[HN Gopher] mRNA's next challenge: Will it work as a drug?
___________________________________________________________________
mRNA's next challenge: Will it work as a drug?
Author : mudil
Score : 137 points
Date : 2020-12-18 18:08 UTC (4 hours ago)
(HTM) web link (science.sciencemag.org)
(TXT) w3m dump (science.sciencemag.org)
| napier wrote:
| Paywalled for me. Perhaps someone could fix that?
| knicholes wrote:
| You could fix it by paying! :D
| cinntaile wrote:
| It seems to cost $15. Which is a bit excessive for what's
| essentially a news article. News articles hardly have any
| worth on its own nowadays.
| Wowfunhappy wrote:
| Because the parent appears to have been downvoted (as of this
| writing), I'd just like to point out that according to the site
| FAQ, their question is perfectly acceptable on HN.
|
| > _It 's ok to post stories from sites with paywalls that have
| workarounds. In comments, it's ok to ask how to read an article
| and to help other users do so. But please don't post complaints
| about paywalls. Those are off topic._
|
| https://news.ycombinator.com/newsfaq.html
|
| https://news.ycombinator.com/item?id=10178989
| macrolime wrote:
| Link to full article
|
| https://sci-hub.se/downloads/2020-12-18/44/10.1126@science.3...
| neonate wrote:
| https://archive.is/h7MNM also works.
| dzhiurgis wrote:
| Does not for privacy respecting dns users
| dsissitka wrote:
| Or Brave users, or... did they ever unblock Finland?
|
| https://en.wikipedia.org/wiki/Archive.today#Finland
| LordDragonfang wrote:
| I'm wondering what a "privacy respecting" dns could
| possibly have to do with breaking a web archival service.
|
| edit: huh
|
| https://www.reddit.com/r/pihole/comments/ao51ko/problem_wit
| h...
|
| https://news.ycombinator.com/item?id=19828702
| colejohnson66 wrote:
| If web.archive.org was used, it would work. Why do people
| prefer archive.is? The Internet Archive is more established
| and less likely to disappear.
| neonate wrote:
| In this case it doesn't have the article.
| colejohnson66 wrote:
| web.archive.org/save/{URL} works
| napier wrote:
| Thanks!
| witweb wrote:
| God bless Sci-Hub. Thanks for linking the full article.
| dmix wrote:
| Donate to Sci-Hub:
|
| https://sci-hub.tech/donation/
|
| They accomplished one of Aaron Schwartz's dreams.
| elektor wrote:
| Is this the legit link to Sci-Hub? I'm a little surprised
| to see Paypal allow donations.
| msla wrote:
| https://web.archive.org/web/20201218214338/https://sci-hub.s...
| wildbunny wrote:
| It's gone down
| CaliforniaKarl wrote:
| It's up for me. You may be in an area, or using an ISP, that
| is blocking access to that domain. Unfortunately I don't have
| any info to hand on alternate access methods, but I know they
| exist.
| h_anna_h wrote:
| Enabling dns over https usually fixes any censorship by an
| ISP issues.
| deadalus wrote:
| https://ipfs.io/ipfs/QmWiWELM9ArjAJvAsSiyZ5jSfjZERir3nGmbySV.
| ..
| macrolime wrote:
| If it doesn't work you can try try replacing .se with .st or
| .do
| ce4 wrote:
| Works for me, check if sci-hub.se resolves to e.g.
| 186.2.163.219.
|
| Or just:
|
| curl --resolve sci-hub.se:443:186.2.163.219 --remote-name
| https://sci-
| hub.se/downloads/2020-12-18/44/10.1126@science.3...
| hikerclimb wrote:
| I hope not
| ineedasername wrote:
| mRNA might not pan out for more general purposes (well,
| specialized for each use case) but it seems kind of crazy that
| the most significant pandemic, social upheaval, and economic
| crisis the world has known in 100 years could also lead to some
| of the most significant advances in medical science & therefore
| quality of & length of life as well.
|
| I'm not trying to downplay the health issues or impact of COVID,
| just saying that it has the potential for one heck of a silver
| lining. Not least of which is that even if other mRNA uses aren't
| forthcoming, we're incredibly more prepared to fight another
| pandemic, especially other Corona strains, that could be more
| harmful.
| maxerickson wrote:
| The technology has been in development for decades, so in that
| sense is a response to the pandemic, but it's not a result of
| the pandemic.
|
| (the first SARS certainly encouraged vaccine research)
| avancemos wrote:
| The question is, how did this start just now? In 2020? How is the
| COVID-19 vaccine the first to use mRNA? Anyone with who has taken
| AP Biology could conceive of and understand the idea behind
| making vaccines rapidly: take some mRNA, inject it, have in
| translated as the antigen in the body. Poof, that's it. I feel
| like the development of mRNA drugs should have started in the
| 70's or 80's. It isn't exactly high-tech or clever.
| dragonwriter wrote:
| > Anyone with who has taken AP Biology could conceive of and
| understand the idea behind making vaccines rapidly: take some
| mRNA, inject it, have in translated as the antigen in the body.
|
| There was quite a lot of development on basic techniques of
| working with RNA necessary before that could even in isolated
| circumstances be easier than, or even competitive with,
| "isolate the antigen, inject it, done".
|
| > The question is, how did this start just now?
|
| It didn't.
|
| Getting a treatment to market isn't the _start_ of application
| of a new technique in medicine; its usually something that
| happens many years, often decades, into work using the
| technique.
| iskander wrote:
| >take[1] some mRNA[2], inject it [3], have in translated as the
| antigen in the body[4]. Poof, that's it.
|
| 1) Develop synthesis technique for large scale high purity mRNA
| without base errors or truncations.
|
| 2) Discover pseudouridine modification to decrease innate
| immune response.
|
| 3) Discover and optimize lipid nanoparticles for encapsulation
| of mRNA to prevent its degradation.
|
| 4) Optimize LNPs and miRNA sites in UTRs for localization to
| desired cell type and to prevent aggregation in undesired or
| dangerous cells/organs.
|
| Poof, that's it!
| inglor_cz wrote:
| "Poof, that's it."
|
| The immune system is incredibly dangerous to its own host if
| mishandled. By stimulating response, you are trying to light a
| cigarette using a white phosphorus flamethrower, so to say.
|
| It took a lot of time to find the optimal way of mRNA delivery
| that a) really does something but b) does not provoke a
| massive, counterproductive response. This is a very narrow
| rocky ledge with precipices on both sides to walk.
