All of Ponder Stibbons's Comments + Replies

The other day,  during an after-symposium discussion on detecting BS AI/ML papers, one of my colleagues suggested doing a text search for “random split” as a good test.

A lot of what you write is to the point and very valid. However, I think you are missing part of the story. Let’s start with

“Unlike drug development, where you’re trying to precisely hit some key molecular mechanism, assessing toxicity almost feels…brutish in nature”

I assume you don’t really believe this. Toxicity is often exactly about precisely hitting some key molecular mechanism. A mechanism that you may have no idea your chemistry is going to hit before hand. A mechanism moreover that you cannot use a straight forward ML to find because your chemistry... (read more)

Yes, I agree, I think it is pretty unlikely. But not completely impossible. As I said it should be pretty easy to find them if they are in the lysate via, HP liquid chromatography. Brain penetrant cyclic peptides should on the whole be significantly less polar than acyclic polypeptides of similar mass.

An excellent analysis and I’m almost sure your mistrust in the pharmaceutical efficacy of Cerebrolysin is well founded. However, having some experience working in the field of brain-penetrant drugs, I can comment that your restrictions on molecular weight and properties are too conservative. Small molecules of >550 dalton are capable of crossing the blood brain barrier if very well tailored. Also small cyclic peptides can hide their polar backbones  within buried intramolecular hydrogen bond networks and become membrane permeable. The bicyclic pept... (read more)

There is an additional important point that needs to be made. Alphafold3 is using predominantly  “positive” data. By this I mean the training data encapsulates considerable knowledge of favourable atom-atom or group-group interactions and relative propensities can be deduced. But  “negative” data, in other words repulsive electrostatic or Van der Waals interactions, are only encoded by absence because these are naturally not often found in stable biochemical systems. There are no relative propensities available for these interactions. So AF3 can ... (read more)

I have similar concerns regarding the ligand sets used to test Alphafold3. I’ve had a cursory look at them and it seemed to me there were a lot phosphate containing molecules, a fair few sugars, and also some biochemical co-factors. I haven’t done a detailed analysis, so some caveats. But if true, there are two points here. Firstly there will be a lot of excellent crystallographic training material available on these essentially biochemical entities, so AlphaFold3 is more likely to get these particular ones right. Secondly, these are not drug-like molecule... (read more)

So after tearing my hair out trying to generate increasingly complex statistical analyses of scientific data in Excel, my world changed completely when I started using KNIME to process and transform data tables. It is perfect for a non-programmer such as myself, allowing the creation of complex yet easily broken-down workflows, that use spreadsheet input and output. Specialist domain tools are easily accessible (e.g chemical structure handling and access to the RDKit toolkit for my own speciality) and there is a thriving community generating free-to-use fu... (read more)

Useful post. I can expand on one point and make a minor correction. Single Particle Cryo-EM is indeed a new(ish) powerful method of protein structure elucidation starting to make an impact in drug design. It is especially useful when a protein cannot easily be crystallised to allow more straightforward X-Ray structure determination. This is usually the case with transmembrane proteins for example. However it is actually best if the protein molecules are completely unaligned in any preferred direction as the simplest application of the refinement software a... (read more)

I’m not going to say I don’t share deep disquiet about where AI is taking us, setting aside existential risk. One thing that gives me hope, however, is seeing what has happened in chess. The doom mongers might have predicted, with the advent of StockFish and AlphaZero, that human interest in chess would greatly diminish, because, after all, what is the point when the machines are so much better than the world champion ( world champion ELO ~2800, StockFish ELO ~4000) . But this hasn’t happened, chess is thriving and the games of the best human players are w... (read more)

I think this is an interesting point of view. The OP is interested in how this concept of checked democracy might work within a corporation. From a position of ignorance can I ask whether anyone familiar with German corporate governance recognises this mode of democracy within German organisations? I choose Germany because large German companies historically incorporate significant worker representation within their governance structures, and, historically, tend to  perform well.

My understanding is that off-label often means that the potential patient is not within the bounds of the clique of patients included in the approved clinical trials. We don’t usually perform clinical trials on children or pregnant women, for instance.  Alternatively, strong scientific evidence is found that a drug works on a related disease to the actual target. It may well make sense to use drugs off label where the clinician can be comfortable that the benefits out-way the possible harms. In other cases, of course, it would be extremely poor medicine. In any case, having statistically significant and validated evidence that a drug actual does something useful, is non-negotiable IMO.

