Nobel Prize in Chemistry Awarded to Bertozzi, Meldal, and Sharpless
nobelprize.org
nobelprize.org
I'd accept:
- elucidating a new signal transduction pathway
- discovering an uncharacterized enzyme
- measuring a biochemical constant of a known molecule (Kd e.g.)
- discovering a new drug target that then gets exploited
Once you get DNA oligos in there you can do computation, as X binds X', and Y to Y'. So you can have all sorts of complex synthetic & designed interactions using chemistry that is both seamless and doesn't interfere with normal molecular biolgy.
Once you have proteins, you can localize particular chemistries.
See https://nautil.us/this-philosopher-helped-ensure-there-was-n... for the story.
That was one of the most fundamental scientific discoveries (well, explanation for an unexpected failure of theory to predict experiment) of all time. In particular, the idea of wave packets replacing particle and wave representations was quite helpful.
https://www.nature.com/articles/508186a
> Before 1940, Nobels were awarded more than 20 years after the original discovery for only about 11% of physics, 15% of chemistry and 24% of physiology or medicine prizes, respectively. Since 1985, however, such lengthy delays have featured in 60%, 52% and 45% of these awards, respectively.
Honestly imo the coolest click chemistry application was as a two-component bonding glue for copper pieces
It's not new, so if someone didn't already know about it, then they are probably unlikely to be in a position to take advantage of it, because it is already how a lot of synthesis in this field is done.
This lets me grow cells with one of the click substrates, say, a methionine substitute that incorporates into every protein, purify out my protein, and then easily do chemistry on that. That's near invaluable.
I can grow a virus and put a different click substrate in each of the DNA, protein, and lipids. Then I can infect cells, and mid-infection, separately label each macromolecule a different color. Then, I can figure out what parts of the virus go into the cell, which sheds light on the mechanism of entry.
Having it bio-orthogonal means the biology is preserved and nothing is messed up until the moment of observation.
> ... methionine substitute that incorporates into every protein, purify out
This is crazy labor intensive, I feel like if you are at this point in considering using this to understand a biological you have really burned through a lot of simpler, more established, and easy to calibrate techniques.
I can click on a strep tag, or a his tag, or a fluorophore of any different color. See: https://clickchemistrytools.com/
Yes, they are all the same chemical addition, but I can label them orthogonally. I can incorporate an azo-amino acid, and click a green alkyne. I can incorporate an alkyne nucleotide, and click a blue azide, etc.
>This is crazy labor intensive, I feel like if you are at this point in considering using this to understand a biological you have really burned through a lot of simpler, more established, and easy to calibrate techniques.
I don't think you are understanding what I'm saying here. What are you saying is labor intensive, purifying protein? That's an incredibly common technique. Yes it's labor intensive, but it's the only way to do huge amounts of experiments. If you're saying click chemistry is labor intensive, well, you're wrong, it's a couple hour experiment, most of which is waiting for incubations.
https://www.nobelprize.org/prizes/chemistry/2001/press-relea...
I haven't looked yet at how many people have been awarded multiple Nobels in the same field.
Imagine lego, but with chemistry.
Side note, "click chemistry" is kind of a marketing term in that it describes a process for modular assembly of moieties in one step in "biocompatible" conditions i.e. water without much poison in it, but which doesn't actually describe how to do that.
The first realization of this vision (or at least the first previously discovered system described as click chem) was copper catalyzed azide-alkyne cycloaddition, and for quite a while this was the only "click" reaction.
Omitting for brevity all the things that were attempted and reasons for doing so as they've been elaborated elsewhere in sibling threads, it was basically impossible to get anything working on/in actual living cells (or "embalmed" cells) although the "click" reaction worked fine in isolation. The parameter space here is pretty big; pharmacology of the things, copper concentration, temperature, time, doing all kinds of things to the cells, and we never figured it out, so it's tricky to find a root cause. One failure mode seemed to be that the copper catalyst caused protein aggregation and the labels being added stuck to the aggregates better than they stuck to the "click handle" alkyne, and there were other failure modes more related to pure pharmacology that probably also contributed (e.g. when the drug sticks to the target it does so in a position that blocks the alkyne "click handle" from being accessible). It was also impossible to reproduce a lot of high profile click labeling papers.
That point now seems like the trough of the hype cycle, so to speak. Apparently Bertozzi's subsequent work with strain promoted cycloadditions (= no protein-aggregating copper) is much more useful.
I'm guessing other people with negative commentary got burned by the early promises of click chem in the real world -- Also, that Sharpless got it for an abstract "product vision" (the award is because "he coined the concept of click chemistry, which is a form of simple and reliable chemistry"), Meldal got it for the CuAAC reaction which actually sucks for biology, and Bertozzi's work doesn't stand on its own.
The site is pretty confusing thought, I don't think I could have found it myself. Now I know the link exists I can find it, but I think putting it behind a dropdown on a box labeled "Summary", and labeling it "Popular Chemistry" isn't great for having people find it.