[HN Gopher] Moderna mRNA sequence released to GitHub [pdf]
___________________________________________________________________
Moderna mRNA sequence released to GitHub [pdf]
Author : aty268
Score : 1190 points
Date : 2021-03-29 21:11 UTC (1 days ago)
(HTM) web link (github.com)
(TXT) w3m dump (github.com)
| husamia wrote:
| if you have understanding of how the sequence mutates then you
| can predict what the next strain is going to be and design spike
| protein that matches it.
| koeng wrote:
| The thinking behind attaching a PDF with colors and not a Genbank
| file is why we can't have nice things in biotechnology.
| rubatuga wrote:
| Wait, you mean you don't extract genomic data from Excel? The
| MARCH1 gene brings many interesting surprises.
| perl4ever wrote:
| Excel finally has a facility for manipulating data that keeps
| it where you put it. It also incorporates a fairly decent
| functional programming language. It's called Power Query, not
| to be confused with all the other things that MS has named
| starting with "Power" and have no relationship at all and are
| mostly awful.
|
| The only real annoyance I have with it is that the editor
| window is modal, like it blocks _all_ the spreadsheets you
| have open on your machine, and it 's primitive even compared
| to VBA, especially for debugging.
|
| It's not just that it's given me the experience of "this is
| the way a spreadsheet or BI tool should work" but also "this
| is the way SQL should work". It's a little cumbersome to do
| the standard SQL-type operations, but the clean integration
| of functions means you can implement anything that's missing.
| Like say, Oracle has grouping sets - you can, and I did, just
| write a function to do that. I always felt that having a
| separate procedural language in your database was wrong, but
| I'd never seen the alternative until now. And I've been
| falling in love with higher order functions.
| andylynch wrote:
| Power query is one of the best things to be added to Excel
| in recent years. I especially like how it makes import/
| cleanups easier to reproduce vs the old ways.
| chromatin wrote:
| I am fond of September 2, myself.
|
| For those not in the know:
|
| https://genomebiology.biomedcentral.com/articles/10.1186/s13.
| ..
| mmmrtl wrote:
| Now SEPTIN2! (and MARCHF1)
| flobosg wrote:
| My thoughts exactly!
|
| Somewhere, Margaret O. Dayhoff is weeping.
| julienchastang wrote:
| Exactly. FAIR (Findable, Accessible, Interoperable and
| Reusable) principles are at a loss here [1]. The "Reusable"
| part seems to be especially problematic as the sequence is
| buried in a PDF file though all aspects of FAIR are compromised
| here. Edit: It looks like there is now a PR to address this
| issue [2]
|
| [1] https://www.nature.com/articles/sdata201618
|
| [2] https://github.com/NAalytics/Assemblies-of-putative-SARS-
| CoV...
| ImaCake wrote:
| Things are getting better, but it still so so bad. The funny
| thing about that Nature article is that I recently had to
| parse a html table from a recent Nature article. Thankgod
| pd.read_html did a decent job and I then only needed another
| hour to hunt down all the typos and weird text issues.
| brian_herman wrote:
| Here you go! https://github.com/brianherman/Assemblies-of-
| putative-SARS-C...
| shellfishgene wrote:
| If there is no annotation or metadata FASTA format is usually
| preferred ;)
| brian_herman wrote:
| Didn't know that TYVM
| https://raw.githubusercontent.com/brianherman/Assemblies-
| of-...
| brian_herman wrote:
| Do you have a list of all popular formats?
| [deleted]
| narrator wrote:
| So I guess Josiah Zayner has to pick up on this now and do a DIY
| Moderna COVID vaccine video. He already did a DIY vaccine video
| with full open source documentation on how to do it yourself.
|
| http://www.josiahzayner.com/2020/12/i-made-covid-19-vaccine-...
| mrfusion wrote:
| So what moves the new protein out of your cells once the rna is
| processed? Don't most proteins stay inside the cell?
| lowdanie wrote:
| There is a system that transports protein fragments to the cell
| surface and "presents" them to the immune cells:
| https://en.m.wikipedia.org/wiki/Antigen_presentation
| mrfusion wrote:
| Thanks. So what makes that happen in this case? Is it because
| internally the cell doesn't recognize the protein? Or it does
| this for all proteins it makes? Does say some hemoglobin get
| transported to the cell surface?
| lowdanie wrote:
| Yes, the even healthy cells are constantly transporting
| protein fragments to the cell surface but the immune system
| learns to ignore these as it is developing.
|
| In addition, B and T cells only detect fragments on the
| surface of active Dendric cells. Dendric cells become
| active in response to alternate and less specific
| indications of infection such as an unusually high amount
| of mRNA translation or families of protein that occur only
| in bacteria and viruses.
| mrfusion wrote:
| The lipid container is weird to me. Is that all it takes to send
| instructions inside a cell? Seems like a security hole. Why
| haven't viruses evolved to have a lipid container?
| inportb wrote:
| > Why haven't viruses evolved to have a lipid container?
|
| They have. https://en.wikipedia.org/wiki/Viral_envelope
| jforman wrote:
| I was going to say you can't get very far without a protein
| vehicle, but then I remembered that's quite incorrect:
|
| https://en.wikipedia.org/wiki/Retrotransposon
|
| The injection is important, however, as it gets the genetic
| material past a whole lot of nucleases that cover your
| epithelia.
| nsxwolf wrote:
| ELI5, Why are the sequences different if they result in the same
| spike protein?
| ssijak wrote:
| Different codons can encode the same amino acids, so different
| sequences can encode the same protein.
| shakow wrote:
| I didn't check it was the only explanation, but the DNA ->
| protein encoding is surjective.
| rnestler wrote:
| Maybe one could compare it to having different recipes for the
| same cake. Or different source code to solve the same problem.
| djmips wrote:
| Where's the JSON versions?
| verytrivial wrote:
| There are people who could memorize this. And it would weirdly be
| more useful than digits of p!
| whitepaint wrote:
| I think memorizing any of these two is pretty much totally
| useless.
| aden1ne wrote:
| Why not in fasta format?
| controlweather wrote:
| 7 years from now everyone is infertile. Wonder why
| buttholesurfer wrote:
| Still not taking it.
| The_rationalist wrote:
| I would love to see the output structure from Alphafold of this
| RNA source code
| jonplackett wrote:
| Rather disappointingly, neither sequence includes the string
| 'GATTACA'
| ImaCake wrote:
| A given combination of 7 bases has a probability of occurring
| of 1/16,384. Since the COVID genome is about 22k bases long I
| guess you have pretty good chance of it appearing in there
| somewhere. This assumes uniformity, which of course is not
| true. COVID's genome is under crazy intense selection pressure!
| shellfishgene wrote:
| The sequence GATTCA appears 4 times in the reference version
| of the COVID genome :) (Go to
| https://www.ncbi.nlm.nih.gov/nuccore/NC_045512, pick "Find in
| this Sequence" on the right)
| jonplackett wrote:
| AWESOME! I just did a text search for it on github. Maybe
| it didn't pick any up that had a line break in the middle.
|
| I'm much happier now.
| calebm wrote:
| That would have been a killer easter egg (possibly literally).
| joe45643234 wrote:
| Whats special about this string?
| Duber wrote:
| It's the title of a cult film:
| https://www.imdb.com/title/tt0119177/
| ibraheemdev wrote:
| Is this all another medical company needs to start manufacturing
| and selling the vaccine themselves? Or is this sequence
| licensed/proprietary in some way?
| akkawwakka wrote:
| No. The RNA still needs to be fit in a lipid nanoparticle which
| is Moderna and BioNTech's secret sauce.
| andrewcl wrote:
| Cool, but it's the lipid delivery system that is the secret
| sauce. This is equivalent to giving the source code without a
| compiler to build it.
| airhead969 wrote:
| Wouldn't the "compiler" be the bioreactor used to mass-produce
| it and the "installer" be the lipid encapsulation? :)
| divbzero wrote:
| In the case the bioreactor "compiler" is actually our own
| cells which read out the mRNA "source code" and translate it
| into protein. The lipid encapsulation delivers the mRNA to
| our cells, so perhaps it's more analogous to a network
| protocol that delivers source code intact across firewalls
| and other defenses.
| [deleted]
| snuxoll wrote:
| InstallGene by Flexera
| Haemm0r wrote:
| Just waiting for first copy protection mechanism for mRNA.
| SafeGene and SecuGene here we come :o
| aneutron wrote:
| Can you imagine, the greedy folk would want some sort of
| Widevine in humans.
| Haemm0r wrote:
| The vaccine will check your implanted payment chip
| receipt number before activating the payload.
| airhead969 wrote:
| _" Drink Brawndo, The Thirst Mutilator."_ in your DNA
| too.
|
| Sony is gonna sneak in some DRM and Mark Russinovich is
| gonna put out a fix.
| airhead969 wrote:
| _" The authorization server is down, no longer signing
| this version of this medication, or this medication has
| expired. Please contact your supplier for more
| information."_
|
| _Shit, I 'm going to have to google for a working hex
| edit or look for a bpatch._
| airhead969 wrote:
| Can't wait for the DNA "chip art" by gene designers.
| Considering we have so much HERV, they might use that as
| an equivalence rationalization to do it.
| ineedasername wrote:
| Maybe the booster shot can be done with a simple apt-get
| update.
| schappim wrote:
| Got the "GPG Error: No Public Key" error. Probably for the
| best!
| airhead969 wrote:
| Fawwwwwk. Gotta edit the
| /etc/apt/apt.conf.d/covid-19-vaccine.conf
|
| Anyone know if sudo works?
| airhead969 wrote:
| Serious. Unless it requires a separate, native-compiled
| adaptive immunity package.
| reddotX wrote:
| a fellow linux user. ubuntu?
| subroutine wrote:
| Meh, they probably just used lipofectamine (which has been
| around since the 90s) or something very similar.
|
| https://en.wikipedia.org/wiki/Lipofectamine
|
| https://www.thermofisher.com/us/en/home/brands/product-brand...
| Duller-Finite wrote:
| lipofectamine is used for in vitro transfection, not in vivo
| gene delivery. The vaccines use lipid nanoparticles rather
| than liposomes
| MuffinFlavored wrote:
| If they didn't use lipofectamine, what did they most likely
| use?
| flobosg wrote:
| Derek Lowe discussed it a few months ago:
|
| https://blogs.sciencemag.org/pipeline/archives/2021/01/11
| /rn...
|
| https://blogs.sciencemag.org/pipeline/archives/2021/02/22
| /mo...
| neuronic wrote:
| I absolutely do not have a link, but I remember reading
| that the lipid nanoparticles are actually created by
| mechanical action (possibly fluid dynamics/turbulence). I
| thought that was pretty neat.
| DrAwdeOccarim wrote:
| But wasn't the whole Pfizer/BioNTech "secret sauce" leaked
| online after the EMA was hacked?
| aty268 wrote:
| 'A group of Stanford researchers has hacked Moderna's messenger
| RNA (mRNA) vaccine for the novel coronavirus, Motherboard first
| reported on Monday, and published its entire genetic sequence on
| the open-source code repository Github.'
|
| https://gizmodo.com/stanford-scientists-post-entire-mrna-seq...
| throwawaysea wrote:
| What does "hacked" mean here? The article makes it sound like
| this wasn't something illegal:
|
| > Fire and Shoura told Motherboard that they had received
| permission from the FDA to collect scraps of vaccines that
| wouldn't have otherwise been used from empty vials and that
| they'd notified Moderna in advance of their plans to publish
| the sequence without receiving any objection in turn.
