[HN Gopher] Nobel Prize in Chemistry Awarded to Bertozzi, Meldal...
___________________________________________________________________
Nobel Prize in Chemistry Awarded to Bertozzi, Meldal, and Sharpless
Author : solarist
Score : 158 points
Date : 2022-10-05 09:48 UTC (13 hours ago)
(HTM) web link (www.nobelprize.org)
(TXT) w3m dump (www.nobelprize.org)
| wrd wrote:
| Former chemist here. I worked in a lab where our main goal was to
| attach a special fluorophore (= fluorescent molecular probe) to a
| protein so we could observe how it changes conformation under
| different conditions. The way we did that was with click
| chemistry: we incorporated a synthetic amino acid
| (homopropargylglycine) into the protein and then used a copper-
| catalyzed click reaction to attach the probe to the synthetic
| amino acid. (Specifically this reaction:
| https://en.wikipedia.org/wiki/Click_chemistry#Copper(I)-cata...).
| It's definitely cool stuff.
| [deleted]
| downvotetruth wrote:
| Talk about an undeserving "click" as if other reactions do not.
| Let's award a patent portfolio. Scripps must be tickled pink.
| twobitshifter wrote:
| This is the second nobel prize for Sharpless. He won in 2001 as
| well.
| ttrrooppeerr wrote:
| No relevant user...surname?
| vixen99 wrote:
| As with Fred Sanger (chemistry) and John Bardeen (physics) who
| also won twice in the same category.
| sizzzzlerz wrote:
| I wonder if, as a child, he was ever told that he wouldn't
| amount to much.
| alpineidyll3 wrote:
| The exception: a well deserved nobel prize.
| tchalla wrote:
| This is the second Nobel Prize in Chemistry awarded to Karl Barry
| Sharpless. In 2001, he was awarded half of the Chemistry prize
| "for his work on chirally catalysed oxidation reactions".
|
| https://www.nobelprize.org/prizes/chemistry/2001/press-relea...
|
| https://en.wikipedia.org/wiki/Karl_Barry_Sharpless
| chrisbrandow wrote:
| he's up to 5/6 of a solo Nobel prize now, since he was
| technically awarded half of his first prize.
|
| I haven't looked yet at how many people have been awarded
| multiple Nobels _in the same field._
| chrisbrandow wrote:
| I guess I should have read the comments below first. :-)
| DrAwdeOccarim wrote:
| For those who are just first learning about click chemistry, it
| makes attaching two larger molecules together very, very simple.
| It can be done under very gentle conditions (like in water), and
| has exceptional selectivity. Like it's so selective you really
| don't need to worry about other things happening on the
| timescales these reactions occur and can be cleaned up (an hour).
| There are two types of click chemistry, one that uses copper as a
| catalyst and one that doesn't. They both opened the world of
| chemically "stapling" two things together to literally all bench
| scientists. I cannot overstate how transformative this has been
| to biological science.
| dmix wrote:
| Do you have an example of some molecules that would be joined
| in an experiment?
| jfarlow wrote:
| Using the above chemistry, you can attach DNA oligos to
| lipids, DNA oligos to proteins, fluorophores to DNA,
| fluorophores to proteins at particular locations or other
| complex drugs to DNA, protein or lipids.
|
| 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.
| hirenj wrote:
| A specific example would describe Bertozzi's work - where
| sugars with a chemical "handle" are installed on to the cell
| surface. You can then click something like a fluorophore onto
| the sugars with handles to figure out where these specific
| sugars are on a cell surface.
| zasdffaa wrote:
| Ah, so we're definitely not talking bolting together the
| little stuff, like pyrrole + benzene ring kind of thing?
| throwawaymaths wrote:
| You can do that (glue together two tiny molecules of
| arbitrary size) but the connector that you get that joins
| the two pieces in the resulting molecule is not
| arbitrary.
| throwawaymaths wrote:
| I'm not aware of any major discoveries that have come about
| from this technique. Can someone correct me?
|
| 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
| [deleted]
| ak_111 wrote:
| This sounds mind-blowing and if it is transformative as you
| state, then why did it take so long to award it the prize, have
| all the most recent previous winners been more worthy?
| throwawaymaths wrote:
| It's very cool but not that transformative. I don't know of
| any major biological discovery that depended on it.
|
| Honestly imo the coolest click chemistry application was as a
| two-component bonding glue for copper pieces
| ak_111 wrote:
| Yeah I think the concept is very cool and probably has lots
| of potential, but the fact that not even most scientists I
| know have heard of it implies that is yet a niche area that
| hasn't yet had a major impact in applications.
| wholinator2 wrote:
| It can sometimes take a long time to get a prize awarded.
