TechTakes

Yeah I used my political positioning in regards to the Dutch political people and the self identification of our political groups (the most rightwing parties after Wilders are self proclaimed liberals here after all (however talking of political ideology and what it implies is a thing that simply never happens in politics here, it is really strange, everybody acts like they have no real nameable ideology (the people not in power have of course))). Which colors my perception of these kind of things.

their original promise was that: you will be able to plug a jar to a controller, download instructions and it will make medicine for you, no knowledge of chemistry needed. i think it was one talk before this one where they claimed to make an antiviral (still under patent) and gave away some pills of it for free. i don't think they made it in a way that matters, they didn't show their pathway, they didn't show analyses they say they made, they don't say what they used as a starting material and how they got it, and they didn't provide anything in way of formulation or other three drugs needed in that treatment (iirc). it might be very well that their costs are even higher per pill than what usual distribution will charge, but they don't say any of that, and it might be just as possible that if more people did that starting material supply would dry out. (or they might be just lying) worse than that, while they might do some analyses, it's not included or expected in jar and controller scenario, so there's no real quality control and if released, this alone can be reasonably expected to kill people. i'm not sure if they even released anything workable in this capacity (they also claim that they made pyrimethamine, but it's also after nilered made it, so they might just copy his process. it's simpler thing)

what they're doing later: there's this horse medicine that you can use as (more dangerous, less effective) ersatz plan B, or this estradiol thing, it's much less sketchy because they don't cook anything, they "just" formulate an API they get from somewhere else, but it's still a fair bit sketchier than using fish antibiotics in humans because for example massive accidental overdose is still quite likely

@Soyweiser @fullsquare

"With software it (as far as I can tell) is also quickly that bigger projects need bigger teams, and that adds a lot of communication problems, and as a non-stacking process you can’t just add more programmers to make stuff go faster"

I bought two copies of that Fred Brooks book so I could read it twice as fast

Think the issue is that some complexity can be removed without problem, and some absolutely cannot. And the problem of figuring out which is which is hard. (Which if you squint, seems to be similar to the chemistry stuff you describe here).

Well, i'm not exactly sure about it, but what i can do is describe how this process works in terms of operations and you can draw your own conclusions. There's not that much complexity in peptides in the first place, because synthetically, all you have to do is to make a lot of amide bonds, and this is a solved problem. Slightly bigger problem is to make it in controlled way, which is reason why protecting groups are used, but this is also a thing that has been around for decades.

The trick is to bind the thing you want to get to resin, which makes it always insoluble and therefore your product always stays in reactor. This can be an actual dedicated automated reactor or a syringe with a filter. We start with

Resin-NH-Fmoc

Fmoc is a protecting group that falls off when flushed with a base, so we do so, wash resin, and get

Resin-NH2

Then we can add coupling agent and protected aminoacid, for example leucine, then wash again, and this gets us

Resin-NH-Leu-Fmoc

then repeat. All operations are add reagent or wash solvent, stir, wait, drain, repeat. Deprotection, solvent, coupling, solvent, repeat. It's all very amenable to automation and it was explicitly designed this way. When all is done, resin is treated with acid which releases peptide, and because resin can be washed there are no leftover reagents.

Of course it can be all done by hand, and this allows for doing things like putting a couple of aminoacids on resin on a big scale, then splitting it into a couple of batches and attaching different things on top of that in parallel. Machine can't do this (at least machine like we have). Machine can instead run all of this while hot and this makes it fast, but sometimes things break this way, and also machine can run unattended for more than one shift (when it's not broken). Sometimes things fail to work anyway and it's a job of specialist to figure it out and unfuck it up. Sometimes peptide folds on itself in such a way that -NH2 end is hidden inside and next residue can't be attached. This can be fixed by gluing two aminoacids in flask and then using a pair instead of a single one in machine, bypassing that problematic step. Or in a couple of other different ways, and picking the right one requires knowing what are you doing.

Solution phase synthesis looks different because every step requires purification after it, which is sometimes a thing you can wing and sometimes not. The advantage is that when you need lots of product, you can just use bigger flasks, while bigger machine (and large amounts of resin) gets prohibitively expensive. Ozempic was made in solution (at least once) for example. Again, doing things by hand gets you extra flexibility, because machine can only make peptide from start to finish in single run, but if it's done in solution instead, you can start from, say, five points and then put pieces together (which starts to look like convergent synthesis, and this also makes it better for large scale). Machine can't do that (unless these pieces are provided, but at this point most of the work is done)

Looking back at these people, even when operations are simplified, there's no deskilling of operators that they aimed for, it's just throughput that increases. They also don't have the benefit of that "keeping the important things always in reactor" thing

i can't find that essay now, but i think it was written in latex, and also complained on top of cobol about java, ada (in military context) and a kind of non-programming where block diagram made by non-programmers was turned into executable