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mRNA's next challenge: Will it work as a drug?
- napier 6y agoPaywalled for me. Perhaps someone could fix that?
- knicholes 6y agoYou could fix it by paying! :D
- cinntaile 6y agoIt 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 6y agoBecause 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/newsfaq.html https://news.ycombinator.com/item?id=10178989 https://news.ycombinator.com/item?id=10178989
- macrolime 6y agoLink to full article https://sci-hub.se/downloads/2020-12-18/44/10.1126@science.370.6523.1388.pdf https://sci-hub.se/downloads/2020-12-18/44/10.1126@science.3...
- wildbunny 6y agoIt's gone down
- CaliforniaKarl 6y agoIt'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 6y agoEnabling dns over https usually fixes any censorship by an ISP issues.
- deadalus 6y agohttps://ipfs.io/ipfs/QmWiWELM9ArjAJvAsSiyZ5jSfjZERir3nGmbySVd7ts7QX https://ipfs.io/ipfs/QmWiWELM9ArjAJvAsSiyZ5jSfjZERir3nGmbySV...
- macrolime 6y agoIf it doesn't work you can try try replacing .se with .st or .do
- ce4 6y agoWorks 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.370.6523.1388.pdf https://sci-hub.se/downloads/2020-12-18/44/10.1126@science.3...
- witweb 6y agoGod bless Sci-Hub. Thanks for linking the full article.
- dmix 6y agoDonate to Sci-Hub: https://sci-hub.tech/donation/ https://sci-hub.tech/donation/ They accomplished one of Aaron Schwartz's dreams.
- elektor 6y agoIs this the legit link to Sci-Hub? I'm a little surprised to see Paypal allow donations.
- dmix 6y agoIt has the same BTC address as the usual sci-hub pages (12PCbUDS4ho7vgSccmixKTHmq9qL2mdSns) so I'd say yes. And please don't give them any ideas. The domain issue is hard enough it seems. Thank god there's hundreds of TLDs now :p Ditto with archive.is and their domain struggles.
- neonate 6y agohttps://archive.is/h7MNM https://archive.is/h7MNM also works.
- dzhiurgis 6y agoDoes not for privacy respecting dns users
- LordDragonfang 6y agoI'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_with_archiveis_domain_on_cloudflare_dns/ https://www.reddit.com/r/pihole/comments/ao51ko/problem_with... https://news.ycombinator.com/item?id=19828702 https://news.ycombinator.com/item?id=19828702
- dsissitka 6y agoOr Brave users, or... did they ever unblock Finland? https://en.wikipedia.org/wiki/Archive.today#Finland https://en.wikipedia.org/wiki/Archive.today#Finland
- colejohnson66 6y agoIf 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 6y agoIn this case it doesn't have the article.
- colejohnson66 6y agoweb.archive.org/save/{URL} works
- Karunamon 6y ago
- napier 6y agoThanks!
- msla 6y agohttps://web.archive.org/web/20201218214338/https://sci-hub.se/downloads/2020-12-18/44/10.1126@science.370.6523.1388.pdf https://web.archive.org/web/20201218214338/https://sci-hub.s...
- avancemos 6y agoThe 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.
- fintler 6y agoIt did start in the 70s! https://www.ncbi.nlm.nih.gov/pmc/articles/PMC433302/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC433302/
- CharlesW 6y agoAnother easily-searchable fact is that the COVID-19 vaccine is not the first RNA-mechanism drug.
- deleted 6y ago[deleted]
- jfarlow 6y agoDelivery 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/ 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.
- vlovich123 6y agoWhy 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.
- newacct583 6y agoEbola, 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.
- fabian2k 6y agoThe 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.
- 6y ago
- petra 6y agoThere is a YC company that has a technology to guide small molecules to cancer cells. Might be able to guide mRNA too.
- jdoliner 6y agoThat would be Shasqi! https://www.shasqi.com/ https://www.shasqi.com/
- nextos 6y agoI 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.
- hikerclimb 6y agoI hope not
- _greim_ 6y agoOkay, 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.
- lucaswoj 6y agoThis is Moderna's goal https://www.modernatx.com/mrna-technology/mrna-platform-enabling-drug-discovery-development https://www.modernatx.com/mrna-technology/mrna-platform-enab...
- strbean 6y agoSeems to be working well so far for COVID vaccines. We're about to witness a very large scale test though.
- flobosg 6y ago> 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 6y ago[deleted]
- elcritch 6y agoThe 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.
- 6y ago
- blakesmith 6y agoI'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-vaccines/mrna.html https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different...
- shiny 6y agoI liked this guy's explanation: https://www.youtube.com/watch?t=1313&v=wb_0FB7XiqA 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?