It is true that most pharma companies concentrate on indications that supply returns to offset the cost of development. The FDA does have a mechanism for Orphan Drug approval, for rare diseases, where the registration requirements are significantly lowered.  According to this site 41 orphan drug approvals were made in 2023. Whether this mechanism is good enough allow the promototion of  rare disease in the larger pharmaceutical industry is a good question. I wonder how many of these drugs, or their precursors, originated in academic labs,, and were then spun out to a start-up or sold on?

Two things that happen in the pharmaceutical industry today despite the FDA.

1. Many drug candidates (compounds with IND status sanctioned by the FDA ) are pushed into clinical investigation prematurely by venture capital funded biotech, that more established and careful pharma companies would stay away from. These have a high rate of failure in the clinic. This is not fraud, by the way, it is usually a combination of hubris, inexperience, and a response to the necessity of rapid returns.
2. Marketing wins over clinical efficacy, unless the difference is large. Ta

Poorly regulated health orientated companies selling products that have little or no value? Seems unlikely.. Oh wait, what about Theranos?

A thought provoking post. Regarding peer reviewed science, I can offer the perspective that anonymous peer review is quite often not nice at all. But, having said that, unless a paper is extremely poor,  adversarial reviews are rarely needed. A good critical constructive review can point out severe problems without raising the hackles of the author(s) unnecessarily and is more likely to get them dealt with properly than an overly adversarial review. This works so long as the process is private, the reviewer is truly anonymous, and the reviewer has the... (read more)

I’m not claiming this view to be particularly well informed, but it seems a reasonable hypothesis that the industrial revolution required the development, dispersement and application of new methods of applied mathematics. For this to happen there needed to be an easy-to-use number system with a zero and a decimal point. Use of calculus would seem to be an almost essential mathematical aid as well. Last but not least there needed to be a sizeable collaborative, communicative and practically minded scientific community who could discuss, criticise and disse... (read more)

Anecdotal, but in the UK, in 1986, as a just graduated PhD I bought a 3 bedroom house for less than 4 times my salary. At present a similar house in a similar location, will cost  roughly 10 times a starting PhD salary. House ownership for most young people in the UK is becoming a distant and ever delayed dream.

“Design is much more powerful than evolution since individually useless parts can be developed to create a much more effective whole. Evolution can't flip the retina or reroute the recurrent laryngeal nerve even though those would be easy changes a human engineer could make.”

But directed evolution of a polymeric macromolecule (E.g. repurposing an existing enzyme to process a new substrate) is so much easier practically speaking than designing and making a bespoke macromolecule  to do the same job. Synthesis and testing of many evolutionary candidates is quick and easy, so many design/make/test cycles can be run quickly. This is what is happening at the forefront of the artificial enzyme field. 

So my personal viewpoint (and I could be proved wrong) is that Bing hasn’t the capability to suffer in any meaningful way, but is capable (though not necessarily sentiently capable) of manipulating us into thinking it is suffering. 

Whilst it may be that Bing cannot suffer in the human sense, it doesn’t seem obvious to me that more advanced AI’s, that are still no more than neural nets, cannot suffer in a way analogous to humans. No matter what the physiological cause of human suffering, it surely  has to translate into a pattern of nerve impulses around an architecture of neurons that has most likely been purposed to give rise to the unpleasant sensation of suffering. That architecture of neurons presumably arose for good evolutionary reasons.  The point is that there is no... (read more)

I think this is a very good point.. Evolution has given humans the brain plasticity to create brain connectivity so that a predisposition for morality can be turned into a fully fledged sense of morality. There is, for sure, likely some basic structure in the brain that predisposes us to develop morality but I’d be of the view the crucial basic genes that control this structure are, firstly present in primates, and at least, other mammals, and, secondly, the mutations in these genes required to generate the morally inclined human brain, are far fewer than ... (read more)

A personal anecdote. Many, many moons ago I started my research career at a large multinational organisation in a profitable steady business. I enjoyed the job, the perks were nice, I did the work and did well in the system. Some years later my group were asked to take a training course run by an external organisation. We were set a scenario “Imagine your company has only money for 6 months? What are you going to do about It?” We, cossetted in our big company mindset, thought the question hilarious and ludicrous.

