9 ms·
We Made One Gram Of Remdesivir
- aerovistae 6y agoReally interesting getting a window into the world of professional chemistry. So impactful on all of us but so much more opaque. We see CS jokes/memes all over the place, even if only those who program get them, but we never see chem jokes, or only sparingly and rarely beyond a high school level.
- someguy101010 6y agoI wish I knew the havkernews equivalent for chemistry, finance, etc. The closest thing I've found was https://www.foundmyfitness.com/news https://www.foundmyfitness.com/news for nutrition.
- dcolkitt 6y agoNuclear Phynance is your best bet for a HN like community in quant finance.
- glaugh 6y agoA semi-random example to prove the point: https://www.nuclearphynance.com/Show%20Post.aspx?PostIDKey=196197 https://www.nuclearphynance.com/Show%20Post.aspx?PostIDKey=1...
- mjthrowaway1 6y agoThat community has been pretty dead for years. Used to love it.
- applecrazy 6y agoIs there a successor to this forum? I’m a CS undergrad and kind of want to explore this field.
- aerovistae 6y ago/r/wallstreetbets :P
- applecrazy 6y agoThat’s just trading. Learning quant finance is More than learning how to trade. Plus, WSB is more of a meme than real education.
- qnt 6y agoNo, there isn’t really. There is a treasure of info on that site though. I also have a CS background before I moved to the quant area. Things that might help pique your interest: - For both academic and practical problems: http://quant.stackexchange.com/ http://quant.stackexchange.com/ - For keeping tabs on new ideas in the blogosphere (generally average, occasionally something useful): https://quantocracy.com/ https://quantocracy.com/ - Useful information on getting started in the field: http://quantstart.com/articles http://quantstart.com/articles Outside of the academic literature, it is quite an insular field, so you have to work to find interesting ideas. If you can make money, you probably won’t be sharing much with anyone. A notable exception might be Rob Carver’s blog (https://qoppac.blogspot.com/ https://qoppac.blogspot.com/). From a CS background, a simple path to see if you might enjoy “quant investing” is to read some old papers from e.g. AQR about factor investing (Momentum, Value) and try to implement it with Interactive Brokers or similar. You should be able to roll something together with very little capital. On the “quant trading” side of things, try the Avellaneda paper for statistical arbitrage, do some digging about RenTech, read the LTCM book, etc etc. Not something you can do without a lot of infrastructure behind you, but there’s enough information around to work out if it’s interesting.
- applecrazy 6y agoThank you for the list of resources. Given the current situation, this will make interesting reading/study material. If you're comfortable, could you please share how you made the transition to quant from a programming/SWE background?
- davikr 6y agoIs there a Hacker News equivalent for Medicine? Maybe r/medicine is really the only similar place..?
- Metacelsus 6y ago>we never see chem jokes, or only sparingly and rarely beyond a high school level. For biochemistry check out r/labrats
- ebg13 6y agoThe writing is so good, I had to double check that it wasn't written by Derek Lowe.
- sq_ 6y agoI absolutely love reading Derek's blog. So informative and funny at the same time. Especially his "Things I Won't Work With" section.
- samcheng 6y agoHere's his most famous article on FOOF (Dioxygen Diflouride) 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... It seems there are multiple chemist-author hybrids out there!
- ggm 6y agoAt seven hundred freaking degrees, fluorine starts to dissociate into monoatomic radicals, thereby losing its gentle and forgiving nature. Gentle and Forgiving nature...
- HarryHirsch 6y agoThe inimitable Martin Poliakoff demonstrates it here: https://www.youtube.com/watch?v=vtWp45Eewtw https://www.youtube.com/watch?v=vtWp45Eewtw
- fuzzfactor 6y ago
- aledalgrande 6y agoLOL at the way process chemists were introduced
- manav 6y agoIt’s been almost two decades since I took a chemistry class, looks more foreign to me than code to a non-programmer.
- ehsankia 6y agoTo be fair organic chemistry is its own beast and far messier than normal chemistry classes.
- HarryHirsch 6y agoYes, there's a difference between pushing electrons on paper and making compounds behave in the lab as they do on paper. Scaleup from lab to pilot plant to production is another different beast.
