[HN Gopher] AlphaProteo generates novel proteins for biology and...
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AlphaProteo generates novel proteins for biology and health
research
Author : meetpateltech
Score : 202 points
Date : 2024-09-05 15:05 UTC (7 hours ago)
(HTM) web link (deepmind.google)
(TXT) w3m dump (deepmind.google)
| bluehat974 wrote:
| Two minute papers video on the subject:
| https://www.youtube.com/watch?v=lI3EoCjWC2E
| deisteve wrote:
| i studied molecular biology and i couldn't help contain my
| excitement when it was able to bind to another protein. I dont
| think HN realizes how huge this is. With this level of
| accuracy, not only can we understand the full mysteries of
| ourselves but literally any biological entity.
|
| With that level of understanding, its easy to fabricate special
| medicines that target specific biochem pathways, but more
| exciting is that we can literally "code in 3d world". We'll be
| able to print and grow organs in mass. We'll be able to design
| structures that will bind to target proteins responsible for
| certain traits. The potential boon to human medicine will be
| enormous.
|
| I got like goosebumps after watching that video because I
| understood the implications of being able to predict folds and
| now generate proteins that will bind to any protein we
| choose!!!!
|
| We just might have discovered a panacea of sorts and Demis and
| his team should receive the Nobel Prize.
|
| I'm just ecstatic that we'll see so much drastic improvement in
| human medicine and importantly how accessible they will be with
| this new discovery.
| kridsdale3 wrote:
| How do you feel about the potential bioterrorism alternate
| angle of this capability?
| deisteve wrote:
| it would be like committing terrorism using silicon wafers
|
| you would have to infiltrate an extremely guarded facility
|
| you would somehow have to bypass QA
|
| its not like somebody on the assembly line for a new
| protein drug sprinkles a dose of PCP
|
| one potential dual use could be somebody modifying a
| popular fruit with birds and then droppin seeds at the
| local organic farm fair
|
| and then when those seeds are consumed by birds they
| produce poop dangerous for other animals to consume
|
| you could absolutely screw around with the ecosystem, like
| whoever has access to this programmable "bio-wafer" will be
| able to play god totally undetected.
|
| the problem is that "bio-wafer" manufacturing process will
| be very tough and regulated like the CNC machines used to
| manufacture jet engines depriving certain countries from
| being able to churn out their own jet engines
| mjcohen wrote:
| Its not regulated if a government does it.
| stanford_labrat wrote:
| > We'll be able to print and grow organs in mass.
|
| I'm a PhD candidate doing my thesis work on stem cell models
| and tissue engineering for organ transplant...I think this
| technology is certainly a large leap forward but I think you
| are a little overzealous with this claim.
| holoduke wrote:
| In 2035 everybody can live forever.
| aquafox wrote:
| > With that level of understanding, its easy to fabricate
| special medicines that target specific biochem pathways
|
| The problem is to find the right target or pathway in the
| first place. Just go to opentargets.org. There are lots of
| potential targets by different metrics but for many diseases
| we haven't identified that single target that let's us
| improve the life of say, 20% of patients, for disease X.
| westurner wrote:
| > _Trained on vast amounts of protein data from the Protein Data
| Bank (PDB) and more than 100 million predicted structures from
| AlphaFold, AlphaProteo has learned the myriad ways molecules bind
| to each other. Given the structure of a target molecule and a set
| of preferred binding locations on that molecule, AlphaProteo
| generates a candidate protein that binds to the target at those
| locations._
| sdenton4 wrote:
| (not to be confused with AlphaProto, which is helps with Google's
| core business of turning protocol buffers into differenter
| protocol buffers.)
| purpleblue wrote:
| I wonder how many prions will be accidentally created by this, or
| if it can even predict if a particular protein will have prion-
| like effects
| DalasNoin wrote:
| The context here is that prions are misfolded proteins that
| replicate by causing other proteins to change their
| configuration into the misfolded form of the prion. Diseases
| caused by prions include Mad Cow disease, Creutzfeldt-Jakob
| disease, and Chronic Wasting disease. All prion diseases are
| incurable and 100% fatal.
| nabla9 wrote:
| If the protein is a novel it does not matter, because it has no
| normal variants in the nature.
| connorgutman wrote:
| Couldn't the underlying tech be applied to non-novel proteins
| by a bad actor?
