15 ms·
What mRNA is good for, and what it maybe isn’t
- InTheArena 5y agoDerek Lowe's articles during covid have been a huge help trying to navigate the coronavirus hellscape we have been in. It's great to see him start to talk post-covid applications of medicine as things maybe wind down a bit. Delta+ willing
- sjg007 5y agoDelta+ and the next variant after that just in time for school in the Fall and a bunch of unvaccinated kids.
- nabla9 5y agoHis "Things I Won’t Work With" articles are really informative and entertaining. https://blogs.sciencemag.org/pipeline/archives/category/things-i-wont-work-with https://blogs.sciencemag.org/pipeline/archives/category/thin... For example: Things I Won’t Work With: Dioxygen Difluoride https://blogs.sciencemag.org/pipeline/archives/2010/02/23/things_i_wont_work_with_dioxygen_difluoride https://blogs.sciencemag.org/pipeline/archives/2010/02/23/th...
- SV_BubbleTime 5y ago> If the paper weren’t laid out in complete grammatical sentences and published in JACS, you’d swear it was the work of a violent lunatic. Favorite part of a good article. Although it seems to me these experiments need to be repeated, for science.
- UncleSlacky 5y agoReminds me of the excellent book "Ignition!" by John D. Clark: https://archive.org/details/ignition_201612 https://archive.org/details/ignition_201612
- wbl 5y agoWe could retarget the mRNA batches tonight if it wasn't for the FDA not taking this seriously.
- H8crilA 5y agoUhm, it is serious if you know anything about drug development history. It always is. The current mRNA Covid vaccines have a pretty high incidence rate of ongoing rapid swelling and rashes (in the 1/100 to 1/1000 range), and it's still unclear what will happen to the hundreds of thousands of affected people. Source: https://en.m.wikipedia.org/wiki/Pfizer%E2%80%93BioNTech_COVID-19_vaccine#Adverse_effects https://en.m.wikipedia.org/wiki/Pfizer%E2%80%93BioNTech_COVI... Also to be found in the adverse reactions database (VAERS) by the CDC.
- astrange 5y agoVAERS reports aren't sufficient to show causation, because they just show whatever people happened to report. It's the same reason drugs show the thing they're treating as a side effect. People are reporting the symptom because they already had it.
- gus_massa 5y agoRetargeting is one of those things that everyone is 99% sure it's safe. But 99% sure in millions of people means thousand of problems and perhaps deaths. So before signing any authorization it's better to wait until the clinical trials are done instead of using gut feelings. (Waiting too much is also bad, so it's a tradeoff.)
- dragonwriter 5y ago> Retargeting is one of those things that everyone is 99% sure it's safe. But 99% sure in millions of people means thousand of problems and perhaps deaths. You seem to be assuming “99% sure it is safe” means “sure that its 99(.9)% safe”. They are...not equivalent.
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- amelius 5y ago> So if you’re going to give patients an mRNA injection and you don’t want to set off alarm bells in the innate immune system, you’re going to have to carefully engineer your sequences at the very least. Isn't that what substituting uracil by pseudouridine solves?
- klevertree 5y agoNo, that substitution helps, but it doesn't solve the problem. You're still introducing foreign mRNA into the body, and the body still has millions of years of evolution telling it that foreign mRNA = invader .
- DrAwdeOccarim 5y agoIt solves the TLR problem, and process/purification solves the cytosolic dsRNA problem.
- klevertree 5y agoI wrote a long essay about the same topic and came to similar conclusions as Derek Lowe: https://trevorklee.com/are-mrna-therapies-the-future-of-pharmaceuticals/ https://trevorklee.com/are-mrna-therapies-the-future-of-phar... One thing that I'd like to emphasize is how unbelievably tiny mRNA therapeutics have to be. It's probably around 30 mg, and it's hard to do it more than once every few weeks, at least judging by siRNA therapeutics (which have similar immune issues). 30 mg is really tiny. It's hard to come up with a meaningful therapeutic in such a small amount of material. People have been hyping up self-replicating mRNA as a solution, but that's still in its infancy, and has its own problems regarding the "compilers"/polymerases that need to be packaged with it.
