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Moderna mRNA sequence released to GitHub [pdf]

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Re: Moderna mRNA sequence released to GitHub [pdf]

#101

Earlier quoted context omitted.

> This is somewhat of a problem for our vaccine - it needs to sneak past our immune system. Over many years of experimentation, it was found that if the U in RNA is replaced by a slightly modified molecule, our immune system loses interest. For real. > So in the BioNTech/Pfizer vaccine, every U has been replaced by 1-methyl-3’-pseudouridylyl, denoted by Ψ. The really clever bit is that although this replacement Ψ pla…

Umm, isn't that kind of scary? Like could you create a virus with this Ψ that our immune system can't fight at all?

RNA is genetic material, but it encodes instructions to make proteins, which form the physical shell of the virus crucial to its function. As a very rough analogy, the RNA is source code and the proteins are the compiled program.

It's often the protein molecules that the immune system learns to recognise and attack.

RNA vaccines work because your body automatically translates them into some recognisable part of the viral protein, and then develops an immune reaction to that.

If a virus had Ψ instead of U in its RNA, it's still going to be making the same type of proteins. I can't see why it would be more likely to evade an immune response.

Re: Moderna mRNA sequence released to GitHub [pdf]

#102
post #81
post #70

Earlier quoted context omitted.

The protein they're trying to manufacture is indeed quite simple - AFAIU both BioNTech and Moderna put together their sequences in a weekend. (Though there was a more involved process of winnowing down the sequences for the most effective ones.) The technically challenging parts are: - delivery mechanism: you need to take a very unstable molecule, protect it from the environment - both external, and when inside the p…

> Hence they feel safe releasing this. Their moat is not the gene sequence, their moat is everything else. One or more of the vaccine developers may have released such details, but this particular file is a reverse engineering effort by unaffiliated scientists based on analyzing the dregs of used vaccine vials (!). Edit: See https://news.ycombinator.com/item?id=26628594 for more substantive discussion about this.

Ah - thanks for pointing this out! Edited to make sure readers see it.

Re: Moderna mRNA sequence released to GitHub [pdf]

#103
post #46

https://github.com/brianherman/Assemblies-of-putative-SARS-C... I posted some txt files with the lines removed and stuff.

If you have the time, it would be nice to transfer the data to the commonly used Genbank format.

https://github.com/brianherman/Assemblies-of-putative-SARS-C...

Re: Moderna mRNA sequence released to GitHub [pdf]

#104
post #46

https://github.com/brianherman/Assemblies-of-putative-SARS-C... I posted some txt files with the lines removed and stuff.

If you have the time, it would be nice to transfer the data to the commonly used Genbank format.

Ask and ye shall recieve! Have a great day!

Re: Moderna mRNA sequence released to GitHub [pdf]

#106
post #31

I'm sure it's more complex than I grasp as a layperson, but I'm utterly amazed at how simple this _appears_. I get the feeling that this is something I have a better chance of understanding than the average SaaS Terms and Conditions. I expected to have to scroll through pages upon pages of indecipherable text. Instead it's no bigger than a large paragraph of text, and I can easily fit it on my screen.

Any individual protein doesn't seem that complex since it's just a combination of some 20 amino acids, but the variations are endless: "Since each of the 20 amino acids is chemically distinct and each can, in principle, occur at any position in a protein chain, there are 20 × 20 × 20 × 20 = 160,000 different possible polypeptide chains four amino acids long, or 20n different possible polypeptide chains n amino acids…

The exponentiation signs got lost in your quote. Would you mind adding them back in?

Re: Moderna mRNA sequence released to GitHub [pdf]

#107

Earlier quoted context omitted.

> This is somewhat of a problem for our vaccine - it needs to sneak past our immune system. Over many years of experimentation, it was found that if the U in RNA is replaced by a slightly modified molecule, our immune system loses interest. For real. > So in the BioNTech/Pfizer vaccine, every U has been replaced by 1-methyl-3’-pseudouridylyl, denoted by Ψ. The really clever bit is that although this replacement Ψ pla…

No wonders some people have an allergic reaction. Those people's immune response is more sensitive to this change.

No they have allergies to the polyethylene glycol PEG compound in the lipid nanoparticles. It is also used in skin creams, toothpastes, condom lubricants and in larger quantities as a laxative. Some people are just allergic to it.

Re: Moderna mRNA sequence released to GitHub [pdf]

#108

Earlier quoted context omitted.