| kennywinker wrote:
| > it isn't exactly high-tech or clever
|
| Read the history section of the rna vaccine wiki:
| https://en.m.wikipedia.org/wiki/RNA_vaccine
|
| You're right, we've understood that this could be done for a
| long time. Not quite the 70s, but.. at least the 90s. But
| believing something is possible and knowing how to do it are
| different:
|
| 1989 - injected rna maybe goes into cells
|
| 1990 - proof injected rna creates proteins
|
| 1994 - proof injected rna creates immune responses
|
| Then:
|
| "2005 they published a joint paper that solved one of the key
| technical barriers by using modified nucleosides to get mRNA
| inside human cells without setting off the body's defense
| system"
|
| That kicked off a ton of research, but:
|
| "Up until 2020, these mRNA biotech companies had poor results
| testing mRNA drugs for cardiovascular, metabolic and renal
| diseases; selected targets for cancer; and rare diseases like
| Crigler-Najjar syndrome"
|
| But why did they spend from 2005 to 2020 working on mRNA drugs
| and not vaccines? Capitalism. Vaccines are not generally
| profitable (take once, you're done) - so vaccines are not an
| appealing target for a startup with investors wanting big
| returns. (Source: https://www.statnews.com/2017/01/10/moderna-
| trouble-mrna/)
| denimnerd42 wrote:
| Yeah seems like vaccine development only started after the
| high profit objectives suffered failure. That doesn't mean we
| can't go back to working on those objectives in the future
| but they needed SOMETHING that would work to show mrna
| promise. Vaccines you only have to take once or twice so the
| side effects of immune response aren't too bad and you have
| an immune response to a vaccine anyways.
| kennywinker wrote:
| Even for the staunchest capitalist, covid has clearly
| outlined that we need medical research that is separated
| from market forces. After sars 1 was controlled, research
| in this area was all but dropped - despite virologists
| warning that it was just a matter of time before... well,
| this.
|
| Medical research needs to be driven by what can help
| people, not by what can make the most money.
| denimnerd42 wrote:
| PPE too. We still don't have N95s for the public or in
| some areas even the medical professionals.
|
| If we had a different administration in the USA we may
| have been able to conquer that quickly with sheer cash
| and coordination since the knowledge how to build melt
| blown N95 machines is there. For whatever reason we just
| didn't.
| [deleted]
| [deleted]
| fintler wrote:
| It did start in the 70s!
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC433302/
| CharlesW wrote:
| Another easily-searchable fact is that the COVID-19 vaccine
| is not the first RNA-mechanism drug.
| [deleted]
| jfarlow wrote:
| Delivery of the RNA is hard. To the right cell type, not
| immediately degraded, not accidentally integrated into a
| critical part of the genome, with a payload that is actually
| effective, etc.
|
| The original gene therapies (early 2000s) were essentially RNA
| therapies (adenovirus). And their unethical rush and subsequent
| failures caused a bit of a 'gene therapy winter' [1]. We've
| since made enormous progress on both the ability to safely
| deliver genes, but also our ability to generate/design new
| useful genes.
|
| [1] https://www.labiotech.eu/in-depth/gene-therapy-history/
|
| > In 1972, a paper titled 'Gene therapy for human genetic
| disease?' was published in Science by US scientists Theodore
| Friedmann and Richard Roblin, who outlined the immense
| potential of incorporating DNA sequences into patients' cells
| for treating people with genetic disorders. However, they urged
| caution in the development of the technology, pointing out
| several key bottlenecks in scientific understanding that still
| needed to be addressed.
| armada651 wrote:
| Can we please not spread the misinformation that mRNA can
| somehow integrate into the genome? It feeds crazy conspiracy
| theories around the vaccines.
| jart wrote:
| The parent was probably confusing RNA with adenovirus which
| IIUC _does_ deliver DNA that integrates itself into the
| genome. There are dozens of COVID vaccines under
| development right. Many of them are in fact DNA vaccines.
| To date they 've only been approved for vaccinating dogs of
| rabies. The mRNA vaccines that companies like Pfizer are
| making have the advantage of not permanently changing the
| DNA in the target cells. Even with DNA vaccine it's not the
| end of the world. For example, herpes simplex (cold sores)
| is an example of a natural virus that integrates itself in
| the DNA. But it's localized and it's not something that
| your children are going to inherit. Another interesting
| fact is that the Pfizer mRNA vaccine and others are
| delivered using lipid nanobots rather than adenovirus which
| I think is cool. But DNA vaccines have even potentially
| cooler applications since it means the medical field might
| for once be able to offer cures to illnesses, rather than
| charging you for a pill every day.
| usrusr wrote:
| "incorporating DNA sequences into patients' cells" is a
| wildly more dramatic approach than temporarily tricking a
| number of cells into manufacturing some protein with mRNA.
| It's almost like the difference between getting the browser
| to run your page's js vs a full remote code execution
| vulnerability.
| postalrat wrote:
| How can you say we made enormous progress when it appears
| this is still an untested therapy.
| jfarlow wrote:
| The number of [nucleic-acid-delivered] gene therapies in
| Phase II & Phase III trials right now is huge - because of
| this progress in delivery [of nucleic acids]. Gene
| therapies for the eye, for hemophilia, for sickle cell,
| many many cancer therapies all rely on the ability to
| 'deliver' nucleic acid payloads to cells. Of those, only 3
| or 4 have been approved - and all in the past 2 years, but
| there are a huge number that are behind that tip of the
| iceberg - quite precisely because it's relatively
| straightforward to do 'same thing but with a different
| sequence' once the first one works.
| johntb86 wrote:
| Wouldn't an adenovirus be delivering DNA? mRNA can't be
| incorporated into the genome (barring some crazy mixing due
| to a retrovirus) because it's RNA.
| flobosg wrote:
| mRNA is not the only type of RNA that can be delivered.
| Another type could be interfering RNA targeting endogenous
| coding or non-coding RNA molecules.
| [deleted]
| c54 wrote:
| I think the theory behind it is straightforward enough (and
| indeed, Moderna was founded 10 years ago with this sort of mRNA
| vaccine as their explicit goal), but the practice is more
| complicated.
|
| Figuring out what sequence of mRNA will be the right one to get
| a cell to produce the right antibodies for the job, getting
| that sequence sliced out of the viral RNA, getting that all
| into a form where it can be absorbed by cells and not just
| instantly degrade are all nontrivial tasks.
|
| The devil's in the details: compare to the field of software or
| cpu engineering... seems straightforward enough to just have
| more instruction decoders, but due to complexities only
| ditching x86 has actually made it possible for Apple to do
| this.
