The Achilles Heel of the Coronavirus • Hacker News Board

Re: The Achilles Heel of the Coronavirus

#51

Post by Clostridium » Mon, May 17, 2021, 9:52 AM UTC

roenxi wrote: post #37

IAmGraydon wrote: post #20

Earlier quoted context omitted.

The article doesn’t say it’s “rarely used”. It says it “rarely happens”. It is not supposed to happen: > Frameshifting almost never happens in our cells. It would lead to dysfunctional cellular proteins. So the drug would disable an aberrant behavior that coronaviruses depend upon to replicate. This doesn’t sound like a bad thing. It’s also why trials exist.

There is a level of confidence in your post which is wholly unwarranted given how complicated the human body is. There is no design committee at work here, nobody is telling any body what the bits are supposed to do. It is all evolutionary equilibriums. The point of this drug is to shut the coronavirus down to the point where it cannot restart; it is not at all out of the question that something obscure but important…

Au contraire, this is exactly the thing that we should look into in an emergency! RNA-slippage is a well-known mechanism that a healthy cell has safeguards against. The corona virus exploits this slippage, so disabling it using a drug is a novel and smart approach as this presents a likely very specific attack surface (meaning side-effects will likely be few). Ignoring this mechanism would be very imprudent. What makes you think the usual precautions (cell lines, animal models, phase I, II, III trials) will not be taken as per usual?

Re: The Achilles Heel of the Coronavirus

#52

Post by FartyMcFarter » Mon, May 17, 2021, 9:56 AM UTC

Does anyone have a sense of why the virus evolved to use this strange "frameshift" mechanism? Is this "hack" somehow advantageous enough for the virus that it would evolve it, rather than using more standard mechanisms?

edit - oh, wikipedia claims this is a compression mechanism, that's amazing! https://en.wikipedia.org/wiki/Ribosomal_frameshift#Function

Re: The Achilles Heel of the Coronavirus

#53

Post by Clostridium » Mon, May 17, 2021, 9:58 AM UTC

roenxi wrote: post #42

ithkuil wrote: post #40

Earlier quoted context omitted.

Not disagreeing on the caution angle. But, let's imagine we find, by the usual trial and error, a chemical compound whose effects are that of curing patients from the coronavirus. Trials show that it has some rare side effects, like many other drugs. How much do we need to "understand" its first, second and third (and fourth) order effects before deciding to use it?

In this case it is using an unproven mechanism that requires proof of a negative ("nothing important in the body uses this mechanism"). It cannot be done safely and quickly. Just because someone survives 12 months and feels fine doesn't tell us anything about the safety of that mechanism. We could literally be injecting people with HIV and it'd only be showing "rare side effects" for the first 12 months as far as sym…

Corona virus exploiting frame shifting using a pseudoknot is not a at all unproven, has been known and researched since 2005

Re: The Achilles Heel of the Coronavirus

#54

Post by Clostridium » Mon, May 17, 2021, 10:03 AM UTC

roenxi wrote: post #47

xorfish wrote: post #45

Earlier quoted context omitted.

I don't think that the idea is to disable it forever.

If we disable oxygen to the lungs for 30 minutes then switching it back on doesn't help. The lung owner is probably dead. Some of this stuff causes permanent changes. There is reason to be optimistic, because if for it to be really bad then there'd need to be: * Permanent change * Causing negative symptoms * Which took a long time to be symptomatic (which, coincidentally, HIV/AIDS exposure is a great example of) Now…

There are always risks, and ignoring a novel approach is also a risk. The issue is to gauge risk intelligently, based on extensive prior medical, biological and physicochemical knowledge and modelling, and on sound clinical testing using randomized controlled trials (the kind of trial that proved dexametasone and disproved ivermectin, hydroxyquinoline etc. as a therapeutic for covid).

Re: The Achilles Heel of the Coronavirus

#55

Post by Clostridium » Mon, May 17, 2021, 10:08 AM UTC

koeng wrote: post #11

I'd say the achilles heel is most likely in the genomic structure, which unlike influenza, is less likely to recombine.

Not true, the genome of viruses is very variable/evolvable due to its high mutation rates.

Re: The Achilles Heel of the Coronavirus

#56

Post by roenxi » Mon, May 17, 2021, 10:14 AM UTC

Clostridium wrote: post #51

roenxi wrote: post #37

Earlier quoted context omitted.

There is a level of confidence in your post which is wholly unwarranted given how complicated the human body is. There is no design committee at work here, nobody is telling any body what the bits are supposed to do. It is all evolutionary equilibriums. The point of this drug is to shut the coronavirus down to the point where it cannot restart; it is not at all out of the question that something obscure but important…

Au contraire, this is exactly the thing that we should look into in an emergency! RNA-slippage is a well-known mechanism that a healthy cell has safeguards against. The corona virus exploits this slippage, so disabling it using a drug is a novel and smart approach as this presents a likely very specific attack surface (meaning side-effects will likely be few). Ignoring this mechanism would be very imprudent. What mak…

> What makes you think the usual precautions (cell lines, animal models, phase I, II, III trials) will not be taken as per usual?