| DalasNoin wrote:
| Someone could fine-tune a model on pairs of existing
| proteins and their misfolded prions and then ask the system
| to come up with new prions for other proteins. ChatGPT
| found these 4 companies that will produce proteins for you
| just based on digital DNA that you send them:
|
| - Genewiz (Azenta Life Sciences)
|
| - Thermo Fisher Scientific (GeneArt)
|
| - Tierra Biosciences
|
| - NovoPro Labs
| connorgutman wrote:
| Whelp, time to move to a small island in the middle of
| the Pacific.
| ben_w wrote:
| One of the few cases where Mars actually is a decent
| planet B.
| UniverseHacker wrote:
| It would be essentially impossible to create a new prion
| disease by accident- generating random-ish new things with
| methods like this would pale in comparison to the massive
| number of weird random-ish things natural biology is already
| creating in the wild.
|
| However, this category of technologies could potentially be
| used to develop new prion diseases on purpose. As well as to
| develop cures for prion diseases that disrupt the misfolding.
| Enginerrrd wrote:
| >As well as to develop cures for prion diseases that disrupt
| the misfolding.
|
| That seems quite plausible actually. You'd need something
| that can target misfolded PrP and bind it up so it can't do
| anything and then hopefully your targeting protein leaves
| normal PrP alone. A bit like an antibody.
| brcmthrowaway wrote:
| Oh this would be 100x worse than the covid lab leak
| eig wrote:
| Maybe this is in the supplement of the whitepaper [0], but I
| would have loved to see more analysis of how novel the designed
| proteins really are.
|
| In the whitepaper they mention that they are novel compared to
| other in silico design techniques, but to my knowledge other
| binders to VEGF and Covid spike protein exist and would already
| be found in the PDB database that Deepmind trained the model on.
|
| This is not to minimize the results- if the history of ML is
| anything to go by, even if AlphaProteo does not currently beat
| the best affinity found by in vitro screens, I do not doubt that
| it soon will!
|
| [0] - https://storage.googleapis.com/deepmind-
| media/DeepMind.com/B...
| vessenes wrote:
| They must be somewhat novel in that the wet lab work verified
| up to 10x stronger binding as predicted. I agree it would be
| interesting to see how they compare to known binding proteins
| dekhn wrote:
| we've been able to design tight binders for quite some time
| now- the issue with synthetic designs is that they tend to
| bind a little too tightly. You want to have a reasonable off-
| rate and the ligand protein should do more than just bind, it
| needs to effect some sort of response from the bound protein.
|
| When you look at these synthetics they often maximize for
| interactions of hydrophobic areas on the surface.
| gilleain wrote:
| Might depend on what your measure of 'novelty' is in protein
| structure. A single residue change (for example) would not
| normally be considered a novel structure - it's just a
| mutation.
|
| However, a new fold - that is, the shape that the backbone
| folds into - would be novel. Potentially also novel would be
| 'chimeric' structures with parts from other structures, as with
| chimeric domain swaps.
|
| There was a structure designed by the Baker lab called 'Top7 -
| https://pubmed.ncbi.nlm.nih.gov/14631033/ that I remember as
| ground breaking at the time :) (in the ancient days of 2003 it
| seems ...)
| eig wrote:
| Exactly. If the proteins suggested in this paper are very
| similar to known good binders in PDB then I am much less
| impressed by the results. You could argue they are generating
| a structure from the training set.
|
| I want more info about how novel these proteins are.
| i_love_limes wrote:
| I have a question that hopefully a molecular biologist can
| answer. Can tools like this potentially create protein structures
| that specifically bind in certain cells? Or is this more about a
| way of being able to create proteins for genes / structures we
| haven't been able to before?
|
| I'm very interested in my research at the moment in pleiotropy,
| namely mapping pleiotropic effects in as many *omics/QTL
| measurements and complex traits as possible. This is really
| helpful for determining which genes / proteins to focus on for
| drug development.
|
| The problem with drugs is in fact pleiotropy! A single protein
| can do quite a lot of things in your body, either through a
| causal downstream mechanism (vertical pleiotropy), or seemingly
| independent processes (horizontal). This limits a lot of possible
| drug target as the side-effect / detrimental effect may be too
| large.
|
| So, if these tools can create ultra specific protein structures
| that somehow _only_ bind in the areas of interest, then that
| would be a truly massive breakthrough.
