[HN Gopher] Chemistry Nobel: Computational protein design and pr...
       ___________________________________________________________________
        
       Chemistry Nobel: Computational protein design and protein structure
       prediction
        
       Author : mitchbob
       Score  : 471 points
       Date   : 2024-10-09 09:54 UTC (13 hours ago)
        
 (HTM) web link (www.nobelprize.org)
 (TXT) w3m dump (www.nobelprize.org)
        
       | nialv7 wrote:
       | People joked maybe the Nobel committee is holding some AI stocks.
       | Now I start to wonder if that is true...
        
         | ramraj07 wrote:
         | This is legitimately deserved though.
        
           | nialv7 wrote:
           | These two aren't mutually exclusive.
        
             | mr_mitm wrote:
             | It does make the first speculation a whole lot less
             | plausible though
        
         | astrange wrote:
         | Maybe the transformers authors will win Literature.
        
           | joelthelion wrote:
           | They are indeed the largest contributors of new books
           | published on Amazon...
        
           | Ekaros wrote:
           | I would actually not even be mad. After all it is fundamental
           | change in production of literature works.
        
         | InkCanon wrote:
         | Next up: The Nobel peace prize is awarded to ChatGPT, because
         | virtually all communiques and peace treaties will be generated
         | by lazy lawyers.
        
         | seydor wrote:
         | The opposite would be less likely nowadays
        
       | paulwetzel wrote:
       | While I am skeptical about yesterdays award in physics, these are
       | totally deserved and spot on. There are few approaches that will
       | accelerate the field of drug development and chemistry as a whole
       | in a way that the works of these three people will.
       | Congratulations!
        
         | ackbar03 wrote:
         | I was just wondering when they were going to award the
         | alphafold2 guys the nobel after after seeing Hinton win the
         | physics one. 100% agree, all three of them totally deserve this
         | one. Baker's lab is pretty much keeping Deepmind in check at
         | this point and ensuring open source research is keeping up.
         | Hats off
        
           | theGnuMe wrote:
           | Baker has been in the protein folding game for a long time
           | and was the leader before Alphafold came in... His generative
           | paper came out what last year (2023)?
           | 
           | I mean this is a fast award cycle.
        
             | divbzero wrote:
             | David Baker's RoseTTAFold was first released in 2021.
             | 
             | [1]: https://www.science.org/doi/10.1126/science.abj8754
             | 
             | [2]: https://cen.acs.org/analytical-chemistry/structural-
             | biology/...
        
         | tomp wrote:
         | Are they? What did Demis do?
        
           | world2vec wrote:
           | He's founder and CEO of the AI lab that build Alphafold?
        
             | devilzhong wrote:
             | Then maybe Sergey and Larry should also get the prize since
             | they founded Google, which owns Deepmind?
        
               | world2vec wrote:
               | They were not equal contributors to the seminal paper
               | that got the prize. From another post in this thread:
               | 
               | "These authors contributed equally: John Jumper, Richard
               | Evans, Alexander Pritzel, Tim Green, Michael Figurnov,
               | Olaf Ronneberger, Kathryn Tunyasuvunakool, Russ Bates,
               | Augustin Zidek, Anna Potapenko, Alex Bridgland, Clemens
               | Meyer, Simon A. A. Kohl, Andrew J. Ballard, Andrew Cowie,
               | Bernardino Romera-Paredes, Stanislav Nikolov, Rishub
               | Jain, Demis Hassabis"
        
               | theGnuMe wrote:
               | They bought it and it runs autonomously (or did mostly)
        
           | onursurme wrote:
           | He writes software in different areas, so he has the
           | potential to get a Nobel prize in any area soon.
        
           | seydor wrote:
           | didn't he lead early successes in RL which popularized it and
           | culminated in protein prediction?
        
         | cowsandmilk wrote:
         | Both Rosetta and DeepMind have made contributions outside of
         | protein structure prediction that are far more important for
         | drug discovery.
        
         | mihaaly wrote:
         | The physics prize should have went to Elon Musk!
         | 
         | Also I really hope the Nobel Prize of Economics goes to Bill
         | Gates! He facilitated sooo much advances by releasing Excel
         | that this must be recognized!
         | 
         | And based on this year's announcements so far I am not sure
         | that my sarcastic comments should be taken as a joke!
        
           | theGnuMe wrote:
           | Except Excel has introduced way to many bugs and how many
           | people has it killed?
        
         | trott wrote:
         | > There are few approaches that will accelerate the field of
         | drug development and chemistry as a whole in a way that the
         | works of these three people will.
         | 
         | As the author of one such approach, I'm skeptical.
         | 
         | AlphaFold 2 just predicts protein structures. The thing about
         | proteins is that they are often related to each other. If you
         | are trying to predict the structure of a naturally occurring
         | protein, chances are that there are related ones in the dataset
         | of known 3D structures. This makes it much easier for ML. You
         | are (roughly speaking) training on the test set.
         | 
         | However, for drug design, which is what AlphaFold 3 targets,
         | you need to do well on actually _novel_ inputs. It 's a
         | completely different use case.
         | 
         | More here: https://olegtrott.substack.com/p/are-alphafolds-new-
         | results-...
        
           | jhbadger wrote:
           | Protein structures are similar to each other because of
           | evolution (protein families exist because of shared ancestry
           | of protein coding genes). It's not a weird coincidence that
           | helps ML; it's inherent in the problem. Same with drug design
           | -- very, very, few drugs are "novel" as opposed to being
           | analogues of something naturally in the body.
        
             | svara wrote:
             | They're referring to the structure of the protein when a
             | drug is bound, that's what's novel. Novel as in, you can't
             | think of it as "just" interpolation between known
             | structures of evolutionarily related proteins.
             | 
             | That said I'm not sure that's entirely fair, since
             | Alphafold does, as far as I know, work for predicting
             | structures that are far away from structures that have
             | previously been measured.
             | 
             | You're quite wrong about small molecule drug structures.
             | Historically that has been the case but these days many
             | lead structures are made by combinatorial chemistry and are
             | not derived from natural products.
        
               | jhbadger wrote:
               | But even drugs made by combinatorial chemistry still
               | generally end up being analogues of natural products even
               | if they aren't derived from them. As Leslie Orgel said
               | "Evolution is cleverer than you are"; chemists are
               | unlikely to discover a mechanism of action that millions
               | of years of evolution hasn't already found.
        
               | adastra22 wrote:
               | > Alphafold does, as far as I know, work for predicting
               | structures that are far away from structures that have
               | previously been measured.
               | 
               | It did very poorly at this last time I checked. Maybe
               | AlphaFold3 is better?
        
             | trott wrote:
             | > It's not a weird coincidence that helps ML; it's inherent
             | in the problem.
             | 
             | This depends on the application. If you are trying to
             | design new proteins for something, unconstrained by
             | evolution, you may want a method that does well on novel
             | inputs.
             | 
             | > Same with drug design
             | 
             | Not by a long shot. There are maybe on the order of 10,000
             | known 3D protein-ligand(drug) structures. Meanwhile, when
             | doing drug discovery, people scan drug libraries with
             | millions to billions of molecules (using my software,
             | oftentimes). These molecules will be very poorly
             | represented in the training data.
             | 
             | The theoretical chemical space of interest to drug
             | discovery is bigger still, with on the order of 1e60
             | molecules in it:
             | https://en.wikipedia.org/wiki/Chemical_space
        
       | rswail wrote:
       | The physics prize was a stretch of the definition of the word
       | "physics", but this one is purely about chemistry.
        
         | onursurme wrote:
         | Not purely. It includes a software development about Chemistry.
        
           | seydor wrote:
           | every science includes software development for a few decades
           | now
        
       | gilleain wrote:
       | David Baker (and colleagues) have always done good work. I guess
       | google have done some things also.
       | 
       | (lol - one of the PDF attachments to that page is 'Illustration:
       | A string of amino acids' : actually it's a bit better than the
       | title implies :).
       | 
       | Actually, Figure 2 - "How does AlfaFold2 Work?" is impressive to
       | fit that on one page. Nice.
        
         | exmadscientist wrote:
         | It is well known around here that Baker does very, very little
         | of the work. He is extremely good at putting his name on his
         | students' work though (this is par for the course in
         | academia)... and removing theirs (this is the bad part). At
         | least he bribes them with lots of happy hours!
        
           | stanford_labrat wrote:
           | username...checks out
        
       | alexmolas wrote:
       | And the literature Nobel will go for ChatGPT
        
         | andy_ppp wrote:
         | Eventually, potentially 10 years away if we continue to see
         | improvements.
        
           | og_kalu wrote:
           | Yes eventually GPT itself may be capable of winning a Nobel
           | off its own writing but before then..the authors of the
           | Transformer might win one ? Certainly seems a lot more
           | plausible now.
        
         | throw310822 wrote:
         | Haha, wrote the exact same.
        
       | gizajob wrote:
       | Whoa. Happy for Demis today. Amazing achievement.
        
       | joelthelion wrote:
       | Did Demis Hasabis actually do any scientific work himself?
        
         | FL33TW00D wrote:
         | I mean he took the risk and founded DeepMind?
        
           | belter wrote:
           | So then Mustafa Suleyman and Shane Legg will want a Nobel
           | also?
        
         | onursurme wrote:
         | He is a chemist now.
        
         | seydor wrote:
         | Yes in neuroscience. But i guess this one is recognition for
         | leading efforts in RL which culminated in this.
        
       | sikimiki wrote:
       | Well deserved! Especially for Alphafold. It is the most impactful
       | invention in structural biology this century along with Cryo-EM.
        
         | onursurme wrote:
         | It doesn't deserve a Chemistry Nobel prize. It deserves a prize
         | about computers.
        
           | seydor wrote:
           | physiology&medicine more likely
        
           | Mklomoto wrote:
           | So the Nobel commite was wrong to decide this because you
           | think otherwise?
           | 
           | Interesting. Any more indepth analys about this?
           | 
           | Btw. you don't just build AlphaFold by doing only
           | 'computers'. Take a look at any good docmentary about it and
           | you will see that they do discuss chemistry on a deep level
        
         | swyx wrote:
         | tldr on Cryo-EM?
        
       | proto-n wrote:
       | Now this one makes more sense. Chemistry Nobel for advancing
       | chemistry using AI.
       | 
       | Contrast that with Phyics Nobel for advancing AI using physics.
        