 Fast forward a number of years, the co... (read more)

    I‘m afraid you’ll have to do more to convince me of the argument that Lavoisierian theory held up the development of chemistry for decades by denying the role of energy. Can you provide some evidence?  Until the discovery of the atomic model, chemistry by necessity had to be an empirical science where practitioners discovered phenomena and linked them together and drew parallels, and progressed in that manner. Great progress was made without a deep underlying theory of how chemistry worked. It was well known that some reactions gave out ... (read more)

Interesting example. I think the movie theatre in practice always has value and counts towards wealth, because even if you don’t have time/inclination to use it, you could in principle sell the house to an appropriate movie buff, for more than you could if you didn’t have the theatre, and use the extra money to do more of what you want to do. So the “potential“ argument still works. This argument could also be applied to a heck of a lot of other things we might own but have little use for.  On that basis, EBay is a great wealth generator!

I see “wealth” not as a collection of desirable things but as a potential or a power. An individual who has some wealth has the potential or power to undertake certain things they would like to do, over and above basic survival. An individual with greater wealth has greater choice of the things they can choose to do. Such things might include eating Michelin 3 star food, or driving a Ferrari along the coast. They also might include a simple afternoon walk in the woods. In the latter case the  “wealth“ required to undertake this activity comprises havi... (read more)

Yes, the lab protocol it actually suggests would likely lead to an explosion and injury to the operator. Mixing sodium metal and a reagent and adding heat does not usually end well unless/even done under an inert atmosphere (nitrogen or argon).. Also there is no mention of a “work-up step,“ which here would usually involves careful quenching with ethanol necessary to remove residual reactive sodium, and then shaking with an aqueous base. 

I did wonder whether one reason it might be hard to commercialise orexins was because, being peptides, delivery would be difficult.

But, apparently not, nasal spray works just fine …

So the domain I’m most familiar with is early stage drug discovery In industry. This requires multidisciplinary teams of chemists, computational chemists, biochemists, biologists, crystallographers etc. Chemists tend to be associated with one project at a time and I don’t perceive part-time working to be beneficial there. However the other disciplines are often associated with multiple projects.  So there’s a natural way to halve (say) the workload without reducing efficiency.  The part-time scientist should be highly experienced, committed to what they are doing, and have few management responsibilities. If that holds then my experience is they are at least as productive than a full time worker,  hour for hour.

Very interesting points. But some of them are surely specific to the size, workforce make-up and activities of your organisation. I’d  like to put an alternative view on point 14,  at least as it applies to an organisation with longer timelines and a more autonomous working regime (so less opportunity for blocking). My experience is that part-time workers can be more productive hour for hour than full-time workers, in the right work domain. A fully committed part-time worker has a ready-made excuse to avoid those meetings that don’t make them pro... (read more)

Adding to my first comment, another basic problem that at least applies to organic chemical assemblies, is that easily constructed useful engineering shapes such as straight lines (acetylenes, polyenes), planes (graphene ) or spherical/ellipsoidal curves (buckminsterfullerene like structures) are always replete with free electrons. This makes them somewhat reactive in oxidative atmospheres. Everybody looked at the spherical buckminsterfullerene molecule and said “wow, a super-lubricant!” Nope, it is too darn reactive to have a useful lifetime. This is actu... (read more)

It’s my opinion that Drexler simply underestimated the basic scientific problems that yet needed to be solved. The discrete nature of atoms and the limited range of geometries that can be utilised for structures at the nanoscale alone make complex molecular machine design extraordinarily challenging. Drug design is challenging enough and all we usually need to do there is create the right shaped static block to fit the working part of the target protein and stop it functioning (OK, I over-simplify, but a drug is a very long way from a molecular machine). A... (read more)

I think you make a good point, but I also think fear of being attacked is not a good excuse for failing to be altruistic, at least if the altruism is through financial means. After all it is easy ( and very common) to give anonymously.

That’s not to say anonymous altruistic acts are entirely sacrificial. Usually there is some significant payback in terms of well-being (assuagement of guilt for the good fortune of one’s own relative affluence, for instance).

In Advanced Driving courses a key component was (and may still be -it’s been awhile) commentary driving. You sit next to an instructor and listen to them give a commentary on everything they are tracking, for instance other road users, pedestrians, road signs,  bends, obstacles, occluders of vision etc; and how these observations affect their decision making, as they drive.  Then you practice doing the same, out loud, and, ideally, develop the discipline to continue practising this after the course. I found this was a very effective way of learning from an expert, and I’m sure my driving became the safer because of it.