|
| Also:
|
| > The research team told Motherboard that they didn't "reverse
| engineer" the vaccine, they simply "posted the putative
| sequence of two synthetic RNA molecules that have become
| sufficiently prevalent in the general environment of medicine
| and human biology in 2021."
|
| I'm not familiar enough with how these sequences to work to
| understand what's being discussed. Is it simply that they took
| a sample of the vaccine and studied its composition using some
| standard machine/process?
| flobosg wrote:
| > Is it simply that they took a sample of the vaccine and
| studied its composition using some standard machine/process?
|
| That's exactly what they did.
| cwkoss wrote:
| It means the gizmodo author is trying to get more views.
| flemhans wrote:
| Despite how complex this really is, and how many "gotchas" there
| might be when using this repository, it's nice that it gets a
| shitload of attention. As a united humanity we should strive to
| solve our common problems.
| dooopy wrote:
| I compared the spike encoding regions, and it looks like they're
| quite different...I wonder if the codons wind up coding for
| different amino acids. And who got it right?
| flobosg wrote:
| Their codon compositions were optimized differently, but both
| coding regions translate to the same amino acid sequence.
| spullara wrote:
| I highly recommend reading about Ribosomes. They are made up of
| two pieces that were likely independent at some time. It becomes
| quite clear that "life" began as a machine that all it could do
| was replicate itself:
|
| https://en.wikipedia.org/wiki/Ribosome
|
| You can think of RNA as a copy of a section of DNA. They look
| very much like computer programs except rather than producing
| code, the Ribosome can read them and translate each codon for an
| amino acid into its corresponding actual amino acid that it then
| binds together into a protein. The execution engine is the
| environment of the cell. All highly probabilistic rather than
| deterministic. I can't imagine any programmer not finding them
| completely fascinating.
| p0rkbelly wrote:
| obligatory:
|
| "I could have done this in a weekend"
| obilgic wrote:
| so how are the first and the second dose different?
| hfjfktmtkrn wrote:
| The second dose is like seeing someone stalking you for the
| second time.
|
| You should really do something about it because it's probably
| serious.
|
| The same way, the immune system gets really triggered when it
| sees the same thing which it supposedly cleared at a later
| date.
| takeda wrote:
| I believe only Sputnik vaccine has different first and second
| dose, but their vaccine is of different category (it belongs to
| the same as AstraZeneca and Johnson and Johnson). The reason is
| that these vaccine use a vector (adenovirus) and there's a risk
| that body will develop antibodies for the vector and the second
| dose might not be as effective.
| meepmorp wrote:
| They're the same. It's just a second dose as a booster.
| jonbaer wrote:
| "Some vaccines require two doses because the immune response to
| the first dose is rather weak. The second dose helps to better
| reinforce this immune response." - I would have to think over
| time that could be optimized somehow to just require one w/ ML
| and test results, etc.
| csense wrote:
| The Human Genome Project was completed almost two decades ago,
| and somebody solved the protein folding problem recently.
|
| Why are we still doing genetics at the machine code level?
| Shouldn't we have some compilers, assemblers and linkers by now?
| zero_deg_kevin wrote:
| Because the problem is significantly more complicated than
| sequencing and folding.
| asdff wrote:
| Because it's a harder problem than it seems at face value.
| baby wrote:
| My thought exactly. So this thing is like a VM with a bunch of
| primitive opcode, why can't someone write a higher-level
| language or at least some gadgets
| WJW wrote:
| The problem with trying to program genetics is that there is
| a bunch of code already running on the system and _every
| variable is a global_. You can 't just start up a new program
| with minimal impact on the stuff that is already running,
| like you can in most human-made computers. Also don't forget
| that the _extremely simplified_ version of the running system
| looks like this: https://www.sigmaaldrich.com/technical-
| documents/articles/bi...
| flobosg wrote:
| I wouldn't call it _extremely_ simplified; you can go
| simpler:
| https://science.sciencemag.org/content/351/6280/aad6253
| 6nf wrote:
| Protein folding is not solved, that headline was overstating
| the actual achievement by Google's protein folding solution.
| Yizahi wrote:
| If I remember correctly "solving" protein folding was
| essentially some high probability prediction that state A
| transform to state B with some reasonably high chance, on a big
| dataset. Or something like that anyway. It's as far from high
| level work with genetics as creating nanotubes a few molecules
| long in lab manually is away from industrial production.
| WJW wrote:
| I feel this XKCD describes the situation particularly well:
| https://xkcd.com/1831/
| neuronic wrote:
| Maybe after 4 billion years of evolving our code we will get
| it right.
| lambdadmitry wrote:
| The most fundamental reason for that is that it's just not
| amenable to human mind. We are quite primitive actually, being
| able to hold only a handful of "things" in our mind at any one
| time and relying on abstraction to think of more complex
| things. However, you can't abstract much in biology; there is
| no locality or separation of concerns, everything affects
| everything.
|
| Take that piece of RNA. An intuitive mental model is that it's
| some form of "instruction" or a bunch of instruction, isn't it?
| It's also wrong, because it just encodes a protein that acts
| the way it does only because of its shape (that is, one of its
| potential energy local minimums) and the shape of other
| proteins around it. That shape is only weakly local, it can be
| affected by far-away sections of peptide sequence. So it's
| almost impossible to systematically break it down, you have to
| consider and model things as a whole , which is insanely
| complex both computationally and cognitively.
|
| If you want a good mental model of how it works, imagine you
| assemble a thing from metal balls and springs. You take a few
| thousands balls and connect most of them with springs of
| different strengths. You then take this thing and throw it on
| the floor; it will assume a shape that is _implicitly_ encoded
| in spring strengths, its environment, and the way you 've
| assembled it. You can even make it change shape if you poke on
| it the right way. That's how biology works in a nutshell; it's
| a nightmare to design anything for systems like that. Again,
| you can't simplify and break down and encapsulate and abstract
| like you do in programming.
| joeyh wrote:
| 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+}CCACCATGTTCGTGTTCCTGG
| TGCTGCTGCC[-T-]{+C+}
| koeng wrote:
| Us folks in biotech have a special tool just for this :)
| https://blast.ncbi.nlm.nih.gov/Blast.cgi
|
| Unfortunately, the core algorithm dates back to 1990, so it can
| be real slow in some cases. Biotech takes a while to improve :(
| asdff wrote:
| You can also run blast locally if you need to throw more
| hardware at it.
| flobosg wrote:
| I think you meant
| https://www.ebi.ac.uk/Tools/psa/emboss_needle/ or
| https://www.ebi.ac.uk/Tools/psa/emboss_water/ ;-)
| flobosg wrote:
| 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
| CCTCTGGTGTCCAGCCAGTGTGTGAACCTGACCACCAGAACACAGCTGCC 128
| ||.||||||..|||||||||.|||||||||||||||.|.||.||||||||
| Moderna 82
| CCCCTGGTGAGCAGCCAGTGCGTGAACCTGACCACCCGGACCCAGCTGCC 131
| type_enthusiast wrote:
| 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?
| batterseapower wrote:
| This very cool article explains the mRNA sequence chunk-by-
| chunk which might give you a flavour of why differences
| exist: https://berthub.eu/articles/posts/reverse-
| engineering-source...
| type_enthusiast wrote:
| That is a super interesting article, thank you for
| posting it!
|
| But, I guess my question is more about why the
| abstraction of "protein chunks" doesn't fall apart when
| there are relatively significant "diffs" in the RNA
| sequence.
| flobosg wrote:
| The most significant diffs between both vaccines occur in
| the untranslated regions located around the protein
| coding sequence and will never be present in the actual
| spike protein.
|
| Regarding the protein coding region, because of the
| degeneracy/redundancy of the genetic code, all changes
| within it are synonymous and code for identical amino
| acids.
| Ericson2314 wrote:
| > Our body runs a powerful antivirus system ("the
| original one").
|
| Awwww
| zbirkenbuel wrote:
| That is a fascinating read (and the perfect level of
| depth in this field for me). How did you happen across
| it? Always looking to add a good source to my RSS feed
| list
| boruto wrote:
| dont know about op, but the link is present in the posted
| git repo readme.
| [deleted]
| [deleted]
| flobosg wrote:
| The sequence can be changed and optimized for several
| reasons:
|
| * There are untranslated regions (UTR) that could influence
| the regulation or stability of the mRNA.
|
| * Since most amino acids are encoded by more than codon,
| the coding region for the spike protein can be codon
| optimized. Altering the codon composition can improve
| protein expression.
|
| * Likewise, enrichment of G:C content in the mRNA sequence
| might result in increased mRNA and expressed protein yields
| _in vivo_.
|
| See https://www.nature.com/articles/nrd.2017.243#Sec4 for
| more information.
|
| Edit:
|
| > Do both of these sequences express the same protein?
|
| In this case both vaccines express exactly the same amino
| acid sequence.
|
| > 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?
|
| It depends on how different the sequence is. For instance,
| if it is a little different the immune response should be
| very similar because, for example, the three-dimensional
| conformation of the spike protein chain should remain very
| similar as well. This is why the vaccines can be effective
| against several SARS-CoV2 variants.
| testplzignore wrote:
| Moderna is better at codon golf.
| sanxiyn wrote:
| Both sequences express the same protein.
|
| Sequences are different because they are differently codon
| optimized. See
| https://en.wikipedia.org/wiki/Codon_usage_bias, especially
| "Effect on transcription or gene expression" section.
| Florin_Andrei wrote:
| > _if Moderna and Pfizer were working from the same
| sequencing data, why would their resulting vaccine mRNA
| sequences be different? Even slightly?_
|
| Ever tried to compile the same source with different
| compilers?
| plattyp wrote:
| Who would have thought it'd be this simple if
| covid?(dna) block_virus(dna) end
| rantwasp wrote:
| read the article linked in the thread. it actually does not
| work against all of the covid virus. it works against the
| spikes.
|
| so, the virus is sort of like a ball with these spikes on top
| (that's where the corona name comes from) and the vaccine helps
| your body develop antibodies against the spikes. so when the
| virus gets in your body, it actually receives a "haircut" which
| leads to it no longer being able to enter the cells and hijack
| their internals to produce more viruses.
|
| it's extremely clever, but it also means that your code is
| wrong ;))
| karolkozub wrote:
| It looks like a machine code snippet. I wonder if we'll develop
| high level languages and compilers for genetic code in the
| future.
| ImaCake wrote:
| I imagine we have tools in that direction, but nothing
| complete. Unlike math and computers, biological systems don't
| really go from a uniform set of simple rules to emergent
| complexity - there is a whole lot of sideways complexity thrown
| in.
|
| Something that might fit the computation vision of your comment
| are the various Ontologies for bioinformatics. The Gene
| Ontology is probably the most complete, although it lags many
| years behind the literature.
|
| http://geneontology.org/
| sp1rit wrote:
| If my little knowledge from biology class serves me correct, RNA
| uses Udenine instead of Thymine. But in this document it uses T.
|
| Can somebody explain to me why?
| rolph wrote:
| DNA uses base pairs [A,T] and [G,C], this code is for a piece
| of DNA,. if you keep a DNA sequence in vials for later use,
| that is much more stable and easier to manipulate, and repair
| when corrupted.
|
| normally RNA in vivo is complexed with protiens that prevent
| RNA from folding, and annealing into structure that is not
| compatible with translation to protien. In the vaccine this
| isnt happening, this is why RNA is hard to work with and the
| vaccine must be kept so cold.
|
| This is not to say that DNA is simple to work with, but it
| solves problems if you dont need direct access to RNA.
| feanaro wrote:
| You probably mean uracil, not udenine (which doesn't exist
| AFAIK).