         | Muller20 wrote:
         | AlphaFold is also a high impact discovery, while Hopfield
         | networks have very little to do with modern AI and they are
         | only a very interesting toy model right now.
        
       | lennertjansen wrote:
       | well deserved
        
       | aborsy wrote:
       | The AlphaFold paper has countless authors, many researchers and
       | company resources underlying it. Hassabis' contribution is
       | management of resources and entrepreneurship, not the actual
       | science. There are hundreds of thousands of scientists out there
       | doing deep technical work, and they aren't recognized.
       | 
       | I think we might be the end of it, as the emphasis shifts to
       | commercialization and product development.
       | 
       | These AI demonstrations require so many GPUs, specialized
       | hardware and data that nobody has but the biggest players.
       | Moreover, they are engineering work, not really scientistic
       | (putting together a lot of hacks and tweaks). Meanwhile, the
       | person who led the transformer paper (a key ingredient in LLMs)
       | hasn't been recognized.
       | 
       | This will incentivize scientists to focus on management of other
       | researchers who will manage other researchers who will produce
       | the technical inventions. The same issue arises with citations
       | and indices, and the general reward structure in academia.
       | 
       | The signal these AI events convey to me: You better focus on
       | practical stuff, and you better move on in the management ladder.
        
         | world2vec wrote:
         | Hasn't it always been like that? The lab director gets to
         | receive the prize, not the whole team (which could have
         | hundreds or thousands of people).
        
         | bonoboTP wrote:
         | The Nobel prize is aimed at the general public. It has a kind
         | of late 19th century progressive humanistic ethos. It's science
         | outreach. This way, at least once a year, the everyday
         | layperson hears about scientific discoveries.
         | 
         | The Nobel isn't a vehicle to recognize hundreds of thousands of
         | deeply technical scientific researchers. How could it be? They
         | have to pick a symbolic figurehead to represent a breakthrough.
         | 
         | They could also simply give it to "DeepMind" similar to how
         | they give the peace prize to orgs sometimes, or how the Time
         | Person of the Year is sometimes something abstract as well
         | (like the cutesy "You" of 2006). But it would be silly. Just
         | deal with it, we can't "recognize" hundreds of thousands, and
         | we want to see a personal face, not a logo of a company getting
         | the award. That's how we are, better learn to deal with it.
        
           | dsign wrote:
           | > The Nobel prize is aimed at the general public...
           | 
           | Which is okay. The Nobel prize is okay.
           | 
           | > This way, at least once a year, the everyday layperson
           | hears about scientific discoveries.
           | 
           | Spot on.
           | 
           | The problem we have is that the everyday layperson hears very
           | little about scientific discoveries. The scientists
           | themselves, one in a million of them, can get a Nobel prize.
           | The rest, if they are lucky, get a somewhat okay salary.
           | Sometimes better than that of a software engineer. Almost
           | always worse working hours.
           | 
           | But I suppose it's all for the best. Imagine a world where a
           | good scientist, one that knows everything about biology and
           | protein folding, gets to avoid cancer and even aging, while
           | the everyday layperson can only go to the doctor...
        
             | madmask wrote:
             | That would be a good incentive to become a good scientist
        
             | mrguyorama wrote:
             | At least one American Nobel laureate has had to sell his
             | nobel prize medal to pay for medical costs in their old
             | age.
             | 
             | Just insane.
        
             | adw wrote:
             | > Sometimes better than that of a software engineer
             | 
             | There is a reason so many of us work as software engineers
             | now; I earn about 5x more than I would as a university
             | lecturer/assistant professor.
        
         | pyb wrote:
         | The paper has a mention : "These authors contributed equally:
         | ..."
         | 
         | However, it appears that some the authors were more equal than
         | others.
        
           | falcor84 wrote:
           | The Nobel prize isn't awarded for a paper. Even if (and
           | that's a large if) all of these contributed equally to the
           | results in the paper, some obviously did more than others to
           | prepare the ground for that study.
        
         | mhandley wrote:
         | The Nobel prize cannot go to a team so they have to pick
         | individuals. This is true for many (most?) nobel prize awards.
         | Consider for example the discovery of gravity waves - the team
         | that built and operated LIGO was huge, but they have to pick.
         | This has commonly been the case since the inception of the
         | prizes - the professor gets the prize, the PhD students and
         | postdocs don't usually. Not saying this is right, but it's the
         | way it is.
        
           | elashri wrote:
           | For gravitational waves discovery, Nobel prize went to the
           | designers of the LIGO which was done long before we actually
           | built it. The example that will fit more your idea would be
           | Carlo Rubbia who got the award in 1984 for leading the CERN
           | team who discovered the W and Z bosons. He did not have any
           | contributions than leading the experiment that did it [1]. It
           | is not like he designed or proposed the way we used to detect
           | them. And the Nobel prize for higgs discovery went to
           | theorists who proposed and predict it not the experimental
           | physicists (thousands) who discovered it in 2012.
           | 
           | [1] https://home.cern/science/experiments/ua1
        
           | erk__ wrote:
           | It is only the Peace Prize that may be given to more than 3
           | people, which have been done 30 times:
           | https://www.nobelprize.org/prizes/lists/nobel-prize-
           | awarded-...
        
         | abm53 wrote:
         | I did raise an eyebrow at it too, but I doubt his contribution
         | was entirely "management of resources".
         | 
         | I think one must also give him the credit for the vision, risk
         | taking and drive to apply the resources at his disposal, and
         | RL, to these particular problems.
         | 
         | Without that push this research would never have been done, but
         | there may have been many fungible people willing to iron out
         | the details (and, to be fair, contribute some important ideas
         | along the way).
         | 
         | I'm not a proponent of the "great man" theory of history, but
         | based on the above I can see that this could be fair (although
         | I have no way of telling if internally this is actually how it
         | played out).
        
           | FrustratedMonky wrote:
           | Agree. Hassabis is more than a manager. He did start DeepMind
           | with just a few people and was a big part of the brains
           | behind it.
           | 
           | Now that it has grown he might be doing more management. But
           | the groundwork that went into AlphaFold was built on all the
           | earlier Alphaxxx things they have built, and he contributed.
           | 
           | It isn't like other big tech managers that just got some new
           | thing dumped in their lap. He did start off building this.
        
         | nsoonhui wrote:
         | So can we expect that Sam Altman will be honored with Nobel
         | prize 2025? After all physics prize went to AI researchers this
         | year, and chemistry prize went to an organizational head.
        
           | patall wrote:
           | He may still win literature this year.
        
             | fuzzfactor wrote:
             | I can only predict a more prestigious prize on the horizon
             | in the future.
             | 
             | Isn't sama on track to end up with more financial resources
             | than Nobel had at his disposal?
             | 
             | Plus I think he's got enough of a philanthropic streak
             | which can prove to be not so shabby.
             | 
             | There could very well be a foundation someday awarding the
             | Altman Prize well into the 22nd century.
             | 
             | Whether or not his most dynamic legacy would be something
             | as simultaneously useful/dangerous as dynamite.
        
               | patall wrote:
               | Hassabis should also be a billionaire by now.
        
               | jsnell wrote:
               | The Nobel prize's prestige comes from its history, not
               | from the size of the monetary award.
               | 
               | For an example, the Millennium Technology Prize is
               | awarded every two years and the prize money is slightly
               | higher than the Nobel prize (1M EUR vs 0.94M EUR). The
               | achievements it's been awarded for tend to be much more
               | practical, immediate and understandable than the Nobel
               | prize achievements. The next one should be awarded in a
               | couple of weeks.
               | 
               | And when that happens, it'll get 1/10th the publicity a
               | Nobel prize gets, because the Nobel prize is older than
               | any living human and has been accumulating prestige all
               | that time, while the Millennium prize is only 20 years
               | old.
        
             | pyb wrote:
             | He's up for the Pulitzer Prize for Fiction.
             | 
             | https://x.com/S_OhEigeartaigh/status/1843979139948355893
        
           | FrustratedMonky wrote:
           | You're really conflating things. Altman is no Hassabis.
           | 
           | Just because there is a ton of hype from OpenAI doesn't
           | detract from what DeepMind has done. AlphaGo anybody?
           | 
           | Are we really already forgetting what a monumental problem
           | protein folding was, decades of research, and AlphaFold came
           | in and revolutionized it overnight.
           | 
           | We are pretty jaded these days when miracles are happening
           | all the time and people are like "yeah, but he's just a
           | manager 'now', what have they done for me in the last few
           | days".
        
             | authorfly wrote:
             | I am missing context here and would love to know more.
             | 
             | Say I know about ATP Synthase and how the
             | proteins/molecules involved there interact to make a sort
             | of motor.
             | 
             | How does AlphaFold help us understand that or more
             | complicated systems?
             | 
             | Are proteins quite often dispersed and unique, finding each
             | other to interact with? Or like ATP Synthase are they more
             | of a specific blueprint which tends to arrange in the same
             | way but in different forms?
             | 
             | In other words:
             | 
             | Situation 1) Are there many ATP synthase type situations we
             | find too complex to understand - regular patterns and
             | regular co-occurences of proteins but we don't understand
             | them?
             | 
             | Situation 2) Or is most of the use of Protein situational
             | and one-off? We see proteins only once or twice, very
             | complicated ones, yet they do useful things?
             | 
             | I struggle to situate the problem of Unknown proteins
             | without knowing which of the above two is true (and why?)
        
         | dist-epoch wrote:
         | > These AI demonstrations require so many GPUs, specialized
         | hardware and data that nobody has but the biggest players.
         | Moreover, they are engineering work, not really scientistic
         | 
         | So is the Large Hadron Collider.
        
         | alkonaut wrote:
         | > The AlphaFold paper has countless authors, many researchers
         | and company resources underlying it. Hassabis' contribution is
         | management of resources and entrepreneurship, not the actual
         | science.
         | 
         | That's usually how you get a Nobel prize in science. You become
         | an accomplished scientist, and eventually you lead a big
         | lab/department/project and with a massive massiv you work on
         | projects where there are big discoveries. These discoveries
         | aren't possible to attribute to individuals. If you look back
         | through history and try to find how many "Boss professor
         | leading massive team/project" vs. how many "Einstein type
         | making big discovery in their own head" I think you'll find
         | that the former is _a lot_ more common.
         | 
         | > This will incentivize scientists to focus on management of
         | other researchers who will manage other researchers who will
         | produce the technical inventions.
         | 
         | I don't think the Nobel prize is a large driver of science.
         | It's a celebration and a way to put a spotlight on something
         | and someone. But I doubt many people choose careers or projects
         | based on "this might get us the prize..."
        