| iscrewyou wrote:
| It's not new. Work had been happening on mRNA. But the vaccine,
| I assume, is humans working under pressure and finally making
| it happen.
|
| I found this video (from 2013) in the other thread today about
| the vaccine Moderna Vaccine taking two days to make:
| https://news.ycombinator.com/item?id=25468959
| LetThereBeLight wrote:
| The technology for synthesizing large quantities of specific
| RNA sequences has only been available recently. Same goes for
| forming the lipid nanoparticles that are used for encapsulating
| and delivering the mRNA. In fact if anyone has more detailed
| information on how these two processes are done I would love to
| learn more.
| rolph wrote:
| PCR, the Polymerase Chain Reation.
|
| https://en.wikipedia.org/wiki/Polymerase_chain_reaction
|
| the emphasis in the wiki article is on DNA, the same basic
| principles apply with RNA.
|
| for example you can start with RNA and use reverse
| trancriptase to produce a DNA sequence, amplify that sequence
| to a large copy number by repeatedly replicating it then
| transcribe the DNA to produce large quantities of RNA.
|
| or you can start with the DNA [in large quantities of purity]
| then create many copies of the RNA by repeatedly transcribing
| the DNA.
|
| The practice of artificial [in vitro] gene synthesis can
| create arbitrary sequences for input to the process[es].
|
| https://en.wikipedia.org/wiki/Artificial_gene_synthesis
|
| liposomes are manufactured via biochemical-mechanical
| process.
|
| https://en.wikipedia.org/wiki/Liposome#Manufacturing
| vlovich123 wrote:
| Given that Moderna is the first ever company to bring such a
| vaccine to market and they've been working on mRNA for the past
| 10 years, I imagine there's a lot of technical complexity to
| actually deliver a therapy and then mass produce it beyond just
| the basic concept.
|
| Reading how Pfizer and Moderna worked on it together, they
| needed detailed gene sequencing to understand how to design a
| potential vaccine. Even then they were left with a lot of
| potential options they still had to whittle down. Finally even
| with all that work they're left with a vaccine with complex
| storage requirements.
|
| So it's entirely possible that we just didn't have the
| surrounding technical ability even if theoretically it was
| possible. The gene sequencing to sequence it quickly and share
| that across the entire world, the compute needed to do try
| different experiments at scale, the manufacturing capabilities,
| Moderna having invested in the space for the preceding 10
| years, existing experience with developing a SARS vaccine, etc.
| Narretz wrote:
| I think you mean BioNTech not Moderna.
| maxerickson wrote:
| Pfizer worked with BioNTech, not Moderna.
|
| Moderna's vaccine is a great deal easier to store than the
| BioNTech/Pfizer vaccine (requires 'normal' freezers for
| storage, can be at refrigerator temperatures for a longer
| period).
| denimnerd42 wrote:
| BioNTech and Moderna both have links to Katalin Kariko so
| while they didn't explicitly work together on this the
| knowledge comes from similar research and sources.
| vlovich123 wrote:
| Why is that the next challenge? Why aren't we using this on other
| diseases we haven't been able to generate vaccines for and just
| continue to research it as a general therapy since that's not yet
| an "engineering" problem?
|
| HIV, Ebola certain cancers, etc. What about using it to train our
| immune system for more complex diseases like Malaria or various
| bacteria? What about investigating if the general techniques can
| also somehow combat simpler diseases like prions which don't even
| have RNA.
| sradman wrote:
| Good question. The article says:
|
| > These drugs face the challenges of targeting mRNA to specific
| tissues and giving strong, lasting benefits without excessive
| side effects.
|
| This innovation reminds me of Virginia Postrel's book _The
| Fabric of Civilization_ : _How Textiles Made the World_ [1].
| Postrel describes several key technological innovations that
| propelled the manufacture of cloth from fiber farming to thread
| weaving to cloth weaving to cloth dying /decorating to
| distribution. Each innovation moved the bottleneck to a
| different layer in the value chain.
|
| The mRNA platforms are ideal for vaccines but ultimately, the
| downstream safety/efficacy trials are the new bottleneck. There
| was a time when futurists obsessed about nanobots but these
| mRNA platforms are the ultimate nanobots, in my opinion. They
| can be configured to program biological cells to manufacture
| simple proteins in situ. This is a very powerful tool, but like
| the historical innovations in spinning and weaving, the
| technology can produced many orders of magnitude more
| potentially useful outputs than the rest of the value chain can
| use effectively (for now).
|
| [1] https://www.basicbooks.com/titles/virginia-postrel/the-
| fabri...
| newacct583 wrote:
| Ebola, Malaria and HPV have working vaccines already, there's
| no particular need for new technology there. HIV would be
| interesting though.
|
| And bacteria aren't in general limited by immune response. The
| immune system has zero difficulty detecting a bacterial
| infection, but it happens at a wildly different scale and can't
| be fought with a fundamentally chemical means like our bodies
| do with virii.
|
| And the point about prions seems to misunderstand this
| technique. The way an mRNA vaccine works is by transmitting
| _blueprints_ for a viral protein (but not the rest of the
| virus) into the body 's cells, where ribosomes then synthesize
| the disembodied proteins, which get detected as "foreign
| invaders" and produce a lasting immune response which would
| then be effective against the real virus.
|
| Prions, remember, are just misfolded versions of your body's
| own proteins. They have the same sequence of amino acids as
| "correct" proteins and just an incorrect shape. mRNA only
| transmits the sequence, not the shape. And in any case your
| cell's DNA already _has_ the sequence encoded, because you 're
| not dead.
| raducu wrote:
| Isn't HIV a special case though?
|
| The reason we don't have an HIV vaccine is because HIV
| embedds itself in the DNA of some cells and some of those
| cells don't start producing virions right away, the immune
| system can't detect them, you clear the visible infection,
| but just weeks after, those hidden cells start producing the
| virus and the infection starts over. So the issue with HIV is
| the hidden reservoir of infected cells, afik.
| fabian2k wrote:
| The mRNA vaccines do also transmit the shape, as the encoded
| viral protein does get expressed in the cells. And the shape
| does get recognized by the immune system when that protein is
| secreted from the cell. But there is also a shape-independent
| mechanism that works on the sequence alone. The proteins in a
| cell are also chopped into tiny pieces and presentend on the
| surface. That part could not distinguish between different
| folded versions of the same protein like with prions.
| vlovich123 wrote:
| I think I was misunderstood a bit. I wasn't proposing that
| mRNA in its current state (or even solely by itself) would
| somehow be able to cure prion diseases.
