> like proposing initial designs for new molecules
James van Geelen Of Citrini research brought up a good point on a podcast this week, that designing the molecules is perhaps 10-20% of the effort in bringing a drug to market. We have more possible drug designs than ever get developed.
Whilst AI drugs might be more likely to pass phase 2 tests than others and AI might be applied to the rest of the process there are still big bottlenecks in the way of AI creating a radical change.
This is a largely agreed upon problem. What isn't clear is why it seems to get sidestepped in discussion so frequently. No one knows how a molecule will interact with human biology. It can't be simulated computationally to generate data (too slow), there isn't a lot of data in the grand scheme of things, so you can't train a model to actually predict the interaction of a molecule with a human.
And nothing I've said here is an original thought or piece of insight.
One might argue that we have calibrated drug safety to such a high degree that the aggregate negative social impacts are far higher than the costs of side effects. Of course we don’t want another thalidomide catastrophe but I think there are large potential test groups to mine who are much less sensitive to the risks. For example, the elderly and those with terminal diagnoses. Right now we only permit drug testing in very limited cases for the latter group, and only when the treatment is related to their terminal diagnosis. I’m seeing older people taking all kinds of experimental anti-aging drugs right now, either off label, or novel. We’re not collecting any of this data empirically because what they’re doing is not legal.
Further, [we are getting much better at simulating drug interactions.](https://pubmed.ncbi.nlm.nih.gov/41155903/) I strongly suspect AI will offer new probabilistic models to funnel novel drugs into more targeted trials which are much more likely to succeed. If we had 90% certainty of success and high certainty of lower adverse reactions I think we could allow much less stringent human trials. That means much lower cost and much faster turn-around.
My wife is a doctorate in pharmacology, I made exactly this argument to her but she dismantled it pretty quickly.
a) We do test on terminally ill people, but after testing in other models.
b) Thalidomide was all roses compared to the horrors you can inflict.
c) Profit-driven industry makes extremely perverse incentives.
Still I do come down more on your side of the argument, and we have historically made massive leaps doing some horrific things.
I wonder if we can get better models based off of human cell-lines / tissues? Like CRISPR did?
> Profit-driven industry makes extremely perverse incentives
People who are specialists in something other than economics often make this argument but it's often a very weak argument, IMO. Liability means that you are incentivized to be quite cautious in pushing a potentially dangerous product. Particularly with pharmaceuticals a class action can be easily and successfully argued in court. Moreover, a relatively small number of dangerous flops will tank your reputation with consumers. I would also add that you can't make any more money selling drugs to people you have killed.
The worst money incentive for drug manufacturers is that market forces push them towards recurring treatments for diseases that effect a large number of people. However that seems less than perverse to me.
> I would also add that you can't make any more money selling drugs to people you have killed.
That assumes that people are playing a long game. If you're looking for your payday and exit, and there are many people out there who are only looking for the next payday, this argument falls apart.
> Moreover, a relatively small number of dangerous flops will tank your reputation with consumers.
One success the anti-vax people have achieved is to muddy the waters around this. Your public reputation is no longer correlated to actual performance.
> Liability means that you are incentivized to be quite cautious in pushing a potentially dangerous product
There's a long list of people throughout history who do not have this caution at all.
You seem to be taking a theoretical economics approach. Reality is different. People are not perfectly rational actors, and consequences are not consistent.
The antivax people are still fringe and by and large people trust that the drugs they take are safe and effective.
Payday and exit is pretty hard in biotech as you need to conjure up billions of dollars in capital, which doesn't often flow to people who payday-and-exit.
What happens in reality is that people try really hard to make safe and effective drugs, they mostly fail, and the ones that are approved are generally safe and effective.
> b) Thalidomide was all roses compared to the horrors you can inflict.
Just to expand on this for the audience. Even a perfectly reasonable synthesis of MPPP, a synthetic opioid, can produce MPTP[1], which will destroy all of your dopaminergic neurons and give you permanent brain damage. This was discovered entirely by accident. Or, Karen Wetterhahn, who got a single drop of organic mercury on her gloved hand and spent the next year suffering from her brain rotting from the inside out.
This only barely scratches the surface from what I can remember, but there's absolutely, unambiguously a lot of good reasons why these barriers are there. These are rules that have been put down through blood and tears.
d) elderly and infirm people are in a weakened state and so are less likely to recover from accidental complications your drug might introduce
e) sickness is itself a confounder for the toxicology effect of a drug. Suppose you take a drug and your liver shuts down - did the drug cause it or was it your underlying illness? This can lead to programs being prematurely shut down and actually prevent the development of treatments that might have gone on to succeed.
Testing a drug in a terminally ill person for something other than their illness is not going to produce meaningful data.
You misunderstand how hard it is to pull signal from a drug being put into a human body, which is why we need large numbers of people who meet extremely narrow criteria (and don't have things like a terminal cancer).
Your latter idea is a good one, and hopefully something AI will help with. As you imply: we will know empirically when it's ready because trial failure rates will trend toward zero. Today we're closer to 90% failures and not even clearly trending in the correct direction.
You're aware that, as a healthy volunteer, you could go sign up for a Phase 1 study today, right? You can even earn a pretty penny doing so.
It's quite a leap to go from the study you linked to thinking AI will create models that will be useful for new trials. The big leaps in AI have required enormous amounts of data. There is no such analogous data sets in biology and no foreseeable way to get it.