           | marcosdumay wrote:
           | > You become an accomplished scientist, and eventually you
           | lead a big lab/department/project and with a massive massiv
           | you work on projects where there are big discoveries.
           | 
           | That's a very recent thing. Up to the 90s, the Nobel
           | committee refused to even recognize it. They just started to
           | award those prizes at the 21 century, and on most fields they
           | never became the majority.
        
       | lr1970 wrote:
       | How come they missed Justin Gilmer? He did most of the original
       | work [0].
       | 
       | [0]
       | https://scholar.google.com/citations?view_op=view_citation&h...
       | 
       | EDIT: typos
        
       | DevX101 wrote:
       | Here's a direct quote from the Alphafold paper:
       | 
       | "These authors contributed equally: John Jumper, Richard Evans,
       | Alexander Pritzel, Tim Green, Michael Figurnov, Olaf Ronneberger,
       | Kathryn Tunyasuvunakool, Russ Bates, Augustin Zidek, Anna
       | Potapenko, Alex Bridgland, Clemens Meyer, Simon A. A. Kohl,
       | Andrew J. Ballard, Andrew Cowie, Bernardino Romera-Paredes,
       | Stanislav Nikolov, Rishub Jain, Demis Hassabis"
        
         | seydor wrote:
         | They didnt give the award to the paper
        
           | onursurme wrote:
           | The paper represents the work which lead to the prize.
           | 
           | if A=B and A=C, then A=C
        
             | SkiFire13 wrote:
             | > if A=B and A=C, then A=C
             | 
             | Technically true, but you might still want to double check
             | your logic.
        
             | fastball wrote:
             | Not all of the work. For example, it doesn't account for
             | the fact that Demis Hassabis, as head of DeepMind,
             | undoubtedly recruited many of the co-authors to participate
             | in this effort, which is worth something when it comes to
             | the final output.
        
               | onursurme wrote:
               | To recruit isn't scientific work.
        
               | fastball wrote:
               | I didn't realize the Nobel specified that the only work
               | which mattered was that of the "scientific" variety.
        
             | warkdarrior wrote:
             | What will the paper do with the prize money?
        
           | Rochus wrote:
           | At least they could have read it before awarding the price.
        
         | t_mann wrote:
         | Here's 8 densely printed pages of contributors to a discovery
         | that lead to a Nobel prize:
         | 
         | https://arxiv.org/pdf/1207.7214#page=26
         | 
         | Guess how many of them were included in the prize. It's a shame
         | that the Nobel committee shies away from awarding it to
         | institutions, but the AlphaFold prize doesn't even make the top
         | 10 in a list of most controversial omissions from a Nobel
         | prize. It's a simple case of lab director gets the most credit.
        
           | throwaway48476 wrote:
           | Perhaps it's time the prize goes to the discovery itself
           | instead of a person.
        
             | BurningFrog wrote:
             | How do you give $1M to a discovery?
        
               | throwaway48476 wrote:
               | $1M ain't what it used to be.
        
           | ascorbic wrote:
           | It's not a case of shying away from it: the rules of the
           | prize don't allow it.
        
             | myworkinisgood wrote:
             | rules of the prize can be changed.
        
               | afthonos wrote:
               | Can they? I mean, in the sense that you can yolo
               | anything, sure, but the prizes were designed in a time
               | when it was (more) reasonable to award them to
               | individuals, and they are defined in a will. There may
               | not be a mechanism for updating the standards.
        
               | hyperbrainer wrote:
               | Yes, they can. In 1901, science was not nearly as
               | collaborative as it is today. Especially considering the
               | need for a Nobel Prize to be experimental and the fact
               | that most major labs today _need_ dozens of people.
        
               | afthonos wrote:
               | That...has nothing to do with my question. It was a
               | procedural and legal question, not an abstract moral one.
        
               | hyperbrainer wrote:
               | Well, it seems like amendments have been made before. [0]
               | > Before the board ... votes on a proposal to amend the
               | statutes ... with the first paragraph, the prize-awarding
               | bodies shall examine the proposal.
               | 
               | https://www.nobelprize.org/organization/special-
               | regulations-...
        
               | achierius wrote:
               | He asked _can_ not _should_: what is the legal mechanism
               | for doing so? Personally I don't doubt there is one but I
               | don't think you know it off the top of your head, so I
               | don't see it as fair to disparage OP for not knowing
               | either.
        
               | hyperbrainer wrote:
               | Well, it seems like amendments have been made before. [0]
               | > Before the board ... votes on a proposal to amend the
               | statutes ... with the first paragraph, the prize-awarding
               | bodies shall examine the proposal.
               | 
               | https://www.nobelprize.org/organization/special-
               | regulations-...
        
         | stenl wrote:
         | And further down: " Contributions
         | 
         | J.J. and D.H. led the research. J.J., R.E., A. Pritzel, M.F.,
         | O.R., R.B., A. Potapenko, S.A.A.K., B.R.-P., J.A., M.P., T.
         | Berghammer and O.V. developed the neural network architecture
         | and training. T.G., A.Z., K.T., R.B., A.B., R.E., A.J.B., A.C.,
         | S.N., R.J., D.R., M.Z. and S.B. developed the data, analytics
         | and inference systems. D.H., K.K., P.K., C.M. and E.C. managed
         | the research. T.G. led the technical platform. P.K., A.W.S.,
         | K.K., O.V., D.S., S.P. and T. Back contributed technical advice
         | and ideas. M.S. created the BFD genomics database and provided
         | technical assistance on HHBlits. D.H., R.E., A.W.S. and K.K.
         | conceived the AlphaFold project. J.J., R.E. and A.W.S.
         | conceived the end-to-end approach. J.J., A. Pritzel, O.R., A.
         | Potapenko, R.E., M.F., T.G., K.T., C.M. and D.H. wrote the
         | paper."
        
           | onursurme wrote:
           | These people aren't in the "These authors contributed
           | equally" list.
        
           | stephencanon wrote:
           | > J.J. and D.H. led the research
           | 
           | Hey, I wonder who these mysterious "J.J." and "D.H." might
           | be?
        
         | DevX101 wrote:
         | The nature of scientific work has changed significantly since
         | 1895, when the Nobel Prizes were established. 100 years ago,
         | lots of scientific work really were driven forward largely by a
         | singular person. That's rarely true today for groundbreaking
         | research. I don't know if this means the Nobel needs to change
         | or we need a another prize that reflects the collaborative work
         | of modern science.
        
           | aleph_minus_one wrote:
           | > The nature of scientific work has changed significantly
           | since 1895, when the Nobel Prizes were established. 100 years
           | ago, lots of scientific work really were driven forward
           | largely by a singular person. That's rarely true today for
           | groundbreaking research.
           | 
           | The question is: is this a necessity for doing good science
           | today, or rather an artifact of how important research is
           | organized today (i.e. an artifact of the bureacratic and
           | organizational structure that you have to "accept"/"tolerate"
           | if you want to do want to have a career in science)?
        
             | DevX101 wrote:
             | So I did a mini research project on Claude to answer your
             | question. From 1900-1930, 87% of Nobel Prizes in Physics,
             | Chemistry and Physiology/Medicine were awarded to
             | individual contributions, 13% were awarded to collaborative
             | contributions.
             | 
             | This ratio has flipped in the past 30 years, from
             | 1994-2023, where 17% prizes were individual, 83%
             | collaborative.
             | 
             | So I'd say yes, collaborative work is increasingly a
             | requirement to do groundbreaking research today. The
             | organizational structures and funding are a part of the
             | reason as you mention. But it's also that modern scientific
             | problems are more complex. I used to have a professor that
             | used to say about biology "the easy problems have been
             | solved". While I think that's dismissive to some of the
             | ingenious experiments done in the past, there's some truth
             | to it.
        
               | afthonos wrote:
               | This begs the question. If all science is now structured
               | as big research teams, we'd expect the breakthroughs to
               | come from such teams. That doesn't _necessarily_ imply
               | that teams are needed.
        
               | aleph_minus_one wrote:
               | Your argument is exactly a central part of the point that
               | I raised.
        
       | seydor wrote:
       | ... and the Nobel in Economics goes to OpenAI for innovations in
       | nonprofit business structures.
       | 
       | it's the year of AI (ChatGPT preparing its acceptance speech)
        
       | KasianFranks wrote:
       | And, at the heart of AlphaFold2 is the language model, the tip of
       | the spear in AI today. 'Language' can come in many forms e.g. a
       | protein or amino acid sequence.
        
         | ddalex wrote:
         | Alpha* is not LLM-based, it's Q-learning based
        
           | jebarker wrote:
           | AlphaFold 2 wasn't Q-learning based. It was supervised SGD
           | and the "evoformer" they introduced is very close to a
           | transformer. So it's not exactly an LLM, but it's a pretty
           | close equivalent for protein data.
        
       | haunter wrote:
       | inb4 Nobel Peace Prize will go to Timnit Gebru
        
       | belter wrote:
       | First Obama got the Peace Prize Nobel, now Demis Hassabis gets
       | the Chemistry Nobel. I expect at a minimum the Nobel Prize in
       | Literature to be Donald E. Knuth.
        
         | mihaaly wrote:
         | The Nobel Prize in Literature should go to Jeff Bezos for the
         | Amazon Kindle, obviously!
        
           | belter wrote:
           | Yeah, as the Head of the Engineering Org...Makes sense.
        
         | boxed wrote:
         | I think a more fitting example would be to give the Literature
         | Prize to my son, aged 8.
        
         | Rochus wrote:
         | The Nobel Committee is not unaffected by the global decline in
         | IQ.
        
       | onursurme wrote:
       | Combine this with the Physics prize, I now have hope to receive a
       | Nobel prize in any area. Seriously, from now on, I won't mention
       | Nobel prizes anywhere anymore.
        
       | balazstorok wrote:
       | Nobel peace prize has countless times been awarded to a group of
       | people or institution. It is differently controlled but the idea
       | is not unprecedented.
        
         | ascorbic wrote:
         | The rules are different
        
       | LarsDu88 wrote:
       | Nobel committee is all in on the AI hype this year!
        