You've skipped one of the usual phases, which is Phase IV trials. Cell lines -> Phases III trials aren't enough to catch long term side effects, because they are all done quickly.

An experimental mechanism passing Phase III trials is insufficient to prove it is safe. It proves that any negative events aren't evident quickly. The drug will probably prove to be safe in time, and I don't mind if people want to take that risk, I'm pretty free market. But it is, nevertheless, risky. We can't be confident that the body isn't using the same trick somewhere or somehow for something delicate that breaks quickly and shows symptoms slowly - biology is complex.

If the mechanism is novel then it wouldn't be suitable for a mass rollout to deal with this pandemic.

Re: The Achilles Heel of the Coronavirus

#57

Post by sokoloff » Mon, May 17, 2021, 10:18 AM UTC

ithkuil wrote: post #40

roenxi wrote: post #37

Earlier quoted context omitted.

There is a level of confidence in your post which is wholly unwarranted given how complicated the human body is. There is no design committee at work here, nobody is telling any body what the bits are supposed to do. It is all evolutionary equilibriums. The point of this drug is to shut the coronavirus down to the point where it cannot restart; it is not at all out of the question that something obscure but important…

Not disagreeing on the caution angle. But, let's imagine we find, by the usual trial and error, a chemical compound whose effects are that of curing patients from the coronavirus. Trials show that it has some rare side effects, like many other drugs. How much do we need to "understand" its first, second and third (and fourth) order effects before deciding to use it?

If it cures COVID-19 patients, you can use that drug on exactly those people whose case is severe enough to justify the risk. Many chemotherapy drugs have terrible side-effects. We break people’s ribs from CPR all the time.

No one argues we should stop breaking those ribs as that’s a fairly easy balance to strike versus a vaccine that you give prophylactically to healthy people. Far more caution is warranted there. (This article is about a therapeutic drug concept, meaning it’s the former case, but I’d still argue caution and where traditional supportive and therapeutic measures are working, I’d not rush to use this mechanism on mild cases.)

Re: The Achilles Heel of the Coronavirus

#58

Post by Clostridium » Mon, May 17, 2021, 10:26 AM UTC

roenxi wrote: post #56

Clostridium wrote: post #51

Earlier quoted context omitted.

Au contraire, this is exactly the thing that we should look into in an emergency! RNA-slippage is a well-known mechanism that a healthy cell has safeguards against. The corona virus exploits this slippage, so disabling it using a drug is a novel and smart approach as this presents a likely very specific attack surface (meaning side-effects will likely be few). Ignoring this mechanism would be very imprudent. What mak…

> What makes you think the usual precautions (cell lines, animal models, phase I, II, III trials) will not be taken as per usual? You've skipped one of the usual phases, which is Phase IV trials. Cell lines -> Phases III trials aren't enough to catch long term side effects, because they are all done quickly. An experimental mechanism passing Phase III trials is insufficient to prove it is safe. It proves that any neg…

Phase IV trials are only undertaken after formal approval by FDA and EDA; they are not relevant in the current context. The current vaccins (including Pfizer, moderna which clearly use a novel mechanism for delivery) also don't have phase IV data yet. Thank God they have been approved though, they are currently clearly the way out of a pandemic that so far has claimed 3.4 million deaths. I really don't understand what you on about, sorry.

Re: The Achilles Heel of the Coronavirus

#59

Post by StavrosK » Mon, May 17, 2021, 10:27 AM UTC

dnautics wrote: post #28

if we targeted this, would the coronavirus simply be able to figure out a way to regulate its proteins some other way?

If we got rid of all living organisms entirely, it stands to reason that the virus wouldn't be able to go on living by itself. Therefore, between the current situation and now, there's a point where it's too hard for the virus to keep existing in its current form.

There's no reason to suspect that the virus will be able to tackle anything we throw at it without just dying out. It might not be the vaccine, but it'll be something (assuming it doesn't just turn into a common cold eventually and we lose interest.

Re: The Achilles Heel of the Coronavirus

#60

Post by flybrand » Mon, May 17, 2021, 11:07 AM UTC

roenxi wrote: post #37

IAmGraydon wrote: post #20

Earlier quoted context omitted.

The article doesn’t say it’s “rarely used”. It says it “rarely happens”. It is not supposed to happen: > Frameshifting almost never happens in our cells. It would lead to dysfunctional cellular proteins. So the drug would disable an aberrant behavior that coronaviruses depend upon to replicate. This doesn’t sound like a bad thing. It’s also why trials exist.

There is a level of confidence in your post which is wholly unwarranted given how complicated the human body is. There is no design committee at work here, nobody is telling any body what the bits are supposed to do. It is all evolutionary equilibriums. The point of this drug is to shut the coronavirus down to the point where it cannot restart; it is not at all out of the question that something obscure but important…

> There is a level of confidence in your post which is wholly unwarranted given how complicated the human body is.

Thank you for saying this, there is a great deal of over confidence bias in the approach to this virus.