| Like I believe Einstein didn't get his prize for years and
| years after he discovered Relativity and even when they
| awarded it to him it was only for the photo electric effect,
| which while important, wasn't perceived as his largest
| contribution
| btilly wrote:
| He didn't get it for relativity in part because of a well-
| known philosopher.
|
| See https://nautil.us/this-philosopher-helped-ensure-there-
| was-n... for the story.
| dekhn wrote:
| "only" for the photoelectric effect?
|
| 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.
| ceejayoz wrote:
| That's entirely normal.
|
| 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.
| coolspot wrote:
| Can it simplify DIY drug/explosive production?
| chrisbrandow wrote:
| I guess it depends on your definition of DIY.
|
| 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.
| tgv wrote:
| You mean: LEGO-like chemistry? Wow, I'd never heard of that.
| Any info on how and what-for it's used in practice?
| j7ake wrote:
| For example, attaching fluorophores to molecules so you can
| track them in a microscope.
| lepetitpedre wrote:
| Of course a Danish person got LEGO into chemistry
| [deleted]
| hoseja wrote:
| Poor balding Morten, that is a very unflattering portrait.
| MagnumOpus wrote:
| Not that much off the mark:
| https://www.ki.ku.dk/Nyheder/Nyhedssamling/crystal_ball_15/N...
| dmix wrote:
| That's a much nicer photo IMO. It just seems very accentuated
| when it's drawn with hard lines.
| netrus wrote:
| The portraits are usually based on the first nice looking
| picture in the Google Image search. In Morten's case they
| appear to have mirrored it :)
| dom96 wrote:
| I disagree. I think it's a cool illustration and he looks good
| in it.
| boomboomsubban wrote:
| That was my first thought, and then I was amazed at how
| dominant the Nobel photo was in a DDG image search 30 minutes
| after it was announced. Now a few hours later and it's only
| Nobel affiliated pictures in the first ~50.
| nh23423fefe wrote:
| I'm sure he is crying about it on instagram
| COGlory wrote:
| People are missing the point. It's not the click that matters.
| It's the bio-orthogonal part.
|
| 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.
| throwawaymaths wrote:
| What "different click substrates" are you talking about? As far
| as I remember There's only one class that's been developed
| (alkyne azide cycloaddition) -- sharpless really wants
| norbornene to take off but no one has developed that afaict -
| and of these only one that can be done in vivo (cyclooctyne +
| azide); the others require copper catalyst which is not awesome
| for living cells.
|
| > ... 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.
| sdbrown wrote:
| Tetrazine/DBCO is also pretty popular IIRC.
| throwawaymaths wrote:
| Fair. This holds a place in my mind as "basically the same
| as alkyne - azide" since Tetrazzine is "more or less azide"
| and dbco is "more or less cyclooctyne". More to the point
| of the thread, I don't think the Tetrazzine/dbco is
| orthogonal to alkyne-azide -- they will cross-react -- am I
| wrong about that?
| elsjaako wrote:
| This sounds like a very interesting technique. Does anyone know
| of a Scientific American level explanation that goes into a bit
| of depth about this?
| ranguna wrote:
| > Scientific American level explanation
|
| Imagine lego, but with chemistry.
| amelius wrote:
| More like: imagine chemistry, but with marketing speak.
| ryan93 wrote:
| Multiple people are having the reaction you are. Is this
| considered undeserved in the chemistry world?
| toufka wrote:
| It seems "simple" from a chemistry perspective. But as
| pointed out, the special part is that this is simple
| chemistry, _that also works in standard biological
| conditions_ without harming biology: bio-orthogonal. So
| it allows complex chemistries to be brought into
| biological contexts easily and completely. So the
| discoveries made with this novel chemistry will be
| biological in nature. That makes for an awkward audience
| when one is siloed either on the chemistry side or the
| biology side and can't quite see how much of a door is
| opened when you combine the disciplines.
| xkcd-sucks wrote:
| Now many years ago, I was in a chemical biology lab (=
| interrogating/modifying "biology" with "chemical" tools,
| half organic synth half pharma/bio) around the time that
| the term "click chemistry" became popular, and the PI got
| really fired up about it. Lots of other lab groups in
| adjacent departments were also really fired up about it.
|
| 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.
| lmz wrote:
| https://www.nobelprize.org/uploads/2022/10/popular-chemistry...
| is linked from the page
| subroutine wrote:
| Wikipedia article:
|
| https://en.wikipedia.org/wiki/Click_chemistry
| FrasiertheLion wrote:
| https://www.quantamagazine.org/molecule-building-innovators-...
___________________________________________________________________
(page generated 2022-10-05 23:02 UTC)