| UniverseHacker wrote:
| Yes, in principle but there are huge limitations and challenges
| to using a protein as a drug in living organisms. It has to be
| injected to avoid digestion, and a protein can't just pass into
| a cell, it needs to get in somehow. Current peptide drugs like
| insulin are identical to, or closely mimic natural small
| peptide hormones that bind to receptors on the outside of a
| cell. However, there is a possibility of using gene therapy to
| directly express a novel protein drug inside of the cell. A
| novel protein is also likely to trigger an immune response- so
| that type of gene therapy is mostly useful when that is
| actually desired, e.g. as a vaccine.
| Pulcinella wrote:
| For anyone who would like to know more about designing proteins
| with a certain function, target, or structure in mind, the term
| to search for is "rational design."
|
| https://en.m.wikipedia.org/wiki/Rational_design
| ampdepolymerase wrote:
| Also "off target effects".
| loopdoend wrote:
| Thank you for this, terms of art are the silent
| gatekeepers...
| elmomle wrote:
| As an aside, learning the precise terms for concepts in
| fields in which I'm a layperson (or simply have some
| cobwebs to shake loose)--and then exploring those terms
| more--is something that I've found LLMs extraordinarily
| useful for.
| highfrequency wrote:
| Not an expert, but you could imagine a protein with two
| receptors that are required for activation. One of them binds
| to a protein that is only present in the cells of interest, and
| the other one binds to the actual target.
| deisteve wrote:
| they can generate proteins that bind to specific structures
| with high accuracy, achieving true cell-specificity and
| avoiding unwanted pleiotropic effects involves many more
| variables beyond just protein-protein interactions. These tools
| are more about expanding our ability to target previously
| "undruggable" proteins rather than solving the cell-specificity
| problem outright. however they could be valuable components in
| developing more targeted therapies when combined with
| comprehensive research on pleiotropic effects across multiple
| omics levels. real breakthrough will come from integrating
| these protein design capabilities with a deeper understanding
| of complex biological systems and developing strategies for
| precise delivery and regulation of these novel proteins in
| vivo.
| ak217 wrote:
| This research is focused on modeling individual protein binding
| sites. Pleiotropic effects and off-target side effects are
| caused by interactions beyond the individual binding sites. So
| I don't think this tool by itself will be able to design a
| protein that acts in the way you describe (and that's putting
| aside the delivery concerns - how do you get the protein to the
| right compartment inside the cell?).
|
| But novel binding domain design could be combined with other
| tools to achieve this effect. You could imagine engineering a
| lipid nanoparticle coated in antibodies specific to cell types
| that express particular surface proteins. So you might use this
| tool to design both the antibody binding domain on the vector
| and also the protein encoded by the payload mRNA. Not all cell
| types can be reached and addressed this way, but many can.
| gman83 wrote:
| What is Google actually doing with these systems? Are they using
| it to develop new drugs themselves? Or licensing it to the
| pharmaceutical industry?
| skadamat wrote:
| Cynical take - mostly to appear like a diverse tech company
| with lots of different products and services so they don't get
| regulated for their strength in the search advertising market.
| aurareturn wrote:
| I think occam's razor might suggest they're trying to
| diversify their revenue so if search declines, they have
| fallbacks.
| DiscourseFan wrote:
| could be both
| kridsdale3 wrote:
| As a Google engineer, I think it's two things:
|
| - Great for recruitment: You're the most talented $SKILL in
| the world? Come to the team that is pushing humanity forward
| in all the ways that matter.
|
| - Larry and Sergei actually care about humanity, and being a
| billionaire is kind of a side-effect of what they would have
| done anyway.
| bawolff wrote:
| Its not like google is the first company to have a will R&D
| department. Xerox invented the mouse. AT&T invented unix &
| c. Etc
| VyseofArcadia wrote:
| I know that you can actually use AlphaFold at least. My wife,
| microbiologist, told me she's used it a couple of times at
| work. I don't know what their monetization model is, if her lab
| had to get a license or anything. But I know scientists are
| using it.
|
| I play Go recreationally. I don't think I can use AlphaGo (or
| its successors) directly, but the published research on AlphaGo
| has inspired other strong Go AIs. Online Go platforms integrate
| them to offer AI matches as well as analyze games between
| humans. I also know that professionally ranked players are
| adopting things learned from AI into their own play, and a lot
| of traditional joseki (analogous to chess openings) are being
| rethought based on insights from AI play.