- franciscop 6y agoOne too many zeroes here: 0.25 x 0.58 x 0.74 x 0.21 x 0.23 = .005 (0.05%) The 0.005 seems to be correct, so that should be 0.5%. The rest of the article also uses "0.5%" correctly.
- deleted 6y ago[deleted]
- Josh_Bloom 6y agoIt’s a running joke between my readers and me. EVERY SINGLE TIME I have done even the simplest of math (n= more than 20) I’ve screwed it up and been corrected by a reader. I don’t know how I made it out of high school.
- franciscop 6y agoNo problem! Basic math mistakes are dangerous because they might take credibility out of the rest of the article, but this one seemed very well written and it shows that you know what you are writing about so I don't think it's a big deal. I noticed only because something ticked on me when I read "0.005 (0.05%)", it "felt wrong" so I double checked.
- fg6hr 6y agoThat's some really complex mess. How much do these chemists get paid?
- mardifoufs 6y agoIn research? Usually not much and thats if you can even manage to find a job. But Chemical engineers are usually well paid and can easily get a job out of college. Though maybe that is changing since the oil industry is usually a big part of the job market. And with most of the energy sector currently on the brink of collapse...
- fg6hr 6y agoI don't get it. The Big Pharma makes some serious money and it needs qualified chemists to make new drugs. The complexity of making these drugs is so high that there should only few chemists good enough for the job.
- barkingcat 6y agoIf they don't have grants, $0. If they work in a lab for someone who has a grant, $0, but with credit on the papers (that's why there's 35 authors on the paper, 1 person got paid, the rest got name credit in the hopes that they get noticed by a commercial company wanting to monetize this process, so in the future they get their own gig). If they work in a commercial lab, maybe they make a little.
- yjftsjthsd-h 6y agoSo... Why does anyone do it? We're talking about throwing years of your life at this work; how on earth is it pulling people in if it can't pay bills?
- astronautjones 6y agoYou're locked in at that point
- 6y ago
- gorgoiler 6y agoVery funny writing style while being incredibly informative. Read from top to bottom with glee. I had a feeling organic synthesis was difficult but not this difficult. Missed a trick not titling it: “(1OO)OMG we made one gram...” :)
- roenxi 6y agoAlthough very interesting, this article isn't a great introduction because a critical part of the picture is missing - the availability of the inputs. Sticking to simple stuff; mines produce iron at a rate measured in thousand-tonnes per hour with yields of potentially sub-30% compared to volume of earth moved. Ammonia and many acids are presumably measured in tonnes or kilograms produced per day. Low yields make the process-oriented sad, but what matters is absolute ability to produce; not yield. All that doesn't take anything away from this article; it just makes it hard to interpret what 'royal pain to synthesize' means in practice. The process isn't basic chemistry; but that isn't really saying much.
- HarryHirsch 6y agoLow yields make the process-oriented sad, but what matters is absolute ability to produce; not yield That would be true if reagents, labour and plant equipment were free, but unfortunately they are not. Consequently you have these strange creatures called process chemists who shave steps of the discovery synthesis, increase the yield, and get around difficult reactions. It's really quite magical. When it comes to bulk chemicals like vinyl acetate (produced at scales of kiloton per day) another consideration is waste. It cuts into profit twice: you lose product and you pay for disposal.
- alkonaut 6y agoExaxtly this. Are the inputs available and we can spend just a few tens of billions on building gigafactories to make this process parallel and controlled? Then it’s like making microchips from silicon or gold from ore. Terrible yield but cheap inputs and a scalable process. If the inputs are expensive or the process can’t scale (to a billion doses in 12 months, say) then that’s worrying and perhaps indicates this isn’t a good candidate vaccine.
- alkonaut 6y agoEdit: remdesivir is a therapeutic, not a vaccine, so it is useful in much smaller quantities than a vaccine.
- eyegor 6y agoThis article really reinforces my choice to drop ochem in college. It's funny how deciphering assembly code seems downright mundane compared to this jargon. Like, I get how given the process you could recreate things, or you could devise possible reactions based on electron shells and bonding tendencies, but how do researchers even figure out how to make these reactions happen? Especially when they require -100C, or +5atm of pressure.
- applecrazy 6y agoIsn’t there analytical chemistry software?