|
| I was thinking more that research into biotech generally
| improves our knowledge. I don't know biology at all but I
| figured some evolution of technologies associated with
| CRISPR + mRNA + other things would be useful as a team in
| solving prion diseases. So maybe mRNA can become efficient
| enough that it's used to train the immune system to target
| the misfolded proteins themselves to try to limit damage
| while the treatment is ongoing. Futuristic now certainly,
| but is it definitely 100% impossible ever even as our
| knowledge & tech improves? Or maybe mRNA can exploit
| something in the prion process we don't yet understand.
| Maybe CRISPR could be part of the overall treatment therapy
| as you inoculate more of the body from whatever is
| propagating the bad code through your body which could be a
| time-consuming process (think vaccine at the genetic level
| - you potentially need to get it to every cell in the
| body).
|
| Obviously this is all sci-fi stuff & some of it impossible
| & out there. I still like to imagine sci-fi is useful as
| potential roadmaps to brainstorm how we might solve
| impossible problems - even if we miss, we'll land somewhere
| useful.
| flobosg wrote:
| > They have the same sequence of amino acids as "correct"
| proteins and just an incorrect shape.
|
| Somatic mutations can trigger the misfolding as well.
| jcims wrote:
| Do prions typically occur because of a defect in the RNA or
| are there just certain protein structures that have
| instability in how they fold?
| kens wrote:
| Prions can happen multiple ways. In familial (i.e.
| hereditary) CJD, a mutation in the PRNP gene (DNA) creates
| an abnormal misfolded protein, i.e. prion. In sporadic CJD,
| it's basically bad luck that the protein gets folded wrong.
| In acquired CJD, exposure to brain tissue with the prion
| protein causes it. Once there's a prion, it causes more of
| the protein to misfold, creating more prions and causing
| the disease.
| strbean wrote:
| In my understanding, a defect in the RNA that affected the
| protein would necessarily result in a different amino acid
| sequence. So for prions to form, they would have to be
| misfolded initially due to chance / environment or re-
| arranged afterwards through some process. The best known
| protein to form prions (PrP, Prion Protein) is known to
| convert from the well-folded form to a misfolded form upon
| interacting with the misfolded form, which could indicate
| that spontaneous formation of prions is due to interaction
| with something after the initial folding. I think this
| could also just be an indication that PrP just has lots of
| very close low-energy states, which would mean a higher
| chance of misfolding initially.
|
| - Mostly lay person view (some bioinformatics experience)
| [deleted]
| type0 wrote:
| because the prions are chaperones, i.e they can fold other
| proteins
| jcims wrote:
| That's how they turn your brain into Swiss cheese right?
| I'm just wondering how they are formed, are they
| misfolded normal proteins or just alien like virii.
| bbojan wrote:
| They are misfolded body's normal proteins, with a nasty
| side effect that they cause the normally folded copies of
| the same protein to also misfold in the same way. The
| result is a chain reaction of sorts.
| rzwitserloot wrote:
| nitpick: virii is wrong.
|
| The latin plural of 'virus' does not exist. It is a nebulous,
| uncountable concept to ancient rome. Like 'malaise' or
| 'ocean' (we can pluralize oceans in english, but hopefully
| you can imagine that a language would treat it as a concept
| for which the concept of pluralization doesn't make sense).
|
| You'd think: Hey, it's `-us`, I know that one, it pluralizes
| to `-i`, but, no. There is no plural. It's a rare form that
| also ends in -us but doesn't work like most of the words you
| know derived from latin that end in -us.
|
| But there is `vir`, latin for 'man', and the plural of that
| is viri.
|
| So, 'viri', as in 'the latin pluralized form of virus', is
| dead wrong.
|
| There is no -ii ending in latin. At all.
|
| The plural of 'virus' in english is 'viruses'. Any other form
| is stupid. Sometimes language does that, but surely you'd
| agree that something like 'irregardless', whilst somewhat
| common, sounds very unprofessional. virii is the same way.
| newacct583 wrote:
| Now _that_ is an HN comment.
| admash wrote:
| > There is no -ii ending in latin. At all.
|
| Should you mean no -ii ending to "virus" at all, it would
| appear to be a reasonable assertion. However if by "at
| all", you mean of any word in Latin, that is demonstrably
| false.
|
| http://latindictionary.wikidot.com/noun:filius
|
| Nominative and vocative plural: filii
|
| Usage example:
|
| "... et nihilo minus amicum gravem virum aut fidelem
| libertum lateri filii sui adiungere, ..."
|
| https://thelatinlibrary.com/quintilian/quintilian.instituti
| o...
| ink_13 wrote:
| I'll bet you 10 denarii you're wrong about suffixes.
| anonymfus wrote:
| But that comment was written in English, not Latin, and
| such irregular pluralisation is better to be treated as a
| feature of the modern English. People generally do this not
| because they someway learned Latin incorrectly but because
| they noticed how other English speakers pluralise Latin
| looking words, and that is exactly how new grammar rules
| are adopted.
|
| Also by referring to ancient Rome you treat Latin as some
| sort of a fixed, dead language, but English speakers do
| that irregular pluralisation to words borrowed from the
| modern languages descented from Latin too (see _cappuccini_
| ), and so for example in Romanian plural of _virus_ is
| _virusuri_ , and in Neo-Latin it's _vira_. Personally I
| want to prefer _virusuri_ just because it 's the funniest
| one.
| thereisnospork wrote:
| > There is no -ii ending in latin. At all.
|
| Triarii?
|
| (My knowledge of latin as a language comes primarily from
| Rome Total War).
| blakesmith wrote:
| I've been a little out of the loop on how COVID vaccines were
| different than others. In case you're like me, here's a nice
| primer on "mRNA vaccines":
| https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different...
| shiny wrote:
| I liked this guy's explanation:
| https://www.youtube.com/watch?t=1313&v=wb_0FB7XiqA
|
| My main questions after watching: how long do the spike
| proteins attach to our cell membranes? Do they get cleaned up
| eventually?
|
| Also, will it lead to damage to the cell in anyway?
| stanford_labrat wrote:
| There is a YC company who are currently using mRNA based drugs
| for telomere extension.
| jart wrote:
| My Google fu is failing me. What company is that? Sounds like
| Elysium.
| stanford_labrat wrote:
| Rejuvenation Tech! (S18)
| _greim_ wrote:
| Okay, layman's speculation: Given we can co-opt cells to
| manufacture proteins for us like this, and given we can predict
| what shape of protein an mRNA strand would produce, does this
| open up all sorts of potential in medical treatments? Tear it
| apart, HN.
