All of chemslug's Comments + Replies

Another way to think about diamandoids is to consider what kind of organic chemistry you need to put them together the "traditional" way.  That'll give you some insight into the processes you're going to be competing with as you try to assemble these structures, no matter which technique you use.  The syntheses tend to go by rearrangements of other scaffolds that are easier to assemble but somewhat less thermodynamically stable (https://en.wikipedia.org/wiki/Diamantane#Production for example).  However, this technique gets arduous beyond 4 o... (read more)

1Metacelsus
Yeah, Woodward was a real trailblazer (interestingly, my undergrad PI was one of his last students)

I geek out about unusual plants.  I find Welwitschia interesting because it's kind of an outlier.  It's a gymnosperm, meaning it doesn't produce flowers, is wind-pollinated, and forms seeds differently than an angiosperm, but it doesn't look like other gymnosperms.  Central examples of gymnosperms are conifers, with less-central examples being things like cycads and ginkgo trees, but Welwitschia looks nothing like those, or really any other plants I can think of.  It's got a central meristem (growth zone) and two leaves that grow from t... (read more)

1Portia
Thank you for explaining. That indeed sounds odd on a marvellous way. :)

Thanks for this!  Austin Vernon took a look at why the nuclear industry isn't growing and came to some broadly similar conclusions here.  I think a lot of environmental groups have gotten themselves into a situation where "nuclear power is evil" is kind of taken as a given, while the techno-optimist crowd is overly sanguine about cost problems being driven by regulations and the chances of those regulations changing.  in other words, there's a lot of people with different assumptions and values talking past one another in this debate.  ... (read more)

1Lone Pine
In my opinion the most baffling (and angering) part of this post was the chart of DOE energy technology research investment from 2009-2018. Forget about the nuclear spending, how is it that, during the Obama administration, we spent more researching fossil fuel tech, which is supposed to be a dead technology, than we spent on what almost everyone agrees will be the future of energy, renewables? I wonder what percentage of that is carbon capture and storage, what percentage is discovery and extraction, and what else we're throwing our money away on. The big oil and gas companies are some of the most profitable companies in the history of the world, can't they pay for it themselves? Why are taxpayers paying to make the environment worse? It's madness!

The lack of context for comparable search spaces is a fair criticism.  The implicit assumption (which I now realize was inappropriate not to spell out for this audience) was that your search would, at some point, involve actually making the molecules in question in order to subject them to some form of experimental characterization.  The comparison of the number of possible small molecules to the amount of available terrestrial carbon was intended to make the point that achieving sizable coverage of the search space experimentally is close to a n... (read more)

2Gunnar_Zarncke
Thanks for the explanation about silicon compounds. As oxygen is always more abundant than silicon, this makes it indeed unlikely to become the basis of silicon-based life.

I should have written 'common proteinogenic' in place of 'naturally-occurring'.  Thank you for the correction.

Solving protein folding doesn't only give you the ability to know how existing proteins fold. It also gives you the ability to design new proteins. 

I don't agree with this claim.  AlphaFold gives you the ability to calculate how a given amino acid sequence is likely to fold.  That is very different from being able to predict an amino acid sequence that performs a specific function or even has a given shape.  Small modifications of known shapes or functionalities would be tractable using AlphaFold's technology, but there are other ways t... (read more)

3ChristianKl
This is basically why you need more then just licensing the technology from AlphaFold. You actually need to employ a bunch of programmers for a few years. It's a hard problem but it's solveable.   Tesla is today worth more then the other car makers combined. The legacy car makers largely understood to late that driverless cars are going to be a core part of their business.  It might be that currently the idea of some big pharma companies is to wait for the equivalent of Cruise and then buy it. Besides understanding what goes on in a cell with computer models and protein design, predicting phase 3 trial outcomes better based on phase 1 data would be another task where a lot of data can be gathered and analysed with machine learning. There's an incredible amount of profit in prediction phase 3 trial outcomes before doing the trial.

Thanks for engaging!  I think there's a real debate to be had about how public research money is spent.  I put a higher expected value on continuing to fund basic cancer research than I think you do.  I also am more bullish on doing working at the object level (going after specific targets) relative to the meta level (technology platforms).  Maybe this is myopia on my part, working as I do in the pharmaceutical industry, but I have also spent a fair amount of time thinking about the problem.

DeepMind beating Big Pharma at protein folding

... (read more)
2ChristianKl
Solving protein folding doesn't only give you the ability to know how existing proteins fold. It also gives you the ability to design new proteins.  If you take a problem like the one of NK cells and cancer immunity against them there will be cases where the machinery that NK cells have by human nature won't be enough and you need to design new proteins for them to properly recognize the cancer cells.  You won't get there by just licensing some protein folding technology from Google.  Compute and programmers are something you can hire. If the big pharma companies would be functional, it would be appropriate for each of them to spend a billion per year on AI. A few years ago I spoke a few times with someone doing new business development at Pfizer. According to his perspective Pfizer is too bureaucratic to effective develop software.  It might be that new biotech companies that can actually manage to employ programmers in a productive way without stiffling them with too much bureaucracy will win out. While not in the cancer area Proteon Pharmaceuticals would be a company where bioinformatics is at the core of their phage therapy product. As they grow and slowly push out most of the antibiotics from the market they have a need for more IT investment to better simulate how changes in phages and hosts interact and which mutations have which effects. It might be that after they have a really good system to simulate phages, they go and reapply their knowledge to NK cells.  A company like Moderna or BioNTech that focus on cancer vaccines might also make major IT investments to optimize target selection and fully simulate the cancer cells to know which antigens they actually present.