- Reelin 6y agoYes, but good luck interpreting the output if you aren't an accomplished synthetic organic chemist.
- fuzzfactor 6y agoAnalysts can benefit tremendously from better knowledge of research, synthesis or process work, and vice versa. But great professionalism can also be developed without as much cross-functionality between subdisciplines. Like many things, detailed efforts unique to the subprofession can be the most essential.
- girvo 6y agoThere is. Some of it is quite powerful, too, but it has some (quite serious) limits: process chemists definitely aren't in danger of losing their jobs just yet!
- fuzzfactor 6y agoYou must utilize the software beyond the vendors' design goals before you can be as effective as you could before there was software.
- Gigablah 6y agoSpeaking of elaborate processes, NileRed’s recent video about the laborious process of making aerogel is a fascinating watch: https://youtu.be/Y0HfmYBlF8g https://youtu.be/Y0HfmYBlF8g
- kccqzy 6y agoRemdesivir is an analog of adenosine, one of the four building blocks of RNA. Just look at the main structure and you'll agree they look similar. It turns out the mechanism of action of this drug is that it's supposed to be confused with adenosine, so that the viral RNA replication process uses remdesivir instead of adenosine, which later breaks the RNA†. Our body, or really, all biological processes can synthesize incredibly complicated molecules that can take human chemists a huge amount of effort to synthesize. It really is amazing how awesome our body is. †: My description here is a dumbed down description. For a more precise description see section 2 of Arguments in favour of remdesivir for treating SARS-CoV-2 infections, Wen-Chien Ko et al, https://www.sciencedirect.com/science/article/pii/S0924857920300832 https://www.sciencedirect.com/science/article/pii/S092485792...
- nbabitskiy 6y ago>> look at the main structure and you'll agree I don't know much about RNA, but this sentence is pure bs. How would I know where to look in RNA sequences?
- cma 6y agoI think he means look in the structure of the adenosine molecule, not the structure of the virus's RNA.
- numpad0 6y agoLet’s call it the Ocean’s Eleven Phenomenon, the moment when two or more experts be like “See that? There.” “Yeah, Christ, that’s totally that” “yeah... 5 years old would notice” and you just stand in between dumbfounded
- Aloha 6y agoI've been stuck in this uncanny valley before, and caused the phenomenon to happen to others too.
- nbabitskiy 6y agoI could certainly believe that "similar" molecules behave alike, but it would be a cheap belief, like e.g. some of my friends believe in psychics. There would be no discovery, just a pseudo-scientific bullying.
- abhisuri97 6y agoThis brings me back to orgo lab. A six step synthesis was torture when you were graded by your final yield exactly bc of the compounding nature of small mistakes in each step. Even if you get fairly good yields of 80 to 90% per step, you’d end up with a 53% at best and hope to god that everyone else did equally badly so the curve would save you.
- mettamage 6y agoThis was a lot of fun to read and quite accessible. I remember that I was horrible at chemistry in high school, but the right things were ELI5'ed. I like HN in general, but this particular article gave me the same feeling that I had when I first discovered HN a couple of years ago.
- Vaslo 6y agoIn my former life I was a graduate organic chemist, but I “quit” with a Masters. I loved Synthetic Chemistry as an undergrad and thought I wanted a PhD in. There were three lousy things (for me) about the career that made me bail. 1). So many syntheses have horrible yields just like this one. You’d start with grams of material to end up with micrograms. I loved solving these problems as an undergrad in books, but reality was far different. You don’t think much about side products until you start doing novel chemistry. 2). So much trial and error. There were happy go lucky chemists that fell into projects that were smooth as butter, while brilliant chemists would toil 12 hour days to try and something to write up as a thesis. I was neither brilliant nor lucky and took 4 different projects over two years before finally landing on something marginally MS worthy. They need a journal of failed chemistry because only the working stuff gets published. So many failures could be logged so I didn’t waste my time doing non-working or poor yielding reactions. 3). Suspicious results in journals. I would read about a reaction and someone would put a 75% yield as their result and I could barely get 20. I always thought I was just bad, but a really smart chemist challenged me one day and tried to do it himself and couldn’t do much better. He tried it 30 different ways over the year as he did other stuff. He never could get a good yield. We talked to our advisor and we wanted to challenge the result, but the advisor didn’t want to start trouble. It was past the time I decided to leave with a masters, but made me feel a little better about my lousy abilities. No one could ever possibly doublecheck every result from every publication anyways. All this said, there are some brilliant and patient scientists out there that drive the field forward. Just a few rough around the edge items I’d love to see change.