> This is somewhat of a problem for our vaccine - it needs to sneak past our immune system. Over many years of experimentation, it was found that if the U in RNA is replaced by a slightly modified molecule, our immune system loses interest. For real. > So in the BioNTech/Pfizer vaccine, every U has been replaced by 1-methyl-3’-pseudouridylyl, denoted by Ψ. The really clever bit is that although this replacement Ψ pla…

Umm, isn't that kind of scary? Like could you create a virus with this Ψ that our immune system can't fight at all?

No. For a number of reasons. First of all, the virus uses the nucleotides (A, G, C and U, for wich Ψ is used as a substitute) produced by the attached cell to create a copy of it's genome (RNA). The nucleotides are produced by the cell, the virus does not instruct the cell to produce them. It just tells the cell to produce and assemble the proteins AND the RNA.

Second, our immune system doesn't just attack and recognize free floating RNA, but the virus itself. And different parts of the virus. First and foremost it will recognize the surface proteins (like the spike protein) because those are the things that it can see while the virus is outside of the cell. Also these are the things that the infected cells present on their surface (MHC II sites, if I'm not mistaken) to the immune system. (As far as I can understand, cells have to present the proteins they produce to the immune system otherwise they get killed. If they produce alien virus proteins that get recognized by the immune system, they also get killed.)

Interesting enough, the immune system somehow also recognizes the so called nucleocapsid protein, which is the one used to wrap the viral RNA inside the virus. (But it gets produced by the cells, so I guess they get presented on the cell surface so the immune system can learn to recognize and counter them.) I didn't look into the details too much, but as far as I can understand it's not clear yet how those antibodies (the ones created against this protein) work, because antibodies are supposed to be used outside of the cells, but the nucleocapsids are only present inside the cells and then inside the virus.

To sum it up: the immune system is much more complex, has several recognition mechanisms, the viral RNA is mostly packed into the viruses (or are inside the cells) and the viruses don't have any way to produce Ψ (or any of the other nucleotides).

Re: Moderna mRNA sequence released to GitHub [pdf]

#109
post #70
post #31

I'm sure it's more complex than I grasp as a layperson, but I'm utterly amazed at how simple this _appears_. I get the feeling that this is something I have a better chance of understanding than the average SaaS Terms and Conditions. I expected to have to scroll through pages upon pages of indecipherable text. Instead it's no bigger than a large paragraph of text, and I can easily fit it on my screen.

The protein they're trying to manufacture is indeed quite simple - AFAIU both BioNTech and Moderna put together their sequences in a weekend. (Though there was a more involved process of winnowing down the sequences for the most effective ones.) The technically challenging parts are: - delivery mechanism: you need to take a very unstable molecule, protect it from the environment - both external, and when inside the p…

> delivery mechanism: you need to take a very unstable molecule, protect it from the environment - both external, and when inside the patient - and insert it into a human cell. (This is called the "platform", and is usually developed independently from the specific payload.)

Of note, the immune system is pretty good at destroying foreign mRNA so you also need to evade it.

This article is pretty good: https://berthub.eu/articles/posts/reverse-engineering-source...

Re: Moderna mRNA sequence released to GitHub [pdf]

#110
post #97
post #85

My first thought was `wdiff pdizer moderna`. It's short enough to post here in its entirity, but I guess I had better not, anyway it's easy enough to extract from the pdf. Add a space after every letter and wdiff can find the common sequences nicely. Short except for flavor, this is from near the beginning: A[-G-]AGA{+A+}GAA{+ATATAAGAC+}CCCG{+GCGCCG+}CCACCATGTTCGTGTTCCTGGTGCTGCTGCC[-T-]{+C+}

A pairwise sequence alignment done with `needle` starts like this: BioNTech_Pfiz 1 -----------GAGAATAAACTAGTATTCTTCTGGTCCCCACAGACTCAG 39 |||||.|.|..|||| ||| || Moderna 1 GGGAAATAAGAGAGAAAAGAAGAGTA----------------AGA---AG 31 BioNTech_Pfiz 40 AGAGA----AC-------CCGCCACCATGTTCGTGTTCCTGGTGCTGCTG 78 |.|.| || |||||||||||||||||||||||||||||||| Moderna 32 AAATATAAGACCCCGGCGCCGCCACCATGTTCGTGTTCCTGGTGCTGCTG 81 BioNTech_Pfiz 79 C…

Knowing nothing about biotech – if Moderna and Pfizer were working from the same sequencing data, why would their resulting vaccine mRNA sequences be different? Even slightly?

Edit: I guess what I'm asking is: presumably these vaccines both target the spike protein. Do both of these sequences express the same protein? Or is there a "close enough!" thing in the immune system, where it can be a little different and still be targeted by the immune system?

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