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> RNA is fragile. So, like in the COVID mRNA vaccines, these instructions can be delivered in a protective fatty bubble called a “lipid nanoparticle.” Think of

> RNA is fragile. So, like in the COVID mRNA vaccines, these instructions can be delivered in a protective fatty bubble called a “lipid nanoparticle.” Think of it like a balloon made of fatty acids, with the instructions nestled inside. Once injected, these lipid nanoparticles take the mRNA instructions into cells, where the fatty bubble degrades, mRNA instructions are released, and the cell’s machinery start to produce whatever protein the mRNA tells it to. I still don't understand how writers about mRNA vaccines gloss over the numerous details that should be important. The picture that she paints lacks a targeting mechanism. Which cells will these lipid nanoparticles enter? She does not say. How much protein from the mRNA will those cells produce? It can't be predictable, right? Will there be significant differences in the dose of the final product between individuals? Is this important? She does not say. Will the cells that engulf those lipid nanoparticles be destined to die, in case the protein they produce is a foreign one, like the spike protein of Covid? They must be, right? After all, that's how immunity works. Is this important, given that there is no targeting mechanism? She does not say. And so on... What makes an mRNA vaccine more appealing than a protein-based one?

virgildotcodes 3y ago
Isn’t this also basically what happens to countless of our cells every day through natural exposure to viruses?
- azangru 3y ago
  Maybe? Although viruses that we are naturally exposed to on a daily basis don't routinely bypass the mucous membrane barrier, and do not roam freely throughout our bodies. And they normally do have a targeting mechanism that allows them to selectively infect certain types of cells. And in any case, viruses are supposed to be bad for the organism; so I am not sure how this consideration helps.
  - virgildotcodes 3y ago
    I mean viruses target everything and nothing, and mutate insanely rapidly. I imagine the majority that enter our bodies aren’t able to perform any function, and then the ones that can will opportunistically infect anything without regard for the consequences. As for whether or not viruses are bad for us, I mean I don’t think we have any choice in the matter anyway, they’re even more numerous than bacteria, and absolutely everywhere. I wonder how many viruses infect our cells every day vs how many “lipid viruses” are in a standard Moderna Covid shot.
s0rce 3y ago
Everything you said sounds interesting, but my experience, as a scientist in a different field, is that media focused for regular non-expert people simply isn't going to capture those kinds of things. You need to find recent papers, review articles or maybe textbooks to get that kind of information, basically its going to be in documents targeted at experts in this field not lay people.
- dapf 3y ago
  You are correct, and the problem with these articles is that they sound too much like a sales pitch and less like a responsible general-public divulgation article. She may not go in detail about the items aforementioned, but she doesn't even mention once that the technology might have have possible dangers, and that one must exercise caution in its evaluation. The article its all about the potential benefits of the technology, without warning the public about its potential dangers. She even mentions that "the FDA is so painfully slow, and so indifferent to human suffering. It takes, on average, eight years to get a new drug through clinical trials." Yeah, those pesky thorough clinical trials, they are a hurdle on the return on investment.
ImPleadThe5th 3y ago
Similarly, my question is if we trick random cells around the body into producing these spike proteins, and they presumably don't stop for a while (no idea on how long), does this not also create an undo burdon on the immune system until the cells artificially producing the protein die? And if there's loose RNA floating around, after these cells die can another cell _also_ start reproducing the protein?
- HPsquared 3y ago
  I think the idea is that the RNA doesn't last long. It's quite fragile. You might get fragments of it though, but not enough to print out the whole protein.
tux3 3y ago
The mRNA vaccine mostly stays near the site of injection: your arm. This is why your arm mostly aches, and the rest of your body not so much. A bunch of cells there will die, because your immune system much prefers an innocent cell dead than a infected cell continuing to multiply. But you have plenty of cells. Really quite a lot. So it is entirely worth it. We can try to optimize how much protein cells will make from the mRNA. The goal is "as much as possible, for as long as possible", but mRNA is not meant to be long lived. And foreign mRNA trying to make its way into cells would be destroyed very quickly without trickery (like the nanoparticle and the pseudouridine). But either way, medicine works just the same (a surprising amount of the time!) in the cases where the precise details and mechanisms haven't been elucidated yet. If it works empirically, the details are just details.
- JPLeRouzic 3y ago
  > But you have plenty of cells. Really quite a lot. We have also a lot of cells that do not divide such as neurons, or some cardiac cells.
- hitpointdrew 3y ago
  > The mRNA vaccine mostly stays near the site of injection: your arm. This patently false, and medical disinformation. It is proven with the Covid vaccines that it spreads to the entire body.
epistasis 3y ago
> What makes an mRNA vaccine more appealing than a protein-based one? Having worked on the same targeting mechanisms for protein based vaccines meant to be personalized cancer therapies, and having followed the mRNA vaccines with envy, the benefits are absolutely massive. But there's not a single alternative. In comparison to each type: Short peptides injection are worse because: minimal immune stimulation, less of a mechanism to train the immune system on the peptide targets, have not been effective. Viral delivery of mRNA, that makes proteins, or more exotic methods like yeast with modified genomes: this is a traditional vaccine with a custom viral genome with the peptides of interest added as part of the viral genome. This is not directly a protein virus, but it does make the cells it infects produce the peptides. This requires cell culture to grow the virus, which requires a unique clean room per vaccine, which can be impractical and expensive for a custom virus. It's also very very slow to produce, QC, and make sure it's safe. mRNA production is faster, cleaner, safer, just all around better in every possible way. As for your other questions, sure they are interesting, but get ready to gear up and read tooooons of literature. Most people don't have any of these questions unless they have a deep distrust of the technology, and don't trust that others have bothered to investigate. Skepticism is good, and if you are truly curious I really applaud you and encourage you to pick up an immunology text book so that you can also read and understand the papers. But mRNA vaccine skepticism has to be the stupidest "skepticism" and falsehoods I have ever seen of a new technology. As the competitor to what I was working on, I must concede that it's better on all metrics, and I am kind of saddened for humanity that all these lies about mRNA seem to dominate over the true and huge technological advancement that has occurred.
- azangru 3y ago
  > Short peptides injection are worse because: minimal immune stimulation, less of a mechanism to train the immune system on the peptide targets, have not been effective. If the problem of peptide vaccines is weak immune stimulation, then wouldn't the problem of mRNA vaccines be autoimmunity?
  - epistasis 3y ago
    No, why would that be? Auto-immunity comes from immune cells targeting healthy cells, and the mRNA peptide translations do not correspond to healthy cells.
thehappypm 3y ago
What makes it more appealing is that you can change the mRNA sequence and change the proteins that are created, meaning you can make arbitrary proteins. Traditional vaccines are far less flexible like that since the process to create proteins has more steps
maxerickson 3y ago
One of the big breakthroughs was techniques to modify the mRNA to increase stability and resulting protein production. So it is somewhat predictable.
Izkata 3y ago
Don't forget reverse transcription into free-floating DNA. That's much more stable and can last a long time, and it was confirmed in a lab back in 2021 or 2022 that our liver cells are capable of doing it with the Pfizer mRNA covid vaccine. There was another study last year on long covid that found some vaccine-specific spike proteins persisting weeks or months after they should have degraded/been removed by the immune system, but IIRC they didn't find a reason why.
1vuio0pswjnm7 3y ago
"What makes an mRNA vaccine more appealing than a protein-based one?" For one, mRNA is easier to produce/manufacture than protein.
sandspar 3y ago
It seems like our hot pace of trendy advances has let non-fiction writers flirt with writing in the science fiction genre. If you see some articles as hard science fiction with a "this is a true story" framing device then they make more sense.