- rolph 6y agocell surface protiens go through a turnover in similar fashion to mRNA. protiens are chemically and phsyically more robust than mRNA however due to thermokinetic damages etc. protiens must eventually be decommisioned and replaced by new updates [likewindows10]. cell membrane turnover also occurs. this is a recovery of the cell toward its central tendency. in strictest terms the expression of the novel protien is damage, but not to the extent that the cell must be destroyed. Cells have timeline leading to proceedural, and also programmed cell death, this is a case of the needs of the many [tissues, whole organism] outwieghing the needs of the one or few. there are many quotes regarding ~every Xmonths you are a new person.
- stanford_labrat 6y agoThere is a YC company who are currently using mRNA based drugs for telomere extension.
- jart 6y agoMy Google fu is failing me. What company is that? Sounds like Elysium.
- stanford_labrat 6y agoRejuvenation Tech! (S18)
- supernova87a 6y agoI 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?
- ch4s3 6y agoProbably 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 6y agoMy 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 6y agoGiven 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.
- localhost 6y agoI 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 https://twitter.com/john_lam/status/1333632894720380929
- ineedasername 6y agomRNA 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 6y agoThe 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)
- ineedasername 6y agoSure, Moderna alone has been working on things for 10 years, but not a whole lot of other "Big Pharma" resources seem to have been thrown at it previously. My guess is that will change now. The situation reminds me of research into serotonin's role in depression. Like mRNA in its field, ideas about serotonin and a little bit of research were bouncing around for a few decades. The drug that was ultimately branded Prozac was developed in the early 70's, but not brought to market until the mid 80's. Then, it's ground breaking efficacy compared to prior drugs & for people not helped by those other drugs acted as a catalyst for research that now forms the foundation for modern treatment of mood disorders-- certainly far from perfect, but also far better than 30-40 years ago. For example, Prozac's minor role as a norepinephrine reuptake inhibitor sparked significant research into that neurotransmitter as well, leading to yet another generation of new drugs, SNRI's like Cymbalta that which are not only a useful for depression & anxiety, but also for the treatment of certain forms of chronic pain & as an aid for quitting smoking. It's too early to tell for sure, but I see the potential for the moment in history to be a similarly catalyzing event for mRNA research & subsequent treatments. (Unless of course the vaccine produces a zombie apocalypse, the relatively small trials by chance not having anyone impacted by that potential "side effect" of zombie-ism, in which case I'll feel pretty silly sitting here a few months from now having to eat my words. And brains, lots of brains.)
- crb002 6y agoYes, 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/ https://www.idtdna.com/
- kliments 6y agoThis article is a great read. It is amazing what scientists have accomplished using mRNA. I have researched on the application of genome editing using the Cas9 protein in cancer therapy. There are many possibilities for utilizing mRNA and proteins. The future of medicine sounds exciting!
- MichaelMoser123 6y agothe article mentions seizures with the OTC deficiency treatment based on mRNA. that got me searching; https://www.healio.com/news/infectious-disease/20201209/uk-advises-against-giving-pfizer-vaccine-to-patients-with-history-of-allergic-reactions https://www.healio.com/news/infectious-disease/20201209/uk-a... here it says that UK authorities advise that people with a history of allergic reactions may not get the mRNA based vaccine, as they may get an anaphylactic event. Now wikipedia says that this is a potentially serious condition https://en.wikipedia.org/wiki/Anaphylaxis https://en.wikipedia.org/wiki/Anaphylaxis Now I am confused, https://www.aafa.org/allergy-facts/ https://www.aafa.org/allergy-facts/ says that some 50 million people in the US suffer from some kind of allergies, does that imply that 15% of the population can't get the mRNA vaccine? Now would that figure have any implications on the effectiveness of vaccination? Should people with allergies get a different kind of vaccine? Many questions remain. I don't see a public discussion of these issues.
- danielmg 6y agoThe advice is actually for "serious" allergic reactions. There's a world of difference between hayfever and something life-threatening like nut allergies. I have hay-fever and Asthma and you won't be able to stop me getting the vaccine. I see far more risk from COVID than the vaccine. I have to question your motivations here. Your post is disingenuous at best.
- MichaelMoser123 6y agoThe linked article mentioned 'allergic reactions', it further links to a cnn article [1] that mentions 'significant history of allergic reaction', both articles don't clarify the condition. Sorry for asking questions. [1] https://edition.cnn.com/2020/12/09/health/covid-vaccine-allergies-health-workers-uk-intl-gbr/index.html https://edition.cnn.com/2020/12/09/health/covid-vaccine-alle... I think they should give some detailed clarifications on the issue to the public, as the producers of the vaccines can't be sued for damages, in the event that something goes wrong. https://theintercept.com/2020/08/28/coronavirus-vaccine-prep-act/ https://theintercept.com/2020/08/28/coronavirus-vaccine-prep... (for the US, don't have any information for GB on that issue) In the EU producers were also seeking exemptions https://www.berliner-zeitung.de/en/covid-19-vaccine-makers-want-eu-taxpayers-to-pay-for-legal-damages-li.101263 https://www.berliner-zeitung.de/en/covid-19-vaccine-makers-w...