| eitally wrote:
| It's licensed through Google Cloud as one hosted option, but
| also open sourced.
| dekhn wrote:
| IIUC most of the commercialization is done through Isomorphic
| (https://www.isomorphiclabs.com/). My guess is that Google
| Research/DM itself wants to stay at the front of the field
| rather than develop drugs (of which protein design is really
| just a tiny contribution).
|
| When I worked at Google I made a case for doing protein
| design/preliminary drug discovery using Google infrastructure
| and it was well received by the leadership. The leadership at
| Google is mostly computer scientists who know about, but can't
| actually do, leading-edge life sciences research, and they want
| to contribute some amount of Google's resources to advancing
| the state of the art. That's the only reason exacycle was
| permitted- because Urs thought we could maybe help save the
| world with protein design (and it wasn't a good approach
| because it wasted enormous amounts of power on unbiased
| sampling of large proteins).
|
| Honestly I don't think Google proper is really a good place for
| this work to be applied, though. Their attention is easily
| diverted, they repeatedly fail to commercialize, and most
| importantly, potential partners are scared Google will steal
| their data, and replace their business.
| rty32 wrote:
| I wonder why things seem to work well with Waymo? Google was
| never in the auto industry, but they were able to create a
| subsidiary that has become a leader in automated driving
| system.
| dekhn wrote:
| Yeah, waymo is a bit of an outlier and I think it's got to
| be a directive from Larry to spend some amount of
| money/engineering effort to move it forward, with the
| expectation that it will transform the world into a better
| place (rather than generate a lot of revenue for Google).
| TrainedMonkey wrote:
| Alphabet has a medical division -
| https://en.wikipedia.org/wiki/Verily . My somewhat cynical take
| is that most extremely wealthy individuals would like to live
| longer.
|
| But more immediately this is an interesting and relevant
| problem to solve, so it servers as a tool to benchmark and
| improve AI... and the current theory is that at some point AI
| will {generate unlimited amount of wealth | lead humanity into
| the post-scarcity society | solve all human problems by
| eliminating humans}.
| idunnoman1222 wrote:
| It generates novel candidates doesn't actually generate proteins,
| and none of these proteins have actually been generated to
| validate whether these candidates are shit or not
| pertymcpert wrote:
| Did you read it?
| idunnoman1222 wrote:
| This is equivalent of ChatGPT generates novel code, but we didn't
| run it. It probably works though.
| vessenes wrote:
| Terrible take. The article details independent lab verification
| with researchers listed by name and a quote from them.
| pertymcpert wrote:
| Making a comment without reading the article? Who would do such
| a thing?
| photochemsyn wrote:
| Interesting work, but there's a huge sector they're missing -
| industrial enzyme and catalysis design. Most of this field is
| concerned with small molecule binding - methane, carbon dioxide,
| ammonia, methanol, acetic acid, etc. Binding is often just the
| first step, as you're typically trying to do highly specific
| chemistry, e.g. attaching a single oxygen to methane or a single
| hydrogen to carbon dioxide, etc.
|
| Working in this area might also be good test of their
| technological approach, as small-molecule binding can be somewhat
| challenging, and even evolved biological systems can struggle to
| achieve high specificity.
| dekhn wrote:
| I want to mention an interesting industrial enzyme project. If
| you ever saw the laundry detergent commercial "Protein gets out
| protein", this is referring to an industrial enzyme in laundry
| detergent. Many years ago, Genentech had built up a significant
| capability in proteases, which are proteins that cut other
| proteins into pieces. In the course of optimizing proteases,
| they made a thermostable, thermoactive protease. Although it
| wasn't super useful for Genentech in a drug discovery context,
| it was recognized that you could put an inactive enzyme into
| laundry detergent that would be activated when the hot laundry
| water hit the detergent, and the resulting protease would be
| good at cleaning stains (many stains are composed of protein-
| blood, food, etc).
|
| Genentech set up a subsidiary with Corning (the glass company)
| that owns the IP for this protease and then licensed it to
| laundry detergent manufacturers; many billions of dollars in
| revenue. I think this is one of the original patents:
| https://patentimages.storage.googleapis.com/d9/ca/6f/2fb89ff...