virgildotcodes 3y ago

Isn’t this also basically what happens to countless of our cells every day through natural exposure to viruses?

azangru 3y ago
Maybe? Although viruses that we are naturally exposed to on a daily basis don't routinely bypass the mucous membrane barrier, and do not roam freely throughout our bodies. And they normally do have a targeting mechanism that allows them to selectively infect certain types of cells. And in any case, viruses are supposed to be bad for the organism; so I am not sure how this consideration helps.
- virgildotcodes 3y ago
  I mean viruses target everything and nothing, and mutate insanely rapidly. I imagine the majority that enter our bodies aren’t able to perform any function, and then the ones that can will opportunistically infect anything without regard for the consequences. As for whether or not viruses are bad for us, I mean I don’t think we have any choice in the matter anyway, they’re even more numerous than bacteria, and absolutely everywhere. I wonder how many viruses infect our cells every day vs how many “lipid viruses” are in a standard Moderna Covid shot.

s0rce 3y ago

Everything you said sounds interesting, but my experience, as a scientist in a different field, is that media focused for regular non-expert people simply isn't going to capture those kinds of things. You need to find recent papers, review articles or maybe textbooks to get that kind of information, basically its going to be in documents targeted at experts in this field not lay people.

dapf 3y ago
You are correct, and the problem with these articles is that they sound too much like a sales pitch and less like a responsible general-public divulgation article. She may not go in detail about the items aforementioned, but she doesn't even mention once that the technology might have have possible dangers, and that one must exercise caution in its evaluation. The article its all about the potential benefits of the technology, without warning the public about its potential dangers. She even mentions that "the FDA is so painfully slow, and so indifferent to human suffering. It takes, on average, eight years to get a new drug through clinical trials." Yeah, those pesky thorough clinical trials, they are a hurdle on the return on investment.