       | thatsadude wrote:
       | Well more deserving than the author of Restricted Boltzmann
       | machine.
        
       | ThePhysicist wrote:
       | Demis Hasabis has a really interesting and unusual CV for a nobel
       | laureate [1], he started his career in AI game programming (he
       | worked e.g. on Popoulous II, Syndicate, Theme Park for Bullfrog,
       | and later for Lionhead Studios on Black & White) before doing a
       | PhD in neuroscience, becoming an entrepreneur and starting
       | DeepMind. I would say this is a refreshing and highly uncommon
       | pick for a nobel prize, really cool to see that you don't have to
       | be a university professor anymore to do this kind of impactful
       | research.
       | 
       | 1: https://en.wikipedia.org/wiki/Demis_Hassabis
        
         | seydor wrote:
         | doesn't beat that patent clerk guy
        
           | singularity2001 wrote:
           | whose father was one of the leading local industrialists
           | 
           | (installing the first electric lighting for the 1885 Munich
           | Oktoberfest)
        
             | nextworddev wrote:
             | It's fascinating how the affluent backgrounds of many
             | famous scientists and entrepreneurs are downplayed. Eg
             | Warren Buffet, Jeff Bezos, etc
        
               | xdavidliu wrote:
               | Bill Gates, but (according to the Isaacson book) not Elon
               | Musk
        
               | concordDance wrote:
               | I'm now curious which of Gates, Musk and Bezos families
               | were wealthier when they started their respective
               | careers...
               | 
               | I suspect Bezos, then Gates, then Musk, but it could be
               | any order.
        
               | throw310822 wrote:
               | I would be very happy to be able to multiply my
               | parents'/family's money by whatever factor Bezos, Gates
               | or Musk have multiplied theirs.
        
               | LightBug1 wrote:
               | The multiplier would be significantly different.
               | 
               | Think the Wright Brothers first aeroplane vs a rocket
               | ship.
        
               | daedrdev wrote:
               | There were at least hundreds of thousands if not millions
               | who had easier starts them Jeff Besos.
        
               | DevX101 wrote:
               | If you gave the $300,000 Bezos got from his father to
               | 10,000 random Americans in 1994, none of them would have
               | created a company the equivalent of Amazon's scale.
        
               | stonemetal12 wrote:
               | How many of those 10k would have the same background? We
               | can pretend Bezos' dad raised him in a "normal" middle
               | class background then randomly dropped 300K on him, or we
               | can acknowledge he is the business equivalent of an
               | Olympic athlete.
        
               | varelse wrote:
               | Bezos? Abandoned by his dad who was literally an
               | alcoholic clown and raised by his mom and her 2nd husband
               | Bezos?
               | 
               | https://en.wikipedia.org/wiki/Ted_Jorgensen
               | 
               | So $300K in 1994 is about $640K. That's nice but about
               | 80th percentile of net worth. It's nice his parents
               | believed in him. How many of your parents would do that
               | for you? I'm sure at 1 in 5 of them have that kind of
               | money because of the distribution here. So the difference
               | here is He was smart, he got lucky, and your parents
               | don't believe in you enough on this front.
               | 
               | But compare and contrast Bezos and Musk. Bezos's mid-life
               | crisis is leaving his wife to run around on his yacht
               | banging models. Musk's mid-life crisis is trying to
               | destroy democracy so he and his mom won't have to pay US
               | taxes. Neither one is a role model, but I don't even get
               | the point of the latter.
               | 
               | Which brings us back to AlphaFold. The AlphaFold team did
               | something amazing. But also, they had a backer that
               | believed in them. David Baker, for better or worse,
               | didn't achieve what they did and he'd been at it for
               | decades. It's amazing what good backing can achieve.
        
               | itishappy wrote:
               | I assumed the parent post was talking about his adopted
               | father. The man who raised and dropped $250k on Bezos was
               | Miguel.
               | 
               | https://en.wikipedia.org/wiki/Miguel_Bezos
        
               | IncreasePosts wrote:
               | Miguel worked at Exxon for 32 years as an engineer and a
               | manager. It's not like he was the CEO or anything close
               | to that. There would literally be hundreds of thousands
               | of people in a similar position to him across the world.
               | 
               | Also worth noting that Jeff Bezos was(and I think still
               | is) the youngest person who ever became a senior VP at DE
               | Shaw. That is a position earned by merit alone.
        
               | adastra22 wrote:
               | I think you are agreeing with the poster you are
               | responding to, right? Bezos is the equivalent of an
               | Olympic athlete: a combination of innate talent as well
               | as opportunity.
        
               | PaulDavisThe1st wrote:
               | 10k _random_ Americans, sure.
               | 
               | 10k random Americans with backgrounds in software and a
               | business idea? Not so clear.
               | 
               | You also seem very certain that Amazon's scale is a good
               | thing, overall, which I remain unconvinced of.
        
               | huijzer wrote:
               | > You also seem very certain that Amazon's scale is a
               | good thing, overall, which I remain unconvinced of.
               | 
               | What do you find unconvincing about roughly 30 billion in
               | net income and free cashflow in 2023?
        
               | PaulDavisThe1st wrote:
               | That's one metric, that only reflects Amazon's function
               | as an income generator.
               | 
               | I view businesses through other metrics as well,
               | including their impact on society in a variety of
               | different ways. From some of those perspectives, it is
               | not clear to me that Amazon (where I was the 2nd
               | employee) is a net benefit.
        
               | concordDance wrote:
               | This Amazon the company specifically or online shopping
               | in general? E.g. if Amazon hadn't been made and some
               | other online retailer had dominated (or even if there had
               | been many!)
        
               | PaulDavisThe1st wrote:
               | Both.
        
               | hn_throwaway_99 wrote:
               | That may be true, but I don't think that's really the
               | crux of the argument. This article talks about how Amazon
               | was initially funded by Bezos' family members:
               | https://luxurylaunches.com/celebrities/jeff-bezos-
               | parents-in.... The bigger point is that relatively _very_
               | few parents (like a couple percent maybe?) would be in a
               | position to give their kid $250k to start a new venture,
               | and it 's not that surprising that the most financially
               | successful people in the world needed both: intrinsic
               | talent and drive, and a huge amount of support from their
               | birth circumstances.
               | 
               | The way I like to put it is that both of the following
               | are true:
               | 
               | 1. Bezos is uniquely talented and driven, and his success
               | depended on that
               | 
               | 2. Bezos' success also depended on him having an uncommon
               | level of access to capital at a young age.
               | 
               | The reason I like to say "both of these are true" is that
               | so often today I see "sides" that try to argue that only
               | one is true, e.g. libertarian-leaning folks (especially
               | in the US) arguing that everything is a pure meritocracy,
               | and on the other side that these phenomenally successful
               | people just inherited their situation (e.g. "Elon Musk is
               | only successful because his dad owned an emerald mine")
        
               | chongli wrote:
               | Because having some degree of runway is almost always
               | necessary but never sufficient. Thousands of Americans
               | receive similar amounts of money from their parents in
               | the form of inheritance of the family home and other
               | major assets. Only one took windfall of that size and
               | created Amazon.
        
               | concordDance wrote:
               | The "necessary, but not sufficient" is unintuitive to
               | most people. Billionaires who come from working class
               | families are almost unheard of, but probably more than
               | half the self made (for a definition, something like
               | multiplied familial investments by at least 100x maybe?)
               | billionaires come from upper middle class families.
               | 
               | I wonder if they are actually more likely to come from
               | upper middle class (where parents are highly paid
               | professionals) than the proper idle rich or even CEOs and
               | company founders...
        
               | timmg wrote:
               | There's another side to this: if you accept the idea of
               | "nature" -- genes capable of carrying "talent" (in some
               | sense) -- it should be common for children of talented
               | people to be talented.
               | 
               | Of course, talent doesn't always mean prosperity. But in
               | a society modeled on meritocracy, it often will.
        
               | km155 wrote:
               | hypothesis : it's not per se affluence. it's the culture
               | of the family and social circle. A dollop of $ to have
               | some free time and maybe buy some books would help and
               | might be necessary.
               | 
               | imagine a family where youngster is encouraged to work on
               | intellectual problems. where you aren't made fun of for
               | touching nerdy things. or for doing puzzles. where the
               | social circle endorses learning. these things more
               | important than $ in a first world economy. (if third
               | world, yes give me some money please for a book or even
               | just food. and hopefully with time, an internet connected
               | device then the cream will rise they can just watch
               | feynman on YouTube...)
               | 
               | that said, it's "better" than it used to be. hundreds of
               | years ago most interesting science, etc. was done by the
               | royal class. not because they are smarter (I assume). But
               | they had free time. And, social encouragement perhaps
               | too.
               | 
               | bill gates and zuck dropped out of Harvard right? it's
               | not per se Harvard, at least not the graduating bit?
               | being surrounded by other smart people is helpful -- and
               | or people who encourage intellectual endeavors.
        
               | bonoboTP wrote:
               | > hundreds of years ago most interesting science, etc.
               | was done by the royal class
               | 
               | Not really true. Newton, Copernicus, Kepler, Galileo,
               | Mendel, Faraday, Tesla... Not from royals, nor from high
               | nobility. Many great scientists were born to merchant
               | families, of a level that wasn't even all too rare.
        
           | BeetleB wrote:
           | The patent clerk guy was almost done with his PhD when he
           | became a patent clerk. Not quite comparable.
        
             | theGnuMe wrote:
             | Uh. Demis finished his PhD...
        
             | huijzer wrote:
             | Are we talking about Einstein? If I remember correctly,
             | according to Walter Isaacson, Einstein managed to get so
             | many good papers out not despite, but _because_ he was not
             | working for an university. It gave him more freedom to
             | reject existing ideas. Also the years I can find on
             | Wikipedia do not seem to support your claim. He started as
             | a clerk in 1903, and had his miracle year and submitted his
             | PhD dissertation in 1905.
        
               | BeetleB wrote:
               | From what I've read, he explicitly sought a position that
               | would give him time to work on his physics ideas. Whether
               | he would or not would have achieved the same working for
               | a university is merely his opinion. In particular, it was
               | _not_ the case that he was working for one, and found it
               | to be incompatible with his research vision, and left
               | academia to become a patent clerk.
               | 
               | He began his work on the PhD prior to 1903.
        