| flobosg wrote:
| > given we can predict what shape of protein an mRNA strand
| would produce
|
| For therapeutic proteins you usually work the other way around:
| You design the shape and try to get a sequence that folds as
| intended. In other words, the inverse folding problem.
| [deleted]
| elcritch wrote:
| The parent is referring to the recent DeepFold success in
| predicting protein shapes from DNA/RNA, which means it
| appears to have solved the inverse folding problem for many
| proteins (modulo more exotic protein "features"). I haven't
| read the article (yet), but presumably being able to go from
| desired protein shape to plausible nucleotide sequences to
| mRNA to produce them would enable a lot of drugs to be
| developed that were cost/resource prohibitive previously.
| Presuming you can get access to DeepFold and the compute time
| to run it on semi-random sequences until you get matching
| shapes.
| kens wrote:
| I'm not sure I understand the question, as that's the point of
| the article. Clinical trials are currently testing mRNA to
| produce proteins to treat cystic fibrosis, heart failure and
| various obscure conditions. There are various problems, such as
| ensuring the the protein is created in the right cells,
| requiring repeated doses so the protein is created over a long
| time, handling side effects, and increasing the amount of
| protein created. So mRNA isn't an easy solution.
| arrosenberg wrote:
| Yeah, that's basically what the article discusses. It will be
| easier for non-targeted treatments that can circulate the whole
| body. This tech (by itself) doesn't really solve the issue of
| delivering site-specific medication.
| tboyd47 wrote:
| On face value, it sounds less risky than the standard vaccine
| development route, which may involve introducing immortalized
| (i.e. cancerous) cells or artificially stimulating an immune
| response with known toxins (adjuvants).
|
| I still have questions about the mRNA vaccine concept. Maybe
| some well-informed HNer can shed light?
|
| 1. If the goal is to get the desired protein inside the
| patient's body, why is injecting mRNA that produces the protein
| more effective than simply introducing the protein itself?
|
| 2. How does the patient's immune system know to treat this
| protein as unwanted if it's being produced by the body's own
| cells?
|
| 3. How do vaccine developers avoid creating an over-active
| immune response in the patient (i.e. an allergy)?
| therein wrote:
| I have been asking the very same questions, especially the
| (2).
|
| So far, nobody has been able to provide a satisfying answer.
| rolph wrote:
| there is a system homologous to machine learning 2factor
| authentication.
|
| in very loose terms both keys must be presented while the
| immune system is in training, the instances where protiens
| are expressed with out cell surface recognition molecules
| in proximity are invalid thus foriegn, and memory immunity
| to this "failed login" is maintained. when both factors
| [protien plus recognition] are present constituitively over
| the course of development the immune response is squelched.
|
| this is known as central tolerance.
|
| https://en.wikipedia.org/wiki/Central_tolerance
| fabian2k wrote:
| The simplistic answer is that the immune system tries out
| new antigen-detecting cells in a safe environment before
| letting them run around with a loaded gun. Any cell that
| activates in that safe environment is destroyed, as it
| recognized one of your own antigens.
|
| The other mechanism is that the immune system doesn't react
| only to foreign antigens, there also needs to be some
| general activation of the immune system in that area for a
| real response.
|
| The full answer is that this is really, really complex like
| pretty much everything involving the immune system. And
| auto-immune diseases indicate that the immune system
| doesn't always get this right.
| tboyd47 wrote:
| How is that general activation achieved in the case of
| this mRNA vaccine and the others that will surely follow?
| fabian2k wrote:
| RNA itself is suspicious because it's a major component
| of many viruses. So some kinds of RNA will activate the
| innate immune system strongly.
| tboyd47 wrote:
| That's really interesting and confirmed with some light
| searching. Thanks!
| BurningFrog wrote:
| > _2. How does the patient 's immune system know to treat
| this protein as unwanted if it's being produced by the body's
| own cells_
|
| The immune system can't know who produced a certain molecule.
| gostsamo wrote:
| 1. A single rna can produce multiple times the protein,
| because it is like the proverb about giving someone fish and
| teaching them fishing.
|
| 2. Someone already said, but a protein has no marker saying
| "local produce". It is either allowed or not and the body
| reacts or not when detecting it.
|
| 3. They hope. Measure the dosage and adjust. As it was
| reported, some people getting the vaccine have an allergic
| reaction, but hopefully it will be rare and under control. So
| far there are only a few cases reported.
| [deleted]
| fabian2k wrote:
| Adjuvants are not toxic, they're simply known to enhance the
| immune system response (so they are something that indicates
| danger to the immune system). The immune system is incredibly
| dangerous and destructive, and you really don't want to
| trigger it without reason. So injecting something unknown
| might not be enough to get the immune system fully alarmed,
| that's why some vaccines add adjuvants to produce a stronger
| response. RNA can be an adjuvant by itself, as it's also a
| typical component of viruses and the immune system reacts to
| that.
|
| So the trick really is to design the RNA and the delivery
| system so that it produces an immune response of the right
| magnitude. Too weak and it doesn't work, too strong and it's
| harmful.
|
| Antibodies that bind to your own proteins are filtered in an
| earlier stage in antibody production. Real viral proteins are
| also produced by your own cells, so that is never a factor by
| which you could distinguish friend from foe.
| raducu wrote:
| 1. I guess for smaller batches it is easier to develop the
| mRNA. Otherwise, we would have monoclonal antibodies and not
| a vaccine(the vaccine has other benefits, it trains the
| T-cells and the B cells remain dormant even after no
| abtibodies are detected in the blood).
|
| 2. The imune system knows all your protein already, t cells
| are evolved in the thymus gland, if they attack anything
| "self", they get destriyed.
| gus_massa wrote:
| > _which may involve introducing immortalized (i.e.
| cancerous) cells_
|
| Which one? I don't remember any vaccine that injects
| immortalized cells.
| tboyd47 wrote:
| Feel free to correct if I'm misinterpreting: https://en.wik
| ipedia.org/wiki/Use_of_fetal_tissue_in_vaccine...
| rolph wrote:
| the vaccine doesnt contain fetal cells, in the case you
| are providing the vaccine is an attenuated virus
| approach.
|
| the cells are used to manufacture quantities of the virus
| in an extremely weakened form. This gives a chance for
| the immune systemto mount a response before the pathogen
| initiates systemic disease response.
|
| the cells in question are not freshly harvested from a
| foetus, the progenitor cells are harvested and kept in
| continual culture for use. the reason immortalized cells
| are used is to escape the "expiry date" of a normal cell.