ImPleadThe5th 3y ago

Similarly, my question is if we trick random cells around the body into producing these spike proteins, and they presumably don't stop for a while (no idea on how long), does this not also create an undo burdon on the immune system until the cells artificially producing the protein die? And if there's loose RNA floating around, after these cells die can another cell _also_ start reproducing the protein?

HPsquared 3y ago
I think the idea is that the RNA doesn't last long. It's quite fragile. You might get fragments of it though, but not enough to print out the whole protein.

tux3 3y ago

The mRNA vaccine mostly stays near the site of injection: your arm. This is why your arm mostly aches, and the rest of your body not so much. A bunch of cells there will die, because your immune system much prefers an innocent cell dead than a infected cell continuing to multiply. But you have plenty of cells. Really quite a lot. So it is entirely worth it. We can try to optimize how much protein cells will make from the mRNA. The goal is "as much as possible, for as long as possible", but mRNA is not meant to be long lived. And foreign mRNA trying to make its way into cells would be destroyed very quickly without trickery (like the nanoparticle and the pseudouridine). But either way, medicine works just the same (a surprising amount of the time!) in the cases where the precise details and mechanisms haven't been elucidated yet. If it works empirically, the details are just details.

JPLeRouzic 3y ago
> But you have plenty of cells. Really quite a lot. We have also a lot of cells that do not divide such as neurons, or some cardiac cells.
hitpointdrew 3y ago
> The mRNA vaccine mostly stays near the site of injection: your arm. This patently false, and medical disinformation. It is proven with the Covid vaccines that it spreads to the entire body.

epistasis 3y ago

> What makes an mRNA vaccine more appealing than a protein-based one? Having worked on the same targeting mechanisms for protein based vaccines meant to be personalized cancer therapies, and having followed the mRNA vaccines with envy, the benefits are absolutely massive. But there's not a single alternative. In comparison to each type: Short peptides injection are worse because: minimal immune stimulation, less of a mechanism to train the immune system on the peptide targets, have not been effective. Viral delivery of mRNA, that makes proteins, or more exotic methods like yeast with modified genomes: this is a traditional vaccine with a custom viral genome with the peptides of interest added as part of the viral genome. This is not directly a protein virus, but it does make the cells it infects produce the peptides. This requires cell culture to grow the virus, which requires a unique clean room per vaccine, which can be impractical and expensive for a custom virus. It's also very very slow to produce, QC, and make sure it's safe. mRNA production is faster, cleaner, safer, just all around better in every possible way. As for your other questions, sure they are interesting, but get ready to gear up and read tooooons of literature. Most people don't have any of these questions unless they have a deep distrust of the technology, and don't trust that others have bothered to investigate. Skepticism is good, and if you are truly curious I really applaud you and encourage you to pick up an immunology text book so that you can also read and understand the papers. But mRNA vaccine skepticism has to be the stupidest "skepticism" and falsehoods I have ever seen of a new technology. As the competitor to what I was working on, I must concede that it's better on all metrics, and I am kind of saddened for humanity that all these lies about mRNA seem to dominate over the true and huge technological advancement that has occurred.

azangru 3y ago
> Short peptides injection are worse because: minimal immune stimulation, less of a mechanism to train the immune system on the peptide targets, have not been effective. If the problem of peptide vaccines is weak immune stimulation, then wouldn't the problem of mRNA vaccines be autoimmunity?
- epistasis 3y ago
  No, why would that be? Auto-immunity comes from immune cells targeting healthy cells, and the mRNA peptide translations do not correspond to healthy cells.

thehappypm 3y ago

What makes it more appealing is that you can change the mRNA sequence and change the proteins that are created, meaning you can make arbitrary proteins. Traditional vaccines are far less flexible like that since the process to create proteins has more steps

maxerickson 3y ago

One of the big breakthroughs was techniques to modify the mRNA to increase stability and resulting protein production. So it is somewhat predictable.

Izkata 3y ago

Don't forget reverse transcription into free-floating DNA. That's much more stable and can last a long time, and it was confirmed in a lab back in 2021 or 2022 that our liver cells are capable of doing it with the Pfizer mRNA covid vaccine. There was another study last year on long covid that found some vaccine-specific spike proteins persisting weeks or months after they should have degraded/been removed by the immune system, but IIRC they didn't find a reason why.

1vuio0pswjnm7 3y ago

"What makes an mRNA vaccine more appealing than a protein-based one?" For one, mRNA is easier to produce/manufacture than protein.

sandspar 3y ago

It seems like our hot pace of trendy advances has let non-fiction writers flirt with writing in the science fiction genre. If you see some articles as hard science fiction with a "this is a true story" framing device then they make more sense.