           | gcanyon wrote:
           | Nobody defeats the patent clerk guy. I love to cite this
           | article that argues he could credibly have been awarded
           | anywhere from 5 to 7 Nobel prizes. https://www.quora.com/How-
           | many-Nobel-prizes-should-Einstein-...
        
         | belter wrote:
         | The infinite polygons are Nobel worth..
        
         | theGnuMe wrote:
         | Yes but he could have been one... He really took to AI and
         | reignited the fire that melted the AI winter.
        
         | lchengify wrote:
         | Didn't know he worked on Black & White. Black & White was
         | really ahead of it's time for 2001, it did a much better job of
         | having NPC simulations in groups based on how you played as a
         | god.
        
         | medo_baayou wrote:
         | don't forget that he was IM 2300 rated chess player at 13 yo
        
         | BeetleB wrote:
         | Syndicate - wow. That brings back memories!
         | 
         | I could never get it working on DosBox (some timing issue).
         | Haven't tried in over a decade, though. Should see if I can get
         | it working.
        
         | mk_stjames wrote:
         | I'm always interested in hearing about these people who go and
         | get a PhD in an unrelated field to their original studies,
         | often years after leaving university and working in an
         | industry. Here it says Hasabis did an undergraduate degree in a
         | computer science program, and them spent a decade working on
         | computer games at studios, and then somehow just rocked up to a
         | university and asked to do a PhD in neuroscience.
         | 
         | I feel if I tried to do that in the US- (where I got a masters
         | degree in engineering, spent a 15 yrs as an aerospace
         | engineer,)- tried to go back and ask to do a PhD in, say,
         | Physics - I'd be promptly told to go fuck myself (or, fuck
         | myself but then enroll in a new undergrad or maaaybe graduate
         | program only after re-taking GRE's. Straight PhD? Never heard
         | it work like that.)
        
           | triceratops wrote:
           | Aerospace engineering masters -> Physics PhD doesn't sound
           | like a big leap to me. I don't think that's accurate.
        
           | shnock wrote:
           | I think PhD's are generally different enough in Europe vs the
           | US that this might be less surprising upon further research
        
           | biofox wrote:
           | I have known a several people who made the jump from Computer
           | Science to Biology at graduate school. Usually, it's either
           | via genomics or neuroscience (as in Hassabis' case), where
           | there is a large need for people who can do data crunching or
           | computational modelling.
        
           | adastra22 wrote:
           | Why do you think that? It's not my experience. At the grad
           | school level they'll take anyone who can do the work and is
           | interested. Outside experience, even in unrelated fields, is
           | often a plus. Grad students just out of undergrad have no
           | idea how the world works.
        
           | bonoboTP wrote:
           | That may be more true in a super crowded and hot area, like
           | AI now where reputable profs get dozens of PhD applicants per
           | position, who all have already published relevant works in
           | the field at top venues during their masters.
           | 
           | In more chill fields where the waters are relatively calm,
           | this may be less of an issue.
           | 
           | But let's also consider the fact that Hassabis did his
           | undergrad at the University of Cambridge, likely with
           | excellent results. He wasn't just some random programmer.
        
           | Windchaser wrote:
           | I made the jump from mostly-math undergrad to materials
           | science PhD (close to chemistry/physics, if you don't know
           | the field). I was welcomed with open arms.
           | 
           | If you've got any math-heavy STEM graduate degree, you can
           | likely jump into a physics PhD. You might need to take some
           | senior-level undergraduate courses to catch up, but the
           | transition is quite doable. At some point, your overall
           | intelligence, enthusiasm, and work ethic matter more than
           | your specific background.
        
           | jltsiren wrote:
           | There is a lot of variation in how PhD studies work. In some
           | places, you are just a faceless candidate applying to a
           | department, which discourages you from contacting the faculty
           | before you are admitted. In other places, you must convince a
           | professor to supervise and fund you before you are even
           | allowed to apply. Some universities require you (or your
           | supervisor) pay tuition fees for a number of years before you
           | can graduate, while others don't care what you do, as long as
           | you can produce a thesis that meets their standards.
           | 
           | You can jump from social sciences to STEM. Your formal
           | admission can wait for a year or two after you actually
           | started. Or you can move to another university and get a PhD
           | in a few months, because the administrative requirements in
           | the original one were too unreasonable. These things happen,
           | because universities are independent organizations that like
           | doing things their own way.
        
           | jerjerjer wrote:
           | PhD is a thankless, low paid position with insane hours and
           | zero guaranteed return. Outside of a few elite programs and
           | universities getting into PhD program is fairly easy - they
           | take anyone qualified.
        
         | nanoxide wrote:
         | Yep. I distinctly remember reading an interview in the German
         | GameStar magazine in '99 or something with him where he talks
         | about his early work with Bullfrog. Over the years I read his
         | name from time to time as he moved towards research. Pretty
         | amazing career.
        
       | mhrmsn wrote:
       | Great achievement, although I think it's interesting that this
       | Nobel prize was awarded so early, with "the greatest benefit on
       | mankind" still outstanding. Are there already any clinically
       | approved drugs based on AI out there I might have missed?
       | 
       | In comparison, the one for lithium batteries was awarded in 2019,
       | over 30 years after the original research, when probably more
       | than half of the world's population already used them on a daily
       | basis.
        
         | pm215 wrote:
         | Arguably awarding early is more in line with the intention
         | expressed in Nobel's will: "to those who, during the preceding
         | year, have conferred the greatest benefit to humankind". It
         | seems to have drifted into "who did something decades ago that
         | we're now confident enough in the global significance of to
         | award a prize". I suspect that if the work the prize recognized
         | reslly had to have been carried out in the preceding year the
         | recipients would be rather different.
        
           | benrapscallion wrote:
           | Shouldn't this be GLP1RAs (semaglutide etc.) for the last
           | year?
        
         | cmavvv wrote:
         | Given that drugs take around 10 years to get to market, and
         | that some time is needed for industrial adoption as well, it's
         | not very reasonable to expect clinically approved drugs before
         | a few years.
        
           | londons_explore wrote:
           | > around 10 years to get to market
           | 
           | This is really sad. A new recipe for feeding honeybees to
           | make tastier honey could get to market in perhaps a month or
           | two. All the chemical reactions happening in the bees gut and
           | all the chemicals in the resulting honey are unknown, yet
           | within a matter of weeks its being eaten.
           | 
           | Yet if we find a new way of combining chemicals to cure
           | cancer, it takes a decade before most can benefit.
           | 
           | I feel like we don't balance our risks vs rewards well.
        
             | wholinator2 wrote:
             | I think the idea is that we're, as a species, much more
             | comfortable with the idea that 15 years down the line that
             | 50% of treated colonies collapse in a way directly
             | attributable to the treatment than we are with the idea
             | that 15 years down the line 50% of treated humans die in a
             | way directly attributable to the treatment.
             | 
             | Now if the human alternative to treatment is to die anyway
             | than i think that balance shifts. I do think we should be
             | somewhat liberal with experimental treatments for patients
             | in dire need, but you have to also understand that
             | experimental treatments can just be really expensive which
             | limits either the people who can afford it, or if it's
             | given for free, the amount the researcher can
             | make/perform/provide.
             | 
             | 10 years is a very long time. I've had close family members
             | die of cancer and any opportunity for treatment (read:
             | hope) is good in my opinion. But i wouldn't say there's no
             | reason that it takes so long
        
       | og_kalu wrote:
       | Yesterday's physics win was rather odd but this I have no problem
       | with!
       | 
       | Lol does this mean there's a chance the Transformer Authors win a
       | Nobel in literature sometime? Certainly seems a lot more
       | plausible than before yesterday.
        
       | boxed wrote:
       | I think it's still too early to know if AlphaFold is a massively
       | overfitted statistical model that will utterly fail on novel
       | structures.
        
         | patall wrote:
         | The prize winners are ultimately selected by a group of mid-age
         | to old professors. And to tell the truth (I work at a research
         | institute in Stockholm), some of the old folks seem to have
         | huge FOMO. They know that they cannot keep up themselves, they
         | have no idea (and no way of finding out) who is actually good
         | and who is just pretending, which leads to recruitment of an
         | 'interesting' bunch of young group leaders. Some of them are
         | surely good, but I know of at least one guy who holds
         | presentations as if he invented AlphaFold himself, while having
         | contributed one single paper of interest to the field. Large
         | turn off for me.
        
           | theGnuMe wrote:
           | I dunno, you should have AI FOMO. Or at least start focusing
           | on computational thinking.
        
             | patall wrote:
             | I do not criticize them for having FOMO. But I have my
             | doubts when it is the 60-year-olds that are the most
             | enthusiastic about something new (as long as it is not a
             | new ABBA album), given the number of grifters out there.
             | And there would have been many others that also deserve a
             | Nobel, those three could easily have waited another 20
             | years. If it really was those that had the highest impact
             | the last year who won the prize, it (or rather "Medicine")
             | should have gone to GLP-1/Semaglutide research.
        
         | flobosg wrote:
         | AlphaFold2 has correctly predicted novel folds:
         | https://www.nature.com/articles/s42003-022-03357-1
        
       | dist-epoch wrote:
       | Calling it, to keep with the theme: the Nobel prize in literature
       | will be given to a LLM author.
        
       | ConcernedCoder wrote:
       | people still folding@home <shrug>
        
       | cool-RR wrote:
       | I wonder why various outlets, including DeepMind's blog, say that
       | John Jumper is a "Senior Research Scientist". That's L5 which
       | sounds like quite a low rank for a Nobel prize winner. I checked
       | his LinkedIn and he's a director, which is around L8. I thought
       | that maybe he was L5 during the publishing of the results, but
       | no, he was either L6 or L7.
        
         | jltsiren wrote:
         | Maybe "Senior Research Scientist" sounds more respectable among
         | the intended audience. A research scientist is usually an
         | independent researcher rather than someone working in another
         | person's team, while "senior" indicates that they have been in
         | an independent role for a while. A director, on the other hand,
         | is someone who failed to avoid administrative duties, and it
         | doesn't imply any degree of seniority.
        
         | tsimionescu wrote:
         | L5 doesn't mean anything to anyone outside of whatever
         | organization you're talking about (Google?). A Senior Research
         | Scientist means "a person who is a scientist, works in
         | research, and is very experienced in that role". Even if this
         | is not the title he holds in his organization, it is an
         | objective title that applies to him.
        
