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The industry process will not change. You still need industrial biologists to generate and validate AphaFold structures, interpret the results as part of the bi

by _RPL5_ 6y ago

The industry process will not change. You still need industrial biologists to generate and validate AphaFold structures, interpret the results as part of the bigger picture, and to finally design the drugs. And, then, of course you still need to validate the drugs in experimental systems (first the test tube, then mice, then humans). So your second guess is correct - one of the steps is much cheaper now, which marginally improves the entire pipeline. As a result, drugs should now arrive to the market faster. As a side note, I am curious what happens to the field of structural biology in 10 to 15 years from now. Every research university has a large structural biology department with super expensive Xray/NRM/Cryo-EM machines, and armies of students who routinely spend 4-6 years of their PhD trying to solve a structure of a single protein. If AlphaFold works as advertised, NIH will gradually shift funding to other problems. (It was predicted that it'd be taxi drivers, not professors, that AI got first. Ironic.)

dalke 6y ago
> "armies of students who routinely spend 4-6 years of their PhD trying to solve a structure of a single protein" Back in the 1990s, when I worked on structure data, I remember that at least some crystallizations were easy enough they could be done as a rotation project. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287266/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287266/ suggests that life is now a lot easier than the 1990s. Quoting the abstract: > Macromolecular crystallography evolved enormously from the pioneering days, when structures were solved by “wizards” performing all complicated procedures almost by hand. In the current situation crystal structures of large systems can be often solved very effectively by various powerful automatic programs in days or hours, or even minutes. Such progress is to a large extent coupled to the advances in many other fields, such as genetic engineering, computer technology, availability of synchrotron beam lines and many other techniques, creating the highly interdisciplinary science of macromolecular crystallography. Due to this unprecedented success crystallography is often treated as one of the analytical methods and practiced by researchers interested in structures of macromolecules, but not highly competent in the procedures involved in the process of structure determination. Certainly some proteins are extremely hard to crystallize, and the new single-atom EM work will help a lot. But are there really "armies of students who routinely spend 4-6 years of their PhD trying to solve a structure of a single protein" these days? I honestly don't know. I'm sure some do. But if so, that army is pretty small compared to the vast numbers who more routinely use crystallography.
- t_serpico 6y ago
  Also, one important thing to realize is that AlphaFold was trained largely on proteins that we were able to crystallize. I'd be very curious to see how its performance fares as a function of 'ease of crystallization'.
- _RPL5_ 6y ago
  You aren't wrong. I got caught up making the comparison between structural biologists and taxi drivers being ran out of business by AI, so I ended up exaggerating the work load that's addressed by AlphaFold. I should been more precise.
- prcrthr 6y ago
  I had a friend who solved the structure of 2 or 3 new proteins pretty much by himself his senior year of college. I also had an acquaintance who was a PhD student in the same lab, who said (jokingly) that she hated him because she had spent 5 years on a single protein and got way worse results than he did. I got the sense from talking to them that the process of figuring out how to get a protein to crystallize is basically just trial and error over and over—my friend himself said he basically got very lucky several times in a row (though he is also a brilliant biochemist). Anyway that anecdote is pretty much the entire sum of my protein crystallography knowledge, but perhaps it explains how your experience and GP's statement can both be true?

by _RPL5_ 6y ago

dalke 6y ago

> "armies of students who routinely spend 4-6 years of their PhD trying to solve a structure of a single protein" Back in the 1990s, when I worked on structure data, I remember that at least some crystallizations were easy enough they could be done as a rotation project. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287266/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287266/ suggests that life is now a lot easier than the 1990s. Quoting the abstract: > Macromolecular crystallography evolved enormously from the pioneering days, when structures were solved by “wizards” performing all complicated procedures almost by hand. In the current situation crystal structures of large systems can be often solved very effectively by various powerful automatic programs in days or hours, or even minutes. Such progress is to a large extent coupled to the advances in many other fields, such as genetic engineering, computer technology, availability of synchrotron beam lines and many other techniques, creating the highly interdisciplinary science of macromolecular crystallography. Due to this unprecedented success crystallography is often treated as one of the analytical methods and practiced by researchers interested in structures of macromolecules, but not highly competent in the procedures involved in the process of structure determination. Certainly some proteins are extremely hard to crystallize, and the new single-atom EM work will help a lot. But are there really "armies of students who routinely spend 4-6 years of their PhD trying to solve a structure of a single protein" these days? I honestly don't know. I'm sure some do. But if so, that army is pretty small compared to the vast numbers who more routinely use crystallography.

t_serpico 6y ago
Also, one important thing to realize is that AlphaFold was trained largely on proteins that we were able to crystallize. I'd be very curious to see how its performance fares as a function of 'ease of crystallization'.
_RPL5_ 6y ago
You aren't wrong. I got caught up making the comparison between structural biologists and taxi drivers being ran out of business by AI, so I ended up exaggerating the work load that's addressed by AlphaFold. I should been more precise.
prcrthr 6y ago
I had a friend who solved the structure of 2 or 3 new proteins pretty much by himself his senior year of college. I also had an acquaintance who was a PhD student in the same lab, who said (jokingly) that she hated him because she had spent 5 years on a single protein and got way worse results than he did. I got the sense from talking to them that the process of figuring out how to get a protein to crystallize is basically just trial and error over and over—my friend himself said he basically got very lucky several times in a row (though he is also a brilliant biochemist). Anyway that anecdote is pretty much the entire sum of my protein crystallography knowledge, but perhaps it explains how your experience and GP's statement can both be true?