| sp1rit wrote:
| Yeah, English is my second language. I just thought of a
| Translation that sounded reasonable rather than looking it
| up.
| koeng wrote:
| DNA is way more stable than RNA. Since you can easily
| synthesize RNA from DNA, and DNA synthesis technology is much
| more mature, folks normally synthesize DNA and then derive/make
| the RNA from it. That makes most researches default to DNA 5'
| to 3', even when talking about RNA.
| Laforet wrote:
| The convention of genomic research is to present all RNA
| sequences as equivalent cDNA sequences. As this will be the
| output of most common sequencing platforms.
|
| https://bioinformatics.stackexchange.com/questions/11353/why...
| shellfishgene wrote:
| Note that independently of the notation used the mRNA of those
| vaccines use even more "weird" bases, such as
| 1-methyl-3'-pseudouridylyl, to make the vaccine mRNA not be
| detected by the immune system [1].
|
| [1] https://berthub.eu/articles/posts/reverse-engineering-
| source...
| Duller-Finite wrote:
| RNA uses uracil/uridine rather than thymine, but uridine is
| actually quite immunogenic. That's what has prevented people
| from using mRNA as a therapy until recently, when the founders
| of BioNTech figured out that they could use pseudouridine
| (abbreviated as Ps) instead. See [1] for more information.
|
| [1]https://www.wired.co.uk/article/mrna-coronavirus-vaccine-
| pfi...
| em3rgent0rdr wrote:
| Are there any visual compilers that simulate the process of using
| these sequences to assemble a protein?
| stjohnswarts wrote:
| ELI5 could this be used by "evil governments" to make designer
| pathogens to release during doomsday situations (say by North
| Korean leaders in their suicide bunkers if things went badly) ?
| a-dub wrote:
| i'm a dna noob: is it possible to do the growing and sampling
| thing to get the sequence from a sample of the vaccine or does
| the bubble of fat get in the way?
| omlet wrote:
| Where is the 5G stack?
| bionhoward wrote:
| we wrote some code last year to build a big Trie of the whole
| transcriptome -- you could use it to fuzzy-search to see if this
| mRNA is within some edit distance of any piece of normal human
| RNA, because then it could theoretically cause side effects via
| RNA interference. stopped the project because I can't afford to
| develop a gene therapy right now, but the fuzzy search worked
|
| https://github.com/bionicles/coronavirus
|
| to make the trie use the function here. the variable K is the
| length of the Kmers (runs of RNA). Larger values are gonna take a
| lot longer. ( warning: big job, uses multiprocessing...pypy
| recommended for speed )
| https://github.com/bionicles/coronavirus/blob/b6f0db9dd8aaf7...
|
| then you could use this recursive function to generate potential
| matches within some cutoff
| https://github.com/bionicles/coronavirus/blob/b6f0db9dd8aaf7...
|
| the function right below it converts the generator to a list.
| then you could save that
|
| enjoy
| omlet wrote:
| Where is the code about 5G modem?
| bvanderveen wrote:
| > .docx.pdf
|
| Cargo-cult much?
| tibbydudeza wrote:
| So you have a header/footer sequence that we sort of know is
| required (remember the MZ and chksum for .EXE files) but we have
| no idea what that bits in between does except we can read the
| letters and copied it in part from the actual virus.
| 6nf wrote:
| We do know that bit in the middle encodes the structural spike
| protein of the virus
| brian_herman wrote:
| https://github.com/brianherman/Assemblies-of-putative-SARS-C... I
| posted some txt files with the lines removed and stuff.
| flobosg wrote:
| If you have the time, it would be nice to transfer the data to
| the commonly used Genbank format.
| brian_herman wrote:
| https://github.com/brianherman/Assemblies-of-putative-
| SARS-C...
| brian_herman wrote:
| Ask and ye shall recieve! Have a great day!
| [deleted]
| stevefrench93 wrote:
| I wouldn't install beta software on a production system though.
| rossdavidh wrote:
| Well we do with anti-malware stuff, when a 0-day comes out and
| we know there are exploits in the wild and beta software is all
| we've got.
| bigbob2 wrote:
| Luckily in that case there is usually a means to roll back.
| kart23 wrote:
| What are the purple and blue sections after the stop codon for? I
| read a little about the 3' region, but for the vaccine, are these
| sections taken from a particular natural human sequence, or
| specially engineered for something else?
| iso1337 wrote:
| It's the 3' (3-prime) UTR (un-translated region). It can affect
| the translation of the mRNA.
|
| https://en.wikipedia.org/wiki/Three_prime_untranslated_regio...
| .
|
| The next thing is the poly-A tail:
|
| https://en.wikipedia.org/wiki/Polyadenylation
|
| blasting the 3' UTR, we see it ~50% of it was copied from the
| human mitochondria
|
| tldr, extra regulatory signals (often not well understood)
| [deleted]
| dnautics wrote:
| Doesn't really make sense for it to copy from the
| mitochondrion; I presume this thing gets expressed in the
| cytosol.
| hfjfktmtkrn wrote:
| Among other things that purple region determines the
| "priority"/"intensity" of the whole sequence.
|
| You want it as high as possible to make as much spike protein
| as possible.
|
| It's proprietary information, mostly they try various
| possibilities until they find one with high expression.
| Asparagirl wrote:
| So it's the mRNA version of _!important_ in CSS?
| hfjfktmtkrn wrote:
| More like font-weight, since !important is binary and this
| is more of a gradient.
| _theory_ wrote:
| That's the part that makes you randomly yell, "Hail Bill
| Gates!"
| fabian2k wrote:
| The 3' and 5' untranslated regions are the parts of the mRNA
| directly before and after the part that encodes the actual
| protein. So they are themselves not translated into amino
| acids.
|
| What they actually do can vary, but essentially they can
| provide places for other things to bind and influence what
| happens with the mRNA. There are some fancier cases like
| riboswitches, but you don't see those in humans. The stuff at
| the start and end of the mRNA also determines stability of the
| mRNA.
| flobosg wrote:
| In the BioNTech/Pfizer mRNA, the 3' (or the latter) half of the
| 3'-UTR comes from human mitochondrial 12S rRNA.
|
| The Moderna one has the 3'-UTR of the alpha subunit of human
| hemoglobin.
| layoutIfNeeded wrote:
| That's the copyright notice.
| person_of_color wrote:
| How long before we can 3d print an mRNA vaccine?
| StaticRice wrote:
| Archive.org mirror:
| https://web.archive.org/web/20210326214140/https://raw.githu...
| ineedasername wrote:
| It's also short enough to post the whole thing to Wikipedia, so
| that's probably inevitable along with some _very_ entertaining
| edit wars.
| VectorLock wrote:
| People joked a lot about "injectible source code / machine code"
| but it is kind of interesting injecting yourself with something
| that has the source on github.
| calylex wrote:
| Just because you see the RNA/DNA sequence on Github doesn't
| mean anything, DNA sequencing has been around since at least
| the early 70s [0]. Many pharmaceutical drugs already employ
| such techniques.
|
| [0] https://en.wikipedia.org/wiki/DNA_sequencing#History
| [deleted]
| dnautics wrote:
| Note that this is a sequencing result, so it will lack a lot of
| nonstandard RNA tricks that these companies are or might be
| using, like pseudouridines, or fluorobases. I think those would
| have to be disclosed in the patent.
| VectorLock wrote:
| Less like original source code, more like a clean room
| reverse engineering.
| vmception wrote:
| We aren't that different from machines, we just need to know
| more about the CPU and all the co-processors and how the logic
| gates interact
|
| But for now we can inject code to trigger protein configuration
| via the immune system
| anyfoo wrote:
| > We aren't that different from machines, we just need to
| know more about the CPU and all the co-processors and how the
| logic gates interact
|
| Except it is unfortunately not that simple, because it
| assumes that distinct components such as CPU, co-processors
| and even logic gates exist in that context, as is totally
| reasonable to assume on devices created by humans.
| Abstracting complex machines into distinct components is a
| proven strategy to engineer a system, but it's not a
| necessity for functioning systems to exist.
|
| In the case of natural organism, they "just" need to work.
| They don't have a blueprint, and they don't need to be
| organized in a way that allows for easy understanding by
| looking at individual parts in separation.
|
| Consider also the difference between machine learning through
| neural networks ("we stuff a lot of training data in there
| and get what we want eventually, we hardly understand what
| the model does or why it fails"), and a QR code reader ("we
| carefully designed the format from the top down, including
| e.g. framing, error correction, and several invariants like
| rotation; if a QR code does not get recognized, we can
| usually tell exactly where and why it failed").
| vmception wrote:
| I am not able to draw the distinction you are trying to
| make. The more we make machines, especially ones to
| interact with inputs from our world, the more easy it is to
| understand our bodies.
|
| Correct, because there is no blueprint then we don't know
| about how the brains and neurons interact. But if there is
| a problem with a heart valve we know exactly where and why
| it failed.
|
| I expect greater convergence in these fields, and as such I
| can't agree with you.
| anyfoo wrote:
| > But if there is a problem with a heart valve we know
| exactly where and why it failed.
|
| I highly doubt that. Even for heart valves, which seem
| less complicated than plenty of other body parts (at
| first glance, I'm sure they are plenty complicated in
| detail), because they are comparatively mechanical. For
| example, Wikipedia says (with citation): "Causes of
| aortic insufficiency in the majority of cases are
| unknown, or idiopathic."
|
| Try a kidney or something related to the nervous system
| next.
|
| > The more we make machines, especially ones to interact
| with inputs from our world, the more easy it is to
| understand our bodies.
|
| FWIW I am making machines, and the more I do, the more
| amazed I am about how intensely complicated our body in
| general and our nervous system specifically is.
| imbnwa wrote:
| "Imagine a being like nature, wasteful beyond measure,
| indifferent beyond measure, without mercy and justice,
| fertile and desolate and uncertain at the same time;
| imagine indifference itself as a power, how could you live
| according to this indifference?"
| callesgg wrote:
| It is actually sort of strange how compartmentalized the
| living cell is.
|
| I guess there is some type of redundancy that comes from
| compartmentalization that is evolutionarily beneficial.
| VectorLock wrote:
| There is a theory "endosymbiotic hypothesis" that
| mitochondria were wholesale absorbed bacteria into our
| DNA line. Which I think is pretty wild, and explains how
| neatly they're compartmentalized.
| anyfoo wrote:
| No doubt, and separate organs with (sometimes rough,
| sometimes very clear) separate functions are also a
| thing, so evolution seems to favor compartmentalization
| for more complex systems. But that does not mean that
| there are not complex overarching interactions that make
| full understanding really hard. The sort of interactions
| you would stay away from when designing a computer, not
| because it would not work, but because it would make
| design, debugging, and iteration upon your system
| prohibitively hard.
| _joel wrote:
| Does that mean a cytokine storm is the equivalent of a buffer
| overflow or a DoS?
| YarickR2 wrote:
| IDS with ability to launch countermeasures, and no negative
| feedback loop
| fabian2k wrote:
| A cytokine storm is when you trick the antivirus into
| thinking all major system files contain a virus.
| Angostura wrote:
| Cytokine storm would perhaps be like the user deleting
| random necessary OS executables in an attempt to get rid of
| malware
| [deleted]
| anonu wrote:
| This is amazing. It appears quite "simple" - of course I know
| nothing about this part of the sciences.
|
| I do think back to the early days of Covid when there were all
| these predictions around when a vaccine would show up. It seemed
| like there was knowledge that the mRNA platform would be the
| likely solution and probably by April we knew a vaccine would be
| possible - it just took 6+ months to test.
