Hacker News Board Hacker News, browsed like a classic message board
Live data from Hacker News

We Made One Gram Of Remdesivir

acsh.org

Post reply on HN
Print view View original

161–170 of 236 posts

Re: We Made One Gram Of Remdesivir

#161

Post by koboll »

kccqzy wrote: 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…

This is such a great description. Compare how Wikipedia describes the same process [https://en.wikipedia.org/wiki/Adenosine#Research]:

> The adenosine analog NITD008 has been reported to directly inhibit the recombinant RNA-dependent RNA polymerase of the dengue virus by terminating its RNA chain synthesis. This interaction suppresses peak viremia and rise in cytokines and prevents lethality in infected animals, raising the possibility of a new treatment for this flavivirus.

Absolute gibberish to someone with limited knowledge of biology.

Re: We Made One Gram Of Remdesivir

#162

Post by djaque »

cushychicken wrote: post #119
djaque wrote: 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?

I'm in accelerator physics. Basically we study the physics of charged particle beams with the goal of improving their properties/developing new applications. I thought it was the perfect combination of engineering, which I like, with pure physics.

Re: We Made One Gram Of Remdesivir

#163

Post by HarryHirsch »

ashildr wrote: post #74
kccqzy wrote: 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…

This mode of action is fascinating, some HIV medications work in a similar way. What I’m curious about is why this huge group attached to the adenosine-like group is needed. It seems to be rather complex for being a shoe to be thrown into cellular gear. Do you have an idea or pointer into the mode of action of this group?

The observation is correct. Remsedivir is a prodrug, the active compound looks like adenosine monophosphate. But that molecule bears too much charge to be able to cross cell membranes. Consequently medicinal chemists put protecting groups on the offending atom, to help the compound get out of the bloodstream and into cells. Once inside, those are cleaved off through nonspecific esterases and the molecule can't get back out.

It's all part of ADMET (absorption, distribution, metabolism, excretion and toxicity) optimization. Pharmacokinetics is an important subject, and that's why you can use the "XY shoved activity in vitro" papers only as starting points.

Re: We Made One Gram Of Remdesivir

#164

Post by djaque »

joshvm wrote: post #148
cushychicken wrote: post #119

Earlier quoted context omitted.

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. Th…

Exactly, the instruments I was talking about are used to measure the properties of photocathodes. It's such a niche field that there's no off the shelf solution. Everybody makes their own device and ours is one of like two in the world with it's grade of sensitivity.

There is one professional engineer in the lab my group is a part of, but they primarily work on the bigger projects. For this, I have to do all of the CAD work and talking to the machinists. I also machined a lot of the parts myself due to time constraints.

Re: We Made One Gram Of Remdesivir

#165

Post by michaelt »

darawk wrote: post #91
djaque wrote: post #84

Earlier quoted context omitted.

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…

> 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…

If the theory says it's possible to juggle five chainsaws but nobody's managed to demonstrate it, and I try it without success, have I proven it impossible? Or have I just proven I'm not good a enough juggler?

Re: We Made One Gram Of Remdesivir

#166

Post by mattkrause »

yjftsjthsd-h wrote: post #45
barkingcat wrote: post #18

Earlier quoted context omitted.

If 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.

So... 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?

You do get paid, though not very much ($15-30k for a PhD student, $40-65k for a postdoc), especially compared to a tech salary. The uncertainty is a lot higher too.

As for why people work at those salaries, there's more to life than money. Discovering stuff is fun and working on stuff that really helps people (not in the "expensive subscription juice service" sort of way) is rewarding. People teach for the same reason.

OTOH, taking a job at these wages is a luxury and chases good people out of the field. My spouse and I are both academic research scientists, but anything happens to one of us, the other's out ASAP.

Re: We Made One Gram Of Remdesivir

#167

Post by dguest »

tralarpa wrote: post #81
dguest wrote: post #70

Earlier quoted context omitted.

In point 3: did you try to contact the authors of the paper you were trying to reproduce? I don't know organic chemistry, but in my field the authors are often willing to discuss their results, especially if it might mean more citations for them.

May I ask what your field is? Is it CS? I am asking because we computer scientists are sometimes a little bit naive when it comes to research and publications. In other fields, like pharmaceutics, where future patents can be worth hundreds of millions of dollars, authors are very careful what they tell others.

> May I ask what your field is?

Collider physics. I'm guessing that a lot of the less applied sciences are the same way: we're looking for fundamental laws so it's more about convincing people that your result is valid than about trying to make money off of some application.

It's very hit or miss of course: there are still some groups that act very secretive and some that are more open.

Re: We Made One Gram Of Remdesivir

#168

Post by BurningFrog »

djaque wrote: post #159
BurningFrog wrote: post #150

Earlier quoted context omitted.

Yet another example of how 2020 institutional science is broken. For the purpose of producing knowledge. It does other things.

Could you please explain why you think this means science is broken? There are real issues in academia, but I disagree that what happened here is wrong. We did publish our data, we just didn't do it in a journal article. In my fields, this is actually fairly typical and journals are less of the norm unless you have a big result. The whole problem is that extraordinary claims require extraordinary evidence. Sometimes…

> Could you please explain why you think this means science is broken?

To be precise, I already think science is broken, and your story seemed to confirm it.

Obviously, that "this is actually fairly typical" is not a counterargument to a systemic belief.

That said, it's entirely possible I jumped the gun here.

I take the reproducibility crisis to be a strong indicator that something is Very Wrong with science. I'm also convinced that the modern peer review system is fundamentally broken.

Re: We Made One Gram Of Remdesivir

#169

Post by IanCal »

ebg13 wrote: post #3

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

I had the same thought, this is wonderfully written. Detailed but accessible for a technically inclined lay audience, fun but not over the top. It's extremely hard to do, so well done and thanks to the author :)

Re: We Made One Gram Of Remdesivir

#170

Post by mattkrause »

auxym wrote: post #123
yjftsjthsd-h wrote: post #45

Earlier quoted context omitted.

So... 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?

That's why I'm clueless at all the politicians and journalists claiming we have a STEM shortage, we need to boost STEM education, need more kids interested in STEM careers... STEM = science technology engineering math CS/software has huge demand and salaries to go with it (yay, ads) Traditional (civil/mech/ee/chem/etc) engineering is OK. You'll never be rich but you'll always be comfortable. (I've had plumbers claim…

It's even worse....

The solutions to the "STEM shortage" are usually to ramp up training (BS/MS/PhD students, occasionally postdocs), without actually creating viable jobs for these folks when they finish. Many smart people don't want to get involved in a cutthroat job market, so either leave the field or never enter it. (The people who "left" science from my grad school cohort were all very smart; almost all of them could have cut it)

Meanwhile, cutting-edge research is mostly done by trainees who are learning as they go. This is important--we need future scientists as well as current ones--but it limits the projects and pace of research.

This is totally fixable too--fund more staff scientist positions and dial down the number of trainees. The NIH funds thousands of studentships and just a few (~50?) "research specialists."

Post reply on HN