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.
> 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.
I can put your fears to bed. That shouldn't happen. How vaccines work is they teach a very specific signature to our bodies so it can be destroyed as soon as it appears. . Therefore, any selection pressure would just be to not have that signature. But, since that signature is only valuable because it is recognized, there's no great loss if it becomes meaningless. So no supervirus issues. This is different from overusing antibiotics, because the selection there is not on signatures, but instead a more general "robustness" to the poison (well, poison to the bacteria).
So they really have far less of a grasp of vaccine effects in even that a very narrow situation than you would think. So I don't think you can just put this to bed with a few sentences starting with "it shouldn't happen"!
So, a vaccine's immunity might not last forever. And?
Whereas antibiotic resistance is something that could develop because antibiotics could be under doses so individuals survived partial exposure or perhaps they worked by a mechanisms which already had some resistance in the population.
It's like, you can breed high lung capacity mammals by having them live in water but you would just kill the species if you jumped straight into holding them underwater for 20 minutes.
Something has to be survivable to genetate selective pressure.
Native Americams had no choice but to go the route of inherited immunity when they began contracting Eurasian diseases. Was it worth living through a literal apocalypse to gain immunity?
I think the only reasonable response to the parent query is to address the core issue ... are there non-overlapping capabilities between "artificial" and "natural" antibodies apart from the speed and health-risk of their development/inoculation. In other words, is "artificial" immunity a better form of immunity in a way that "natural" immunity can never match? If so, seems like a pretty obvious case of "lock in".
Without being an expert, I imagine it isn't a trivial question to answer, as the evolutionary capabilities of a pathogen are a key factor, and well, we're still wrestling with predicting protein folding.
mRNA vaccines, by contrast, causes no viral replication so the virus doesn't get these lottery tickets.
Of course, either type of vaccine is going to place evolutionary pressure on a disease to evolve an escape. That's just what happens.
One side note: one of the things about mRNA vaccines is that they can be very specific. Now, that may not be great for Covid where we would like to be more general. However, that may be absolutely essential against Epstein-Barr where a chunk of the virus looks like nervous system proteins. A standard vaccine is likely to prime the immune system just like the virus and cause multiple sclerosis as a side effect. An mRNA vaccine, by contrast, could target only those sections of the E-B virus that look sufficiently different from the nervous system and prime the immune system without risking friendly fire.
Rather the idea seemed to be to stop making more vaccines for COVID - kind of like how we deal with colds now.
It still triggers the immune system, but mutations in any of the major receptors or the like will cause it to be less effective too.
Mutations are random, nothing really is preventing a virus from replicating rapidly and killing a lot of its hosts in the short term, it's just the long-term evolutionary advantage of such traits are small, because killing hosts quickly reduces replication, potentially.
But that doesn't stop viruses and bacteria from mutating into something deadly and killing a lot, or all, of its hosts. However just that has happened throughout evolutionary history on Earth, and even in humans' history. We've seen plenty of pandemics wage war against humans and cause considerable casualties.
There's also plenty of equilibria deadly viruses can reach with their hosts, where they kill a relatively large amount of hosts, but not enough to wipe them out.
On the other hand, faster replication is also often selected for, which often corresponds to more virulence.
Both trends have been observed, depending on a whole lot of complex factors.
An example of this happening is the Spanish flu, which was a mutation of the common flu that was widespread and uncontrolled with vaccines at the time.
Antibiotic resistance in bacteria is mainly from misuse in humans and animals, and disease spread between the two, along with ineffective waste treatment and the leaching of antibiotics into the environment[1]. About 80% of antibiotics sold in the US are used in agriculture[2], where they are given to animals not to treat infections, but to prevent them and to stimulate growth. Over 60% of infectious diseases in humans are spread from animals, and 75% of new diseases in humans are spread from animals[3]. Shooting a few micrograms of vaccines into humans' arms is nowhere near the scale of antibiotic use or accumulation in the environment.
It's also possible to achieve herd immunity with vaccines, whereas antibiotics do not leave lasting immunity. To be effective, antibiotics must be taken when there's a bacterial infection, and their effectiveness diminishes as they leave the body.
Are these "worries" consistent? Where is the worry that polio vaccination might create worse strains of polio?
[1] https://en.wikipedia.org/wiki/Antimicrobial_resistance
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638249/
[3] https://www.cdc.gov/onehealth/basics/zoonotic-diseases.html
By cutting down the population of live covid virus particles in the wild, that is, living in human hosts, the possibility of a hard to kill variety to evolve will diminish by a very big probability.
In fact, the new more dangerous varieties are theorized to have evolved in single individuals, who lack a strong immune system, and can't kill a single virus infection for months, and then the virus accumulates changes over these months before jumping onto the general population.
That'd be a valid question if we didn't ready have non-live vaccines with very good proven track records for polio, hepatitis, the flu, etc.
> Current Covid strains don’t seem all that bad, basically everyone I know has been infected now.