|
| Thinking about that timeline amazes me.
| zappo2938 wrote:
| Wow Looks like it is analogous to having a header on a TCP
| packet. [0] Here is an animation of mRNA encoding translated to
| proteins inside a ribosome. [1]
|
| "The ribosome is composed of one large and one small sub unit
| that assemble around the messenger RNA, which then passes through
| the ribosome like a computer tape. The amino acid building
| blocks, that's the small glowing red molecules, are carried into
| the ribosome attached to specific transfer RNAs; that's the
| larger green molecules also referred to as tRNA. The small sub
| unit of the ribosome positions the mRNA so that it can be read in
| groups of three letters known as a codon."
|
| Very analogous indeed.
|
| [0] https://xerocrypt.wordpress.com/2014/07/22/how-to-read-
| almos...
|
| [1] https://www.youtube.com/watch?v=TfYf_rPWUdY
| retrac wrote:
| Some parts of gene transcription are so straightforward one can
| almost be tricked into thinking it has the logic of a computer
| program. It may be an illusion. To stretch the metaphor, TCP
| parsers don't match probabilistically along the entire length
| of the packet in parallel, and they don't interpret the same
| part of a packet as data in some contexts, and a header in
| others.
| robbiep wrote:
| I ended up majoring in biochemistry and molecular biology in my
| undergrad because I was browsing on Wikipedia one day and came
| across an article written on an E. Coli variant that had
| sentences like:
|
| 01J3 e. Coli has a DNA Polymerase that contains 3k'-5'
| proofreading capability and 5'-3' error correcting with a
| polymerisation rate of 50bps
|
| I've made the above up because I have never been able to find a
| Wikipedia page winxe that as succinctly pointed out to me that
| biology was a machine and I was hooked
| [deleted]
| jturolla wrote:
| Please someone... create some abstraction language for this bio-
| assembly code. Can we make LLVM compile this? :joy:
| jakeogh wrote:
| Checkout https://github.com/clasp-developers/clasp
|
| "Clasp: Common Lisp using LLVM and C++ for Designing
| Molecules": https://www.youtube.com/watch?v=0rSMt1pAlbE
| singularity2001 wrote:
| tangential: do biologists sometimes use some form of base 64
| encoding for their triplets? so instead of AAG.TCA.GGA just g5F
| or something?
|
| other than the obvious advantage of being shorter, it would also
| be easier to read: the boundaries would be unambiguous and each
| char would correspond directly to and amino acid (if
| applicable/coding)
| jebus989 wrote:
| Proteins are written in standardised IUPAC amino acid codes
| that carry some semantic meaning, e.g. Alanine: A, Glycine: G
| etc. Also viral genomes often have overlapping transcription
| with shifted open reading frames. Biology is not as simple as
| you think.
| ur-whale wrote:
| What this does, as a non-biotech person, I believe I understand
| at a high level: plonk this code into a ribosome and out comes
| the desired protein.
|
| What I don't understand is: a) how the m-RNA
| code relates to the produced protein (i.e I can read C-code and
| get an idea of what is does fairly quickly, but can the same be
| said of m-RNA and the resulting protein)? b) how did
| they get their hands on that code in the first place? Do the
| coronaviruses use m-RNA as well? Was then a coronavirus somehow
| "dissected" to get at the spike protein "source code"?
| flobosg wrote:
| a) Yes, you can translate a mature[1] mRNA sequence, codon by
| codon, from the start until the stop codon, and it will give
| you the sequence of the protein it encodes.
|
| b) Coronaviruses have a RNA genome. Researchers extracted it
| from wild-type viruses and then sequenced it.
|
| [1]: mRNAs can undergo several maturation steps, such as
| splicing, which removes regions that won't be translated into
| protein.
| koeng wrote:
| Answers:
|
| a) From the mRNA you can learn the amino acid sequence of the
| protein very quickly. You absolutely cannot (yet) learn the
| function of the protein from that sequence - normally, people
| just do comparisons with proteins whose functions ARE known.
| Oftentimes in enzymes there are "domains" or little functional
| regions that stay consistent over long periods of time, so
| that's a good way to assign function (given knowledge of other
| proteins in the same family)
|
| b) Yep. Every virus at some point in their lifecycle use mRNA.
| You can just sequence the virus and get all that data (I've
| done that on SARS-COV-2, it's honestly pretty easy). Then you
| just do homology alignment (as stated above) and you can figure
| out approximately what each gene does.
|
| The problem of de-novo protein prediction is ONE OF THE HARDEST
| PROBLEMS IN BIOTECH, but just like getting amino acid sequence,
| doing homology searches, sequencing viruses, etc, is basic
| biotech and I'd expect an eager high schooler or undergrad to
| be able to do them.
| ur-whale wrote:
| Thanks !
| [deleted]
| azernik wrote:
| a) I don't know if protein-folding software is good enough to
| figure out the exact structure of the resulting protein given
| just the gene, but I suspect you could figure out through the
| equivalent of the strings command - looking for sub-chains of
| the protein, and looking for matching sequences in the gene
|
| b) Coronaviruses happen to be RNA viruses; that is, their
| genomes are RNA rather than DNA. DNA viruses also exist and are
| common. We got full genomes from sequencing early in the
| pandemic, and continue to use it to monitor the evolution of
| the virus (see e.g. [1], where the results are available for
| download). Sequencing is very cheap and easy these days - you
| take a sample from a patient, use chemicals to break down all
| the cell membranes and such, sequence all of the DNA and RNA in
| it, and look through the results for a virus genome (i.e.
| something that isn't a human chromosome and isn't a known virus
| or bacterial genome). "m"RNA is more a description of the
| function than the chemical - tRNA and rRNA are short snippets
| of RNA used for manufacturing purposes inside the cell, while
| mRNA is the long chunks that actually carry information from
| the DNA to the protein manufacturing sites. Virus RNA basically
| functions as imposter mRNA, getting those manufacturing systems
| to make more viruses.
|
| [1] https://www.ncbi.nlm.nih.gov/datasets/coronavirus/genomes/
| - SARS-CoV-2 is the COVID-19 virus. As of my fetch, there are
| 71,509 full sequences of the virus, reflecting slight mutations
| over time and space.
| grey413 wrote:
| Everyone else has had good answers, but I'm also going to note
| that we knew a ton about covid's general molecular biology well
| before it ever came into existence. Covid (more properly, SARS-
| CoV-2) is a cronovirus. Cronoviruses have been studied for some
| time since some of them cause common colds, and studied very
| intensely since 2002 when SARS showed pandemic potential. So
| when Covid showed up, there was a ton of prestablished
| information and expertise avaliable to help every element of
| the pandemic response.
| andred14 wrote:
| No thanks I'm good
| pknerd wrote:
| Can someone give me the link of FASTA files of these sequences?
| sktrdie wrote:
| No package.json found, won't install.
| wonderwonder wrote:
| We are simply programmable machines, its pretty interesting that
| all of human life can be reduced down to 30k editable
| microservices.
| qbasic_forever wrote:
| Sure, but if you took that 30k of data and dropped it on a
| planet just like earth it would still take 10k years or so for
| us to build civilizations as we know it again.
| ngcc_hk wrote:
| Not 10k year as it needs to go through the million years
| scale - rna, hot, uv then dna ... with no oxygen to oxygen
| etc. Then million of years of evolving ... scale is a bit
| off.
| r-zip wrote:
| He's saying if you wiped out human civilization it would
| take O(10k) years to rebuild, because knowledge/culture
| isn't stored in the genes.
| qbasic_forever wrote:
| Yep exactly, but also that's a fun problem to think about
| how long it would take if we sent our DNA on an
| asteroid/space probe to another earth-like planet. :)
| [deleted]
| hutzlibu wrote:
| "its pretty interesting that all of human life can be reduced
| down to 30k editable microservices."
|
| I don't know much about DNA and co, but it sounds as
| microservice is not the right metapher. Rather just 30k
| sourcecode?
|
| Because a microservice is something that is already compiled
| and running..
| wonderwonder wrote:
| Was looking at it as each gene is a microservice and performs
| a role. Those microservices can be added to, edited /
| eliminated or swapped out.
| 8note wrote:
| That gives me the feeling that those reflexion models could do
| some help for improving our understanding of those
| microservices
| flobosg wrote:
| > So how different is the mRNA in the Moderna, BioNTech/Pfizer &
| CureVac vaccines? There are 1274 codon positions. 808 are
| identical across all 3 vaccines. 103 are unique to Moderna, 249
| unique to BioNTech, 230 to CureVac
|
| https://twitter.com/PowerDNS_Bert/status/1375091898797453326
| savrajsingh wrote:
| My question is does the Johnson & Johnson DNA-based vaccine
| encode for the exact same spike protein, or a different one they
| chose to target? From this PDF I conclude both the moderna and
| Pfizer vaccines target the same protein.
| elliekelly wrote:
| I'm a little confused by the title? Looking at the document, it
| seems to me (knowing next to nothing about this field) it
| includes both Pfizer and Moderna's protein spike sequence in
| figures 1 and 2, respectively. Is that correct?
|
| It's also interesting the way it's worded: that the sequence was
| "assembled from $vaccine". Does that mean whoever published this
| has backed into these sequences rather than having gathered this
| information directly from the source(s)?
| hfjfktmtkrn wrote:
| They sequenced vaccine leftover remaining in used vials.
|
| So reverse engineering basically.
| usrusr wrote:
| And reverse engineering only sounds dramatic until you take a
| step back and acknowledge that it's what they literally do
| all the time. Only that usually the sequences they read are
| not the outcome of some human development effort but of
| naturally occurring evolutionary processes.
| flobosg wrote:
| The authors reverse engineered the sequences of the vaccines,
| obtaining them from the remaining mRNA present in the vials.
|
| "Assembly" in this case means that they merged several short
| sequences they obtained, each representing a fragment of the
| whole mRNA sequence.
| phcordner wrote:
| You are correct. The researchers here sequenced each vaccine
| starting with the bit of vaccine left in the vial after
| administration. The goal was to get a raw sequence of the
| Moderna mRNA component so it can be easily filtered out as
| being a signal of therapeutic origin. Pfizer's sequence has
| already been published; it's incldued here to confirm that the
| result achieved experimentally matches the published sequence.
| squarefoot wrote:
| As a software/hardware guy who knows less than zero about the
| subject: is this something that (given the right resources) makes
| possible to replicate the vaccines? I mean in countries where
| they can't afford enough vaccines but already have or could
| invest in the ability to replicate them without caring about
| patents.
| yrral wrote:
| Related: Here's a article from late last year describing and
| explaining the source code of Pfizer vaccine:
|
| https://berthub.eu/articles/posts/reverse-engineering-source...
|
| It's a very interesting read and I hope the author makes another
| post explaining the differences of the two mrna vaccines.
| throwawaysea wrote:
| From that link:
|
| > The injection contains volatile genetic material that
| describes the famous SARS-CoV-2 'Spike' protein. Through clever
| chemical means, the vaccine manages to get this genetic
| material into some of our cells.
|
| > These then dutifully start producing SARS-CoV-2 Spike
| proteins in large enough quantities that our immune system
| springs into action. Confronted with Spike proteins, and
| (importantly) tell-tale signs that cells have been taken over,
| our immune system develops a powerful response against multiple
| aspects of the Spike protein AND the production process.