I have a lot to say about this but I will keep it short.  First, I think you're underselling the insight that cancer isn't a single disease (the Atlantic headline was shitty; of course cancer is a disease).  This wasn't obvious a priori.  The fact that every case of cancer is a unique and horrible snowflake means that we can't expect "a cure for cancer" any more than we can expect "a cure for car trouble".  You're right, however, that some things are more likely to go wrong than others, and routine sequencing of tumors from each individ... (read more)

2ChristianKl
It can also help with amputating parts of people's body for no useful medical purpose.  This does suggest that cancer treatments aren't completely worthless. The fact that the US manages compared to other OECD countries relatively low lifespan, high cancer survival rate and high cancer death rate however still points to goodharting to be responsible for a large part of the high cancer survival rate among OECD countries.  There's a difference between natural NK cells and NK cells that gene manipulate to avoid features of the immunosuppressive enviroment. If a NK cells assumes that a cancer cell should have some tumor marker but the cancer cells of a particular patient don't have that particular tumor marker you can alter the NK cells to not care about that tumor marker.  At current technology we can't sequence a tumor and know what we have to change in the NK cells to make them work in the particular immunosuppressive environment of a particular patient for the NK cell to be operational in that enviroment, and then change them. It's still technology that we can build.   One of my main points was that working on cancer therapy targets is not where most of the attention should go but on underlying technology platforms. DeepMind beating Big Pharma at protein folding prediction suggests relatively little investment in the basic technology. It's quite plausible that you actually need working protein folding prediction to do what I pointed towards above for modifying the NK cells to work in more immunosuppressive environments. I'm completely okay with the private sector developing therapies whenever they think that they can develop a working therapy and bring it profitably to market. My post was more about how the large chunk of government and non-profit money should be spent.  If would also be okay with simply redirected the cancer research budget elsewhere (like anti-aging) and leaving the problem completely to the private sector but there's political desire to us

This is what I meant by "it's a trivial exercise in orbital mechanics, so maybe all of you do this instinctively".  I got there empirically. :)

What an "aspiring chemist" should do depends a lot on age and where they are in the educational process.  For children below high-school age, I think there are lots of great experiments you can do to illustrate principles of chemistry.  Lack of originality isn't a bug there, it's a feature.  In high school, if you think you like science, take chemistry!  There should be a lab component in most schools, so you can at least get a flavor for what working with chemicals is like.  Access to equipment like this is an underrated component... (read more)

3DirectedEvolution
Many of the coolest and most useful activities for learning are sealed off from non-professionals, or at least are expensive and time confusing to obtain certification or access. Usually for good reason. This seems like a fundamental dilemma of the role of school. To make students directly see what’s cool about different subjects, they need lots of hands-on experience. But the vast majority of their time, and most of their evaluation prior to grad school, comes from book work. Access to hands-on projects and a sense of freedom and agency is limited at best. And ultimately, that’s for reasons of safety and expense, which we can’t just criticize away. It seems then that a big learning skill is maximizing access to such applied projects. I wonder, then, if it would be better to orient school around single subjects from an earlier age. It makes more sense to give a student heightened access to mentorship, equipment, and materials if that stuff is their obsession. And for a self-studier, it seems important to figure out first what you want to obsess yourself with, and then focus on getting maximum access to applied learning environments.

There are a few problems with DIY organic chemistry.  The first one is that many of the reagents are toxic.  Some of those are volatile or readily absorbed through the skin.  Others will spontaneously burst into flame when exposed to air.  Sometimes the dangers of working with chemicals is overstated, but sometimes it's very much not.  In academic or industry labs we solve mitigate those problems with fume hoods and personal protective equipment (and no, the exhaust fan above your stove is not an acceptable substitute).  The s... (read more)