And here comes the covid denial argument. Relentlessly repeating the same loaded arguments again and again.
> Might we run the risk of making things worse at this point?
Yeah, but what about wind turbine's rare earth ? It's really polluting ! And what if climate change has more benefits than problems once we have adapted, uh ?
Be aware that live virus vaccines are certainly not monoclonal antibody injections.
As well, rather than spending your mental energy developing excuses to dismiss, why not think on the subject at hand? You should wonder why this mouse model produces broadly neutralizing antibodies in response to COVID spike proteins while the human immune system does not.
That’s a bit interesting to the subject of COVID, isn’t it? Certainly more so than windmills and politics.
No, I am singling out another comment which spreads doubts and denial by hiding them among good faith arguments. For instance:
> (that the successive COVID variants have proven less debilitating and deadly)
Doesn't mean it's not debilitating and deadly.
> basically everyone I know has been infected now.
And I haven't and neither my best friend nor my parents did. But my brother did and another friend did. Guess which one is complaining 6 months later of symptoms that are not going away ?
> As well, rather than spending your mental energy developing excuses to dismiss, why not think on the subject at hand? You should wonder why this mouse model produces broadly neutralizing antibodies in response to COVID spike proteins while the human immune system does not.
> That’s a bit interesting to the subject of COVID, isn’t it? Certainly more so than windmills and politics.
I believe Covid was and is still dangerous and not to be taken lightly because "most people I know has been infected and successive strains are less deadly" (the last one being also dodgy since it might as well be less deadly for an individual but more deadly for a population if it infects much more people, anyway...). That's as worthy to discuss as the core of the submission is.
It is literally in the HN rules that you are supposed to assume good faith, not concoct false attributions of intent and conspiracy. I did not intend to hide anything, I was earnestly asking a question (clearly shared by plenty others in this post). It should not upset you this much. I apologize for anything triggering to you that I said, that wasn't my intent.
The question pertaining to the core of the submission does not upset me, nor do I find it in bad faith (that one I assume good faith since it's legitimate).
> Current Covid strains don’t seem all that bad, basically everyone I know has been infected now.
This, does. Because it has nothing to do with the submission but all with covid minmizing thrown in after a legitimate question.
> I apologize for anything triggering
and
> Assume good faith - its in the rules friend (https://news.ycombinator.com/newsguidelines.html)
This wording (emphasis mine) tells me all there is to know about why I shouldn't explain myself to you.
Question: how low does the IFR have to be so we can call a disease "not so bad" without "minimizing" it?
If that is what you took from my comment I apologize that isn't what I intended to convey at all. I did however intend to ask a question about the topic at hand (broader vaccines) in our current situation which is categorically improved relative to early covid
The first observation is false, the second, very far from universal.
Besides which, there are numerous EU member states whose vaccination rate remains below the population immunity level. More broadly, the global chain of infection, and the consequences thereof (preventable suffering and death), has not (yet) been interrupted by a sufficient global reservoir of acquired immunities.
Furthermore, "not as deadly" hardly corresponds to "don’t seem all that bad". Mustard gas is "not as deadly" as VX. Let's not move the goalposts. In the same vein, it would be a mistake to implicitly assume that future COVID variants will be less deadly.
> "not as deadly" hardly corresponds to "don’t seem all that bad".
That is a simply a judgement call really isn't it? We live with all sorts of terrible things. Cars kill over a million people each year and while terrible, they really aren't "all that bad"
I'm not trying to make light of something so serious only speaking in relative terms compared to what we've already been through. Also what is wrong with including vaccinated exactly? They have some level of immunity, that is what counts here right?
>you expressed a common fear that vaccination development becomes counter-productive
That is just false. I was asking if by developing such broad vaccines (as opposed to those that we have developed in the past) if we ran the risk of selecting for worse viruses. As best as I can tell the answer is no, but there isn't anything wrong with asking the question right?
I struggle to comprehend the mindset that allows anyone to think killing a million people "isn't all that bad".
> I was asking if by developing such broad vaccines (as opposed to those that we have developed in the past) if we ran the risk of selecting for worse viruses.
Whilst you were responding I edited that remark from my comment, since it does not lead to a worthwhile discussion. Nonetheless I'll stand by it as an appropriate characterization.
Please read again, I said cars are not all that bad, if you are going to have discussion please assume good faith (see hn rules please https://news.ycombinator.com/newsguidelines.html)
Junk foods like ice cream, pizza, soda etc. I think can be good but they also lead to the deaths of millions a year (albeit more indirectly). The world just isn't black and white. It is complex and there is nuance.
This discussion may as well end here, because I can have no meeting of minds with someone whose moral compass spins so freely as to wave away millions of human lives on frippery. The only other entity I've had a dialogue with willing to express a similar worldview was GPT-3. That AI was trained on a wide spectrum of human expression, so evidently someone out there agrees with such sentiment, but to me it's downright repugnant.
Source: https://news.gallup.com/opinion/gallup/354938/adults-estimat...