|
| >>Some vaccines currently available were developed using
| cell strains cultured from two fetuses aborted for other
| purposes in the 1960s.[6]<<
|
| i lifted this link from the wiki page provided:
|
| https://en.wikipedia.org/wiki/Immortalised_cell_line
| tboyd47 wrote:
| Thanks.
| theophrastus wrote:
| A layman's speculation followed by a layman's (at least in
| terms of immunology) question: introduce a novel mRNA, cells
| produce novel protein, it is presented to the immune system as
| something to foment a defense again: vaccine. But the article
| talks about using this mechanism to replace a functional copy
| of a genetically missing enzyme. How is it assured that this
| will assume the opposite goal and not become another target for
| the immune system to guard against?
| strbean wrote:
| Seems to be working well so far for COVID vaccines. We're about
| to witness a very large scale test though.
| ryanianian wrote:
| On the opposite side: how do we effectively convince people
| this new type of vaccine is safe long-term? I'm not a biology
| person, so I trust the biology people when they say it's safe,
| but many don't.
|
| My intuition is that many cancers can start when proteins are
| mis-copied, and mRNA therapy seems to rely on copying to work
| very reliably. Does introduced mRNA increase the risk or
| impacts of mis-copying?
|
| Is there an ELI5 intuition for why mRNA therapy is safe and
| won't lead to cells becoming cancerous?
| raducu wrote:
| I don't think mRNA spreads from cell to cell, the mRNA enters
| a limited number of cells and those cells start producing
| certain proteins the mRNA tells them to.
| sveiss wrote:
| I'll state upfront that I'm not a biologist, but here's my
| attempt at the explanation.
|
| The ELI5 version:
|
| Think of the cell as a factory for proteins. The blueprints
| for all of the different kinds of proteins it can produce are
| encoded in DNA and stored in the foreman's office. When the
| cell wants to make a particular protein, the foreman copies
| the instructions from the blueprint onto slips of paper
| (mRNA), and sends them to the assembly line workers. This
| type of copying happens all the time, and is pretty reliable
| -- and even if it's not, the end result is just some wasted
| time and a junk part. The blueprints are unaffected. mRNA
| vaccines sneak some unauthorized instructions to the workers,
| who then run a ghost shift to produce the protein we want to
| cause an immune response to.
|
| When we need to create a second factory, we need to photocopy
| all the blueprints for the new cell. This uses a totally
| different process (a photocopier assembled specifically for
| the job of copying whole blueprints onto more blueprint
| paper, and not the work-order slips sent to the assembly
| line). The photocopier is pretty reliable too, but
| occasionally it introduces artifacts, and eventually, enough
| of these errors can build up to create mistakes in the
| blueprints. The blueprints have instructions on how to deal
| with errors in a new factory (by blowing it up), but if
| enough of those failsafe instructions are obscured by copier
| artifacts, you now have a potentially cancerous cell.
|
| The foreman's office doesn't usually make changes to the
| blueprints based on work order slips. It's possible with a
| special copy machine -- this is how HIV works, by sneaking
| that machine in -- but without a work order slip to blueprint
| copier, it doesn't matter how many fake work order slips we
| pass into the cell. They will only affect the production
| line, not the foreman's office.
|
| The more detailed, and almost certainly wrong-in-the-details
| version:
|
| There are three types of encoding for genetic material: in
| DNA, in RNA, and in proteins.
|
| In order for the information encoded in genetic information
| to be active in a biological system, it has to be expressed
| as a protein -- a physical manifestation with binding sites
| and the ability to interact with other molecules. Ribosomes,
| a component of the cell, do the "assembly" part of
| transferring genetic information to a protein. This is called
| "translation".
|
| DNA is the long-term storage of the information eventually
| expressed as proteins -- it's a collection of templates in
| long term storage. So there has to be a process to get
| information from the long-term storage of DNA, in the nucleus
| of the cell, to the ribosomes elsewhere in the cell.
|
| Messenger RNA is the intermediary molecule which carries the
| genetic information from the DNA to the ribosomes. It's
| produced in the nucleus of the cell by a mechanism called
| "transcription", which copies a subset of a DNA molecule into
| a complementary RNA molecule encoding the same information.
| The DNA double-helix is "unzipped", a complementary RNA
| strand is assembled, and the double-helix reforms. The mRNA
| can then be transported to the ribosomes.
|
| mRNA is a useful vaccine mechanism, because we're co-opting a
| late stage of the cell's protein production pipeline. We
| don't have to assemble the target protein by hand and figure
| out how to modify it make it stable for distribution -- a
| task that would need to be repeated for each protein we
| wanted to make. Instead, we can figure out how to synthesis
| mRNA, and we don't need to worry about either synthesis or
| stability for the end protein product.
|
| When we talk about cancer and mis-copying, this is at a much
| earlier stage in the pipeline. When a cell splits into two
| cells through mitosis, we don't want a subset of the protein
| templates in the cell's genetic material; we want a complete
| copy. This is a separate biological pipeline, which involves
| the cell building up a mechanism to do the copying,
| dissolving the membrane of the nucleus, and ultimately
| producing and collating copies of all the DNA from the
| nucleus. This is an entirely separate process, and messenger
| RNA isn't involved at all.
|
| There is a route for information to travel from RNA back to
| DNA, and this is the mechanism retroviruses use, and HIV is
| the most famous example. A complete retrovirus particle
| includes reverse transcriptase, an enzyme which allows them
| to transfer information from RNA back to DNA. This is the
| reverse of the normal DNA -> RNA pattern described above,
| hence the name _retro_virus. Without that enzyme or something
| like it, there isn't a pathway to convert RNA back to DNA,
| and human cells don't normally express an enzyme which has
| this function.
| delecti wrote:
| Cancers start when DNA is mis-copied. Typically DNA is copied
| to RNA, which is then used to generate protein, and there
| isn't usually a mechanism for that RNA to go back a step to
| become DNA again. I don't want to say it's impossible, or
| that there's no conceivable negative effects, but cancer
| seems like an implausible result from mRNA therapy.
| dharma1 wrote:
| Not related to mRNA therapy, but retroviruses use reverse
| transcriptase to attach their RNA to the DNA of the host
| cell
| delecti wrote:
| Thank you, that's a good addition. I knew it didn't
| happen with mRNA, but also knew that there was _a_ route
| from RNA to DNA, though I couldn't remember what. That's
| why I hedged my statement with "usually".
| mamon wrote:
| > how do we effectively convince people this new type of
| vaccine is safe long-term?
|
| Same as always: do a long-term clinical trial and look for
| any side effects.