- zabzonk 5y ago> 30 mg is really tiny Not really. For example the amount of beta blocker I take for my heart problems is 5mg per day - the pill size goes down to 2.5mg.
- H8crilA 5y agoNot to mention LSD, which is a well below 1mg thing. Also not sure why it matters at all, if it's under 1g you can administer it pretty much any way you need to.
- FPGAhacker 5y agoPretty sure they meant micrograms, not milligrams.
- varjag 5y agoThen they should not have used the SI milli- prefix.
- GuB-42 5y agoI think you meant 30 µg (micrograms). And it is indeed tiny. Even for LSD "the only drug measured in micrograms", a typical dose is around 100µg. Most drugs (both the legal and illegal kind) are in the tens of milligram range.
- lazyjones 5y agoI am worried about the low level of intact mRNA in those vaccines, esp. as an IT guy. https://www.medicalnewstoday.com/articles/early-concerns-raised-over-levels-of-intact-mrna-in-pfizer-vaccine#Instructions-for-making-protein https://www.medicalnewstoday.com/articles/early-concerns-rai... 25-45% randomly modified or defective mRNA doesn't sound safe. It's a bit like machine code with random errors, isn't it?
- wahern 5y agoWhat's the replication accuracy of SARS-CoV-2?
- lnwlebjel 5y agoAt least 95% I would wager
- nabla9 5y agoThat's why there are clinical trials. Humans testing to find out what happens. All mRNA disappears from body in few days anyway.
- pjscott 5y agoRNA uses an error-correcting code, and if that fails all that should happen is that some of the proteins your ribosomes create will be misshapen. Your body is good at dealing with foreign proteins.
- tgb 5y agoWhat error correction does RNA have? Are you just referring to the third base in the codons? DNA has some but I don't know of any for RNA, and it hardly seems worth it for most organisms to have RNA error-correction: it's better to just degrade the RNA and retranscribe it.
- fastaguy88 5y agoRNA and DNA essentially use the same genetic code, which is degenerate and thus somewhat error correcting.
- readams 5y agoWorth noting that even if it's good for literally only infectious disease vaccines, we're still taking about an enormous breakthrough with the potential to save hundreds of millions of lives. Imagine vaccines for malaria, HIV, Zika, and many others.
- DrAwdeOccarim 5y agoTotally! We are entering a golden age of vaccinology.
- vibrio 5y agoWhile mRNA vaccines were great in the COVID situation, they have been in development over the last decade and I'm not sure an HIV vaccine will be as simple as putting HIV envelope protein into this technology. I'm not aware of attributes to the mRNA technologies that will dramatically simplify the development challenges. I believe the more substantial step for is that we (Pharma, Investors, Governments)now realize infectious diseases are a problem for people beyond the developing world. Will that commitment hold?
- espenwa 5y agoWhen it comes to the problem of targeting, one interesting and promising tech is photochemical internalisation [https://en.m.wikipedia.org/wiki/Photochemical_internalization https://en.m.wikipedia.org/wiki/Photochemical_internalizatio...], where you put the mRNA inside photosensitive molecules (and not lipids) and then shine some light on the tissue/organ where you want the mRNA delivered. Where activated by the light, the molecules then enter the cells, dissolves and deliver the mRNA. The Norwegian company PCI Biotech has a tech they call fimaNAc for doing this with naked mRNA. https://www.pcibiotech.no/nucleicacids https://www.pcibiotech.no/nucleicacids This presentation has a lot of illustrations and explanations: https://www.pcibiotech.no/s/PCI-Biotech-SMi-RNA-Therapeutics-presentation-10-Feb-2021.pdf https://www.pcibiotech.no/s/PCI-Biotech-SMi-RNA-Therapeutics...
- monocasa 5y agoWhat happens to the unactivated mRNA in that case? I was under the impression that it was typically the actual use of the mRNA by the ribosomes that broke them down generally, but I could be off base there.
- gus_massa 5y agoThe same mRNA can be used by multiple ribosomes. More info and "photos": https://biology.stackexchange.com/questions/54752/can-mrna-be-used-by-ribosomes-more-than-once https://biology.stackexchange.com/questions/54752/can-mrna-b...