       | atmosx wrote:
       | > Oppenheimer was nominated for the Nobel Prize for Physics three
       | times[...] pondered why he was never bestowed the honor.
       | 
       | > "To understand this [...] you have to first examine the man's
       | academic life before and after the war."
       | 
       | Quote from: https://discover.lanl.gov/news/0609-oppie-nobel-
       | prize/
       | 
       | Not anymore. You're not required to know or have studied
       | Chemistry to get a Nobel in Chemistry.
        
         | og_kalu wrote:
         | The Nobel Prize has always prioritised advances in the field
         | over specific training.
         | 
         | Curie was a trained chemist when she won her prize in physics.
         | Michelson was a Naval Officer. Of course naturally, being able
         | to win a Nobel usually means you studied the field your entire
         | life but that has never been a requirement.
        
       | ilaksh wrote:
       | For some reason this web page doesn't render properly in my
       | browser. The main text overlaps the table of contents.
       | 
       | I'm using Chrome on KDE (Ubuntu) on a 1920 wide display (minus
       | the side panel). I checked and I don't have the page zoomed.
       | 
       | https://i.imgur.com/fOOQ3Av.png
        
       | aithrowawaycomm wrote:
       | I think putting AlphaFold here was premature; it might not age
       | well. AlphaFold is an impressive achievement but it simply has
       | not "cracked the code for protein folding" - about 1/3rd of its
       | predictions are too uncertain to be usable, it says nothing about
       | dynamics, suffers from the same ML problems of failing on
       | uncommon structures, and I was surprised to learn that many of
       | its predictions are incorrect because it ignores topological
       | constraints[1]. To be clear, these are _constructive_ criticisms
       | of AlphaFold in isolation, my grumpiness is directed at the Nobel
       | committee.  "Cracked the code for protein folding" is simply not
       | true; it is an ML approach with high accuracy that suffers the
       | same ML limitations of failing to generalize or failing to
       | understand deeper principles like R^3 topology that cannot be
       | gleaned stochastically.
       | 
       | More significantly: it has yet to be especially impactful in
       | biochemistry research, nor has its results really been carefully
       | audited. Maybe it will turn out to deserve the prize. But the
       | committee needed to wait. I am concerned that they got spun by
       | Google's PR campaign - or, considering yesterday's prize, Big
       | Tech PR in general.
       | 
       | [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10672856/
        
         | InkCanon wrote:
         | I think looking back five years from now, this will be viewed
         | as another Kissinger/Obama but wrt STEM. Given far too
         | prematurely under pressure to keep up with the Joneses/chase
         | the hype.
        
           | aithrowawaycomm wrote:
           | I am not so confident or dismissive: the real problem is that
           | testing millions of predictions (or any fairly bold
           | scientific development like AlphaFols) takes time, and that
           | time simply has not elapsed. Some of the criticisms I
           | identified might be low-hanging fruit that in 5 years will be
           | seen as minor corrections - but we're still discovering the
           | things that need to be corrected. It is concerning that the
           | prize announcement itself is either grossly overstated:
           | With its help, they have been able to predict the structure
           | of virtually all the 200 million proteins that researchers
           | have identified [the word 'virtually' is stretched into
           | meaninglessness]
           | 
           | or vague, could have been done with other tools, and hardly
           | Nobel-worthy:                 Among a myriad of scientific
           | applications, researchers can now better understand
           | antibiotic resistance and create images of enzymes that can
           | decompose plastic.
           | 
           | I am seriously wondering if they took Google / DeepMind press
           | releases at face value.
        
             | InkCanon wrote:
             | I have the same views as you (although admittedly the
             | Kissinger comparison didn't convey that, because we all
             | know how that turned out). It's at best quite premature. At
             | worst, should never have been given in hindsight. Will
             | probably land somewhere in between.
             | 
             | Second point is spot on. I really, really hope they didn't
             | just fall for what is frankly a bit of SV style press
             | release meant to hype things. Similar work was done on
             | crystal structures with some massive number reported. It's
             | a vastly other thing than the implied meaning that they are
             | now fully understood and able to be used in some way.
        
             | refulgentis wrote:
             | Chew on this a little, I stripped out as much as possible,
             | but I imagine it still will feel reflexively easy to
             | dismiss. Partially because its hard to hear criticism, at
             | least for me. Partially because a lot was stripped out: a
             | lot has gone sideways to get us to this point, so this may
             | sound minor.
             | 
             | The fact you have to reach for "I [wonder if the votes were
             | based on] Google / DeepMind press releases [taken] at face
             | value." should be a red blaring alarm.
             | 
             | It creates a new premise[1] that enables continued
             | permission to seek confirmation bias.
             | 
             | I was once told you should check your premises when facing
             | an unexpected conclusion, and to do that before creating
             | new ones. I strive to.
             | 
             | [1] All Nobel Prize voters choose their support based on
             | reading a press release at face value
        
           | matsemann wrote:
           | Original intent of the prizes is, however, to reward those
           | that recently contributed good. Not to be a lifetime award
           | after seeing how things pan out.
        
             | InkCanon wrote:
             | Yes, but the good has to be extraordinary. If there's logic
             | to it, in these cases they are predicting the good will
             | come much later. Which is an incredibly difficult
             | prediction to make.
        
         | j7ake wrote:
         | I would say alphafold is to structure prediction as crispr is
         | to gene editing.
         | 
         | Crispr did not solve gene editing either, but has been made
         | accessible to the broad biochemistry and biology researchers to
         | use.
         | 
         | Both similar impact and changed the field significantly.
        
           | beanjuice wrote:
           | Entire fields are based upon the existence of crispr now, it
           | demonstrated its impact. It has been 2? 3? years, people who
           | were making papers anyway have implemented AlphaFold, it
           | hasn't exactly spawned a new area.
        
       | sega_sai wrote:
       | Physics prize one goes to AI, chemistry too. What next? Nobel in
       | Literature goes to ChatGPT?
       | 
       | Jokes aside, I think the chemistry prize seems to make a bit more
       | sense to me than physics one.
        
         | theGnuMe wrote:
         | I think it is definitely possible for ChatGPT to win the Nobel
         | Prize in Literature.. maybe not this version or the next but
         | eventually -- especially if it is by proxy aka as is the
         | premise in "The Wife" (a good book/movie btw).
         | 
         | There's already precedent for anonymous creators, aka Banksy.
        
       | bdjsiqoocwk wrote:
       | Anyone else think that giving a nobel prize to the CEO of the
       | company is absurd?
        
       | eig wrote:
       | I think I disagree with most of the comments here stating it's
       | premature to give the Nobel to AlphaFold.
       | 
       | I'm in biotech academia and it has changed things already. Yes
       | the protein folding problem isn't "solved" but no problem in
       | biology ever is. Comparing to previous bio/chem Nobel winners
       | like Crispr, touch receptors, quantum dots, click chemistry, I do
       | think AlphaFold already has reached sufficient level of impact.
        
         | singularity2001 wrote:
         | >>  I do think AlphaFold already has reached sufficient level
         | of impact.
         | 
         | how so?
        
           | cmavvv wrote:
           | https://www.pnas.org/doi/10.1073/pnas.2315002121
        
           | eig wrote:
           | Well I'm sure one could look at number of published papers
           | etc, but that metric is a lot to do with hype and I see it as
           | a lagging indicator.
           | 
           | A better one is seeing my grad-school friends with zero
           | background in comp-sci or math, presenting their cell-biology
           | results with AlphaFold in conferences and at lab meetings.
           | They are not protein folding people either- just molecular
           | biologists trying to present more evidence of docking
           | partners, functional groups in their pathway of interest.
           | 
           | It reminds me of when Crispr came out. There were ways to
           | edit DNA before Crispr, but its was tough to do right and
           | required specialized knowledge. After Crispr came out, even
           | non-specialists like me in tangential fields could get
           | started.
        
             | tananan wrote:
             | In both academic and industrial settings, I've seen an
             | initial spark of hope about AlphaFold's utility being
             | replaced with a resignation that it's cool, but not really
             | useful. Yet in both settings it continued as a playing card
             | for generating interest.
             | 
             | There's an on-point blog-post "AI and Biology"
             | (https://www.science.org/content/blog-post/ai-and-biology)
             | which illustrates why AlphaFold's real breakthrough is not
             | super actionable for creating further bio-medicinal
             | applications in a similar vein.
        
               | whimsicalism wrote:
               | That article explains why AI might not work so well
               | further down the line biology discoveries, but I still
               | think alphafold can really help with the development of
               | small molecule therapies that bind to particular known
               | targets and not to others, etc.
        
               | tananan wrote:
               | The thing with available ligand + protein recorded
               | structures is that they are much, much more sparse than
               | available protein structures themselves (which are
               | already kinda sparse, but good enough to allow
               | AlphaFold). Some of the commonly-used datasets for
               | benchmarking structure-based affinity models are so
               | biased you can get a decent AUC by only looking at the
               | target or ligand in isolation (lol).
               | 
               | Docking ligands doesn't make for particularly great
               | structures, and snapshot structures really miss out on
               | the important dynamics.
               | 
               | So it's hard for me to imagine how alphafold can help
               | with small molecule development (alphafold2 doesn't even
               | know what small molecules are). I agree it totally sounds
               | plausible in principle, I've been in a team where such an
               | idea was pushed before it flopped, but in practice I feel
               | there's much less use to extract from there than one
               | might think.
               | 
               | EDIT: To not be so purely negative: I'm sure real use can
               | be found in tinkering with AlphaFold. But I really don't
               | think it has or will become a big deal in small drug
               | discovery workflows. My PoV is at least somewhat educated
               | on the matter, but of course it does not reflect the
               | breadth of what people are doing out there.
        
             | adastra22 wrote:
             | But Crispr actually edited genes. How much of this
             | theoretical work was real, and how much was slop? Did the
             | grad students actually achieve confirmation of their
             | conformational predictions?
        
               | eig wrote:
               | Surprisingly, yes the predicted structures from AlphaFold
               | had functional groups that fit with experimental data of
               | binding partners and homologues. While I don't know
               | whether it matched with the actual crystallization, it
               | did match with those orthogonal experiments (these were
               | cell biology, genetics, and molecular biology labs, not
               | protein structure labs, so they didn't try to actually
               | crystalize the proteins themselves).
        
         | fedeb95 wrote:
         | what has changed? I think people need more from a comment than
         | blind trust.
        