- twomoretime 6y agoYour anecdote seems to confirm a number of problems which are ravaging academia at large. Having gone through a master's myself, I think when we pushed two generations of children into college, we generally lowered the bar - across the board, effectively. And that's related to what's happening in the US today.
- wesleywt 6y agoYou are describing my life. Except I am in biotechnology.
- ngngngng 6y agoI've never learned a bit of Chemistry. I assume there are formulas to determine how substrates and reagents will react with each other? And the process chemists understand these formulas better than most? Apologies for the assumptions in these question, but are there many reactions in organic chemistry that are completely unknown? This actually seems pretty fun. I'd love to have a reason to study it and a means to do something with my studies.
- Reelin 6y ago> I assume there are formulas to determine how substrates and reagents will react with each other? Well there are things we've experimentally tested, and things we haven't. Most reactions fall into the latter, and we can only make educated guesses about them. If we could analytically solve the Schrödinger equation (we can't), we could accurately predict outcomes under perfect reaction conditions. > are there many reactions in organic chemistry that are completely unknown? Yes, the vast majority. But bear in mind that we can make educated guesses based on patterns, so we're not completely clueless.
- joyj2nd 6y ago"I assume there are formulas to determine how substrates and reagents will react with each other?" There are rules, yes, of cause. But always the question: how much will react? And not: will I get the (reaction) product? But: how many (different) reaction products will I get. This is actually the reason why you need the purification steps after each reaction. Otherwise you would get an "reaction tree", in the end, byproducts reacting with other byproducts and you would get a, basically infinite amount of different end products.
- Symbiote 6y agoWhich country's education system doesn't have any chemistry at all? Chemical formulae are required study for 11-14 year olds in England, for what it's worth. (Probably starting with words: methane + oxygen → carbon dioxide, and later writing a balanced equation: CH₄ + 2O₂ → CO₂ + 2H₂O.) The reaction presented is obviously much, much more complicated, but the same concept. Edit: catalysts are covered too, although I don't know if the notation of putting them above the → is introduced at this age. https://www.bbc.co.uk/bitesize/guides/zqd2mp3/revision/6 https://www.bbc.co.uk/bitesize/guides/zqd2mp3/revision/6
- Josh_Bloom 6y ago@ebg13 Thank you! That may be the biggest compliment I’ve ever gotten. Derek is the god of carbon as far as I’m concerned. Josh
- quickthrower2 6y agoFunny just saw this comment on reddit. Related https://www.reddit.com/r/Political_Revolution/comments/fuuuyw/im_meredith_mattlin_a_24yearold_cancer/fmeu2pp https://www.reddit.com/r/Political_Revolution/comments/fuuuy...
- est31 6y ago> Here are the real numbers for the reactions in Scheme 1: 0.25 x 0.58 x 0.74 x 0.21 x 0.23 = .005 (0.5%) This reminds me of the problems to scale up EUV lithography which are bottlenecked on producing strong enough EUV light. They put in 20 kW of power to get out 200 W at the target wavelength of 13.5 nm, so light generation itself only has 1% efficiency, and then you need to reflect it at mirrors etc. to focus it (lenses don't work at those wavelength) and that makes only 2% of the light actually reach the waver [2]. [1]: https://www.laserfocusworld.com/blogs/article/16569161/the-secret-of-euv-generation https://www.laserfocusworld.com/blogs/article/16569161/the-s... [2]: https://en.wikipedia.org/wiki/Extreme_ultraviolet_lithography#Light_source_power,_throughput,_and_uptime https://en.wikipedia.org/wiki/Extreme_ultraviolet_lithograph...
- failuser 6y agoThis makes the biological chemistry so awe-inspiring. Everything is done at about the same body temperature and at the same pressure, just with right catalysts.
- franciskim 6y agoStrange that there's not one mention of Avigan / Favipiravir.