- monocasa 5y agoSure, it isn't destroyed immediately and the mRNA is used multiple time, but that's still ultimately the ribosomes damaging the mRNA from use. My question is around how they break down if there aren't ribosomes involved (ie. if the capsules above aren't opened because they weren't exposed to the light trigger).
- sudosysgen 5y ago
- DaniloDias 5y ago“The huge success of the mRNA vaccination platform” Does anyone know what the agreed upon criteria for asserting the success of mRNA vaccinations is? Aren’t we anticipating an uptick in cases in the US as we approach winter? Why are we assuming success already?
- maxerickson 5y agoI'm not sure what you mean by "agreed upon", but they are, blatantly, obviously, preventing (lots of) infections in lots of countries at this point.
- redis_mlc 5y agoOr, you know, corona is a highly contagious disease and after a year we've reached herd immunity in the US. Which is basically what the NIH just reported on June 22, 2021: https://www.nih.gov/news-events/news-releases/nih-study-suggests-covid-19-prevalence-far-exceeded-early-pandemic-cases https://www.nih.gov/news-events/news-releases/nih-study-sugg... The NIH report debunks two common tropes on HN: 1) That consumer masks work - they don't stop the spread of corona. 2) That COVID-19 vaccines are necessary for herd immunity - we already had it beforehand. This was obvious (and I mentioned that here several times) since early 2020 if you look at the Santa Clara hospital ICU utilization, which averaged only 10% throughout most of the pandemic because of daily flights from China to SFO causing widespread infections in SF and SC. Sorry for reporting actual science (with data) on HN, instead of the garbage discussed here since early 2020. My bad.
- didibus 5y ago> Why are we assuming success already? I guess a combination of how little side-effects they've had at scale, and of how effective the data shows they are at preventing the first virus and the earlier variants, which is what it was designed for. I think the uptick expected is with regards to unvaccinated people, and to new variants for the most part. You should also still see a 5% to 10% of cases in vaccinated people, as the vaccines show a range of effectiveness only around the 90%, so an uptick will still occur, but the overall numbers should be much lower in vaccinated people. To conclude, success is not on our fight against Covid, though you can say it definitely helped a lot, but the vaccine technology has definitely shown success here.
- whiddershins 5y agoFrom the jump this article seems confused, considering to flag it.
- twaway 5y agoMy newborn was diagnosed with Sturge–Weber syndrome and mRNA sounds like a potential solution. The issue is it's rare and united States government approval is expensive and slow. Not something that works well with a degenerative disease. I'm a bit insane right now admittedly, but given my background and wealth, I'm considering DIY. The technology is there, government is the hold up. Would you let your kid have seizures and cognitive problems because of red tape?
- didibus 5y ago> So mRNA-based techniques have a lot of power and a lot of promise. But there’s definitely a low-hanging-fruit area here, and that’s infectious disease vaccines. Beyond that the promise holds up, big-time, but the difficulties mount up as well. It’s going to be a long story with a lot of plot twists, but I’m glad we’re telling it. Just want to emphasize the conclusion, because if you stop reading before the end, you might think that the article is dismissive of mRNA, its not, just realistic in the remaining challenges for some of the more ambitious outcomes of it.
- ummonk 5y agoIt's not clear that mRNA holds any actual advantage for that low-hanging-fruit relative to other approaches though (e.g. protein subunit or DNA-based vaccines).
- tiahura 5y ago“The mRNA vaccine seems to be highly effective, two doses of that vaccine against this variant,” Gottlieb said, referring to the Moderna and Pfizer/BioNTech vaccines. “The viral vector vaccines from J&J and AstraZeneca also appear to be effective, about 60% effective. The mRNA vaccines are about 88% effective.”
- smnrchrds 5y agoHigher efficacy does not have a 1-to-1 relationship with using mRNA technology. CureVac is an mRNA vaccine and is less than 50% effective. Novavax does not use mRNA and is more than 90% effective. https://www.cnn.com/2021/06/14/health/novavax-covid-19-vaccine-us-phase-3-trial-study/index.html https://www.cnn.com/2021/06/14/health/novavax-covid-19-vacci...
- ummonk 5y agoI'm talking about protein subunit and DNA-based technologies, not adenovirus viral vector. Protein subunit vaccines at least (e.g. the novavax and GSK vaccines) have proven themselves against COVID-19 as well.
