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We Made One Gram Of Remdesivir

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Re: We Made One Gram Of Remdesivir

#141

Earlier quoted context omitted.

As an IT guy, I am wondering why this is still a mostly manual and rather dangerous process. Surely programmable machines can be built to process reagents in a safe and flexible way?

This is especially true since the number of possible "instructions" is pretty low. Heat it, cool it, mix it, filter it, centrifuge it, compress it, take a sample and put it through a test instrument. Pretty much all chemistry is some sequence of the above.

But your number of inputs is huge, and cleaning steps in between others in a reusable/reconfigurable machine is a difficult challenge to overcome all on its own. It’s not impossible and smart people are working on it, but it is incredibly hard.

Re: We Made One Gram Of Remdesivir

#142
post #9
post #3

The writing is so good, I had to double check that it wasn't written by Derek Lowe.

Here's his most famous article on FOOF (Dioxygen Diflouride) https://blogs.sciencemag.org/pipeline/archives/2010/02/23/th... It seems there are multiple chemist-author hybrids out there!

“sand won’t save you this time” is also excellent. https://blogs.sciencemag.org/pipeline/archives/2008/02/26/sa...

“i always recommend a good pair of running shoes”, indeed.

Re: We Made One Gram Of Remdesivir

#143
post #13
post #9

Earlier quoted context omitted.

Here's his most famous article on FOOF (Dioxygen Diflouride) https://blogs.sciencemag.org/pipeline/archives/2010/02/23/th... It seems there are multiple chemist-author hybrids out there!

At seven hundred freaking degrees, fluorine starts to dissociate into monoatomic radicals, thereby losing its gentle and forgiving nature. Gentle and Forgiving nature...

We used to do this under pressure in heavy-walled alloy cylinders being irradiated with megawatts of microwave energy behind a blast shell facing into the deep woods at the far end of the specialty fluorochemical research plant.

Re: We Made One Gram Of Remdesivir

#144

Earlier quoted context omitted.

I'm a controls engineer. We're very good at making machines that will do a single process over and over. It's insanely difficult to do arbitrary processes with one machine.

Hi, That is a very good question. In my PhD I built, among other things, a very primitive parallel stirring system in order to speed up the synthesis of test batches. Although a very crude device, there was tons of stuff that I needed to optimize. There are many steps in the practical work that is chemical synthesis. It might be removing air, adding reagents in different elemental states, cooling/heating/keeping and…

[deleted]

Re: We Made One Gram Of Remdesivir

#145
post #22

Remdesivir 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 i…

There has been exciting work on directed evolution of enzymes for drug synthesis, particularly for transamination (conversion of a ketone to an amine). This is I believe being used commercially now, for example for the production of the diabetes drug sitagliptin.

https://blogs.sciencemag.org/pipeline/archives/2010/10/06/ch...

https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002...

Re: We Made One Gram Of Remdesivir

#146
post #91

Earlier quoted context omitted.

> My advisor's explanation on publishing was that if we had great results that followed our initial theory of what's going on then we could write a paper and nobody would question it. But, now that we contradict theory the threshold of evidence is much higher and he doesn't want to go ahead with it. Isn't that sort of the most important thing to publish? Something that contradicts theory means something new. Seems li…

In a vacuum yes. In the world of academia and its perverse incentives, no. Publishing something that goes against the grain means a lot more scrutiny on your work and bigger humiliation for any mistakes made. If you're publishing against the grain, you have to double triple check every single detail to make sure it's all iron-clad. This costs a lot of additional time and money. When publishing research that preaches…

Really academia needs a way to request comment on an experimental procedure without requiring results or conclusions. Then you could publish negative or questionable results and seek speculation from other researchers.

