Ponder Stibbons

Karma: 106

Ponder Stibbons 30 Jul 2022 10:11 UTC
22 points
7
on: Drexler’s Nanotech Forecast
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). Additionally the simulation tools needed to design molecular machines are only now becoming accurate enough, largely because it is only now that we have cheap enough and fast enough compute power to run them in reasonable real time.
It will happen, in time, but there is still a large amount of basic science to be done first IMO. My best guess is that self-assembling biomimetic molecular machines, based on polypeptides, will be the first off the blocks. New tools such as AlphaFold will play an important role in their design.

So has AI conquered Bridge ?

Ponder Stibbons2 May 2022 15:01 UTC

16 points

3 comments14 min readLW link

Ponder Stibbons 15 Jan 2023 16:32 UTC
12 points
9
on: Core Concept Conversation: What is wealth?
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 having the leisure time available for the activity, the personal good health that allows for enjoyable walking, clothing of suitable quality for the activity to be pleasurable, and a means of fairly effortlessly getting to the woods in the first place.
It follows that, whilst “wealth” might have a roughly linear relationship to “money”, the amount of surplus money one has to attain a certain “wealth” will be different for everybody, principally because we all different ideas of how we might use our wealth, some of which will cost more than others. Additionally, some wealth doesn’t necessarily cost any money to create or to acquire. Consider a coder who makes a compelling game and puts it out as open source. The coder has created “wealth” because they have created the potential for others to undertake something they would like to do, namely, play the game. The coder has used their own time and little else. If the creation of the game was an enjoyable activity for the coder then the wealth has been created at zero cost.

Ponder Stibbons 2 Jul 2022 7:59 UTC
11 points
3
on: What Are You Tracking In Your Head?
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.

Ponder Stibbons 17 Mar 2022 14:21 UTC
9 points
on: Dual use of artificial-intelligence-powered drug discovery
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 (to my own disappointment—this is what I spend many a working day on) at finding better examples, at least in a single property optimisation. This is largely because, in predicting stronger chemicals, the models are generally moving beyond their zone of applicability. In point of fact, the field of acetylcholine esterase inhibition has been so well studied (much of it in secret) it is quite likely IMO that the list of predicted highly toxic designs is, at best, only very sparsely populated with significantly stronger nerve agents than the best available. Identifying which structures those are, out of potentially thousands of good designs, still remains a very difficult task.
This is not to take away from the authors’ main point, that ML models could be helpful in designing better chemical weapons. A practical application might be to attempt to introduce a new property (E.g brain penetration) into a known neurotoxin class that lacked that that property. An ML model optimised on both brain penetration and neurotoxicity would certainly be helpful in the search for such agents.

Ponder Stibbons 28 May 2022 11:35 UTC
7 points
on: Can growth continue?
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 various technical and geopolitical problems necessary to get at least one of these technologies to where we need it to be. My point is this, what if physics either didn’t allow, or made it technologically too difficult; for any of these three possibilities to come to fruition ? We’d be at roughly the same place in terms of development, but without the potential safety net these technologies could give us. What likelihood of continued progress then? And so on. A greater population (of humans at least) in the future will certainly provide a greater fund of technological ideas, but to keep the world in a healthy enough state to support that population may require physics that is either unavailable to us, or just too difficult to exploit.
In regard to the amazing possibilities available to us by manipulating macromolecules, I am completely with you. We have only just scratched the surface of what is achievable using the physics we have readily to hand, IMO.

Ponder Stibbons 27 Jan 2024 8:53 UTC
5 points
−2
on: Surgery Works Well Without The FDA
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. Tagamet was the first drug for stomach ulcers released in the late ’70s.It was rapidly overtaken by Zantac, in the ’80s, through aggressive marketing, despite minimal clinical benefit. Today there is a large industry of medical writers sponsored by the pharmaceutical industry, whose job it is to present and summarise the clinical findings on a new drug in the most favourable way possible without straying into actual falsehood.
The scientists working at the sharp end of drug discovery, who fervently believe that what they do benefits mankind (this is, I believe, a gratifyingly large proportion of them) generally respect the job the FDA do. This is despite the hoops they force us to go through. Without the FDA keeping us honest, the medicines market would be swimming with highly marketed but inadequately tested products with dubious medicinal value. Investors would be less choosy about following respected well thought-out science, when placing their money. True innovation would actually be stifled because true innovation in drug discovery only shows its value once you’ve done the hard (and expensive) yards to prove medical benefit over existing treatments. Honest and well enforced regulation forces us to do the hard yards and take no short cuts.
In 2023 55 new drugs were approved by the FDA, hardly a sign that innovation is slacking. Without regulation the figure might be ten times higher but clinicians would be left swimming in a morass of claims and counter claims without good guidance (currently generally provided by the FDA) of what treatments should be applied in which situation.