| lucaswoj wrote:
| This is Moderna's goal https://www.modernatx.com/mrna-
| technology/mrna-platform-enab...
| localhost wrote:
| I did some reading on this back when this was all announced, and
| wrote it down on Twitter. This tweet [1] links to a Nature paper
| that describes applying mRNA vaccines to cancer. If you scroll
| up, you'll also see pointers to other papers that I found along
| the way when I was learning about mRNA vaccines in general.
|
| [1] https://twitter.com/john_lam/status/1333632894720380929
| supernova87a wrote:
| I would love to know (to assuage any family members' doubts) --
|
| Are there _any_ possible long term side effects of using such an
| mRNA drug that are yet unanticipated? All the short term side
| effects are known / will soon be. Anything beyond that, we
| haven't had enough experience to know?
| AntiImperialist wrote:
| > _Are there any possible long term side effects of using such
| an mRNA drug that are yet unanticipated?_
|
| I'm not sure but I strongly assume yes.
|
| The MAIN reason for this skepticism is that if it was just
| possible to introduce RNA such that we could have a net
| positive benefit against coronavirus, a virus that has existed
| for almost as long as mammals have, we'd have naturally evolved
| this ability.
|
| The reason we haven't is because it will introduce more
| problems than it solves down the line.
|
| It could very well be that with a limited understanding of
| human immune system, we have stumbled upon a solution to a
| problem that has affected us for millions of years. So, I think
| some people should try it. But forcing it on the masses is a
| terrible idea.
| macksd wrote:
| Look, I'm more willing than most to agree that forcing a
| medical procedure on the masses is a terrible idea. I'm even
| more willing than most to agree that not every vaccine will
| have a sufficient cost/benefit trade off for everyone. I have
| low-exposure and low-risk to COVID so I'm content to wait a
| while for the vaccine. I have questions in my mind about how
| we're so sure that a big shot of mRNA can't somehow cause a
| risk of birth defects, etc. But...
|
| >> The reason we haven't is because it will introduce more
| problems than it solves down the line.
|
| This is just not sound reasoning, and it's a terrible
| argument against the vaccine. Have you ever taken
| antibiotics? Or have you ever benefited long-term from
| anything medical that we didn't "evolve" through natural
| selection? Because I sure as hell have. How does this not
| apply to other vaccines, which have clearly saved an
| astonishing number of lives, and have, almost without
| exception, not produced the kind of long-term existential
| threats to humanity you seem to be hinting at.
| reissbaker wrote:
| This take implies that no medicine for deadly diseases can
| work because otherwise we would have evolved the medicines
| ourselves.
|
| Also, COVID-19 has not been around "for millions of years."
| Other coronaviruses, such as the common cold, have. The
| evolutionary benefits of defense against the common cold are
| fairly different than benefits against COVID-19. And immunity
| against one coronavirus doesn't grant immunity against all
| other coronaviruses.
| throwaway316943 wrote:
| Two points, the most effective treatments we have for
| deadly diseases are vaccines which are effective precisely
| because they rely on our naturally evolved defences.
| Antibiotics are a runner up but are eventually rendered
| ineffective by evolution of bacteria they target. Second,
| Covid-19 is only new to humans, given time it will adapt to
| us and will likely attenuate.
| majormajor wrote:
| > The MAIN reason for this skepticism is that if it was just
| possible to introduce RNA such that we could have a net
| positive benefit against coronavirus, a virus that has
| existed for almost as long as mammals have, we'd have
| naturally evolved this ability.
|
| We'd have naturally evolved the ability to train our immune
| systems against specific things it hasn't seen before? How
| would that POSSIBLY work?
|
| The novelty of this particular coronavirus is sort of the
| problem here, since people don't already have immunity, so
| your "millions of years" thing is completely off base.
|
| You seem to be arguing against the possibility of a
| "universal vaccine" for all viruses but that's entirely not
| what this is. It's very specifically targeted and the idea
| that we'd evolve the ability to target things specifically
| _without actually being exposed to them_ in the same way is
| plainly nonsense.
| blackbear_ wrote:
| Actually, the ability to respond to never-seen-before
| threats is the whole purpose of the adaptive immune system
| [1].
|
| > How would that POSSIBLY work?
|
| Through a process called V(D)J recombination [2].
| Essentially, every lymphocyte gets a different receptor of
| random shape, and purely by chance there will be a few
| lymphocytes with a receptor that matches the shape of the
| invading viruses (in most cases).
|
| [1] https://en.wikipedia.org/wiki/Adaptive_immune_system
|
| [2] https://en.wikipedia.org/wiki/V(D)J_recombination
| ch4s3 wrote:
| Probably not. There was about 20yrs of research on using mRNA
| for gene therapy before the CRISPR/Cas9 discovery. It was
| abandoned as a route for gene therapy specifically because it
| wasn't long lasting. The mRNA isn't incorporated into the DNA,
| so it isn't reproduced by the cells and eventually breaks down.
| Things inside of cells are flying around at high speeds and
| constantly colliding, so it's not a very stable environment.
|
| There are people that this was tested on still hanging around
| with no lasting negative effects (to my knowledge).
| marvin wrote:
| My partner, a biochemist, has mentioned the potential
| possibility of RNA viruses causing the RNA of the vaccine to
| stabilize as some sort of DNA structure. Normally RNA is
| quickly broken down by RNase, but apparently RNA viruses have
| a mechanism to defend against this, that it's possible to
| imagine having an interaction with an RNA vaccine.
|
| I don't know anything about biochemistry, and I'm aware that
| the above is just remote speculation. It is meant as an
| example of food for thought. But I do wonder when a whole
| field of scientists state "there is no possibility of
| unexpected long-term side effects" to a therapeutic tool that
| has never been used at anything resembling this scale.
|
| Would love to hear more experts discuss why this is
| considered sufficiently long-term safe to make the decision
| of vaccinating a billion people after nine months of testing.
| Am I missing something, or is it just a question of the
| precautionary principle in this case being considered too
| costly?
| jgable wrote:
| Given that this pandemic has killed millions, shut down the
| world economy, and caused untold long term damage to
| children due to lack of stable schooling: yes, it's because
| the precautionary principle is too costly.
|
| Edit: sorry, my comment may have sounded snarky, which was
| not my intention. World-wide vaccinations do carry a risk.
| It's just that such a risk clearly pales in comparison to
| the very known downsides of the current situation. I am in
| no way a vaccine expert and cannot comment intelligently on
| why long-term risks are considered to be low.
