Coming up with candidate drugs is the easiest part of the process. It’s possible that that could be improved a little (not sped up, but suggesting compounds in silico less likely to fail) and possibly have suggestions for scale up, but those are all hard, and the latter is less amenable to being “read” during trains phase.
This has been one of the target AI applications since the 1960s.
(Former drug developer who will never touch the life sciences again)
Interesting. In TFA they don't focus on that, they say:
"Developing a drug involves many varied tasks: doing early research to identify a target for a drug and the right type of drug to engage it, designing a molecule with the right properties, optimizing it to be manufactured reliably at scale, drafting the regulatory filings needed to run clinical trials, designing and administering those trials, and much more.
Our strategy to realize AI’s medical benefits is based on having AI increasingly involved in all of these tasks."
That's all true, but they don't mention the relative costs of those different tasks, or how AI helps them.
Optimizing molecular properties of a lead is important, but ultimately not a huge source of costs. In any case, LLMs probably have as much chance of predicting outcomes as anyone else (i.e. very small).
Manufacturing is somewhat expensive, but most of the cost sits in actually creating a production process, which is not a thing LLMs can do.
Clinical trials are where most of the costs lie, but unless you can create a magical classifier that can tell me if my drug will make it past phase 3, you're not significantly bending the cost curve.
Calling these "machines" LLMs seems to sell the process short. Using the same style of attention in a different domain is very valuable. An LLM wasn't what created a video of a panda on the moon. I am not remotely an expert, just a software person with a lot of interest over the years.
My reading of the hypothesis is this, interested in your thoughts:
> unless you can create a magical classifier
A generator could concentrate on pockets while remaining unable to judge most drugs. And LLM RLVR a) works well, and b) is black box optimisation and so is suited since it doesn't need system identification (which you can't do for complex biological systems). So the hypothesis is that, yes making a classifier is very very hard, but you could through some (lots?) initial interactive data, end up with our generator outputting with high probability drugs-that-end-up-passing-trials-with-probability-p. Whether these drugs thus generated are drugs we care about (i.e, whether `p` is good enough) and whether the whole pocket it generates in is large enough, and how jagged this behaviour is (i.e distribution of `p` across taxonomies of drugs), are the few questions we want answered.
Well first off: molecular screening (which is basically what you're describing) is inadequate for drug discovery. There are too many other factors that matter: water positions, molecular flexibility, short and long-range electrostatics, entropy loss, coordinating ions, and more. You need not only the "pocket", but an accurate model of the system's conformational change over time, to have any hope of understanding binding energetics. It's a bigger problem for small molecule drug discovery than biologics, but it still matters.
That said, we have extremely well-refined force fields that attempt to model the underlying physics, and still fail to do this well. There's absolutely no reason to believe that a generic LLM will bring anything to the table that improves the situation. Even with the hand-wavy assertion that we (somehow) get "lots and lots of data", and somehow train a purpose-built model to do the same, it's kind of like saying that we could turn a minivan into a formula one car with enough effort. Different tools for different jobs.
I actually do believe that informatics approaches will be helpful given lots of system-specific data, but when I say that, I mean "a bespoke neural energetic model that is trained specifically for some molecular system down to customized force-field parameters", not "Claude".
So sure, maybe Anthropic will invest lots of time and money and energy into making these kinds of molecular simulation models, which they can then use for high-throughput screening experiments. But even if they do all of that, there's still no guarantee that they'll bring anything to the party that hasn't been done before...because this is the lowest-value step of drug discovery, and a model like that won't tell you if your drug is going to be toxic, or have off-target effects, or have metabolic problems, or...a million other things, which are what kill drug programs in phase 1 and beyond.
Administering phase 3 drug trials is the most expensive part of the process by far. They conveniently put that at the end.
They put it at the end because they list the parts chronologically...
It would be pretty reckless to do it any other way. That is, to evaluate whether it makes sense to distribute as a product without having any reason to believe that it is safe for humans and has any effect at all.
