2 ms·

We don't know too much about the exact model they made but it looks sufficiently generalizable to be able to give a candidate protein structure for any given se

We don't know too much about the exact model they made but it looks sufficiently generalizable to be able to give a candidate protein structure for any given sequence. It doesn't automatically cure cancer and inject the drug but that by itself is an amazing tool that if available to everyone will revolutionize biology experimentation. I will definitely blame the protein structure field in multiple levels though. It was always frustrating to me to open up Nature or Science and see it filled with papers about structure - like they are innovating so much that half of the top science magazines every week have papers in that field, yet it's not going anywhere? Or is it simply just a bunch of professors tooting their own horns about ostensible progress in a field that's archaic by decades if not years? The overall protein structure field internalised some dogmas in self defeating ways to everyone's detriment and finally events like this (and Cryo em, maybe) will jolt them out or make them fully irrelevant so we can move on. it's only doubly ironic that this came from a team in a company with minimal academic ties showing how toxic that entire system is. I only feel pity for the graduate students still trying to crystallize proteins in this day and age.

timr 6y ago
"We don't know too much about the exact model they made but it looks sufficiently generalizable to be able to give a candidate protein structure for any given sequence. It doesn't automatically cure cancer and inject the drug but that by itself is an amazing tool that if available to everyone will revolutionize biology experimentation." They say on their own press-release page that side-chains are a future research problem, and nothing about their method description makes me believe they've innovated on all-atom modeling. This software seems able to generate good models of protein backbones; these kinds of models certainly have uses, but a backbone model is not enough for drug design. This is certainly an advancement, but you're exaggerating the scope of the accomplishment. " I only feel pity for the graduate students still trying to crystallize proteins in this day and age." Nothing about this changes the fact that protein crystallography is a gold-standard method for determining a protein structure. CryoEM has made it possible to obtain good structures for classes of proteins we could never achieve before, and it's certainly interesting if we can run a computer for a few days to get a 1Å ab initio model for a protein sequence, but we could already do that for a large class of proteins with homology modeling. These predicted structures still aren't generally that useful for drug design, where tiny details of molecular interactions matter. To put it in perspective: protein energetics are measured on the scale of tens of kcal / mol. Protein-drug interactions are measured in fractions of a kcal. A single hydrogen bond or cation-pi interaction or displaced water molecule can make the difference between a drug candidate and an abandoned lead. Tiny changes in backbone position make the difference between a good structure and a bad one. Alphafold isn't doing that kind of modeling.
- ramraj07 6y ago
  Of course, they havent solved everything, but you seem to be doing exactly what I accuse that entire field (and academia in general) of doing - which is to insist a problem is intractable or hard and undermine someone potentially challenging that. When they released the 2018 results tbey field did embrace it (for sure I'd consider the groups organizing CASP as at least forward thinking) but was still skeptical on how much more progress it can make; now they blow everyone's minds again by a monumental leap and again people want to come say of course this is the last big jump! I understand the self preservation instincts that kick in when there's a suggestion that the entire field has been in a dark age for a while, but I hope you can see that there might be something fundamentally wrong with how research is done in academia and that is to blame for why this didn't happen sooner, and why it's so hard for many to embrace it. Regarding your comments on the inapplicability of this current solution for docking, I'm sure that's the next project they're taking up, and let's see where that goes. This is exactly the same type of progression that happened with Go, where when their software bet a professional player everyone's like "yeah but I bet he wasn't that good". A few years later and Lee Sedol just decided to retire. I am interested to see what happens to that entire academic field in a similar vein, though my interests are more in knowing how science can advance from more people thinking this way.
- deeviant 6y ago
  > Nothing about this changes the fact that protein crystallography is a gold-standard method for determining a protein structure. Yes it does. Protein crystallography is/was the gold-standard. Once this result is verified and accepted by the scientific community as a whole, that changes.
  - deleted 6y ago
    [deleted]
- blinding-streak 6y ago
  Are you always so dismissive of Nobel-level achievements?
dekhn 6y ago
The reason for your second paragraph is pretty straightforward. There has been an immense amount of support for proteins as "the workhorses of the cell" for hundred+ years. I call it the "protein bias". We've seen in many times- for example when it was first hypothesized and then proved that DNA, rather than protein, is the heredity-encoding material, and seen many times, for example in the denial that RNA could act as an enzyme or the functional core of the ribosome could be a ribozyme. I think what basically happened is a very influential group of scientists mainly in Cambridge around the 50s and 60s convinced everytbody that reductionist molecular biology would be able to crystallize proteins and "understand precisely how they function" by inspecting the structures carefully enough. I learned, after reading all those breathless papers about individual structures and how they explain the function of protein is that in the vast majority of cases, they don't have enough data to speculate responsibility about the behavior of proteins and how they implement their functions. There are definiteyl cases of where an elucidated structure immediately led to an improved understanding of function: "It has not escaped our notice (12) that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material." but most papers about how cytochrome "works" aren't really illuminating at all.
- smt1 6y ago
  What's interesting is sometimes it boils down to the words effect or an affect in modern English. I think it's actually more interesting when you zoom out and look at bias caused to a lingua franca of standard modern discourse (it's probably counted in units relative to pi and Euler's consts on modern computers). If you switch individual words from roman (latin-1) to greek (I only was englightened to this by reading history book about the Byzantine empire, which the author had tried de-latinifying many words). You'll see the huge ae-bias, the large effect on greek logic thought its effect on math. Now, what's even more interesting is to also take a look at the east. Indo-European languages are all subclassed together in a morphological sense. Most classic Indic languages are heavily prosodic. Sanskrit is a very syntaxic heavy language. Actually the Dali Llama's take on it was quite interesting (see: Universe in a Single Atom) about how ancient wisdom, and indeed Buddhism spread from India to Tibet in the first place. It was over the himilaways so the trek was akin people trying to invade the Swiss during the Middle Ages. The vedas seemed to be like early particle physists (and where basically describing the world using all possible of the word were equipossible with basic afterlife being measurable via some abstract karma) who wiped out the memory but indirectly mentioned other Decartes (mind/body)-like sects. I wonder if it had anything to do with humidity needing that much 'state space'. Celsus the greek school of thought (so). The rate at our technology reinvention or more weakly put our transmission of knowledge about nature and what words mean relative to the experiments and phenomenon they describe has rapidly gotten better, but words cannot simply express intent content in and between n-ary multiple brains in a global enough semantic way. I think various IEEE/W3C and even Unicode will help debias and preserve aboriginal cultural behavior.