Ponder Stibbons 20 Sep 2022 22:47 UTC
5 points
1
on: How my team at Lightcone sometimes gets stuff done
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 productive. They will use their slack time to be thinking of their work, coming up with ideas at leisure, and creating an effective plan for their next work period. They can be flexible in their work hours so as to attend the important meetings and one-to-ones and to avoid blocking anyone (Especially if they also WFH some of the time- so can dip into work for an hour in a day they normally don’t work). They can use (E.g computational) resources more effectively so that they are rarely waiting for lengthy production runs (or calculations, say) to finish. Lastly, they are often less stressed through not being overworked (and hence more effective).
Clearly this will not be true for all work domains. Nevertheless it has been recently reported in the UK press that an international experiment to test a 4 day (32 hr) work week at 100% salary has resulted in no loss of productivity for many of the companies involved, and many of them are continuing with the scheme.

Ponder Stibbons 5 May 2024 17:42 UTC
4 points
0
on: introduction to cancer vaccines
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 assumes a perfectly random 3D orientation of the many thousands of protein copies imaged on the grid. In practice this is not so easy to achieve and corrections for unwanted preferred orientation need to be made.

Ponder Stibbons 23 Jan 2023 11:34 UTC
4 points
0
on: Recursive Middle Manager Hell
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 company closed our site down and I went off and joined a start-up, Very soon we all found ourselves in exactly the scenario depicted in the training exercise. We managed to survive. I’ve worked in small/smallish organisations ever since. There have been ups and downs but on the whole I wouldn’t have changed anything.
This is perhaps slightly tangential, though likely consequential to the Middle Manager Hell the OP describes. The big company environment made it easy for us to be complacent and comfortable, and hard for us to follow up the high risk high/profit ideas that might have made a big difference to the bottom line.
This was a long while ago and since then at least some big companies have tried various initiatives to change this kind of mindset. So perhaps things have changed in some large multinationals. Can anyone else comment?

Ponder Stibbons 22 Sep 2022 20:02 UTC
4 points
0
in reply to: Raemon’s comment on: How my team at Lightcone sometimes gets stuff done
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.

Ponder Stibbons 25 Jun 2022 22:45 UTC
4 points
2
on: Unforgivable
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.

Ponder Stibbons 9 Jun 2022 21:08 UTC
4 points
on: The “mind-body vicious cycle” model of RSI & back pain
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.

Ponder Stibbons 19 Mar 2024 8:55 UTC
3 points
0
on: The Worst Form Of Government (Except For Everything Else We’ve Tried)
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.

Ponder Stibbons 27 Jul 2023 15:19 UTC
3 points
0
on: Why no Roman Industrial Revolution?
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 disseminate applied mathematical ideas and apply them in physical experiments. All these three items were extant in Britain in the late 17th century, the latter being exemplified by the Royal Society. These, combined with the geologically bestowed gifts of coal and iron ore, would set Britain up to be in the best position to initiate the Industrial Revolution.
Now, can a proper historian of science critique this and show how this view is incorrect?

Ponder Stibbons 27 Mar 2024 12:28 UTC
2 points
−2
on: The other side of the tidal wave
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 widely streamed and analysed and their brilliancies greatly admired. The machines have actually been of great benefit. They have, for instance demonstrated that the classical swashbuckling 19th century style of chess, replete with strategic sacrifices that lead to beautiful attacks, is a valid way to play, because they often play that way themselves. This style of play was for a long period overshadowed by a preference for the more stifling positional chess, the gaining of small advantages. The machines also provide instant feedback in analysis on what is ground truth, whether a particular move is good, bad or neutral. This too has augmented the chess players enjoyment of the game rather than reduced It.
Maybe we can hope that the same situation will apply in other fields of human endeavour.

Ponder Stibbons 17 Feb 2023 20:56 UTC
2 points
0
on: Tinker Bell Theory and LLMs
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 reason an analogous architecture could not be created within an AI, and could then cause suffering similar to human suffering when presented with an appropriate stimulus. The open question is whether such an architecture could possibly arise incidentally, or whether it has to be hardwired in by design. We don’t know enough to answer that but my money is on the latter.

Ponder Stibbons 27 Jan 2023 9:56 UTC
2 points
0
in reply to: Davidmanheim’s comment on: Alexander and Yudkowsky on AGI goals
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 need be represented by 7.5 MB of information.
One thing both the genome and evolution have taught us is that huge complexity of function and purpose can be generated by a relatively small amount of seed information

Ponder Stibbons 2 May 2022 20:42 UTC
2 points
in reply to: Evan R. Murphy’s comment on: So has AI conquered Bridge ?
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.

Ponder Stibbons 29 Jan 2024 12:02 UTC
1 point
0
in reply to: Wbrom42@gmail.com’s comment on: Surgery Works Well Without The FDA
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.

Ponder Stibbons

So has AI con­quered Bridge ?

So has AI conquered Bridge ?