           | dekhn wrote:
           | It solidly answered the question: "Is evolutionary sequence
           | relationship and structure data sufficient to predict a large
           | fraction of the structures that proteins adopt". the answer,
           | surprising few, is that the data we have indeed can be used
           | to make general predictions (even outside of the training
           | classes), and also surprising many, that we can do so with a
           | minimum of evolutionary sequence data.
           | 
           | That people are arguing about the finer details of what it
           | gets wrong is support for its value, not a detriment.
        
             | timr wrote:
             | That's a bit like saying that the invention of the airplane
             | proved that animals can fly, when birds are swooping around
             | your head.
             | 
             | I mean, sure, prior to alphafold, the notion that sequence
             | / structure relationship was "sufficient to predict"
             | protein structure was merely a very confident theory that
             | was used to regularly make the most reliable kind of
             | structure predictions via homology modeling (it was also
             | core to Rosetta, of course).
             | 
             | Now it is a very confident theory that is used to make a
             | slightly larger subset of predictions via a totally
             | different method, but still fails at the ones we don't know
             | about. Vive la change!
        
               | dekhn wrote:
               | I think an important detail here is that Rosetta did
               | something beyond traditional homology models- it
               | basically shrank the size of the alignments to small (n=7
               | or so?) sequences and used just tiny fragments from the
               | PDB, assembled together with other fragments. That's sort
               | of fundamentally distinct from homology modelling which
               | tends to focus on much larger sequences.
        
               | flobosg wrote:
               | > and used just tiny fragments from the PDB
               | 
               | 3-mers and 9-mers, if I recall correctly. The fragment-
               | based approach helped immensely with cutting down the
               | conformational search space. The secondary structure of
               | those fragments was enough to make educated guesses of
               | the protein backbone's, at a time where _ab initio_ force
               | field predictions struggled with it.
        
               | timr wrote:
               | Yes, Rosetta did monte carlo substitution of 9-mers,
               | followed by a refinement phase with 3-mers. Plus a bunch
               | of other stuff to generate more specific backbone "moves"
               | in weird circumstances.
               | 
               | In order to _create those fragment libraries_ , there was
               | a step involving generation of multiple-sequence
               | alignments, pruning the alignments, etc. Rosetta used
               | sequence homology to generate structure. This wasn't a
               | wild, untested theory.
        
               | flobosg wrote:
               | > Rosetta used sequence homology
               | 
               | Rosetta used _remote_ sequence homology to generate the
               | MSAs and find template fragments, which at the time was
               | innovative. A similar strategy is employed for
               | AlphaFold's MSAs containing the evolutionary couplings.
        
               | dekhn wrote:
               | I don't know that I agree that fragment libraries use
               | sequence homology. From my understanding of it, homology
               | implies an actual evolutionary relationship. Wheras
               | fragment libraries instead are agnostic and instead seem
               | to be based on the idea that short fragments of non-
               | related proteins can match up in sequence and structure
               | space. Nobody looks at 3-mers and 9-mers in homology
               | modelling; it's typically well over 25 amino acids long,
               | and there is usually a plausible whole-domain (in the
               | SCOP terminology).
               | 
               | But, the protein field has always played loose with the
               | term "homology".
        
         | mhrmsn wrote:
         | Crispr is widely used and there are even therapies approved
         | based on it, you can actually buy TVs that use quantum dots and
         | click chemistry has lots of applications (bioconjugation etc.),
         | but I don't think we have seen that impact from AlphaFold yet.
         | 
         | There's a lot of pharma companies and drug design startups that
         | are actively trying to apply these methods, but I think the
         | jury is still out for the impact it will finally have.
        
           | nextos wrote:
           | AlphaFold is excellent engineering, but I struggle calling
           | this a breakthrough in science. Take T cell receptor (TCR)
           | proteins, which are produced pseudo-randomly by somatic
           | recombination, yielding an enormous diversity. AlphaFold's
           | predictions for those are not useful. A breakthrough in
           | folding would have produced rules that are universal. What
           | was produced instead is a really good regressor in the space
           | of proteins where some known training examples are closeby.
           | 
           | If I was the Nobel Committee, I would have waited a bit to
           | see if this issue aged well. Also, in terms of giving credit,
           | I think those who invented pairwise and multiple alignment
           | dynamic programming algorithms deserved some recognition.
           | AlphaFold built on top of those. They are the cornerstone of
           | the entire field of biological sequence analysis.
           | Interestingly, ESM was trained on raw sequences, not on
           | multiple alignments. And while it performed worse, it
           | generalizes better to unseen proteins like TCRs.
        
             | flobosg wrote:
             | > A breakthrough in folding would have produced folding
             | rules that are universal.
             | 
             | Protein folding [?] protein structure prediction
             | 
             | > I think those who invented pairwise and multiple
             | alignment dynamic programming algorithms deserved some
             | recognition
             | 
             | I would add BLAST as well but that ship has sailed, I'm
             | afraid.
        
               | dekhn wrote:
               | The value in BLAST wasn't in its (very fast) alignment
               | implementation but in the scoring function, which
               | produced calibrated E-values that could be used directly
               | to decide whether matches were significant or not. As a
               | postdoc I did an extremely careful comparison of E-values
               | to true, known similarities, and the E-values were spot
               | on. Apparently, NIH ran a ton of evolution simulations to
               | calibrate those parameters.
               | 
               | For the curious, BLAST is very much like pairwise
               | alignment but uses an index to speed up by avoiding
               | attempting to align poorly scoring regions.
        
               | nextos wrote:
               | BLAST estimates are derived from extreme value theory and
               | large deviations, which is a very elegant area of
               | probability and statistics.
               | 
               | That's the key part, I think, being able to estimate how
               | unique each alignment is without having to simulate the
               | null distribution, as it was done before with FASTA.
               | 
               | The index also helps, but the speedup comes mostly from
               | the other part.
        
               | j7ake wrote:
               | If blast used a neural network it may have had a chance!
               | 
               | The question is: has blast made more of an impact than
               | alpha fold? I think so at the moment.
        
         | causal wrote:
         | I agree. For those not in biotech, protein folding has been the
         | holy grail for a long time, and AlphaFold represents a huge
         | leap forward. Not unlike trying to find a way to reduce NP to P
         | in CS. A leap forward there would be huge, even if it came
         | short of a complete solution.
        
           | flobosg wrote:
           | > Let me get the most important question out of the way: is
           | AlphaFold's advance really significant, or is it more of the
           | same? I would characterize their advance as roughly two CASPs
           | in one
           | 
           | --https://moalquraishi.wordpress.com/2018/12/09/alphafold-
           | casp...
        
         | divbzero wrote:
         | I agree that it's not premature, for two reasons: First, it's
         | been 6 years since AlphaFold first won CASP in 2018. This is
         | not far from the 8 years it took from CRISPR's first paper in
         | 2012 to its Nobel Prize in 2020. Second, AlphaFold is only half
         | the prize. The other half is awarded for David Baker's work
         | since the 1990s on Rosetta and RoseTTAFold.
        
         | pama wrote:
         | Agreed. There are too many different directions of impact to
         | point out explicitly, so I'll give a short vignette on one of
         | the most immediate impacts, which was the use in protein
         | crystallography. Many aspiring crystallographers correctly
         | reorganized their careers following AlphaFold2, and everyone
         | else started using it for molecular replacement as a way to
         | solve the phase problem in crystallography; the models from AF2
         | allowed people to resolve new crystal structures from data
         | measured years prior to the AF2 release.
        
           | flobosg wrote:
           | Same with Rosetta, and even Foldit[1]! -
           | https://www.nature.com/articles/nsmb.2119
           | 
           | [1]: https://en.wikipedia.org/wiki/Foldit
        
         | roughly wrote:
         | It also proved that deep learning models are a valid approach
         | to bioinformatics - for all its flaws and shortcomings,
         | AlphaFold solves arbitrary protein structure in minutes on
         | commodity hardware, whereas previous approaches were, well,
         | this: https://en.wikipedia.org/wiki/Folding@home
         | 
         | A gap between biological research and biological engineering is
         | that, for bioengineering, the size of the potential solution
         | space and the time and resources required to narrow it down are
         | fundamental drivers of the cost of creating products - it turns
         | out that getting a shitty answer quickly and cheaply is worth
         | more than getting the right answer slowly.
        
           | flobosg wrote:
           | AlphaFold and Folding@home attempt to solve related, but
           | essentially different, problems. As I already mentioned here,
           | protein structure prediction is not fully equivalent to
           | protein folding.
        
             | roughly wrote:
             | Yeah, this is what I mean by "a shitty answer fast" -
             | structure prediction isn't a canonical answer, but it's a
             | good enough approximation for good enough decision-making
             | to make a bunch of stuff viable that wouldn't be otherwise.
             | 
             | I agree with you, though - they're two different answers.
             | I've done a bunch of work in the metagenomics space, and
             | you very quickly get outside areas where Alphafold can
             | really help, because nothing you're dealing with is similar
             | enough to already-characterized proteins for the algorithm
             | to really have enough to draw on. At that point, an actual
             | solution for protein folding that doesn't require a
             | supercomputer would make a difference.
        
               | flobosg wrote:
               | > this is what I mean by "a shitty answer fast" -
               | structure prediction isn't a canonical answer
               | 
               | A proper protein structural model is an all-atom
               | representation of the macromolecule at its global minimum
               | energy conformation, and the expected end result of the
               | folding process; both are equivalent and thus equally
               | canonical. The "fast" part, i.e., the decrease in
               | computational time comes mostly from the heuristics used
               | for conformational space exploration. Structure
               | prediction skips most of the folding pathway/energy
               | funnel, but ends up at the same point as a completed
               | folding simulation.
               | 
               | > At that point, an actual solution for protein folding
               | that doesn't require a supercomputer would make a
               | difference.
               | 
               | Or more representative sequences and enough variants by
               | additional metagenomic surveys, for example. Of course,
               | this might not be easily achievable.
        