timr 6y ago

"We don't know too much about the exact model they made but it looks sufficiently generalizable to be able to give a candidate protein structure for any given sequence. It doesn't automatically cure cancer and inject the drug but that by itself is an amazing tool that if available to everyone will revolutionize biology experimentation." They say on their own press-release page that side-chains are a future research problem, and nothing about their method description makes me believe they've innovated on all-atom modeling. This software seems able to generate good models of protein backbones; these kinds of models certainly have uses, but a backbone model is not enough for drug design. This is certainly an advancement, but you're exaggerating the scope of the accomplishment. " I only feel pity for the graduate students still trying to crystallize proteins in this day and age." Nothing about this changes the fact that protein crystallography is a gold-standard method for determining a protein structure. CryoEM has made it possible to obtain good structures for classes of proteins we could never achieve before, and it's certainly interesting if we can run a computer for a few days to get a 1Å ab initio model for a protein sequence, but we could already do that for a large class of proteins with homology modeling. These predicted structures still aren't generally that useful for drug design, where tiny details of molecular interactions matter. To put it in perspective: protein energetics are measured on the scale of tens of kcal / mol. Protein-drug interactions are measured in fractions of a kcal. A single hydrogen bond or cation-pi interaction or displaced water molecule can make the difference between a drug candidate and an abandoned lead. Tiny changes in backbone position make the difference between a good structure and a bad one. Alphafold isn't doing that kind of modeling.