|
| What happens to the "volatile genetic material" at the end of
| this? Does it just linger in the body indefinitely? Or does it
| somehow get destroyed (and what does that mean)? From my
| reading of the above excerpt, it's the produced spike proteins
| that get destroyed but not the original genetic material that's
| injected. The reason I'm asking is to understand how the
| vaccine designers determine if there are any long-term effects
| of having this artificial material inside your body. They
| couldn't have tested it over a long time frame given how
| quickly all this moved.
| outworlder wrote:
| > The reason I'm asking is to understand how the vaccine
| designers determine if there are any long-term effects of
| having this artificial material inside your body
|
| The properties of mRNA are well known and have been for
| decades. Your cells are constantly producing more from the
| nucleus. It degrades, even more so when it gets transcribed.
| That's the beauty of this, it's self-limiting.
|
| The only 'artificial' thing about it is the special base
| that's added to avoid detection by the immune system.
| Everything else is the exact same compounds present in your
| cells.
| throwawaysea wrote:
| What happens once it degrades? Does it eventually get
| decomposed into constituent molecules? Or removed from your
| body somehow? And what happens to that base?
| atleta wrote:
| Read the article, it answers your question in detail:
|
| > 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.
|
| Also, your cells continuously make mRNAs, depending on what
| proteins they need to synthesize. And those (have to) get
| discarded too. And also this is what happens to the actual
| viral RNA when the virus attacks you for real.
| throwawaysea wrote:
| Can you explain what "discarded" means there? Does the body
| somehow flush it out?
| atleta wrote:
| My understanding was that it gets cut into pieces
| (probably nucleotides in the end) and then reused. I've
| done a quick google search and it seems that there are
| multiple mechanisms:
| http://www.eb.tuebingen.mpg.de/remco-sprangers/mrna-
| degradat... and also
| https://en.wikipedia.org/wiki/Messenger_RNA#Degradation
|
| But the main idea is that it degrades with use until it
| becomes unusable and actively gets destroyed.
| alexobenauer wrote:
| It is worth noting that the studies are still ongoing. The
| Phase 3 trials are two years.
| fabian2k wrote:
| The mRNA is stable for a few hours or so, it is both
| chemically unstable in solution under the conditions in a
| cell and also actively degraded by various mechanisms.
| rjvir wrote:
| This should be an NFT, I'd love to own an NFT of the RNA sequence
| of the Moderna vaccine.
| cwkoss wrote:
| No reason you can't make your own NFT of it. Heck, if you
| promise to pay at least 1.337 ETH I'll figure out how to do it
| myself and make it for you. :-P
| rjvir wrote:
| Done, load it up!
| drtz wrote:
| 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.
| xjlin0 wrote:
| "but I'm utterly amazed at how simple this _appears_."
|
| Remind me the joke of the consultant engineer knows where to
| make X by the chalk. LOL
| learnstats2 wrote:
| The genetic code itself is reasonably comparable to ASCII in
| complexity - every 6 bits is the code for one amino acid in a
| string, which will fold itself into the required protein.
| weinzierl wrote:
| > _" Instead it's no bigger than a large paragraph of text, and
| I can easily fit it on my screen."_
|
| When I saw it, I thought that it could almost fit in a tweet,
| so I just did it:
|
| https://twitter.com/weinzierl/status/1376807707957719041?s=2...
|
| The sequence takes 16 tweets, 15 if you don't split at line
| endings and remove spaces (4175 nucleobases / 280
| nucleobases/tweet ~ 14.9 tweets).
| lifthrasiir wrote:
| Or you can use base2048 [1] to compress it down to 3 tweets
| (4175 nucleobases * 2 bits per nucleobase / 3080 bits per
| base2048 tweet = 2.7 tweets).
|
| [1] https://github.com/qntm/base2048/
| azernik wrote:
| 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 patient - and insert it into a human cell.
| (This is called the "platform", and is usually developed
| independently from the specific payload.)
|
| - manufacturing: both producing the mRNA itself at a large
| scale, and inserting it into the delivery mechanism, at a large
| scale and in low-temperature conditions
|
| - testing: the newly-developed payload and the existing
| platform were integrated at small scales within weeks, but
| testing the thing for safety and efficacy took months
|
| EDIT: As schoen pointed out, this was not actually released by
| Moderna, but reverse engineered by third-party researchers.
| Original text was: "Hence they feel safe releasing this. Their
| moat is not the gene sequence, their moat is everything else."
| robinsord wrote:
| Okay. I'll bite:
|
| Why do all vaccines have such heavy metal loads? Why are we
| OK with aluminum and other metals being loaded into these
| vaccines and shot into our bodies? I'm baffled as to why
| every tech breakdown of these vaccines sidesteps this
| fundamental question. Meanwhile we judiciously avoid heavy
| metals in our food for obvious reasons: like preventing
| Alzheimer's.
| MuffinFlavored wrote:
| > but testing the thing for safety and efficacy took months
|
| What kind of tweaks were made from "the version they threw
| together in a weekend" to "the version that is in production
| now"? What's a typical "mRNA" feedback iteration loop like?
| shellfishgene wrote:
| I'm not sure if there were changes in the sequence at all
| necessary during testing, however if you align the
| sequences given in that link from Biontech and Moderna, you
| see they encode the exact same protein (which is of course
| necessary). However the RNA sequence contains quite a few
| differences between the companies, they often use a
| different codons. This could be to make the translation
| more efficient, and can be a thing to optimize.
| [deleted]
| mschuster91 wrote:
| > - 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.)
|
| The most amazing thing is that now that the _platform_ is
| proven secure in dozens of millions of people, it should be
| be very easy and fast to get approval for other payloads.
| Biontech for example wants to go after cancers - a platform
| that can deliver payloads targeted to an individual 's cancer
| is nothing short of a game changer in cancer treatment
| because the current standard of blasting the patient's body
| with a lot of highly toxic chemicals is arcane compared to
| letting the body's immune system do the cleanup.
| azernik wrote:
| Even if the platform is safe, the payload itself needs to
| have its safety proven. Remember, the payload is just
| instructions, and those instructions make your cells pump
| out oodles of arbitrary proteins. That in itself can cause
| health problems. see e.g. the AstraZeneca vaccine's safety
| issues, which were caused IIUC by immune responses to the
| manufactured proteins. DNA vaccine, not mRNA, but the
| principle is the same.
|
| re: cancers, that is actually what this technology was
| originally developed for! Moderna has been spending about a
| decade getting this tested and proven out for the cancer
| role, and they're quite close. From my quick reading of the
| literature, there seems to be some regulatory confusion
| about how exactly to run approval for this kind of
| personalized drug design (testing the method of generating
| the individual drugs?), but the bar is usually much lower
| for cancers with high mortality rates.
| amelius wrote:
| Would it be possible to use the same delivery mechanism for
| other mRNA sequences?
| azernik wrote:
| Almost certainly - e.g. the J&J vaccine (a DNA vaccine, not
| mRNA, but same principle) is using a viral delivery
| platform that they'd had sitting on the shelf for years and
| have used for other vaccines.
|
| After the massive capex that has gone into mass-production
| of encapsulated mRNA delivery systems, I suspect this new
| technology will be _very_ cost-competitive for the big
| markets like the annual flu vaccine.
| schoen wrote:
| > 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.
| azernik wrote:
| Ah - thanks for pointing this out! Edited to make sure
| readers see it.
| Yizahi wrote:
| Additional reading (was posted here some time ago):
|
| https://blogs.sciencemag.org/pipeline/archives/2021/02/02/my.
| ..
|
| Why manufacturing of these vaccines is a hard part.
| dnautics wrote:
| sequence is actually released by Moderna in their patent:
|
| https://www.modernatx.com/sites/default/files/US10702600.pdf
|
| though they _do_ present multiple sequences, so I guess you
| 'd have to go to the FDA application to figure out exactly
| which one got used.
| vadiml wrote:
| Usually you can't patent facts. If it is natural (not
| synthetic) gene sequence they shouldn't be able to patent
| it...
| mikehollinger wrote:
| Reading the primary claim is fascinating: "A composition,
| comprising: a messenger ribonucleic acid (mRNA) comprising
| an open reading frame encoding a betacoronavirus (BetaCoV)
| S protein or S protein subunit formulated in a lipid
| nanoparticle."
|
| I have a "I'm sure that means something to somebody"
| feeling. It's also surprising that the remaining claims
| seem to describe the resulting bits of the sequence, and
| that that primary claim can stand on its own. Of course,
| I'm by no means an expert.
| mlyle wrote:
| > I have a "I'm sure that means something to somebody"
| feeling.
|
| Break it down! It's not so bad:
|
| > A composition
|
| A bunch of stuff
|
| > a messenger ribonucleic acid (mRNA)
|
| mRNA are cellular instructions on how to make proteins
| that are read by ribosomes that make those proteins as
| they read along.
|
| > an open reading frame
|
| This is something that starts with a "start codon" and
| ends with an "ending codon" and encodes valid
| instructions to make a protein between.
|
| > encoding a betacoronavirus (BetaCoV) S protein or S
| protein subunit
|
| The instructions refer to the spike protein of a
| betacoronavirus, or a fragment thereof, because this is
| what we want the immune system to pay attention to (and
| make antibodies to bind to and neutralize).
|
| > in a lipid nanoparticle
|
| The immune system gets _pissed off_ about mRNA floating
| around, because that 's one of the things that happens
| with active infection. So if you want this to get into
| cells and tell them to make your protein, you need to
| encase it so that it mostly escapes immune notice itself.
| mrfusion wrote:
| Why haven't viruses or bacteria evolved to use a lipid
| nano particle to evade the immune system? Seems like a
| big security flaw in our cells?
| azernik wrote:
| They have. That spike protein is part of their envelope
| ("nanoparticle").
|
| The envelopes used in an RNA vaccine are generally
| simpler, because they're working under different
| constraints than viruses. For example, their envelopes
| don't need to be easily manufactured in a cell.
|
| But some RNA and DNA vaccines do use viruses as their
| delivery mechanisms, eg the J&J COVID vaccine.
| scotty79 wrote:
| Maybe those lipid particles are too unstable if they are
| not spiked with various proteins?
|
| Moderna vaccine has to be kept in -70 C. Viruses that can
| survive for any extended period of time only in -70 C
| won't find many hosts.
|
| Also maybe the process of creating virus shell can't
| naturally be done without protein scaffold.
| [deleted]
| issamehh wrote:
| Don't give them any good ideas
| schoen wrote:
| I remember someone coming up with a song to encourage
| people to wash their hands more thoroughly much earlier
| in this pandemic.
|
| https://twitter.com/vesselofspirit/status/123748864242514
| 739...
|
| According to the song lyric, "novel coronavirus / has a
| lipid outer shell". So it seems like some viruses _have_
| taken advantage of this.
| ricardobayes wrote:
| That stupid ebola song came to mind. It's very catchy.
| https://www.youtube.com/watch?v=XGltVAJ4JCk
| retSava wrote:
| Yeah I think that's the reason for the 20-30 second wash
| since it takes time for the soap to break down the fatty
| layer.
| ufo wrote:
| If you squint you could say that viruses are already
| doing that. A lipid bilayer is a key component of several
| kinds of membranes. All of our cells have a lipid
| bilayers separating the inside from the outside. The
| corona virus is also built from these same lipids, which
| is why it's vulnerable to soap.
|
| Anyway, I think the important thing that the other
| commenter was saying is that mRNA needs to be carefully
| packaged to be medically useful. You can't inject pure
| RNA as a vaccine because not only is the mRNA going to be
| quickly degraded before it gets anywhere but if the
| immune system sees any RNA floating around by then it
| kicks itself into a frenzy because free-floating RNA is
| usually a sign that something nasty is afoot.
