11 ms·

Let's say a piece of mRNA has a 1E-12 chance of causing you to grow a third arm by virtue of a defect. Two pieces of mRNA would have very close to a 2E-12 chanc

Let's say a piece of mRNA has a 1E-12 chance of causing you to grow a third arm by virtue of a defect. Two pieces of mRNA would have very close to a 2E-12 chance of causing you to grow a third arm. That's linearity. If you've doubled the defect rate, you've doubled the risk. This contrast with e.g. sports brain trauma, where one sports brain trauma might be relatively moderate risk, but two might be very high risk (much more than double). Or risk from ibuprofen, where 600mg is has close to zero risk, but an overdose of 60,000mg poses a significant risk of death (much more than 100x the risk of death of a 600mg dose). That's nonlinear. I'm not sure how risk from mRNA defects would be anything but linear. It would take an extraordinary set of coincidences.

tobmlt 6y ago
it would appear you are sampling an unknown distribution, finding it mostly to be negligible in its effects, and calling it linear? I’m confused so let me try an analogy with DNA: most mutations do nothing. Every now and then, cancer. Sample a large number of mutations for a short duration, and you have proven nothing regarding nonlinearity globally. Roughly speaking. Another example: I can measure a the air near (but not to near) a shockwave, or just under (By human scale) the free surface of the ocean, and find pretty much linear behavior if no other pathologies are present. The underlying physics however, is not linear, it is only my approximation which is. Maybe it’s valid over configurations of interest. But then I better know something about the limits of my approximation.
- omegaworks 6y ago
  The thing about DNA damage is that it replicates. mRNA is pretty much designed to be degraded almost immediately after it is transcribed. If I understand woofie11 correctly, it means that the probability that an error in a single mRNA corresponds with an error in another mRNA to cause a larger perceivable effect is small. The errors would have to be made in the exact same way.
  - tobmlt 6y ago
    Ah okay. Thanks for that insight! That seems key.
    - woofie11 6y ago
      Or alternatively, the odds of a particular mRNA mutation doing something harmful are astronomically low. With 7 billion people being injected with large amounts of mRNA, you have a very small number times a very big number, so I can't estimate how likely something is to happen, but we know it's small since we haven't learned about anything critical with tens (hundreds) of millions of injections so far. If an mRNA mutation were to make a self-replicating virus, or make something which damages DNA leading to cancer, or something wonky like that, I guess that's in abstract possible. It can make abstract proteins, and we don't know what those will do. In that case, if I have twice as much mutated mRNA in my body, the odds of that happening almost exactly double. It's like rolling a 1-trillion sided die twice instead of once and seeing if I roll a 1. With one roll, I have a 1-in-a-trillion chance. With two rolls, I have a 2-in-a-trillion chance (minus 1-in-a-septillion of having the same thing happen twice, which we don't know what it would do, but is a small enough possibility we can ignore). But yeah, unless something really wonky going on, I'm not going to end up with hundreds of strands of mutated mRNA in my body *all doing the same thing*.
      - tobmlt 6y ago
        The large sample size in cross section is not compelling to me - On its on - over a short duration of time. Because I know nothing about long term possibilities from that. The statistics as derived from the dynamics of “how rna works” - yeah that’s compelling. This: “If an mRNA mutation were to make a self-replicating virus, or make something which damages DNA leading to cancer, or something wonky like that, I guess that's in abstract possible. It can make abstract proteins, and we don't know what those will do.” Sounds astronomically I likely, but with unknown error bars. Sounds like our If our cross section test Is large enough going on long enough, we might just get there.
        6y ago
darawk 6y ago
Is there any reason to think it's unlikely that mRNA defects would have the same risk profile as Ibuprofen? The body is full of thresholding processes, where up to X% blood concentration the organs filter things out fine, and there's no issue, but over that level danger escalates quickly. I don't know immunology basically at all, but is there some reason to think it doesn't have processes that behave like this?
- ceejayoz 6y ago
  Yes; they're vastly different mechanisms. Ibuprofen reaches a threshold of toxicity; a level at which our body's ability to manage it gets met and then exceeded. Things go rapidly wrong at that point. Degraded mRNA just... doesn't work. It'd be a problem if all the mRNA in your cells started suddenly degrading faster than usual, for sure, but that's because you need the resulting protein output to live. If the vaccine degrades too fast, it just doesn't produce the proteins it was supposed to, but we didn't need them to function. Lost efficacy, but you don't wind up growing extra arms.