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- rob_c 5y agoIt's almost asif this is in relation to a new strain of a family virii we've seen before that doesn't make you grow a new hand out your forhead. When did medicine and healthcare start seeing zebras everywhere and fail at providing a step up for everyone in every situation in life? Seriously polio vaccine fantastic, aids vaccine if we ever get one ground breaking, but why does this end up with industries which are driven more by outcry and public misinformation than raw benefits to the species as a whole...
- joelbondurant 5y agoPray to the Government for forgiveness, our holy religion of Science must never be allowed to be questioned!!!
- headsoup 5y agoI'm not clear on one thing from this: early on the author states that mRNA treatments do not create a permanent immune system memory response and need repeated treatments for continued response. But then when the author switches to the 'mRNA vaccines' section he instead refers to cancer treatment, finally circling back at the end to say 'infectious disease vaccines' are the low hanging fruit. Is that still referring to mRNA? How are they getting long term immune system 'memory' from mRNA? I can't quite understand how the articles explains that among the forward looking prospects for cancer etc.
- weaksauce 5y agothe theraputics part is different than the immune system response part. they said in the theraputics part you don't get to use the immune system memory because the immune system memory is there to make a foreign enough protein that looks like the virus receptors so the body learns how to kill those proteins. a therapeutic doesn't want you to kill the proteins it creates because the proteins created need to be able to go and do work on other cells... so it needs to look somewhat like "normal" proteins that a body would create naturally.
- headsoup 5y agoThanks. If I'm correct then the mRNA vaccine introduces proteins that reflect the virus and trigger the immune response? I think I was reading the article as mostly focused on vaccines, but it was focused on cancer treatment, hence my confusion...
- Vecr 5y agoThe article is talking about multiple possible uses for mRNA drugs, including prophylaxis and non-prophylaxis vaccines (you would not take a vaccine for a cancer before you get it, unless it is to prevent an infection that could cause cancer (HepB, HPV, etc)), and mRNA therapeutics, including ones from protein replacement. For protein replacement, you would have to take the mRNA often, because mRNA degrades. Your immune system has memory, but you won't keep making random proteins after the mRNA goes away.
- user7582 5y agoWho writes this anti-science? The injections are conveniently useless against the current strain. It made $$$ but it clearly didn't work DARPA
- thaumasiotes 5y ago> mRNA can only be used to make the body make proteins that, well, the body can make. This might seem obvious, but it’s a pretty key part of where Moderna’s “software of life” analogy falls flat. It’s a limited software with limited toolkits. You’re not going to use mRNA in humans to make, say, an antibiotic that’s naturally produced in fungi. Hmm? I keep hearing about plants and bacteria that have been genetically modified to secrete e.g. animal proteins. Do fungi assemble their proteins from a different set of amino acids than animals do?
- ejstronge 5y agoAntibiotics are not necessarily proteins but can be arbitrary ‘small molecules’ which could require a suite of enzymes instead of just one enzyme
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- manwe150 5y agoI don’t see that exact quote, but the article seems to be a list of many of the reasons just inserting the same mRNA sequence may not work as desired. To compare contextually also, researchers now spend substantial effort to teach simple monocellular organisms to produce various proteins of interest, because the pathway and other influences in the cell can influence whether it is translated and how the protein folds.
- G3rn0ti 5y agoPlants and bacteria lack an immune system like the human‘s. Fully fledged immune systems with antibodies, T killer cells and B memory cells is something mammals „invented“.
- vinay427 5y agoYour point of course stands, but from what I can tell (as someone very much not an expert, i.e. glad to be corrected), the history of the adaptive immune system is far more continual and definitely precedes mammals, with the "fully-fledged" versions found in early vertebrates and some mechanisms preceding that as well. The abstract here seems quite well-written: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919748/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919748/
- caf 5y agoThis sort of mRNA work isn’t immune-driven at all, in theory, and if you need your target cells to keep producing your desired protein, you’re going to have to keep telling them that by sending them more mRNA. Once a day? Once a week? Who knows? That’ll need to be worked out by experiment. This doesn't seem like a problem from the point of view of those who are in the business of selling mRNA :)
- lanevorockz 5y agomRNA is the ultimate biohacking tool. You can potentially use it for weight loss by improving metabolism without exercising and a few other things.