| EamonnMR wrote:
| Some do: https://en.m.wikipedia.org/wiki/Viral_envelope
| PetitPrince wrote:
| And it's pretty common; the flu viruses have one.
| Taniwha wrote:
| Doesn't this describe almost ANY vaccine - I think that
| it's probably bad public policy to allow anyone to patent
| ALL COVID vaccines - I think that patenting a particular
| vaccine (a particular mRNA string) should be allowed, but
| not effective wildcards in the RNA
| mlyle wrote:
| No. It doesn't describe the viral vector vaccines
| (J&J/AstraZeneca). It doesn't describe the inactivated
| virus vaccines. It doesn't include the viral fragment
| (NovaVax) vaccines. And it wouldn't describe some
| possible mRNA vaccines because of differences in
| formulation or differences in targeting.
|
| While this particular Moderna claim would likely affect
| BioNTech/Pfizer's mRNA vaccine, it's not clear whether it
| would survive in litigation, too.
|
| As to a "specific string"-- if you could just pad a few
| codons onto the end and not be violating the patent,
| that's not too worthwhile.
| bdonlan wrote:
| Claims are read in the context of the body of the patent
| and generally known and/or cited knowledge in the field
| in question. As long as you define precisely what you
| mean by your terms in the body, you can be as succinct as
| you want in the claims.
| jcims wrote:
| This is a great animation of the life cycle of an HIV
| virus. It's not exactly what happens with the pandemic
| virus but it gives you a good idea of the complexity of
| the process of viral reproduction (vaccine or immune
| response isn't covered here):
|
| https://vimeo.com/260291607
|
| Animation of transcription from mRNA:
| https://youtu.be/TfYf_rPWUdY
| retSava wrote:
| The "SARS-CoV-2 entry" video was really interesting too,
| and I recommend watching them both to see how they are
| different.
|
| https://vimeo.com/510310488
| jcims wrote:
| Nice!!! I didn't even notice that was uploaded! The
| differences between HIV and SARS-CoV-2 makes me wonder
| what reliability there is in this process, and if some
| viruses are more reliably able to enter the cell than
| others (presumably those that are more infectious?)
| nielsbot wrote:
| It blows my mind to see how life (and death) work at the
| molecular level--it's almost like some kind of manmade
| machine, but far more subtle and complex.
| dnautics wrote:
| Just remember that it's not really orchestrated. All of
| the molecules involve are kind of randomly blundering
| about and it's one-in-a-million collisions that are
| responsible for getting shit done (on membranes it's more
| like one in a thousand and on ropelike structures like
| dna or actin it's one in a hundred).
| ssener2001 wrote:
| Yes.One must know all programming of molecules and all
| laws current in the universe. perfect hierarchy from
| atoms to the cells, from cells to plants, animals from
| animals to earth, from earth to stars
| shadowofneptune wrote:
| These might interest you then: 3d visualizations of
| cellular processes in real time. I was shown them in my
| intro to biology class, which filled me with the same
| interest.
|
| Transcriptase: https://youtu.be/5MfSYnItYvg DNA
| polymerase: https://www.youtube.com/watch?v=bee6PWUgPo8
| The Ribosome: https://youtu.be/TfYf_rPWUdY
| shpongled wrote:
| As a biochemist, that's one of the things that has kept
| me interested in the work - it's truly mind boggling what
| is going on at the molecular level every second of our
| lives.
| jcims wrote:
| I love reading articles around biology, micro/molecular
| biology in particular, and looking for references to
| agency in the text. 'selects', 'filters', 'checks',
| 'seeks', etc when the reality is that the whole thing is
| just a massive chemical reaction.
| JonathonW wrote:
| Coronavirus replication is pretty dramatically different
| from HIV replication-- coronaviruses are not
| retroviruses, and do not have a step where viral RNA is
| converted into DNA and integrated into the host cell's
| genome. Instead, coronavirus RNA is directly interpreted
| by the cell's ribosomes to make the proteins that
| ultimately build and comprise the replicated viruses.
|
| The mRNA vaccines work in much the same way-- it's just
| that the mRNA vaccines only include the code for the
| spike protein and not the _rest_ of the virus 's
| machinery. So you get the vaccine and your body produces
| a bunch of spike protein by itself, which gives your
| immune system the opportunity to learn how to identify
| and react to the spike protein before it sees it on a
| real virus.
| ethbr0 wrote:
| It's an interesting structure, but probably partly out of
| patent law. To wit, SARS-nCoV-2 is non-patentable, being
| of natural occurance.
|
| But a specific composition that encodes its spike
| protein, encapsulated in a lipid nanoparticle? That's
| much more of a creative work.
| Benjamin_Dobell wrote:
| > _That 's much more of a creative work._
|
| Probably worth noting that patents are not required to be
| creative. That's copyright terminology.
|
| I think the terminology used for patents is something
| like "inventive and useful".
| redis_mlc wrote:
| > To wit, SARS-nCoV-2 is non-patentable, being of natural
| occurance.
|
| Looks man-made (modified in a lab) by most informed
| people.
| mikehollinger wrote:
| > It's an interesting structure...
|
| I think that's the question. I'm very much used to
| reading "A machine-readable medium, comprising..." I'm
| curious what bits are unique to COVID-19, and what bits
| are generally protecting the idea of using a carrier to
| send a specific protein. In this case, is it the "S"
| protein phrasing that protects the specific embodiment of
| COVID19's spike?
| mlyle wrote:
| Here what is claimed is encoding for _any_
| betacoronavirus 's spike protein.
| mikehollinger wrote:
| > Here what is claimed is encoding for any
| betacoronavirus's spike protein.
|
| Aha! That's what is surprising to me - I assumed that
| that would have been done previously / protected
| previously. That explains it.
| The_rationalist wrote:
| If it's just the spike protein encapsulated in a lipid
| nanoparticule (for isolation and transportation?), that
| looks like something not creative and quite established
| for people in the field of genetic material transport.
| ethbr0 wrote:
| My layperson's understanding is that the actual spike
| protein and/or mRNA are modified from the natural
| versions. Both for stabilization (if either falls apart
| quickly, they're of no use) and for response
| optimization.
|
| So somewhat like how a fishing fly differs from the
| insect it represents.
| dylan604 wrote:
| > put together their sequences in a weekend
|
| meh, I could do that over a weekend never sounded so scary,
| or impressive at the same time. That weekend just so happened
| to stand on the shoulders of prior decades of research
| though.
|
| i guess this is big pharma's version of `apt-get install`
| o-__-o wrote:
| Modern a has been working on mRNA since 2010 and mRNA
| vaccines since 2012. They have the process down pretty
| solid, but vaccines do not bring in the bacon.
| hcayless wrote:
| The big money's going to be in cancer treatments. If they
| can use this to target tumors, they'll do quite well.
| o-__-o wrote:
| Bad news, it's not looking very successful right now.
| Moderna is making back all the lost revenue with the
| emergency authorization tho
| DrAwdeOccarim wrote:
| Can you share some of the bad news links? I've only seen
| the positive ones.
| justmedep wrote:
| And Biontech since 2008 and CureVac was founded in 2000
| (after their initial CEO made a discovery that enabled
| Biontech + Moderna).
|
| https://en.wikipedia.org/wiki/Ingmar_Hoerr
| azernik wrote:
| Now that they've spent a year developing the mass-
| production methods and infrastructure, it might bring in
| the bacon! e.g. there's a steady annual market for a flu
| vaccine for whatever the latest strain is, and being able
| to get that to market faster than the competition could
| give them an edge.
|
| I just don't think it was every profitable enough for
| them to put in this enormous capital expenditure.
| dylan604 wrote:
| When you can have Uncle Sam cover that capex, it makes it
| even more financially appealing.
| hutzlibu wrote:
| " but vaccines do not bring in the bacon."
|
| As in, "do not generate enough income"? Really? Now?
| [deleted]
| retrac wrote:
| Yes, really. Typical vaccines are like $5 to $200 or so.
| And worst of all, usually just one or two doses.
|
| For all the horror HIV has wrought, global spending on
| vaccine development for HIV has been around $1 billion a
| year for the last few years. In contrast, the USA federal
| government spends $3 billion a year for HIV antiviral
| drugs for low-income Americans. $20,000 per patient per
| year for life. Unsurprisingly, new antivirals are where
| most of the research is.
|
| It can sound almost like a conspiracy if I put it like
| that, but it's just the economics incentives. Especially
| since the developed countries where most of the market
| for charging a decent markup is, have the smallest market
| for most new vaccines, while having the largest markets
| for therapeutics for chronic conditions.
|
| Now HIV is genuinely devillish to develop a vaccine for
| despite our attempts. But vaccines for hepatitis C,
| gonorrhea, HSV, among others appear to be possible. We
| almost certainly could develop effective vaccines for
| these with existing techniques, if someone coughed up the
| funding. Maybe all the buzz about mRNA vaccines will spur
| some progress here.
| eeZah7Ux wrote:
| > It can sound almost like a conspiracy if I put it like
| that, but it's just the economics incentives
|
| Talk about market failures! It's completely obvious that
| this economical system is not placing the good of the
| whole human species as its first priority.
| hutzlibu wrote:
| "es, really. Typical vaccines are like $5 to $200 or so"
|
| But since the demand is 14 000 000 000 doses, there
| should still be a little bit of money in it?
| kube-system wrote:
| Yes, but a pandemic only comes around every hundred years
| or so. Moderna happened to be in the right place at the
| right time for this one, but delivering vaccines for a
| pandemic is not much of a solid business plan.
| retrac wrote:
| Yes, clearly. With COVID-19, there is pretty much
| guaranteed market for about ten billion doses. Along with
| direct investment by governments in wealthier countries.
| Most people, including politicians, want a COVID-19
| vaccine real bad.
|
| The parent poster was describing the situation with
| vaccine development in general, to which COVID-19 is
| quite the exception. A potential hepatitis C vaccine for
| example has very different economics, as it would not be
| deployed anywhere nearly as widely or quickly. Consider
| that, 40 years after hepatitis B immunization became
| available, the majority of Americans haven't been jabbed
| with it.
| azernik wrote:
| Now is a very atypical situation :-P
| technick wrote:
| You've never been to Florida have you?
| refurb wrote:
| Vaccines can be very lucrative. Pfizer has billions in
| sales for Pentacel.
| hadlock wrote:
| Current pricing for mRNA vaccines is something in the
| $4-7 dollars (that's $7.00 dollars, not $7,000.00
| dollars) range. Compare that to one of the Hepatitis C
| treatments, which costs north of $350,000 by several
| accounts. Even remdesivir is something like $3000 for a
| course.
| hutzlibu wrote:
| "Hepatitis C treatments"
|
| We don't really need the same quantities of that, though.
| mikecoles wrote:
| https://www.hhs.gov/hepatitis/learn-about-viral-
| hepatitis/da...
|
| It can be said that hepatitis care is more necessary than
| covid.
| hutzlibu wrote:
| The world is not in lockdown becuse of hepatitis, though.
| TeMPOraL wrote:
| Hepatitis isn't airborne, though, so it doesn't have an
| exponent threatening to blow up in everyone's face.
| failwhaleshark wrote:
| There are roughly 75 million HCV infections in the world.
|
| That translates to a total cure cost of:
|
| 75M * $350k = $26.25T
|
| There are other ARV treatments available which cost now
| roughly $50-100k and cure in 3 months.
|
| Whereas immunizing everyone against coronaviruses
| currently costs:
|
| 8B * $7 = $56B
|
| Clearly, the costs of the HCV cure are predatory and
| unreasonable because it doesn't lead to eradication and
| it's inaccessible to the poor and the third-world.