tobmlt 6y ago

it would appear you are sampling an unknown distribution, finding it mostly to be negligible in its effects, and calling it linear? I’m confused so let me try an analogy with DNA: most mutations do nothing. Every now and then, cancer. Sample a large number of mutations for a short duration, and you have proven nothing regarding nonlinearity globally. Roughly speaking. Another example: I can measure a the air near (but not to near) a shockwave, or just under (By human scale) the free surface of the ocean, and find pretty much linear behavior if no other pathologies are present. The underlying physics however, is not linear, it is only my approximation which is. Maybe it’s valid over configurations of interest. But then I better know something about the limits of my approximation.

omegaworks 6y ago
The thing about DNA damage is that it replicates. mRNA is pretty much designed to be degraded almost immediately after it is transcribed. If I understand woofie11 correctly, it means that the probability that an error in a single mRNA corresponds with an error in another mRNA to cause a larger perceivable effect is small. The errors would have to be made in the exact same way.
- tobmlt 6y ago
  Ah okay. Thanks for that insight! That seems key.
  - woofie11 6y ago
    Or alternatively, the odds of a particular mRNA mutation doing something harmful are astronomically low. With 7 billion people being injected with large amounts of mRNA, you have a very small number times a very big number, so I can't estimate how likely something is to happen, but we know it's small since we haven't learned about anything critical with tens (hundreds) of millions of injections so far. If an mRNA mutation were to make a self-replicating virus, or make something which damages DNA leading to cancer, or something wonky like that, I guess that's in abstract possible. It can make abstract proteins, and we don't know what those will do. In that case, if I have twice as much mutated mRNA in my body, the odds of that happening almost exactly double. It's like rolling a 1-trillion sided die twice instead of once and seeing if I roll a 1. With one roll, I have a 1-in-a-trillion chance. With two rolls, I have a 2-in-a-trillion chance (minus 1-in-a-septillion of having the same thing happen twice, which we don't know what it would do, but is a small enough possibility we can ignore). But yeah, unless something really wonky going on, I'm not going to end up with hundreds of strands of mutated mRNA in my body *all doing the same thing*.
    - tobmlt 6y ago
      The large sample size in cross section is not compelling to me - On its on - over a short duration of time. Because I know nothing about long term possibilities from that. The statistics as derived from the dynamics of “how rna works” - yeah that’s compelling. This: “If an mRNA mutation were to make a self-replicating virus, or make something which damages DNA leading to cancer, or something wonky like that, I guess that's in abstract possible. It can make abstract proteins, and we don't know what those will do.” Sounds astronomically I likely, but with unknown error bars. Sounds like our If our cross section test Is large enough going on long enough, we might just get there.
      - 6y ago

darawk 6y ago

Is there any reason to think it's unlikely that mRNA defects would have the same risk profile as Ibuprofen? The body is full of thresholding processes, where up to X% blood concentration the organs filter things out fine, and there's no issue, but over that level danger escalates quickly. I don't know immunology basically at all, but is there some reason to think it doesn't have processes that behave like this?

ceejayoz 6y ago
Yes; they're vastly different mechanisms. Ibuprofen reaches a threshold of toxicity; a level at which our body's ability to manage it gets met and then exceeded. Things go rapidly wrong at that point. Degraded mRNA just... doesn't work. It'd be a problem if all the mRNA in your cells started suddenly degrading faster than usual, for sure, but that's because you need the resulting protein output to live. If the vaccine degrades too fast, it just doesn't produce the proteins it was supposed to, but we didn't need them to function. Lost efficacy, but you don't wind up growing extra arms.