- KSteffensen 5y agoI won't be injecting any mRNA to loose a few kilos anytime within the next multiple decades. Metabolism is complicated and there are some really nasty and weird metabolic diseases out there, based on some small regulatory feedback loop being broken. Don't fix a working system! If your weight bothers you, just go for walk or a swim once in a while. Have a salad.
- jhayward 5y ago> If your weight bothers you, just go for walk or a swim once in a while. Have a salad. It is super annoying when people post crap like this, as though that's all it would take to address the obesity epidemic. By the way, there is approximately zero effect on weight in response to "going for a walk or a swim once in a while".
- KSteffensen 5y agoI have lost 5 kg since january going from ~102kg to ~97kg. This has happened from two changes: going for a run 2-3 times per week and reducing the amount of cake I eat. I still have fries with mayonnaise with my hamburgers. I acknowledge that there is an issue around cheap food being unhealthy food and people being forced to eat chips for lunch for financial reasons, but for anyone in the middle class or above I really don't understand why it's more complicated than 'move more, eat less'. It's hard. But it's not complicated.
- xiphias2 5y agoOf course now after the fact that mRNA vaccines are hugely outperforming other technologies in COVID, we know that they are our best bet for other infectious diseases as well (including having a much better flu vaccine), but Moderna+BioNTech got a lot of money last year to find it out, and this was not that clear 1 year ago. What the article doesn't answer to me, is how to cure my 40 year old ex girlfriend with metabolic breast cancer. Sorry, but giving up on people just because it's technically challenging is not an answer to me. If the CAR-T or TIL therapies can cure her, I agree that the mRNA therapy route should be stopped, but right now trying all possible routes is my best bet to not be at her funeral.
- jdthedisciple 5y agomRNA vaccines are not "hugely outperforming other technologies in COVID". Sputnik V has around the same efficacy after 1 dosis that Biontech has after 2. That's 1-0 for Sputnik in my book.
- jdthedisciple 5y agoAaaaand here come the downvotes from the adherents of the religion of mRNA Technology :D Scientific objectivity is LONG GONE! "With the Pfizer/BioNTech vaccine, protection against symptomatic COVID-19 was found to be 52% from 12 days after the first dose (immunity takes time to build). Protection then rose to 95% after the second dose." [1] "Vaccine efficacy, based on the numbers of confirmed COVID-19 cases from 21 days after the first dose of vaccine, is reported as 91·6% (95% CI 85·6–95·2), and the suggested lessening of disease severity after one dose is particularly encouraging for current dose-sparing strategies." [2] Dear mRNA-ists, how is 95 % after second dosis (mRNA) vs 91·6% after first dosis (non-mRNA) worth being called "hugely outperforming"? And I didn't even go into the severe side effects of mRNA vaccines (AZ: Blood clotting in brain and/or lung; Biontech: Myocarditis, Anaphylaxia) vs virtual absence of side effects in traditional vaccines. But how dare I point those out, that's heresy, right? :O [1] https://theconversation.com/covid-19-vaccines-why-its-important-you-get-your-second-dose-161940 https://theconversation.com/covid-19-vaccines-why-its-import... [2] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00191-4/fulltext https://www.thelancet.com/journals/lancet/article/PIIS0140-6...
- grammers 5y ago> mRNA can only be used to make the body make proteins that, well, the body can make. That's an important point we need to keep in mind: mRNA can be used to fix the body where it is broken/or not producing specific proteins when it would be needed. But it doesn't give us superpowers or change us into other beings than what we are.
- hammon 5y ago"The first distinction is between vaccines and therapeutics" LOL This comment is dedicated to people downvoting me saying the same. People is not even able to have argument on thing anymore. Sad.
- zomars 5y agoI'm kinda surprised no one's talking about Robert Malone (the inventor of mRNA vaccine tech) mentioning the protein Spikes causing unexpected issues [1]. [1]: https://www.youtube.com/watch?v=Du2wm5nhTXY https://www.youtube.com/watch?v=Du2wm5nhTXY