| adgjlsfhk1 wrote:
| It's also worth noting that if it's $7 for the payer,
| there's a lot less than $7 of profit.
| failwhaleshark wrote:
| The true unit cost is probably $6 per dose. The COVID
| vaccines may break-even short-term. Long-term, it's
| probably worth keeping an extra 120M potential customers
| alive for what will probably result in a small profit.
|
| The true unit cost of HCV cures is unknowable but
| possibly half of the current price.
| molbioguy wrote:
| Not only did Moderna have a decade of experience with mRNA
| as 'drug', but the mechanism of coronavirus infection was
| well-understood from SARS research, namely the importance
| of the spike protein. All the parts were in place and just
| waiting for the specific SARS-CoV-2 sequence. They designed
| it as soon as they had access to the Wuhan sequence.
| wespiser_2018 wrote:
| from what I've gathered, the rate limiting step for
| production as of yet, is creating the lipid vesicles and
| getting the RNA inside of them. Only a few companies have a
| process for this, and the supply chain for the precursors is
| limited as well.
| _joel wrote:
| Could be wrong but AFAIU the Pfizer one doesn't encapsulate
| in a lipid, hence why it needs lower temperatures.
| Exmoor wrote:
| They're both encased in lipids. Pfizer didn't have long
| term data on long-term storage at standard freezer
| temperatures, but has since confirmed their vaccine can
| be stored at similar conditions to Moderna.
| xjlin0 wrote:
| Pfizer one does contain 4 kinds of lipids to encase the
| RNA. The encapsulation percentage is however unknown.
| https://www.technologyreview.com/2020/12/09/1013538/what-
| are...
| wespiser_2018 wrote:
| RNA would get thrashed by your immune system if it isn't
| encapsulated by something: liposome deliver of
| therapeutic RNA is really next-generation tech, and the
| fact that the RNA does what it's supposed inside the your
| cells is no small feat either.
|
| From the CDC "ingredients" for the BioNTech/Pfizer
| vaccine, along with cholesterol (which modulates the
| stability of lipid membranes), they report using this
| molecule, which would form a phospholipid bylayer, just
| like our own cells use: https://www.sigmaaldrich.com/cata
| log/product/avanti/850365P?...
| The_rationalist wrote:
| _- 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.)_
|
| Sounds like a problem you solve once and for all, for any
| vaccine. And also that this problem was already solved since
| decades (e.g viral vectors)
|
| _- testing: the newly-developed payload and the existing
| platform were integrated at small scales within weeks, but
| testing the thing for safety and efficacy took months_ And so
| many people have been killed by this overly conservative
| testing, phase ~ <2.5 was enough
| baq wrote:
| a bad vaccine could kill much more than that. remember that
| RNA vaccines are developed for 10+ years now and COVID19 is
| the first time they actually worked without side effects.
| TeMPOraL wrote:
| > _Sounds like a problem you solve once and for all, for
| any vaccine._
|
| I strongly doubt it. It's more like a problem you solve
| once for a particular class of payload _and_ particular
| destination. Biology doesn 't do packet switching -
| everything is just rapidly bumping into everything else at
| random, so your envelope needs to be designed in a way
| that's ignored by everything else than molecules at your
| target site, _and_ it needs to not react with the payload
| it 's carrying.
|
| > _And so many people have been killed by this overly
| conservative testing, phase ~ <2.5 was enough_
|
| Overly conservative? That's what super-accelerated testing
| looks like. We're lucky it went well; had they screwed up,
| it would scare a lot more people away from vaccinating,
| lengthening the pandemic and increasing death toll.
| outworlder wrote:
| > 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...
| dnautics wrote:
| I wouldn't even say the immune system, your body has a ton
| of nonspecific RNA-digesting enzymes floating around to
| patrol for exactly this sort of thing happening, even by
| accident, as cells can sometimes rupture. It's a problem
| enough that good RNA researchers have a reputation of being
| clean freaks. Some RNA labs I've been in had a lingering,
| slightly sweet smell, that's the nonspecific RNAase
| inhibitor that gets sprayed on everything.
| azernik wrote:
| RNA is also just generally fantastically unstable and
| reactive. You don't want any surface to be too alkaline,
| for example. There's a reason that basically every life
| form switched to DNA.
|
| (Though RNA may have been _more_ stable under the high-
| UV-exposure conditions the early Earth.)
| azernik wrote:
| Though AFAIU once you've gotten the RNA inside the cell,
| you're home free.
| amluto wrote:
| It appears simple, but a whole lot of work went in to producing
| that string even pte-COVID. Some of it is generic in the sense
| that it might apply to any mRNA vaccine. Some is quite
| specific:
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584442/
|
| There's also (IIRC, no citation right now) prior work
| suggesting that coronavirus vaccines against the spike are
| likely to be effective and that vaccines against the N protein
| might be counterproductive.
| purple_ferret wrote:
| 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 x 20 x 20 x 20 = 160,000 different possible
| polypeptide chains four amino acids long, or 20n different
| possible polypeptide chains n amino acids long. For a typical
| protein length of about 300 amino acids, more than 10^390
| (20^300) different polypeptide chains could theoretically be
| made. This is such an enormous number that to produce just one
| molecule of each kind would require many more atoms than exist
| in the universe."
| Gatsky wrote:
| Then there are also post translational modifications, like
| addition of acetyl or phosphate groups, and sugars to the
| protein (glycoproteins).
|
| I mean, I can understand how an eye or a brain can evolve by
| natural selection, but I'm still stunned by abiogenesis. I
| guess we'll never know for sure how it all started.
| MauranKilom wrote:
| The exponentiation signs got lost in your quote. Would you
| mind adding them back in?
| abfan1127 wrote:
| proteins are also unique in that not just their sequence
| matters, but also their physical shape. 2 proteins can have
| the same sequence but a different physical shape, and
| therefore have different impacts on the body's chemistry. I
| started a PhD researching DSP methods for matching protein
| sequences and locations of amino acids. Fun stuff.
| DecoPerson wrote:
| Check out this video by The Thought Emporium to see how far
| we've come in these matters:
|
| https://youtu.be/J3FcbFqSoQY
|
| This should hopefully provide you with some useful perspective.
| fnord77 wrote:
| each one of those letters represents a ~15 atom molecule, so in
| a way it is a compressed representation
| mattnewton wrote:
| I think it's a bit like a private key- the difficulty is in
| finding some combination that works in an absolutely massive
| space of possible proteins, not necessarily in the length of
| the protein.
| nraynaud wrote:
| the way I see it we're just at the beginning, and we're mainly
| copy/pasting a lot of code, we understand some small parts, and
| generally in the teenage years of genome programming.
|
| I don't know how long it will be before we get a bit more
| serious with it, but geneticists have a big obstacle in their
| understanding, any change might needs a thousand strong
| lifelong population study to be understood. That's way crappier
| than dumping the assembly or only having the documentation in
| Chinese.
|
| I will add that moreover the developers might have been even
| more conservative in their code because they knew it was going
| for large scale deployment, they probably avoided the cutting
| edge as much as they could.
| flobosg wrote:
| Sequencing technologies have improved immensely over the last
| decade and a half. And, in this particular case, getting the
| sample RNA is incredibly easy, since its purity and integrity
| in the vial is quite high.
| shellfishgene wrote:
| I didn't look at the details of how they sequenced it, but
| given that there are chemically modified bases in the mRNA
| vaccines there is a chance the normal methods for sequencing
| (and the first step of translating to DNA) don't work. Well,
| I guess in practice they did.
| flobosg wrote:
| While not completely equal to the naturally occuring bases,
| the modified bases in the vaccine mRNA need to be able to
| complement to the non-modified ones present in tRNA
| anticodons during translation. If they can pair to their
| corresponding natural bases, then the chemically modified
| RNA can be also used as a template by the reverse
| transcriptase to generate the complementary DNA needed for
| the sequencing reaction.
| shellfishgene wrote:
| Generally I agree, but it could be the case that the
| modified bases work just well enough for tRNA matching in
| the ribosome, but not with the reverse transcriptase.
| flobosg wrote:
| The mechanism of base complementarity is identical in
| both cases. If a modified uracil complements an adenine
| in tRNA, it will complement an adenine in the RT primer
| or an adenine being added to it.
| ceratin6 wrote:
| _> I 'm sure it's more complex than I grasp as a layperson, but
| I'm utterly amazed at how simple this _appears_
|
| The genetic code is simple. But possibly not the _nanobot_ that
| I felt like attached to my optical nerve with a slightly
| painful prick behind my right eye.
|
| I'm not kidding. I never have eye pain and within a day or two
| of my vaccination, I had a prick feeling once in the back of my
| right eye, later accompanied by light coming from within my eye
| as it was closed in the dark for only a monent for a small part
| in or close to the middle of my visual field.
|
| I wish I was making this shit up. It was really the only weird
| side effect, coincidental or not, of the vaccine for me.
|
| The good part is that my vision in that eye has been slightly
| better since.
|
| I'm not recommending not to get the vaccine. You should get it.
| But this experience was weird enough to share.
|
| I had a fleeting thought of buying an eyepatch for privacy.
| lettergram wrote:
| It really is that "simple."
|
| Getting it designed and building it is more difficult.
|
| At its core, it's a piece of mRNA that creates a protein. That
| code gets transcribed into a protein (often those are
| relatively short). That protein then triggers your bodies
| immune response, which trains it to attack covid19.
|
| Inject this mRNA into a cell and it'll create the protein.
| Anything can be injected at this point once the mechanism for
| injection is developed
| wombatpm wrote:
| Which makes me wonder. Could you place the entire virus
| genome in these liposomes and get them to hijack the
| machinery to make an entire virus? Like plasmid but for viral
| structures?
| amelius wrote:
| Why would you want to do that if you can use the virus
| itself as the delivery mechanism?
| lettergram wrote:
| Yes, that's one of the concerns many have about this
| technology. Literally, anything can be injected and done at
| this point.
|
| Not sure where the technology is exactly at, but I suspect
| we're no more than 5 years from major incident related to
| this.
|
| Even this vaccine, we really don't know the long-term
| impacts or risks involved with this. For instance, this
| vaccine does appear more risky than the standard flu
| vaccine:
|
| https://wonder.cdc.gov/controller/saved/D8/D137F981
|
| Presumably this is due to increased inflammation. It's not
| hard to imagine that we'll be doing genetic editing soon
| enough with this (if we aren't already).
| kickopotomus wrote:
| Do you happen to have a more verifiable source for your
| claim that COVID-19 vaccines are more risky than the flu
| vaccine?
|
| Excerpt from the disclaimer in your source:
|
| > VAERS accepts reports of adverse events and reactions
| that occur following vaccination. Healthcare providers,
| vaccine manufacturers, and the public can submit reports
| to VAERS. While very important in monitoring vaccine
| safety, VAERS reports alone cannot be used to determine
| if a vaccine caused or contributed to an adverse event or
| illness. The reports may contain information that is
| incomplete, inaccurate, coincidental, or unverifiable.
| Most reports to VAERS are voluntary, which means they are
| subject to biases. This creates specific limitations on
| how the data can be used scientifically. Data from VAERS
| reports should always be interpreted with these
| limitations in mind.
| sterlind wrote:
| How do you edit genes with an mRNA vaccine? You'd need
| DNA, enzymes (maybe requiring post-translational
| modification) to splice them in, etc.
|
| Also, you might not even be able to print full viruses
| with this platform. manufacturing mRNA is different from
| manufacturing all the random types of RNA in a virus,
| isn't it?