| ray__ wrote:
| My guess is that this area is much harder to break into-enzymes
| facilitate challenging chemical transformations by stabilizing
| high-energy transition states in chemical reactions. These
| states are usually highly transient and therefore much harder
| to capture using the structural biology techniques that
| generate the structural data that AlphaFold and similar methods
| are trained on. Even though there are many structures of
| enzymes in the absence of their substrate, I would imagine that
| the small number of structures for states that represent actual
| catalytic intermediates would make it difficult for a model to
| internalize the features that distinguish a good
| enzyme/catalyst from a bad one.
|
| Another consideration is that most protein structure prediction
| methods only generate the backbone, and the sidechains are
| modeled in afterwards. Enzyme efficiency requires sub-A level
| structural precision in the sidechains that are actually doing
| the chemistry involved in catalysis, so it could also be the
| case that the current backbone-centric methods aren't good
| enough to predict these fine-tuned interactions.
| dataking wrote:
| Interested observer here, not an expert: My understanding is
| that they are using another model called FermiNet for chemistry
| research https://deepmind.google/discover/blog/ferminet-
| quantum-physi...
| pokot0 wrote:
| Safety is the new gatekeeping.
| cultofmetatron wrote:
| new?
| VyseofArcadia wrote:
| It's extremely refreshing that DeepMind is still working on using
| AI to solve hard problems instead of attempt to put creatives out
| of work.
| gman83 wrote:
| I wonder if the backlash they received from inventing
| transformers and then allowing OpenAI to eat their lunch has
| changed their attitude towards how they'll commercialize future
| inventions.
| Improvement wrote:
| I am sorry for my naivety, but what is the practical benefits of
| this?
| space_fountain wrote:
| It varies, but as the article says it can be used for things
| like drug discovery. Imagine there's a new virus running
| rampant. It works by using a very specific protein to latch
| onto a cells so it can pull itself in. You would like to
| develop a drug to stop it doing that and one way to do that is
| to find a protein that wants to strongly latch on to an
| important part of the virus. If it's holding onto the virus the
| virus probably won't be able to penetrate cells because you're
| engineered protein will get in the way. This is part of how
| antibodies work to stop viral infections naturally
| letitgo12345 wrote:
| One question is how specific the binding is -- what's the level
| of off-target effects, etc.
| flobosg wrote:
| In my humble opinion, this work is not that innovative: _de novo_
| protein binders have been done to death, either by AI approaches
| or otherwise. Check out the work by David Baker's group, for
| instance. They have a myriad of examples already.
|
| That being said, as others have commented, my hopes are that all
| these advancements lead _finally_ to reliable design methods for
| novel biocatalysts, an area that has been stalling for decades,
| compared to protein folds and binders.
| boywitharupee wrote:
| what kind of model architecture was used for this? is it safe to
| assume they used a transformer model or a variant of it?
| animanoir wrote:
| yeah yeah whatever another protein discovered oh wow... When are
| we going to see actual results? Hurry up Deepmind!
| muaytimbo wrote:
| This is interesting work but I think something has been
| intentionally overlooked. Creating proteins is difficult and it's
| also unclear how many of these sequences folded into the
| predicted 3d structure. Small molecule synthesis is still easier,
| cheaper, and more scalable than protein therapeutics. I think
| this would've been more impactful had they focused on improving
| on the SOTA small molecule - protein interaction models.
| flobosg wrote:
| > it's also unclear how many of these sequences folded into the
| predicted 3d structure
|
| The whitepaper depicts some successful cases, determined by
| X-ray crystallography or cryo-EM.
| parhamn wrote:
| Question for bio folks here, and not to steal from the joy of
| this article but I've been recently curious how far are we from
| engineering something like a virus that targets a subset of the
| population (e.g. via specific genetic markers). This sort of tech
| being commoditized feels much much scary than the LLM safety talk
| - by a mile.
| bongodongobob wrote:
| Making proteins is nothing like designing life or viruses. It's
| barely even related.
| parhamn wrote:
| Yeah I figured as much. Hence the "[t]his sort of tech" -- I
| imagine progress would be made soon on those fronts as well?
| Or am I mistaken?
| bongodongobob wrote:
| This sort of tech is like inventing a new type of
| screwdriver and asking how it will affect car production.
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