               | roughly wrote:
               | > ends up at the same point as a completed folding
               | simulation.
               | 
               | Well, that's the hope, at least.
               | 
               | > Or more representative sequences and enough variants by
               | additional metagenomic surveys, for example. Of course,
               | this might not be easily achievable.
               | 
               | For sure, but for ostensibly profit-generating
               | enterprises, it's pretty much out of the picture.
               | 
               | I think the reason an actual computational solution for
               | folding is interesting is that the existing set of
               | experimentally verified protein structures are for
               | proteins we could isolate and crystalize (which is also
               | the training set for AlphaFold, so that's pretty much the
               | area its predictions are strongest, and even within that,
               | it's only catching certain conformations of the proteins)
               | - even if you can get a large set of metagenomic surveys
               | and a large sample of protein sequences, the limitations
               | on the methods for experimentally verifying the protein
               | structure means we're restricted to a certain section of
               | the protein landscape. A general purpose computationally
               | tractable method for simulating protein folding under
               | various conditions could be a solution for those cases
               | where we can't actually physically "observe" the
               | structure directly.
        
               | dekhn wrote:
               | Most proteins don't fold to their global energy minimum-
               | they fold to a collection of kinetically accessible
               | states. Many proteins fail to reach the global minimum
               | because of intermediate barriers from states that are
               | easily reached from the unfolded state.
               | 
               | Attempting to predict structures using mechanism that
               | simulate the physical folding process waste immense
               | amount of energy and time sampling very uninteresting
               | areas of space.
               | 
               | You don't want to use a supercomputer to simulate
               | folding; it can be done with a large collection of
               | embarassingly parallel machines much more cheaply and
               | effectively. I proposed a number of approaches on
               | supercomputers and was repeatedly told no because the
               | codes didn't scale to the full supercomputer, and
               | supercomputers are designed and built for codes that
               | scale really well on non-embarassingly parallel problems.
               | This is the reason I left academia for google- to use
               | their idle cycles to simulate folding (and do protein
               | design, which also works best using embarassingly
               | parallel processing).
               | 
               | As far as I can tell, only extremely small and simple
               | proteins (like ribonuclease) fold to somewhere close to
               | their global energy minimum.
        
           | adastra22 wrote:
           | AlphaFold doesn't work for engineering though. Getting a
           | shitty answer ends up being worse than useless.
           | 
           | It seems to really accelerate productivity of researchers
           | investigating bio molecules or molecules very similar to
           | existing bio molecules. But not de novo stuff.
        
             | roughly wrote:
             | Eh, in many cases for actual customer-facing commercial
             | work, they're sticking remarkably close to stuff that's in
             | genbank/swissprot/etc - well characterized molecules and
             | pathways, because working with genuinely de novo stuff is
             | difficult and expensive. In those cases, Alphafold works
             | fine - it always requires someone to actually look at the
             | results and see whether they make sense or not, but also
             | "the part of the solution space where the tools work" is
             | often a deciding factor in what approach is chosen.
        
           | jltsiren wrote:
           | > It also proved that deep learning models are a valid
           | approach to bioinformatics
           | 
           | A lot of bioinformatics tools using deep learning appeared
           | around 2017-2018. But rather than being big breakthroughs
           | like AlphaFold, most of them were just incremental
           | improvements to various technical tasks in the middle of a
           | pipeline.
        
         | JangoSteve wrote:
         | Interestingly, the award was specifically for the impact of
         | AlphaFold2 that won CASP 14 in 2020 using their EvoFormer
         | architecture evolved from the Transformer, and not for
         | AlphaFold that won CASP 13 in 2018 with a collection of ML
         | models each separately trained, and which despite winning,
         | performed at a much lower level than AlphaFold2 would perform
         | two years later.
        
       | YeGoblynQueenne wrote:
       | Looks like science is out, black box prediction is in. It's like
       | the era of epicycles all over again.
       | 
       | Oh well. Fellow realists, see you all 1500 years from now!
        
         | pelorat wrote:
         | There are things so complex in science that a human mind can
         | never understand them, but a large neural network can.
        
           | outworlder wrote:
           | For some definition of 'understanding'.
        
         | bonoboTP wrote:
         | It was big blind luck that the laws of planetary motion turned
         | out to be so simple. There's no reason to think that protein
         | folding can similarly be reduced to some elegant description
         | without needing large blackbox models.
        
         | ayakang31415 wrote:
         | Science is just a methodology to test hypothesis. It does not
         | matter how you get the result as long as the result is
         | empirically scrutinized.
        
       | uptownfunk wrote:
       | To me this is more controversial than Geoffrey Hinton winning it
       | for physics.
        
         | ocular-rockular wrote:
         | They should've given this prize to Hinton too, for making the
         | machine learning of Alphafold possible.
        
       | dekhn wrote:
       | I wasn't expecting to see David Baker in the list (just Demis and
       | John). But I'm really glad to see it... David is a great guy.
       | 
       | At CASP (the biannual protein structure prediction competition)
       | around 2000, I sat down with David and told him that eventually
       | machine learning would supplant humans at structure prediction
       | (at the time Rosetta was already the leading structure
       | prediction/design tool, but was filled with a bunch of ad-hoc
       | hand-coded features and optimizers). he chuckled and said he
       | doubted it, every time he updated the Rosetta model with newer
       | PDB structures, the predictions got worse.
       | 
       | I will say that the Nobel committee needs to stop saying "protein
       | folding" when they mean "protein structure prediction".
        
         | jboggan wrote:
         | The models and tools designed for the CASP competition were an
         | example of running around the solution space at a glacial pace
         | and getting stuck in local minima. I can't speak for Rosetta by
         | my labmates had fairly successful tools that usually ranked
         | right behind Baker's lab, and they were plagued by issues where
         | the most successful models had impossible or idiosyncratic
         | terms in them.
         | 
         | For example, a very successful folding model had the signs
         | reversed on hydrophobic and some electrostatic interactions. It
         | made no sense physically but it gave a better prediction than
         | competing models, and it was hard to move away from because it
         | ranked well in CASP.
        
           | dekhn wrote:
           | Which model had the signs reversed?
           | 
           | Yes, CASP was prone to getting stuck in local minima. I think
           | the whole structure prediction field had become moribund.
        
         | throwawaymaths wrote:
         | Refreshingly good. Bakers "early" (not really early, but
         | earlier than AlphaFold) work (having humans with no background
         | solve folds) really laid the groundwork to proving that
         | heuristic methods were likely to outperform physical forcefield
         | and ab initio/DFT methods for structure prediction. And AI
         | structure prediction if nothing else is heuristic protein
         | folding.
        
         | siver_john wrote:
         | They had to put David Baker on here, his work on protein design
         | if nothing else was ground breaking. I've expected him to win
         | it at some point in a, it's not a matter of if but of when.
        
       | hanjeanwat wrote:
       | excellent longread on the development of AlphaFold - with
       | interviews with Baker + Jumper and more:
       | https://www.quantamagazine.org/how-ai-revolutionized-protein...
        
       | jboggan wrote:
       | Congrats to David Baker and his lab!
        
       | photochemsyn wrote:
       | AlphaFold is a useful tool but it's unsatisfying from a physical
       | chemistry perspective. It doesn't give much if any insight in to
       | the mechanisms of folding, and is of very limited value in
       | designing novel proteins with industrial applications, and in
       | protein prediction for membrane-spanning proteins, extremophilic
       | microbe proteins, etc.
       | 
       | Thus things like folding kinetics of transition states and
       | intermediates, remain poorly understood through such statistical
       | models, because they do not explicitly incorporate physical laws
       | governing the protein system, such as electrostatic interactions,
       | solvation effects, or entropy-driven conformational changes.
       | 
       | In particular, environmental effects are neglected - there's no
       | modeling of the native solvated environment, where water
       | molecules, ions, and temperature directly affect the protein's
       | conformational stability. This is critical when it comes to
       | designing a novel protein with catalytic activity that's stable
       | under conditions like high salt, high temperature etc.
       | 
       | As far as Nobel Prizes, it was already understood in the field
       | two decades ago that no single person or small group was going to
       | have an Einstein moment and 'solve protein folding', it's just
       | too complicated. This award is questionable and the marketing
       | effort involved by the relevant actors has been rather misleading
       | - for one of the worst examples of this see:
       | 
       | https://www.scientificamerican.com/article/one-of-the-bigges...
       | 
       | For a more judicious explanation of why the claim that protein
       | folding has been solved isn't really true:
       | 
       | "The power and pitfalls of AlphaFold2 for structure prediction
       | beyond rigid globular proteins" (June 2024)
       | 
       | https://www.nature.com/articles/s41589-024-01638-w
        
         | pelorat wrote:
         | The mechanisms of folding is most likely impossible for a human
         | mind to comprehend.
        
       | bawolff wrote:
       | AI is cleaning up at the nobel prizes!
        
         | optimalsolver wrote:
         | This is what extreme FOMO looks like.
        
       | muenalan wrote:
       | Surely, it is helpful to consider the achievement in terms of the
       | contest setup to detect a Nobel-worthy breakthrough:
       | https://en.m.wikipedia.org/wiki/CASP
       | 
       | It moved the needle so much in terms of baseline capability. Let
       | alone Nobel's original request: positive impact to humanity; well
       | deserved.
       | 
       | In biology/medicine it is still awed like coming from a different
       | planet; tech before was obviously that lacking.
        
       | hilux wrote:
       | I'm not always a Lex Fridman fan, but the interview with Demis is
       | well worth a listen.
        
       | phtrivier wrote:
       | Feeling a bit down today, so just asking: when can we
       | realistically expect to see the (positive) effects of this Nobel
       | in daily life, and what would they be ? (I understand it's
       | helping biotech a lot, but helping them do... what exactly ?)
        
         | Dumblydorr wrote:
         | The drug development process takes around 10+ years typically,
         | a lot of long planning of multiple phases of studies needs to
         | be done. This will help in the initial steps and in finding
         | good starting points, and in theory should help the subsequent
         | stages be more successful. I wouldn't expect new drugs this
         | decade.
         | 
         | Other aspects of biotech and research could well be affected
         | far faster than the consumer drug market, but again you'll need
         | a few years for those early stage developments to aid real
         | world applications.
        
       | kragen wrote:
       | Huh, so both the chemistry Nobel and the physics Nobel were for
       | neural networks this year. That's astounding.
        
       | ggm wrote:
       | As a computer scientist who is oppositional to AGI boom-bubble
       | mania, it was easy to decry the Nobel in physics. But,
       | contextually given who Murray Gell-Mann was and what field he was
       | in (astrophysics) I feel a very strong Gell-Mann Effect here
       | because I am happy to accept THIS use of computational systems to
       | advance (bio)chemistry is worthy, and I find myself wondering why
       | I am so uncritical about it?
        
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