| lettergram wrote:
| Theres really no reason you can't have a multitude of
| mRNA deployed, you definitely don't need DNA to do
| editing.
|
| There are people already doing gene editing with mRNA
| methods:
|
| https://m.jpost.com/health-science/israeli-scientists-
| use-mr...
|
| I'm not sure about these particular platforms, but I
| wouldn't be surprised if we see gene editing technology
| deployed live in the next 3 years.
| airstrike wrote:
| > and I can easily fit it on my screen.
|
| ...with GATACCA right in the middle, but unfortunately with no
| GATTACA that I could find.
| staplung wrote:
| Heh. Technically, there isn't even GATTACA in there since
| it's RNA and hence all the T's are actually U's. It's just
| convention to use the T's. GAUUACA doesn't have the same ring
| to it.
| pyinstallwoes wrote:
| See RadVac: https://radvac.org/
|
| Make your own, open-source. Really cool.
|
| A user on lesswrong made their own (with no prior experience):
| https://www.lesswrong.com/posts/niQ3heWwF6SydhS7R/making-vac...
| hfjfktmtkrn wrote:
| It's not really that simple.
|
| Only two companies in the world succeeded, the French company
| Sanofi which also tried making a mRNA vaccine failed.
| WheelsAtLarge wrote:
| True, most pharmaceuticals can't do it now but given the
| right knowledge, which is known, it can be done relatively
| fast. I suspect in the next few years there will be many
| companies that will be able to replicate and advance the
| process.
| fermienrico wrote:
| It's like looking at the binary file and saying "that's
| pretty simple" while ignoring the massive amount of machinery
| that allows us to run that file and use it (CPUs,
| Motherboards, computers, etc).
|
| I presume a whole bunch goes into making vaccine and this is
| just the top of the iceberg.
| jldugger wrote:
| Liken it to the 4kb demoscene: it's amazing what can be done
| with a little bit of information, as long as you don't have to
| describe the machine running it.
|
| Or the distribution method, or even really invent the thing,
| since you're mostly just copying someone else's work. Plus it
| doesn't have to even do anything. In fact, doing anything might
| be a problem, so best to just sit there and look menacing (and
| spikey).
| GuB-42 wrote:
| > Liken it to the 4kb demoscene
|
| Coincidentally, the mRNA sequences for both vaccines are
| about 4kb (kilobase) long.
| puzzlingcaptcha wrote:
| Here is a breakdown https://berthub.eu/articles/posts/reverse-
| engineering-source... discussed previously
| https://news.ycombinator.com/item?id=25538820
| tablespoon wrote:
| > 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 Ps. The
| really clever bit is that although this replacement Ps
| placates (calms) our immune system, it is accepted as a
| normal U by relevant parts of the cell.
|
| Neat.
| grey413 wrote:
| We are really quite fortunate that there was a ton of work
| done on coronaviruses, mRNA vaccines, adenovirus vaccines,
| etc prior to the pandemic. It seems like a pandemic even a
| year or three prior would have made the vaccine rollout
| considerably slower.
| WheelsAtLarge wrote:
| No wonders some people have an allergic reaction. Those
| people's immune response is more sensitive to this change.
| lamontcg wrote:
| 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.
| seiferteric wrote:
| Umm, isn't that kind of scary? Like could you create a
| virus with this Ps that our immune system can't fight at
| all?
| carlmr wrote:
| Maybe I'm thinking too simplified here, but wouldn't this
| only work on the first iteration? After all the virus
| would replicate with Us in your cells and then the
| replicas wouldn't have the advantage anymore.
| bobthebuilders wrote:
| By that point the cell would be producing the associated
| protein though. Getting it inside the cell is the goal
| here from what I've read.
| IgorPartola wrote:
| My exact question when I read that.
| maxerickson wrote:
| It's part of an instruction to cells to make something.
| Viruses replicate by instructing cells to make viruses.
| Our cells don't know how to make Ps, so the replicated
| virus would have the normal instruction.
| seiferteric wrote:
| Thanks, that is reassuring and makes sense. *at least
| until we figure out how to put the instructions to make
| it in the virus code :)
| babypuncher wrote:
| 1) As someone else pointed out, this molecule
| substitution would not persist during replication. New
| viruses being produced in your cells would be made with a
| normal "U".
|
| 2) Your immune system does not usually attack the RNA
| housed inside a virus, but rather protein fixtures on its
| "body".
| jeroenhd wrote:
| As denoted in the linked article [1]:
|
| "Many people have asked, could viruses also use the Ps
| technique to beat our immune systems? In short, this is
| extremely unlikely. Life simply does not have the
| machinery to build 1-methyl-3'-pseudouridylyl
| nucleotides. Viruses rely on the machinery of life to
| reproduce themselves, and this facility is simply not
| there. The mRNA vaccines quickly degrade in the human
| body, and there is no possibility of the Ps-modified RNA
| replicating with the Ps still in there. "No, Really, mRNA
| Vaccines Are Not Going To Affect Your DNA[2]" is also a
| good read."
|
| As far as I could tell, this would work well for getting
| a synthetic virus into the human body, but without the
| necessary mechanics within our cell, the special Ps
| chemical won't be reproduced by the virus. That'd mean
| the replicated virus would get snatched up by the immune
| system as soon as it'd get released from the cell.
|
| Theoretically, a complex enough RNA string could be used
| to have our cells build the necessary cellular machinery
| to properly reproduce the virus, but that's a kind of
| altering DNA that's a whole different can of worms.
| There's probably cheaper and easier way of defeating the
| immune system, for example by simply "enhancing" ebola or
| HIV to make them more infectious and more resistant to
| our current drugs.
|
| [1]: https://berthub.eu/articles/posts/reverse-
| engineering-source... [2]:
| https://www.deplatformdisease.com/blog/no-really-mrna-
| vaccin...
| randalluk wrote:
| 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 Ps 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.
| atleta wrote:
| No. For a number of reasons. First of all, the virus uses
| the nucleotides (A, G, C and U, for wich Ps 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 Ps (or any of the
| other nucleotides).
| schoen wrote:
| In case others don't know this, the reason this is
| abbreviated Ps (psi) is that Ps is the first letter of
| Greek pseudes 'false, lying', the origin of the prefix
| pseudo-.
| anxrn wrote:
| Not Moderna, but this [1] was a very useful primer on grokking
| how the Pfizer vaccine works, especially for computer
| programmers.
|
| [1] https://berthub.eu/articles/posts/reverse-engineering-
| source...
| phreeza wrote:
| People tend to think of genetic code as a sort of assembly
| language which is very verbose, but I wonder if the correct way
| to view it is in fact a very terse domain-specific language,
| because it actually depends on the entire complex machinery of
| the cell to be present in order to work, which in itself
| contains a lot of information?
| jldugger wrote:
| > I wonder if the correct way to view it is in fact a very
| terse domain-specific language
|
| Honestly, na. It's pretty verbose. There's a lot of weird ass
| things in there like "Skip basepairs until you find the
| matching terminating sequence" (I think it's AG .* GA but its
| been a decade since my bioinformatics course), but you still
| have to include the non-AA-coding basepairs in the middle of
| that.
|
| Compensating for that is the fact that there are like,
| multiple independent programs; if a ribosome is offset by a
| single base pair, the result is entirely different. If it
| runs the other strand, the result is different. And instead
| of crashing like any program would, biology just learns to
| use all of those possible encodings. In part, this works
| because there are 64 possible codons but only 20 amino acids,
| and the redundancy allows a substitution to affect only some
| of the offsets.
| Tuna-Fish wrote:
| Yes. Another important metaphor is that the common idea of
| DNA as blueprints is entirely wrong. It's not blueprints,
| it's a recipe. A blueprint describes what something is. A
| recipe describes the steps needed to make something, making
| use of a lot of complex existing machinery and parts with
| only a reference to them.
| mattkrause wrote:
| The nucleotide sequence is obviously important, but people
| also sometimes forget that DNA and RNA are real things with
| 3D structure too. That matters too: it's as if builders
| make errors where the blueprint rolls up or pages stick
| together.
|
| The whole thing is absolutely fascinating and wild.
| wubbfindel wrote:
| Interesting reasoning. But isn't it true to say that the
| "complex existing machinery and parts" which interprets the
| DNA was itself put together from instructions found in
| other DNA? I suppose that metaphors are rarely entirely
| comparable.
| andagainagain wrote:
| I'm estimating roughly 90-ish characters in a row, roughly 40
| rows encoding the spike protein. So about 3600 base pairs.
| There are 3 base pairs per amino acid, so That's 1200 amino
| acids.
|
| For comparison, the smallest chain that they technically call a
| protein is 100 amino acids that's an arbitrary limit to
| separate proteins from enzymes. So this thing isn't tiny tiny.
|
| But Titin (also called connectin), a giant protein responsible
| for passive elasticity in mucles, is ~27,000-35,000 amino
| acids. So this thing isn't even close to the biggest proteins
| out there.
| flobosg wrote:
| > that's an arbitrary limit to separate proteins from enzymes
|
| Do you mean "to separate polypeptides from proteins"?
| Enzymatic activity has nothing to do with size. For example,
| one of the smallest enzymes in humans has 62 amino acid
| residues. And, under certain conditions, even single amino
| acids can be catalytic.
|
| But yeah, the polypeptide-protein threshold can get fuzzy,
| especially with the recent advances in miniprotein
| characterization.
| andagainagain wrote:
| yes, that is what I meant. It's been a long time since I've
| used that info.
|
| The story I remember was that Insulin was the first protein
| that was sequenced, which is funny because it was before
| they made the distinction. It's actually too small to be
| considered a protein now.
| Black101 wrote:
| so, explain it to me ?
| softwaredoug wrote:
| Great quote from Maurice Hilleman, creator of many (most?) of
| our childhood vaccines goes something like "Don't be smart.
| Instead be careful and accurate"
|
| Lots of these things aren't complicated. It's the careful
| systematic testing and public trust building that's the hard
| part.
| gremlinsinc wrote:
| The way it reads like source code, truly makes me circle back
| to the idea we're all living in a simulation.
| fiftyfifty wrote:
| The New York Times published an article last year with the
| entire genome of the SARS-Cov-2 virus, with a breakdown of
| different sections to explain what protein the RNA codes for
| and what that protein does. Like you said it was amazing that
| it all fit within an [albeit long] newspaper article. It
| doesn't surprise me that the RNA for the vaccine, which only
| targets a single protein, is even smaller than that. Here's the
| NY Times article I was referring too:
|
| https://www.nytimes.com/interactive/2020/04/03/science/coron...
| gerdesj wrote:
| "but I'm utterly amazed at how simple this _appears_."
|
| Biology is a funny old thing. You can look at that concise
| description - the orange and so on blocks of a few letters and
| a few short groupings.
|
| Now ATCG are basic building blocks but they consist of quite a
| lot of stuff. I think it's a bit more complex than that because
| this is RNA not DNA so ATCG might not be quite right. Each of
| those bases are horrifically complicated depending on scale.
| Search "ATCG" - this is a good start:
| https://en.wikipedia.org/wiki/Nucleobase
|
| Now dive into one of those bases and decompose it to its
| constituent atoms. Now look at the maths around this stuff. It
| gets quite complicated, quite quickly.
|
| That said, the fact that a bloody complicated thingie can be
| described so concisely is absolutely amazing and as you say it
| looks so simple.
| flemhans wrote:
| It'd be cool to make an easy-to-use interface, still.
| devenvdev wrote:
| I remember a lot of features and especially bug fixes where I
| had to change one line of code, it took hours to figure out how
| exactly though. I guess this is kinda similar?
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