5 ms·

Evolution is climbing mount improbable. And natural selection (even in the face of in this case intelligently designed selectors) funnels organisms into potenti

Evolution is climbing mount improbable. And natural selection (even in the face of in this case intelligently designed selectors) funnels organisms into potential dead ends which they can’t evolve out of - they’ve gone up the ‘north face’ and in order to reach fitness in the face of their selectors, they actually need to be on a completely different mountain. An antibody that dead ends all current evolutionary trends for an organism means that they can’t evolve out of the dead end natural selection has funnelled it down. So no, this isn’t a ‘might make it worse’, this is a ‘end of covid’ agent. That’s if the antigenic trigger can be made into a vaccine. More likely what the research is describing is that it is now possible to make a monoclonal antibody that can work as an infusion and is active against all known and future possible variants with the same efficacy.

maegul 4y ago
So, from the article: > 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?
- robbiep 4y ago
  > 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?* 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.
  - maegul 4y ago
    Thanks! Can’t help but wonder how conserved the relevant site actually is. 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.
    - robbiep 4y ago
      >’SP1-77 binds the spike protein at a site that so far has not been mutated in any variant’ 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
- mlyle 4y ago
  > * 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? 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.
- d0mine 4y ago
  If you never see bullet holes in some part of a fuselage, it likely means those planes that do have holes in those places never return home that they are vulnerable area which require more armor. https://en.wikipedia.org/wiki/Abraham_Wald https://en.wikipedia.org/wiki/Abraham_Wald If you don't see some part of a virus ever mutate, it marks a vulnerable location.
jjcon 4y ago
How are we sure it is a dead end and how sure are we? It sounds as if this would put extraordinary selective pressures on the virus, if we are wrong I’d fear we would just make things worse
- stefs 4y ago
  if all oxygen in the air was suddenly (by magic) replaced by carbon dioxide it would put extraordinary selective pressure on humans to evolve something other than oxygen-depending lungs. the most likely outcome would be that we'd all die instantly though.
  - jjcon 4y ago
    I like the metaphor! I'd suggest two points, if humans evolved as fast as viruses and we couldn't replace all the oxygen on earth at once (and likely not at all in some places just as we can't get vaccine everywhere at once and not in some places at all) I would think it far more likely for human evolution to figure it out. Unlikely still, but maybe not outside the realm of possibility? 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.
- hoffs 4y ago
  Well if it isn't then you just make other antibodies that treat the one that you can't deal with. Like it's a dead end at current time with current understanding. And as for making things worse, well it could or it could make things better by becoming lesser variant.
- robbiep 4y ago
  How are we sure and how are we sure 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

maegul 4y ago

So, from the article: > 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?

robbiep 4y ago
> 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?* 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.
- maegul 4y ago
  Thanks! Can’t help but wonder how conserved the relevant site actually is. 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.
  - robbiep 4y ago
    >’SP1-77 binds the spike protein at a site that so far has not been mutated in any variant’ 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
mlyle 4y ago
> * 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? 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.
d0mine 4y ago
If you never see bullet holes in some part of a fuselage, it likely means those planes that do have holes in those places never return home that they are vulnerable area which require more armor. https://en.wikipedia.org/wiki/Abraham_Wald https://en.wikipedia.org/wiki/Abraham_Wald If you don't see some part of a virus ever mutate, it marks a vulnerable location.

jjcon 4y ago

How are we sure it is a dead end and how sure are we? It sounds as if this would put extraordinary selective pressures on the virus, if we are wrong I’d fear we would just make things worse

stefs 4y ago
if all oxygen in the air was suddenly (by magic) replaced by carbon dioxide it would put extraordinary selective pressure on humans to evolve something other than oxygen-depending lungs. the most likely outcome would be that we'd all die instantly though.
- jjcon 4y ago
  I like the metaphor! I'd suggest two points, if humans evolved as fast as viruses and we couldn't replace all the oxygen on earth at once (and likely not at all in some places just as we can't get vaccine everywhere at once and not in some places at all) I would think it far more likely for human evolution to figure it out. Unlikely still, but maybe not outside the realm of possibility? 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.
hoffs 4y ago
Well if it isn't then you just make other antibodies that treat the one that you can't deal with. Like it's a dead end at current time with current understanding. And as for making things worse, well it could or it could make things better by becoming lesser variant.
robbiep 4y ago
How are we sure and how are we sure 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