5 ms·

ACE-2 is a popular target for blood-pressure related medications, but I highly doubt the vaccine is creating enough spike proteins to cause a systemic effect. O

ACE-2 is a popular target for blood-pressure related medications, but I highly doubt the vaccine is creating enough spike proteins to cause a systemic effect. Otherwise you'd see people showing up with oxygenation and other blood/lung related issues, just like actual COVID patients. You just create a little bit of spike protein to give your immune system a benign target to work off of.

jcims 6y ago
One thing I haven't been able to find yet is how many spike proteins are generated per strand of mRNA. Is it 1:1 or is the mRNA reused a few/buncha times before it degrades?
- usrusr 6y ago
  I don't know, but I think that if it was just 1:1 it would be far easier to get the protein manufactured by cells living in a petri dish (that can be subjected to much more drastic changes) and inject those protein copies directly instead of mRNA wrapped in some fancy vector molecules.
  - tachyonbeam 6y ago
    The fancy vector molecules are just oils. AFAIK the reason they use mRNA is precisely because it's easy to make lots of it quickly through simple chemical processes. Proteins are much more complex, and harder to synthesize using traditional chemical processes.
- tachyonbeam 6y ago
  Not all the mRNA makes it into your cells, but for the mRNA that does, it probably produces thousands of spike proteins before degrading.
  - jcims 6y ago
    Whoa. That's cool. A while back I wondered if we could just synthesize the proteins externally, but this way we only have to figure out how to synthesize, package and deliver mRNA and the process could be used to generate an arbitrary set of proteins. Presumably the proteins themselves are going to vary as much as the tissues in the human body, so the synthesis might be the same but the packaging and delivery parts would seem to vary widely based on characteristics of the protein.
    - KyleJ61782 6y ago
      To the best of my knowlede, the Novavax vaccine actually does this. Instead of delivering an mRNA nanoparticle, it delivers a spike protein nanoparticle. In fact, they just started phase 3 trials: https://www.sciencemag.org/news/2020/12/novavax-launches-pivotal-us-trial-dark-horse-covid-19-vaccine-after-manufacturing https://www.sciencemag.org/news/2020/12/novavax-launches-piv...
- arrosenberg 6y ago
  It's definitely not 1:1, but the mRNA degrades fairly quickly at body temperature (thus, 2 doses). Here is a study of the effects - https://www.nejm.org/doi/full/10.1056/NEJMoa2024671 https://www.nejm.org/doi/full/10.1056/NEJMoa2024671. It doesn't directly address your question, but it does show how the vaccine performs to control (labeled pbs) in terms of viral load and immune system activity when challenged with a dose of the virus.
  - shellfishgene 6y ago
    The mRNA produced for the vaccines have various modifications that cause greater stability than normal mRNA. The two shots have nothing to do with mRNA stability, they improve immunity, as in any other vaccine given in two or three shots.
- fattire 6y ago
  My understanding is the mRNA is reused over and over-- the AAAAAAs at the end of the vaccine sequence are there to extend their tiny little lives a bit as the end breaks off after each reading.
  - KyleJ61782 6y ago
    Basically like little vaccine telomeres?
- mrep 6y ago
  It is reused many times as this super interesting article that I highly recommend [0] explains and I'll quote: The very end of mRNA is polyadenylated. This is a fancy way of saying it ends on a lot of AAAAAAAAAAAAAAAAAAA. Even mRNA has had enough of 2020 it appears. mRNA can be reused many times, but as this happens, it also loses some of the A’s at the end. Once the A’s run out, the mRNA is no longer functional and gets discarded. In this way, the ‘poly-A’ tail is protection from degradation. Studies have been done to find out what the optimal number of A’s at the end is for mRNA vaccines. I read in the open literature that this peaked at 120 or so. The BNT162b2 vaccine ends with: UAGCAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAGCAUAU GACUAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAA This is 30 A’s, then a “10 nucleotide linker” (GCAUAUGACU), followed by another 70 A’s. [0]: https://news.ycombinator.com/item?id=25538820 https://news.ycombinator.com/item?id=25538820
  - mensetmanusman 6y ago
    I love the image of the mRNA yelling AAAAAAAAAAA throughout the body warning of the virus that is about to come (and then slowly losing energy and dissolving into nothing as all screams do).
  - jcims 6y ago
    Damn, I bookmarked that article to read later. I should have read it before posting...it answered basically all of my questions lol
  - m3kw9 6y ago
    I thought it gets broken down after one use? A related question: How does the mrna move itself back into the copy machinery?
    - jcims 6y ago
      It tends to 'degrade' from the end, which is why all of the additional 'A' nucleotides are tacked on to the end, it's basically a NOOP sled that gets shorter and shorter until the instance is disabled. The mRNA isn't intended to be copied in the body. Once the dose is used up there should be no more spike proteins created.
rswail 6y ago
As someone who takes an ACE inhibitor, I've just tried to read up and ACE inhibitors are for ACE-1, not ACE-2. They are two different things. ACE-1 is a precursor that generates the protein/enzyme that eventually connects to the ACE-2 receivers on cell walls that SARS-Cov-2 uses to invade cells. Reading https://theconversation.com/what-is-the-ace2-receptor-how-is-it-connected-to-coronavirus-and-why-might-it-be-key-to-treating-covid-19-the-experts-explain-136928 https://theconversation.com/what-is-the-ace2-receptor-how-is... there is a section that explains the difference between ACE-1 inhibitors (like in ramipril etc) and ACE-2 inhibitors. Wikipedia has the layman's details of the RAAS system: https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_syst...