- unnouinceput 6y agoQuote: "Fortunately, there are creatures called "process chemists" – guys who laugh at the discovery synthesis, insult as many of us as possible, and then make it better so that the yields are higher and some of the most dangerous chemical reagents and solvents – ones you really don't want to use on a large scale – are replaced by others. They are generally a bunch of mutants, but they do a great job in "fixing" the synthesis used by the discovery chemists." This really cracked me up. In my IT world the equivalent for "mutant" would be refactoring, right? I did "mutated" this way a few times in the past to much of the horrors of my boss(es)/manager(s) when they learned the next day.
- jluxenberg 6y agoPress release from Gilead published yesterday says they aim to have 500,000 treatment courses by October (they reduced a 12 month production process to 6 months): https://www.gilead.com/stories/articles/an-update-on-covid-19-from-our-chairman-and-ceo https://www.gilead.com/stories/articles/an-update-on-covid-1...
- endorphone 6y agoChemistry is absolutely fascinating. One of my long-time goals has been to make a learning chemistry game of some sort. Players building bonds and molecules, solving problems by creating reactions, etc. Orbits and ions and quantum states. Something truly educational, and of course one of the people I wanted to educate was myself by forcing myself to learn much more than my high-school level of chemistry. I've gone down this road a few times, each time giving up on the absolutely scale of even the most rudimentary understanding.
- joyj2nd 6y ago"liquid chromatography, is frequently used. On a small scale this is fine, but when kilograms of material are required the process becomes unwieldy." I did not understand this. liquid chromatography scales up quite well. There are other methods like Electorphoresis, salt precipitations etc., that don't.
- Metacelsus 6y ago>liquid chromatography scales up quite well Not compared to recrystallization or distillation. Try running a column on 10kg scale and get back to me. (I worked in an o-chem lab for 2 years in undergrad, and the biggest we could do was ~20 grams at once)
- bionhoward 6y agoML is useful to design the reaction pathways to make these chemicals. If we find safer/better/cheaper ways to make medicines like Remdesivir with deep learning, and publish them, then chemists may have an easier time of it. If Remdesivir data looks good this month, there will be a rush to produce it, and if there’s only one published way to do that, then the ingredients for that one approach will potentially be hard to find. Thus we can benefit from different approaches which start from different raw materials. Lots of cool Arxiv papers on this and Graph Neural Nets, Soft actor-critic, or Transformers can be interesting approaches. The transport theory seems like a good way to make a value function. How much time and money does it take to produce a given chemical by a given set of reactions? That’s a gajillion dollar question. I spent way too much time last year looking at permutation-invariant distance metrics similar to Fused Gromov Wasserstein to invent an Atom Mover Distance, please let me know if you figure that out! DeepChem library is a solid framework, as are Tensorflow and Pytorch... If anyone’s looking for a way to contribute to the COVID-19 response, open source data/algorithms to design synthesis pathways can be a strong approach. Everyone loves to use Deep Learning to design drugs, but it is valuable to design ways to make drugs, too!
- tikej 6y agoI want to make remark about organic synthesis from the perspective of person who is engineer of chemistry by training as did his fair share of organic synthesis (and eventually moved to computational atomic and molecular physics). It is one of the oldest and very established fields. Unfortunately practices aren’t great. The preparation formulas are often vogue, imprecise and difficult to reproduce. This comes from the fact that often the sizes and types of glassware are not specified, some informations are omitted (how quickly something is changed not only to what value e.g. heat up to 100 degrees but it does not say over what time) etc. Chemists usually (except some theoretical/computational specialisations) don’t have any training in algorithms or programming. There are novel developments such as https://www.gla.ac.uk/news/archiveofnews/2018/november/headline_624196_en.html https://www.gla.ac.uk/news/archiveofnews/2018/november/headl... and references therein. I’m optimistic about them but I expect strong opposition from older faculty. They see synthesis as more than art and think that one has to have “good hand” in order to be a good organic chemist. I think some generational shift will be necessary in order to change this discipline to more reproducible, strict and reliable. It will come but not that soon :)
- Scoundreller 6y ago"(2) The one-gram dose is a guess based on the doses of other antiviral medicines." You're in luck, the first dose is 200mg, and then 100 mg daily after that. Unfortunately, it's also IV, so you have a number of extra steps after synthesis to ensure sterility.