It really is hard to see AI improving the trial process meaningfully. We are more likely to see progress with better trial design and regulatory regimes.
They use more sophisticated domides based off Thalidomide these days (2nd gen Lenalidomide, 3rd gen Pomalidomide, and next gen Mezidomide is in trials).
But yes, it was very effective as a treatment. When it was approved for cancer use, we actually had no idea how it worked, only that it worked really well. Thalidomide has saved a few orders of magnitude more lives than it took/damaged.
its pretty obvious why that gets sidestepped isnt it? There are multiple companies trying to go public with trillion dollar valuations on the premise that AI will change everything, it would be mad if they weren't spending hundreds of millions to billions in shaping public opinion that everything can be solved with AI.
Anthropic and others already have "AI-powered wet labs". Not sure to what extent they are able to automate lab operations. I recall seeing a post about specifically running automated in-vitro experiments controlled by agents, though. I don't think it's being sidestepped, I think it is being handled. Or at least they are trying; maybe the labs operate at a "Theranos-spraying-blood-everywhere" level.
I am incredibly optimistic on AI, especially for drug discovery. However, the belief that AI drugs will be more likely to pass phase 2 tests than others is either based on the assumption that AI will mostly be used to attack safe indications (me too drugs for targets that already have therapies operating on the same mechanism), or on some belief that perhaps in a distant future the transfer to human biology is better understood by the AI but not documented or shared with humans. Although I think the latter will come true, eventually, people right now tend to forget that because of the extreme cost of human clinical trials, the preclinical candidate has undergone every possible test that regulatory agencies, consultants, the internal company knowledge have suggested. So the failure on a new drug is only related to the “surprise” differences in humans vs all the tests in animals, cells, or in vitro setups that were previously done. Right now AI can help you get to the clinical candidate much faster and with fewer resources than before, but I believe that the translation to success rate improvement has some assumption that is probably not correct in the context of a fixed/novel target. I am open to the possibility that I miss something fundamental and would love feedback.
It's also the case that preclinical candidates developed this way are even harder to translate into human trials, because regulators and drug developers don't know how to build a safe and informative trial given the novelty of the methods that produced the candidate. So you essentially end up redoing a lot of the work that the AI allowed you to skip in order to do the work that remains. Perhaps a future innovation in "explainable" AI could help here, but that such a technology would itself need to be clinically validated in order to solve this problem.
Source: spent 9 years at a AI drug discovery startup. We advanced 8 clinical candidates and every one of them ran into some variant of this issue.
There are also players working on accelerating later stages of drug development with AI, e.g. https://atlas.bio/ probably just a matter of time until the big AI labs also start working on this.
this hot take is more important than we all think. While adding features is more optimised than ever (e.g. auto software development) many systems and processes are fairly optimised already. Many agent implementations I have seen don't optimise the process but replicate/automate it. This has made me think that some things are already optimised, there is always room for improvement but those gains might not weigh up always in the race use AI for everything.
This said optimization is a multi-dimensional problem space.
While the process may not be directly cheaper with AI it may side step other problems that profit seekers run into, like people wanting days off or pesky things like human rights.
Maybe Anthropic could provide a Claude tier where you get access to Max-tier subscriptions in exchange of participating in experimental drug programs? Would be a huge boon for AI enthusiasts and other tech optimists.
Consider commuting with a friend in the morning: if you get dressed and get out of the door in 5m instead of 10m, but then have to wait for me to come pick you up, and then we both sit in a car for 5m to get to the train, and then we sit on that for 50.. then your speed up doesn't really matter.
I don't know if this is the case for drug development but as GP said, we already have more designs than we can test.
It's also not the magical thing that will solve all diseases like some people who are starting to think we're going to enter the singularity soon seem to think.
But if that 20% is not the bottleneck then at most your market is replacing the labor required to get that 20% to the next phase, plus you will probably not be able to capture full value here because of lab/model competition.
Choosing the molecules is by far the most important part of drug discovery. It may only be 20% of the work, but everything downstream relies on it. If ai is able to change the odds of discovering a molecule that ends up passing phase 3 from eg 5% to 10% then you only have to do half as many trials to get the same number of drugs. So even though drug discovery doesn’t take a ton of time doing a better job at it can save huge amounts of time down the line.
It’s only a benefit if it doesn’t bog the next stage down in noise. At that point it could be detrimental.
We already see that with software. It will be exactly the same with drug design.
My daughter is a leading biochem at one of the big pharma companies and that’s their principal worry about this. It’s really easy to create a lot of information these days which compromises the entire process.
The next step is already mostly noise. Less than 15% of drugs that go through phase 1 trials end up passing phase 3. The goal here isn’t to do drug discovery faster, it’s to get that 15% number up.
Already 20 years ago, medical corporations had facilities to scan millions of molecules as potential drugs candidates. This did use knowledge found manually over the years and vast computing resources. This already found more good candidates than what could be clinically tested. To find drug candidates is not remotely the bottleneck in drug development, so unless the candidates are vastly higher quality, nothing is gained.
James van Geelen Of Citrini research brought up a good point on a podcast this week, that designing the molecules is perhaps 10-20% of the effort in bringing a drug to market. We have more possible drug designs than ever get developed.
Whilst AI drugs might be more likely to pass phase 2 tests than others and AI might be applied to the rest of the process there are still big bottlenecks in the way of AI creating a radical change.
https://podcasts.apple.com/gb/podcast/monetary-matters-with-...