6 ms·

For me sounds scary to disable a mechanism in all our cells that is "rarely used". Negative knowledge covers what we don't know and what we don't know that we

For me sounds scary to disable a mechanism in all our cells that is "rarely used". Negative knowledge covers what we don't know and what we don't know that we don't know, and that rarely could be less rare than we thought, doing maybe not do frequent but anyway essential things, for all or some cells.

DennisP 5y ago
I wouldn't want to do it permanently but doing it temporarily, to treat a severe acute infection, seems like a pretty good tradeoff. Especially after you've done your clinical safety trials to be sure.
bawolff 5y ago
Doing it just long enough in people with a severe infection so they don't die of the infection seems like a reasonable trade off. Nobody's suggesting we use this as a daily supplement in healthy people.
IAmGraydon 5y ago
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.
- ampdepolymerase 5y ago
  "Dysfunctional proteins" is a vast understatement. Too much frameshifting leads to cancer.
  - aaron_m04 5y ago
    I don't see how it could lead to cancer. We are talking about a translation error, not a replication error.
    - dnautics 5y ago
      it could, in theory lead to cancer, but you'd have to be super unlucky. (frameshift -> accidentally leads to some sort of oncogene agonist)
      - pygy_ 5y ago
        Even then, frame shifts are one off events, so you’d end up with a single instance of an oncogene that would quickly get recycled.
        dnautics 5y ago
        exactly. Don't know about quickly. Half lives of single proteins can be highly variable. You can have a single protein live long enough to destroy an entire cell (ricin); it evades degradation by not having many lysines and never being ubiquitinated.
- deleted 5y ago
  [deleted]
- roenxi 5y ago
  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 in the human body uses the same mechanism and would similarly be permanently disabled. New technologies are all very well, but this is not the sort of approach that should be rolled out in an emergency. If someone has 10 years of safety data from some trial and can put their hand on their heart to swear there are no suspicions of a problem then that is one thing, but otherwise there is no way this approach is safe for an emergency mass deployment. It probably won't be relevant for the current pandemic.
  - ithkuil 5y ago
    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?
    - roenxi 5y ago
      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 symptoms go.
      - xorfish 5y ago
        I don't think that the idea is to disable it forever.
        5y ago
ARandomerDude 5y ago
Yeah I always laugh for the same reason when people describe organs as "vestigial."
- pessimizer 5y ago
  We can say that confidently because plenty of people have lived long lives of average health without those organs.
fabian2k 5y ago
This is not actually a mechanism in our cells. The virus RNA folds in a particular way that interferes with how the ribosome usually works. Imagine it like a machine that takes in a an RNA strand, and you make a knot in the strand. The machine can untangle the knot with some force, but slips while it is doing this and the alignment of the strand shifts and the machine continues on a different position on the strand than before. What they propose is to target the knot with a drug, not our cells.
- TacticalMalice 5y ago
  Translational frameshifting is a feature of the human PEG10 mRNA, https://www.genecards.org/cgi-bin/carddisp.pl?gene=PEG10 https://www.genecards.org/cgi-bin/carddisp.pl?gene=PEG10 http://recode.ucc.ie/search?q=homo+sapiens http://recode.ucc.ie/search?q=homo+sapiens lists a number of other recode events.

DennisP 5y ago

I wouldn't want to do it permanently but doing it temporarily, to treat a severe acute infection, seems like a pretty good tradeoff. Especially after you've done your clinical safety trials to be sure.

bawolff 5y ago

Doing it just long enough in people with a severe infection so they don't die of the infection seems like a reasonable trade off. Nobody's suggesting we use this as a daily supplement in healthy people.

IAmGraydon 5y ago

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.

ampdepolymerase 5y ago
"Dysfunctional proteins" is a vast understatement. Too much frameshifting leads to cancer.
- aaron_m04 5y ago
  I don't see how it could lead to cancer. We are talking about a translation error, not a replication error.
  - dnautics 5y ago
    it could, in theory lead to cancer, but you'd have to be super unlucky. (frameshift -> accidentally leads to some sort of oncogene agonist)
    - pygy_ 5y ago
      Even then, frame shifts are one off events, so you’d end up with a single instance of an oncogene that would quickly get recycled.
      - dnautics 5y ago
        exactly. Don't know about quickly. Half lives of single proteins can be highly variable. You can have a single protein live long enough to destroy an entire cell (ricin); it evades degradation by not having many lysines and never being ubiquitinated.
deleted 5y ago
[deleted]
roenxi 5y ago
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 in the human body uses the same mechanism and would similarly be permanently disabled. New technologies are all very well, but this is not the sort of approach that should be rolled out in an emergency. If someone has 10 years of safety data from some trial and can put their hand on their heart to swear there are no suspicions of a problem then that is one thing, but otherwise there is no way this approach is safe for an emergency mass deployment. It probably won't be relevant for the current pandemic.
- ithkuil 5y ago
  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?
  - roenxi 5y ago
    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 symptoms go.
    - xorfish 5y ago
      I don't think that the idea is to disable it forever.
      - 5y ago

ARandomerDude 5y ago

Yeah I always laugh for the same reason when people describe organs as "vestigial."

pessimizer 5y ago
We can say that confidently because plenty of people have lived long lives of average health without those organs.

fabian2k 5y ago

This is not actually a mechanism in our cells. The virus RNA folds in a particular way that interferes with how the ribosome usually works. Imagine it like a machine that takes in a an RNA strand, and you make a knot in the strand. The machine can untangle the knot with some force, but slips while it is doing this and the alignment of the strand shifts and the machine continues on a different position on the strand than before. What they propose is to target the knot with a drug, not our cells.

TacticalMalice 5y ago
Translational frameshifting is a feature of the human PEG10 mRNA, https://www.genecards.org/cgi-bin/carddisp.pl?gene=PEG10 https://www.genecards.org/cgi-bin/carddisp.pl?gene=PEG10 http://recode.ucc.ie/search?q=homo+sapiens http://recode.ucc.ie/search?q=homo+sapiens lists a number of other recode events.