- Glosster 6y agoDoes anyone know what's the probability that Remdesivir is indeed a solution against Coronavirus?
- saadalem 6y agoI was able to create several small molecule candidates which achieved docking scores of almost -18 but they still need to be assessed for their synthetic feasibility. (Docking scores of leading existing drugs (HIV inhibitors) are around -10 to -11 (the more negative the score the better), Remdesivir drug is around -13 which already entered clinical testing. I know that binding affinity has been shown not to be the best indicator of efficacy always, but I want to know if it's feasible, if someone can help
- person_of_color 6y agoAre you a chemist?
- deleted 6y ago[deleted]
- aazaa 6y ago> n-BuLi is short for n-butyllithium, which bursts into flame if exposed to oxygen or water. It looks like the author is overselling some of the dangers here. While you really don't want to dump n-BuLi into water, you have no reason to either. The problem child of the class to which n-BuLi belongs is t-BuLi. That will spontaneously ignite in air, whereas n-BuLi will not. There was a very high-profile case I believe at UCLA a few years back in which a student using t-BuLi in the lab caused a fire with it and ended up dying. https://cen.acs.org/articles/87/i31/Learning-UCLA.html https://cen.acs.org/articles/87/i31/Learning-UCLA.html Also, I find this article confusing in the way it's written. Take the title, for example. It gives the impression that the author is describing his own efforts to make remdesivir ("we"). What he's really describing is some preps he found in the literature. And with a little too much hyperbole for my taste.
- Metacelsus 6y agonBuLi is tame compared to tBuLi, I agree. But on large scale the reaction with air can generate enough heat to ignite. (And with humid air it's worse.)
- jijji 6y agofavipiravir is alot cheaper to synthesize and is used as a drop in replacement for remdesivir all over asia... Good things to have on hand during this covid-19 pandemic (because you can't rely on hospitals to give it to you) are: 1) hydroxychloroquine sulfate taken orally 400 mg per day for a week ($180/kg on alibaba) 2) azithromycin taken orally 500 mg per day for a week ($150/kg on alibaba) 3) Camostat mesilate taking orally 200 mg three times a day for a week [1] ($50/g on alibaba) 4) favipiravir one dose of 1600mg two times on the first day, and then 600mg twice per day after that for a week [2]. ($40/g on alibaba) 5) covid-19 rapid test kits that use blood antibody tests and produce results between 3 to 10 minutes and cost about $1.50 per kit [3] .... although it looks like in the last week or so Alibaba has been blocking searches for these kits for some reason... although the search below does work but you have to look at the suppliers to find the ones that are actually selling it. all this stuff can be bought on Alibaba and delivered in a week [1] https://clinicaltrials.gov/ct2/show/NCT04321096 https://clinicaltrials.gov/ct2/show/NCT04321096 [2] https://www.medicalnewstoday.com/articles/anti-flu-drug-effective-in-treating-covid-19#Favipiravir-maycombat-SARS-CoV-2 https://www.medicalnewstoday.com/articles/anti-flu-drug-effe... [3] https://m.alibaba.com/products/covid-19_rapid_test_kit.html https://m.alibaba.com/products/covid-19_rapid_test_kit.html
- autonoshitbox 6y agoA drop-in replacement for something that barely just finished clinical trials. Ok. Stop suggesting people buy dangerous drugs from Alibaba. This should be bannable.
- garmaine 6y ago> remdesivir, possibly the most promising candidate Is there any evidence of this? It was a highly anticipated drug, but the first studies it was in showed only slight improvement over expected outcomes, far less than was seen with the chloroquine/zinc/antibiotic combo treatment. I mean I think it's still interesting as a possible drug to add to the cocktail for maximum effectiveness. But let's not oversell it.
- VSerge 6y agoOh the pain of biochemistry! Thanks to the author for making this available to everyone, and reminding these of us who ran screaming from the labs why our decision is not among the ones we might regret. Joking aside, I hope this molecule can be synthesized efficiently, and that it can be preempted from Gilead somehow, as this company has a history of price gouging of the worst kind. They are down there with the oxy makers, the worst of the worst, causing deaths through their pricing policies, and resulting lack of affordable treatment. The ideals of medicine mean nothing to these, and public health should take precedence over the interests of such despicable companies.