| darkerside wrote:
| There could certainly be a logical error in play here, but
| considering this is mRNA, and not DNA, it seems like it
| would be fairly amazing for it to spontaneously form into
| DNA. Similar to a load of parts spontaneously forming into
| a bicycle.
|
| That's not to say it isn't possible, but many things are
| possible but sufficiently unlikely that we take those
| risks. We eat, drink, and breathe many things every day
| that we don't fully understand the ingredients or impacts
| of.
| greedo wrote:
| Just a slight correction; as I understand it, these
| vaccines are prophylactic, not therapeutic.
| akiselev wrote:
| _> Would love to hear more experts discuss why this is
| considered sufficiently long-term safe to make the decision
| of vaccinating a billion people after nine months of
| testing. Am I missing something, or is it just a question
| of the precautionary principle in this case being
| considered too costly?_
|
| FDA approvals aren't a black and white affair. Some drugs
| are approved as orphan drugs through trials designed to be
| much cheaper than Phase 1-3 trials when they treat diseases
| that wouldn't be profitable for pharma, for example, and
| there is a path for preliminary compassionate use approvals
| and accelerated development for stuff like chemo where the
| disease is terminal anyway. The FDA works with each company
| to tailor the process to their needs (although, obviously,
| they stick to a strict standard unless there's good
| justification).
|
| Likewise, the vaccine rollout won't be all or nothing. We
| won't even have a billion doses for a long while and the
| focus will (likely) be on vaccinating those for whom the
| benefits outweigh the extra risk like front line medical
| staff and the immunocompromised or elderly. I don't expect
| the world to get vaccinated at gun point, although the
| rules for schools and other institutions will quickly
| accumulate to cover most of the population.
|
| Personally, I'm not going to be taking the vaccine for a
| while since no one in my family is at risk and we're
| (mentally) preparing for several years of varying levels of
| isolation and other precautions. I have faith in the system
| for the most part since I've worked on an FDA application
| before (clinical diagnostics, not therapeutics), but the
| kind of geopolitical and economic pressure its under right
| now is unprecedented and should keep epidemiologists up at
| night (hell, it probably does). It's going to be up to each
| individual to balance their risks and obligations at least
| until we get more data.
| MrBuddyCasino wrote:
| Has there ever been an instance of genetic transformation as
| a consequence of a mRNA vaccine? Saw this listed as a
| potential risk in a paper[0], but I have no expertise at all
| to judge if this a possibility or not.
|
| [0] https://www.mdpi.com/2076-393X/8/2/212/pdf
| blackbear_ wrote:
| If you are referring to the following sentence in the
| introduction, I understood it to mean the opposite:
|
| > Moreover, mRNA vaccines induce transient antigen
| expression, while DNA vaccines provide a long-lasting
| expression, thus mimicking an acute viral infection.
| Although a transitory gene expression might be desirable as
| it minimizes potential risks of genetic transformation,
| this inevitably affects mRNA potency, thus necessitating a
| dose increase.
|
| This means that mRNA reduce the risk of genetic
| transformation compared to DNA vaccines, but it comes as a
| price because you have to deliver a larger dose of mRNA.
| aazaa wrote:
| Some clinical work has been done with mRNA vaccines as
| treatments for other diseases, including cancer. Nothing has
| made it to Phase 3 yet (other than for Covid-19), but on this
| page you'll find links to a slew of clinical trials over the
| years.
|
| https://www.modernatx.com/pipeline/modernas-mrna-clinical-tr...
|
| A handful of studies are currently recruiting for Phase 2, so
| that means there was a successful Phase 1 some years ago. So
| those people would, I believe, be the longest-surviving
| patients to have received an mRNA vaccine.
| Scoundreller wrote:
| The Phase 1 study might just mean it didn't immediately harm
| the people that got it.
|
| They might be followed closely for a long time; but it may
| only be a handful of people too.
| biophysboy wrote:
| I work with RNA, but not in medicine. mRNA is not a long-term
| molecule in the body, so its difficult to imagine direct long-
| term effects. Of course, immune responses can cause long-term
| damage. So the question is: should we wait to find out?
|
| The doses have 30-100 ug. Assume 1)this is pure RNA, and 2)the
| molecules are about the same size as the spike protein
| sequence. With these assumptions, a dose gives you 10^10 RNA
| molecules. Average sputum samples show about 10^6 molecules/mL;
| max samples show 10^9/mL. I don't know how vaccines dilute when
| you inject it into somebody's shoulder, but it doesn't seem
| unreasonable to say the final conc will be between 10^6 and
| 10^9 RNA/mL.
|
| So RNA is going to be in us, whether we want it or not. The
| question is, do you want the whole genome, or part of the
| genome. I'm picking the one that doesn't make more virus.
| IfOnlyYouKnew wrote:
| The difference to "traditional" vaccines is really not
| significant with regards to risk.
|
| The mRNA is translated to a protein, which is the actual target
| your immune system then recognises as foreign, attacks, and
| remembers.
|
| In a sense, it's a lot like a prodrug, which is a "traditional"
| small-molecule that is turned into the actual drug by some
| interaction with your body-your stomach acid, for example.
|
| "mRNA" might sound scary. But it isn't going to change your
| genome or anything like that; it's strictly downstream from
| DNA. Any virus, bacteria, or salad you eat contains far more
| mRNA in addition to DNA or RNA, and the first of those really
| does come with mechanisms to insert itself into your cells' DNA
| and has evolved to defend itself against your defences, and to
| slowly take over your body in some way or other.
|
| There are some short-term risks on the order of, say, eating
| lobster for the first time. Allergies, for example, which can
| be quite severe and even deadly. But those are exactly the
| risks the trials would have uncovered, and the people possibly
| at risks of such things would already know they are
| susceptible.
|
| There is no known mechanism for any risk that would not
| manifest within the first day or two.
| petra wrote:
| There is a YC company that has a technology to guide small
| molecules to cancer cells.
|
| Might be able to guide mRNA too.
| jdoliner wrote:
| That would be Shasqi!
|
| https://www.shasqi.com/
| nextos wrote:
| I think RNAs are great as a cell therapy. Not necessarily
| mRNAs, but other ncRNAs which can be used to silence enhancers.
| This would be great for many diseases.
|
| mRNAs are great as a vaccine to trigger an anti-cancer
| response, combined with checkpoint inhibitors. The big
| challenge is to choose a good personalized mix of peptides
| (encoded as mRNAs) in a way that scales to thousands of
| patients.
| crb002 wrote:
| Yes, especially in an insulin pump so you can do time release.
|
| This is now industrialized. Print the mRNA, slap it in lipids,
| inject. https://www.idtdna.com/
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