That's my understanding as well. Seems like they're improving a $20 part of a billion dollar process, and a part that was already heavily using state of the art AI/simulation at that. The computers already spit out more potential candidates than what can be reasonably tested in vitro.
> Seems like they're improving a $20 part of a billion dollar process, and a part that was already heavily using state of the art AI/simulation at that. The computers already spit out more potential candidates than what can be reasonably tested in vitro.
This is the fundamental problem with nearly all tech-meets-drugs startups. They almost always focus on the part of the problem where there isn't a bottleneck, because the parts where there is a bottleneck are the parts we don't understand at all.
> This is the fundamental problem with nearly all tech-meets-drugs startups. They almost always focus on the part of the problem where there isn't a bottleneck, because the parts where there is a bottleneck are the parts we don't understand at all.
Are they doing the thing where they develop the technology first, then hunt around for problems for it to solve and hype up potential applications?
Sort of. There’s also a big helping of intellectual arrogance, wherein the tech people think they can apply their l33t skills to biology, and get the same results (I say this as a person who has spent a non-trivial portion of my life as one of those people.)
That said, the LLM version of this is perhaps more solution-seeking-problem than past iterations. LLMs are obviously useful [1]. Scientists already use them. The labs are just desperate to find a multi-billion-dollar application outside of coding, and they’ve all decided that “drug development” is lucrative, so they're gonna apply their magic to that problem and collect profits!
[1] In the way that photocopiers are useful in drug development: as a tool. A powerful tool, but still a tool.
I don’t see the issue really though, if the $20 part still produces something more likely to get through the billion dollar parts what’s the problem ?
It doesn’t. That’s what I mean when I tell you the bottleneck is somewhere else. Obviously everyone claims that they do this with new technology X, but empirically, it isn’t helpful.
Re-ranking pre-clinical leads is the scientific equivalent of that old saying about opinions.
Few years back many SWE people would say, including me, that the bottleneck is not in coding. We were all very wrong.
Not even close to a relevant metaphor. Compared to drug development, coding is trivial. It was always obvious that coding would be the first to fall: there’s a corpus of all the code ever written, the system is fixed in scope and relatively small, the data is text, and it’s all easily validated by machine for correctness.
There is no objective function you can optimize your way to a drug discovery machine, let alone a fundamental understanding of how the underlying system works.
I'd take your overly dismissive words as credible (but still wrong) only if you did the career in both disciplines which I assume you didn't. You're wrong, and your view of SWE discipline is a great example of DK effect. Not something one would expect from a PhD in computational biology, yes?
Indeed. Just think about how much people meme here "in mice" when stuff gets posted. There's a very long process between computational screening and getting an actual drug into actual humans.
What is the hard part then? My read from here is that it is testing drugs on humans, or rather getting the approvals needed to begin human trials. Is this understanding correct?
yes. you have to recruit a diverse and representative population, which is very difficult and time-consuming. then, you have to spend several years conducting the trial. most of the time, the drug either has no effect or is actively harmful. 90% of drugs that go to clinical trials fail!
Is simulating the effects on humans not an option? Or is it that simulation technologies are not good (accurate) enough?
Thank you for entertaining my curiosity! I have been meaning to educate myself on this but don't know anybody in my circle who is knowledgeable in this field.
Humans are incredibly complex systems (and systems of systems) and our knowledge of how these systems work and interact is very limited despite the amount of work put into improving our understanding of them.
We can try to simulate the interaction between a drug and a protein, but most of the time the data to say what the downstream effects (if any) are simply does not exist. This is further complicated by the fact that these downstream effects can be extremely varied depending on both the tissue/disease you are targeting and the person you are treating.
Of course we are always generating more data from more diverse populations and more conditions, but there is a very very long way to being able to simulate drug trials like this.
What turned you off from life sciences? I've been investigating moving into it and would be interested to hear your experience.