Re: We Made One Gram Of Remdesivir

#147
post #102
post #22

Remdesivir 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 i…

Out of curiosity: We seem to have a very good understanding how synthesis in biological processes works (from DNA to the eventual molecules), we are able to create DNA/RNA molecules with arbitrary content and we're increasingly able to simulate what molecule a particular nucleotide sequence would produce. So, putting the three together, would it be possible to use actual biosynthesis for designed molecules by basical…

in theory it's possible, in practice it's not. DNA encodes the information on how to produce to proteins. Proteins can catalyze chemical reactions. But there's no straightforward to look at a nucleotide sequence and figure out what it's corresponding protein does. Nor can we design proteins with arbitrary functions.

The entire thing is so unimaginably complex. For example, for a lot proteins that are catalysts (aka enzymes) the actual catalytic part is a metal ion and the protein mostly provides scaffolding. A nucleotide sequence alone doesn't directly tell you what ion is needed. In some cases, multiple ions can fit, but only one actually results in the protein work. This the basis for how a lot of toxic metal exert their toxic effects.

It's also not as simple as a nucleotide sequence codes for a protein and that's it. Proteins fold into their final shape from the chain of amino acids that DNA encodes. Protein folding in general is a hard problem. Biological proteins may have other proteins (called chperonins) that help them fold into their proper configuration. Then proteins may also be modified after they've folded (again by other proteins). Some proteins are made up of multiple sub-units as well.

Re: We Made One Gram Of Remdesivir

#148
post #79

Earlier quoted context omitted.

Thanks, that's good to hear. Fortunately I do have two papers in the works right now, one of them from an instrument I made and another from some simulation work. The engineering really is the crux of the problem. I personally find it very interesting and I feel like an oddity in my department for that. Most other physicists kind of look down on the "e-word" to the point that my advisors made me change references to…

What field would you go into if you were interested in making instruments for scientific research? Would that be engineering physics?

Instrumentation is field-specific. It really depends how bespoke your requirements are. Some places buy stuff off the shelf, others fabricate in-house.

In astronomy it's called instrumentation. Astro has relatively sane nomenclature. You have observational (looking at stuff and gathering data), theoretical (theory and simulations) and instrumentation (building stuff). Everyone in the field understands those terms. That said, instrumentation spans everything from construction, design, calibration/characterisation, etc.

In other branches, as the OP pointed out it may be "experimental" physics. Problem with that term is it's extremely vague. That's essentially anything which doesn't involve theory or simulation - lab work. That doesn't necessarily mean you actually build anything though. I was surprised at how little we got taught about instrumentation during my physics degree. Of course we had labs, but it was more about using kit than how it was built. It's almost as if it's someone else's problem, even though that's not how research actually works.

The irony of physicists sneering at engineers is that most labs employ a bunch of them who do most of the actual design and build work. They tend to be less focused on publication, but they are absolutely critical employees. The sorts of people who've spent 20-30 years working on some uber niche detector tech and know more than the people writing the papers for sure. A good chunk have physics PhDs.

When you get to big money stuff like particle accelerators and telescopes, a lot of this is contracted out. Physicists and engineers are responsible for designing the spec, but it's less tinkering in a lab with hardware. In industry it's mostly called engineering (e.g. optical, mechanical, electrical), but I've seen engineering physics too. That tends to be in companies that build very niche equipment specifically for physics research.

Re: We Made One Gram Of Remdesivir

#149

One 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.

It’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.

No 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.

Re: We Made One Gram Of Remdesivir

#150
post #84
post #73

Earlier quoted context omitted.

What branch of physics? There are hundreds of published null results looking for dark matter or Supersymmetry, for example. Instead of documenting a failed search, the papers focus on what versions of the theories the experiment excludes to 95% confidence.

I'm in acceleraror physics and study photocathodes. Unfortunately the state of those projects is that we thought a material should have great photoemission properties under some very specific circumstances. When we measured it, the material was actually terrible and we don't understand why it's that way outside of some speculation. Unfortunately it also feels like our lab doesn't have the type of expertise to explain…

Yet another example of how 2020 institutional science is broken.

For the purpose of producing knowledge. It does other things.

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