ramraj07 6y ago
Of course, they havent solved everything, but you seem to be doing exactly what I accuse that entire field (and academia in general) of doing - which is to insist a problem is intractable or hard and undermine someone potentially challenging that. When they released the 2018 results tbey field did embrace it (for sure I'd consider the groups organizing CASP as at least forward thinking) but was still skeptical on how much more progress it can make; now they blow everyone's minds again by a monumental leap and again people want to come say of course this is the last big jump! I understand the self preservation instincts that kick in when there's a suggestion that the entire field has been in a dark age for a while, but I hope you can see that there might be something fundamentally wrong with how research is done in academia and that is to blame for why this didn't happen sooner, and why it's so hard for many to embrace it. Regarding your comments on the inapplicability of this current solution for docking, I'm sure that's the next project they're taking up, and let's see where that goes. This is exactly the same type of progression that happened with Go, where when their software bet a professional player everyone's like "yeah but I bet he wasn't that good". A few years later and Lee Sedol just decided to retire. I am interested to see what happens to that entire academic field in a similar vein, though my interests are more in knowing how science can advance from more people thinking this way.
deeviant 6y ago
> Nothing about this changes the fact that protein crystallography is a gold-standard method for determining a protein structure. Yes it does. Protein crystallography is/was the gold-standard. Once this result is verified and accepted by the scientific community as a whole, that changes.
- deleted 6y ago
  [deleted]
blinding-streak 6y ago
Are you always so dismissive of Nobel-level achievements?

dekhn 6y ago

The reason for your second paragraph is pretty straightforward. There has been an immense amount of support for proteins as "the workhorses of the cell" for hundred+ years. I call it the "protein bias". We've seen in many times- for example when it was first hypothesized and then proved that DNA, rather than protein, is the heredity-encoding material, and seen many times, for example in the denial that RNA could act as an enzyme or the functional core of the ribosome could be a ribozyme. I think what basically happened is a very influential group of scientists mainly in Cambridge around the 50s and 60s convinced everytbody that reductionist molecular biology would be able to crystallize proteins and "understand precisely how they function" by inspecting the structures carefully enough. I learned, after reading all those breathless papers about individual structures and how they explain the function of protein is that in the vast majority of cases, they don't have enough data to speculate responsibility about the behavior of proteins and how they implement their functions. There are definiteyl cases of where an elucidated structure immediately led to an improved understanding of function: "It has not escaped our notice (12) that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material." but most papers about how cytochrome "works" aren't really illuminating at all.

smt1 6y ago
What's interesting is sometimes it boils down to the words effect or an affect in modern English. I think it's actually more interesting when you zoom out and look at bias caused to a lingua franca of standard modern discourse (it's probably counted in units relative to pi and Euler's consts on modern computers). If you switch individual words from roman (latin-1) to greek (I only was englightened to this by reading history book about the Byzantine empire, which the author had tried de-latinifying many words). You'll see the huge ae-bias, the large effect on greek logic thought its effect on math. Now, what's even more interesting is to also take a look at the east. Indo-European languages are all subclassed together in a morphological sense. Most classic Indic languages are heavily prosodic. Sanskrit is a very syntaxic heavy language. Actually the Dali Llama's take on it was quite interesting (see: Universe in a Single Atom) about how ancient wisdom, and indeed Buddhism spread from India to Tibet in the first place. It was over the himilaways so the trek was akin people trying to invade the Swiss during the Middle Ages. The vedas seemed to be like early particle physists (and where basically describing the world using all possible of the word were equipossible with basic afterlife being measurable via some abstract karma) who wiped out the memory but indirectly mentioned other Decartes (mind/body)-like sects. I wonder if it had anything to do with humidity needing that much 'state space'. Celsus the greek school of thought (so). The rate at our technology reinvention or more weakly put our transmission of knowledge about nature and what words mean relative to the experiments and phenomenon they describe has rapidly gotten better, but words cannot simply express intent content in and between n-ary multiple brains in a global enough semantic way. I think various IEEE/W3C and even Unicode will help debias and preserve aboriginal cultural behavior.