There is the saying “Genius will out” and it was true for the four individuals you mention. But there are equally, cases where an enlightened teacher in an unpromising school has recognised genius, perhaps emerging from a lowly background, and helped it flourish, when perhaps it otherwise would have withered. Gauss comes to mind as one example. In decent schools today I would be pretty hopeful that genius, even if coupled to unconventionality, would be identified and nurtured. Of course not all schools are decent.

I also disagree strongly with that paragraph, at least as it applies to higher mammals subject to consistent, objective and lengthy study.  If I read it to include that context ( and perhaps I’m mistaken to do so), it appears to be dismissive (trolling even) of the conclusions of,  at the very least, respected animal behaviour researchers such as Lorenz, Goodall and Fossey. 

Instead of appealing to  “empathy with an animal“ as a good guide,  I would rather discuss body language. “Body language“ is called such for good reason. Before... (read more)

I think this hypothesis for some kinds of chronic pain makes sense and is helpful to me. Thanks for posting. The only thing I would comment on is in regard to the physiological mechanism at work. For me, the vicious cycle enabler of my own chronic pain (neck - ascribed to incipient arthritis, wheneverI ask a professional) is, I’m pretty sure, not blood flow restriction but muscle spasming. I wonder if others might say the same? I do find it is frequently self-fulfilling. If I think I’m going to get a seriously stiff neck in the night, then I will get a seriously stiff neck by morning plus accompanying serious headache.  I too have no medical training so disclaimers as to what is really going on.

We may not run out of ideas but we may run out of exploitable physics. For instance what is most needed at the moment is a clean, cheap and large scale energy source that can replace gas,  oil, and coal, without which much of the technological and economic development of the last hundred and fifty years or so would have been impossible. Perhaps fusion can be that thing. Perhaps we can paper over the Sahara with photovoltaics. Perhaps we can design fail-safe fission reactors more acceptable to the general population. Let’s assume we will solve the vari... (read more)

I agree with you on both counts. So, I concede, saving millions in research costs may be small beer. But I don’t see that invalidates the argument in my previous comment, which is about getting good drugs discovered as fast as is feasible. Achieving this will still have significant economic and humanitarian benefit even if they are no cheaper to develop. There are worthwhile drugs we have today that we wouldn’t have without Structure-Based Design. 

The solving of the protein folding problem will also help us to design artificial enzymes and molecular machines. That won‘t be small potatoes either IMO.

Not a bottleneck so much as a numbers game. Difficult diseases require many shots on goal to maximise the chance of a successful program. That means trying to go after as many biological targets as there are rationales for,  and a variety of different approaches (or chemical series) for each target. Success may even require knocking out two targets in a drug combination approach. You don’t absolutely need protein structures of a target to have a successful drug-design program but using them as a template for molecular design  (Structure-Based Dru... (read more)

OK, the question asked for demonstration of economic value now and I grant you AlphaFold,  which is solely a research enabler, has not demonstrated that to date. Whether AlphaFold will have a significant role in breaking Eroom’s law is a good question but cannot be answered for at least 10 years. I would still argue that the future economic benefits of what has already been done with AlphaFold and made open access, are likely to be substantial. Consider Alzheimer’s. The current global economic  burden is reckoned to be $300 B, p.a. rising in futu... (read more)

I agree with your assessment of the BridgeBase ‘bots. They can appear to play very well a lot of the time but often make plays that look foolish, or sometimes bizarre. Nook played against the best (by competition) bridge ‘bots available. However, against Nook, as I understand, even these ‘bots sometimes made poor plays that quite average human players would know not to make.

I think this idea absolutely hits the spot.  A well worn saying is that good workers are generally promoted beyond their own capability. This is true but often because they get bogged down with meetings, fire-fighting, admin, pleasing the (Wo)Man etc.., lots of reactive stuff. My experience exactly. I changed jobs, gave up management, went down to three days a week (gaining two days of slack), declined as many meetings, as I could getaway with and became more productive than any time previously, largely because of having time to let ideas slowly gestate, play with stuff, notice the subtle things, and thereby make progress in useful directions.  I swear my employer effectively gets 5 days out of me. I should be paid more!

I think there is a danger that the current abilities of ML models in drug design are being overstated. The authors appear to have taken a known toxicity mode ( probably acetylcholinesterase inhibition - the biological target of VX, Novichok and many old pesticides) and trained their model to produce other structures with activity against this enzyme. Their model claims to have produced significantly more active structures but none were synthesised. Current ML models in drug design are good at finding similar examples of known drugs, but are much less good ... (read more)