind of research: find “mission critical” highly conserved genes and then clinically target them.

And yet, scanning the paper’s abstract and introduction (the paper is linked in the posted article) I couldn’t find any mention of any highly conserved genome site. As a layperson I may have missed it, but still, if it’s a fundamental premise, I would have expected a conspicuous statement.

Instead, the paper reads to me like one concerned with a novel method for developing new antibodies with new methods of action. Not, as the article states, mechanisms of action against “mission critical” genes.

If I’m wrong, please let me know. But at the moment, I’m suspecting a misstep on the part of the scientific journalism here.

Is the section you are looking for that says ‘this section is highly conserved throughout all known variants’.

The novel method appears to be the the humanisation of mouse cells - ‘The researchers first inserted two human gene segments into the mice. This pushed the mice’s immune cells to quickly produce a diverse repertoire of antibodies resembling those our bodies might make.’

Since that’s all the detail they give it’s not possible for me to comment on just how unique this technique is, because humanisation of mouse white cells isn’t totally unprecedented, so maybe there’s some scientific press release licence here

Checking now the Results section of the paper, they do address how conservative the relevant genome site is, extracted below (emphases mine). TLDR: very but just short of completely conserved. Seems hopeful.

---

> Comparison of SP1-77 footprint to the mutations on the RBD of variants.

When the SP1-77 footprint was projected onto modeled RBDs from different SARS-CoV-2 variants (Fig. 5, A and B), it was evident that most mutations were located outside of the SP1-77 binding site, except for the Arg346Lys in the Mu and Omicron-BA.1.1 variants, and the Gly339Asp and Asn440Lys in all current Omicron sub-variants (50).

The modeled interfaces of SP1-77 bound to the Mu and Omicron RBDs, based on the SP1-77/G614 S complex, indicated that the conservative Arg346Lys mutation would preserve the interaction with HC CDR3 and would not have much impact on binding. Likewise, the Gly339Asp and Asn440Lys mutations were at the edge of the SP1-77 epitope with their side chains pointing away from the binding interface, explaining why Omicron variants were sensitive to SP1-77 neutralization (Fig. 5C).

While mutations near the Asn343-glycan in Omicron reconfigure the orientation such that the carbohydrate projects away from the protein surface (51), such mutations had minimal impact on binding and neutralization activity of SP1-77 (Fig. 5C).

Thus, these studies provided a structure-driven hypothesis for why SP1-77 potently and broadly neutralized all tested SARS-CoV-2 variants through Omicron BA.5.

Finally, we compared the SP1-77 footprint with the new mutations on the recently emerged BA.2.75 sub-variant. The N460K mutation in BA.2.75 was far from the SP1-77 footprint (Fig. 5, A and B); while the BA.2.75 G339H and G446S mutations were close to but did not overlap with SP1-77 footprint as described for BA.1.

These findings made us hopeful that SP1-77 also will bind and robustly neutralize BA.2.75.

If you don't see some part of a virus ever mutate, it marks a vulnerable location.

Yes -- A lack of mutations on the site is a strong hint that it is functionally important. If virions with mutations at this site were equally fit, you'd expect more variation.

This is basic evolutionary theory that has been subsequently played out in both the lab and in the wild. You can't prove a negative but your requirement for reassurance will only be assuaged by furthering your own understanding of evolution on a molecular level, it doesn't seem like anything I could say to you in a reply to an internet post would make the slightest bit of difference to your skepticism and you'd have to get the basic grounding in yourself. The full answer would require 3-4 years of fulltime study, the shorter answer could be arrived at by reading the blind watchmaker and climbing mount improbably, two highly accessible books on evolutionary biology

I think this is fair, even if a bit frustrating that the explanation can't be broken down simpler to laymen.

Or is it a logical reality? i.e. we know the possible permutations of the RNA and from its current state it could not reach an escape branch?

Edit: FYI, my biology is weak but it has occured to me that there must be a topology of evolution.

You first spoke as if it was an absolute certainty ("This is basic evolutionary theory") and now are saying, "all of the normal caveats apply" which is exactly what I was getting at in my OP thread. The "normal caveats"/edge cases are exactly what this whole discussion is about. Clearly we are speaking past one another, I apologize for my role in whatever went wrong here.

The problem is you haven't grasped that they're actually the same answer. It can be true that a field driven by stochastic behaviour consists mostly of degrees and probabilities, and still, due to the realities of how evolution and natural selection work, mean that it is impossible for an extremely highly conserved component of spike protein to jump to a new configuration, that at the same time escapes antibody response for the conserved region and maintains any degree of fitness in the wild.

Please park your antagonism and if you are actually interested, walk through the door and explore the field yourself. It's fascinating

See this is exactly the sort of quantification I was asking for from the beginning (albeit still somewhat vague). Others in the thread have already answered most of my questions (read the other threads if you like) but you just kept talking past them until now. I appreciate you taking the time to respond.

> walk through the door and explore the field yourself. It's fascinating

That is precisely what I am trying to do here because I do find it fascinating as well. I have to be allowed to ask questions (even stupid ones) and I do those primarily in discussion forums like HN.

In keeping with the metaphor though and as others have pointed out in the thread - non oxygen lungs wouldn't make humans super humans, just different and if anything more likely to be weaker than their oxygen breathing counterparts as they adapt to a new environment? I think that is the running idea I'm getting at least.