jcims 6y ago

One thing I haven't been able to find yet is how many spike proteins are generated per strand of mRNA. Is it 1:1 or is the mRNA reused a few/buncha times before it degrades?

usrusr 6y ago
I don't know, but I think that if it was just 1:1 it would be far easier to get the protein manufactured by cells living in a petri dish (that can be subjected to much more drastic changes) and inject those protein copies directly instead of mRNA wrapped in some fancy vector molecules.
- tachyonbeam 6y ago
  The fancy vector molecules are just oils. AFAIK the reason they use mRNA is precisely because it's easy to make lots of it quickly through simple chemical processes. Proteins are much more complex, and harder to synthesize using traditional chemical processes.
tachyonbeam 6y ago
Not all the mRNA makes it into your cells, but for the mRNA that does, it probably produces thousands of spike proteins before degrading.
- jcims 6y ago
  Whoa. That's cool. A while back I wondered if we could just synthesize the proteins externally, but this way we only have to figure out how to synthesize, package and deliver mRNA and the process could be used to generate an arbitrary set of proteins. Presumably the proteins themselves are going to vary as much as the tissues in the human body, so the synthesis might be the same but the packaging and delivery parts would seem to vary widely based on characteristics of the protein.
  - KyleJ61782 6y ago
    To the best of my knowlede, the Novavax vaccine actually does this. Instead of delivering an mRNA nanoparticle, it delivers a spike protein nanoparticle. In fact, they just started phase 3 trials: https://www.sciencemag.org/news/2020/12/novavax-launches-pivotal-us-trial-dark-horse-covid-19-vaccine-after-manufacturing https://www.sciencemag.org/news/2020/12/novavax-launches-piv...
arrosenberg 6y ago
It's definitely not 1:1, but the mRNA degrades fairly quickly at body temperature (thus, 2 doses). Here is a study of the effects - https://www.nejm.org/doi/full/10.1056/NEJMoa2024671 https://www.nejm.org/doi/full/10.1056/NEJMoa2024671. It doesn't directly address your question, but it does show how the vaccine performs to control (labeled pbs) in terms of viral load and immune system activity when challenged with a dose of the virus.
- shellfishgene 6y ago
  The mRNA produced for the vaccines have various modifications that cause greater stability than normal mRNA. The two shots have nothing to do with mRNA stability, they improve immunity, as in any other vaccine given in two or three shots.
fattire 6y ago
My understanding is the mRNA is reused over and over-- the AAAAAAs at the end of the vaccine sequence are there to extend their tiny little lives a bit as the end breaks off after each reading.
- KyleJ61782 6y ago
  Basically like little vaccine telomeres?
mrep 6y ago
It is reused many times as this super interesting article that I highly recommend [0] explains and I'll quote: The very end of mRNA is polyadenylated. This is a fancy way of saying it ends on a lot of AAAAAAAAAAAAAAAAAAA. Even mRNA has had enough of 2020 it appears. mRNA can be reused many times, but as this happens, it also loses some of the A’s at the end. Once the A’s run out, the mRNA is no longer functional and gets discarded. In this way, the ‘poly-A’ tail is protection from degradation. Studies have been done to find out what the optimal number of A’s at the end is for mRNA vaccines. I read in the open literature that this peaked at 120 or so. The BNT162b2 vaccine ends with: UAGCAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAGCAUAU GACUAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAA This is 30 A’s, then a “10 nucleotide linker” (GCAUAUGACU), followed by another 70 A’s. [0]: https://news.ycombinator.com/item?id=25538820 https://news.ycombinator.com/item?id=25538820
- mensetmanusman 6y ago
  I love the image of the mRNA yelling AAAAAAAAAAA throughout the body warning of the virus that is about to come (and then slowly losing energy and dissolving into nothing as all screams do).
- jcims 6y ago
  Damn, I bookmarked that article to read later. I should have read it before posting...it answered basically all of my questions lol
- m3kw9 6y ago
  I thought it gets broken down after one use? A related question: How does the mrna move itself back into the copy machinery?
  - jcims 6y ago
    It tends to 'degrade' from the end, which is why all of the additional 'A' nucleotides are tacked on to the end, it's basically a NOOP sled that gets shorter and shorter until the instance is disabled. The mRNA isn't intended to be copied in the body. Once the dose is used up there should be no more spike proteins created.

rswail 6y ago

As someone who takes an ACE inhibitor, I've just tried to read up and ACE inhibitors are for ACE-1, not ACE-2. They are two different things. ACE-1 is a precursor that generates the protein/enzyme that eventually connects to the ACE-2 receivers on cell walls that SARS-Cov-2 uses to invade cells. Reading https://theconversation.com/what-is-the-ace2-receptor-how-is-it-connected-to-coronavirus-and-why-might-it-be-key-to-treating-covid-19-the-experts-explain-136928 https://theconversation.com/what-is-the-ace2-receptor-how-is... there is a section that explains the difference between ACE-1 inhibitors (like in ramipril etc) and ACE-2 inhibitors. Wikipedia has the layman's details of the RAAS system: https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_syst...