3Mary Chernyshenko
I guess one can make soap, as an applied project. Some paper chromatography can be done without a hood, outdoors (but then one still needs to dispose of the materials safely). Gall-based inks are, in a way, on the fence between organic and inorganic (also, playing around with homemade dyes is cool, e.g. from avocado seeds, alder bark or walnut skins - the colours fade, but you can stain paper so it looks old and then draw maps of treasure on it). Cooking is instructive (although people often underestimate the dangers of vinegar "because everybody has it in their kitchen".) Also, blacklight might be fun here. But my most engaged instructors told us a real chemist develops a "sense of substance", like they often can tell things apart by their physical appearance and not even their chemical properties (given a set of familiar chemicals). There are different shades of colour, different granularities, different translucencies... it's just not something you can show at home. And separately, my botany instructors said they always make a student identify at least three species of a genus, whenever possible. For triangulation. If you give students only one species, that's how they will think of the genus as a whole. Give them two, and they will think about the differences between them, but not about the genus. But give them three, and they see the common features. Again, I don't think it's possible to show sufficient variety of chemical substances at home.
3DirectedEvolution
Always enjoying your thoughts. Thanks chemslug. My expectation is that there are more safe and tractable micro-projects out there than the average student takes for granted. But I am also raising these questions to confirm a suspicion I have: that despite our love for the idea of "learning by doing," there are many disciplines where a long slog of paper-based learning, punctuated by a few carefully regulated experiments, has to precede any kind of creative or independent hands-on activity. LessWrong's steeped in "move fast and break things" Silicon Valley culture, which seems to inform a fair bit of the perspectives on education I see shared here. One reason why I appreciate your comments here is that you bring insight from a less-represented discipline, one with a different set of norms and requirements than we find in Programland. Do you think that most aspiring chemists would do well to figure out how to set up their own home lab, figuring out how to manage the risks and invest in some equipment? A fume hood costs a few thousand dollars, which is pricey but not completely impossible. Or is there a pretty hard norm that you don't do any serious chemistry outside a professional lab setting? At what point do chemists become qualified to design and execute their own projects?
3lsusr
From the link. Wow.
Answer by chemslug80

My visual imagination is pretty much constantly on when I read chemistry papers.  There's a stereotype that you read a synthesis or catalysis paper by (1) carefully looking at the figures, (2) reading the experimental procedures, and then maybe (3) reading the text if you need clarification on a point or two.  Lots of areas of chemistry (organic, biological, materials science) benefit greatly from visualization because of the fundamental idea that structure determines function.  If you can't visualize a catalyst in 3D, it becomes much more difficult to explain things like stereoselectivity or reaction mechanism.

If covalent vs. noncovalent bonds are something you're not familiar with, it sounds like you'd benefit from reading the chapter(s) on chemical bonding (every gen chem textbook should have one). I'd also infer from that that you won't have much of a background in thermodynamics, which rears its head when you try to understand the energy-storing and energy-releasing reactions of metabolism.

1Maxwell Peterson
That’s right, I don’t - I was talking to a friend about vaccines expiring and he said “things want to be in a low energy state”, which sounded like the kind of thing people say a lot and is probably right, but I didn’t, like, feel it. Thanks for your recommendations!
Answer by chemslug40

When I was an undergraduate we used Atkins and Jones' Chemical Principles: the Quest for Insight (link is to a slightly older edition because it's not a field whose basic principles have changed much in the last few years).  If memory serves, it was pretty good.  I'd also recommend checking out the MIT OCW site for 5.112 (that course will do a better job of preparing you for organic chemistry than 3.091, which is more materials focused).  

It is certainly possible to start with an organic chemistry textbook as long as you have a good grasp of... (read more)

1Maxwell Peterson
I want to learn biochemistry so I can reason about stuff that goes on in the body! I’ve started Lehninger’s Principles of Biochemistry and I mostly get it, but some of the stuff it assumes (e.g. covalent vs. noncovalent bonds) I’m not familiar with.

Wow, that was more vehement than I was expecting.  I remember reading 1984 and Brave New World near one another, and thinking that Brave New World was significantly better.  I guess I wasn't as put off by the pro-traditionalist vibes in BNW as you were, and I remember thinking that the government in 1984 was way too capital-E Evil to be very interesting.  I'd argue that BNW is about the way things can still go wrong even when you get a lot right (ending sickness and poverty), while 1984 just seemed like Stalin's USSR with better surveillance tech.

2habryka
Yeah, I am not fully sure what made it such a miserable experience for me, and it's totally plausible there is more intellectual merit in there that I didn't successfully pick up on, but I sure really despised my time with it. Epistemic state of the above should probably be modeled as "I had a terrible time, your experience might differ".

I know it's not perfect, but "achieve human potential" sounds like a reasonable moral axiom to start with.  A big "no thank you" to the wireheading for me.

I really enjoyed this post!  Look wistfully at pictures of Welwitschia, indeed!  I got to see some in person a few years ago when we went to the Kirstenbosch Botanical Gardens in Cape Town, and my wife was very forbearing with my gaping at the unassuming piles of green straps.

If you're interested in learning more about what the plant developmental toolbox looks like and how it's been deployed throughout plant evolution, I'd recommend David Beerling's Making Eden.  It's a pop-science book but pitched at the upper end of that range.  Merl... (read more)

1Portia
Can you give a hint or link as to why that plant is so exciting? A cursory google left me at a loss. I love learning why other people are excited, and sharing their excitement.

Thanks for the pointer.  There's more there than I remembered.  I originally bounced off that sequence after this post, where EY spends a lot of time worrying about whether there will be enough math puzzles to go around after the singularity.  I remember thinking that his conception of fun was so far from mine that there wasn't much point in continuing.  Maybe I should revisit that conclusion.

Thanks for your thoughts!  I think you've put your finger on an important difference between how an individual experiences a society and what a society is capable of accomplishing.  It's the stunting in the second category that makes Brave New World a clear dystopia for me.  As for the islands, their influence on the remainder of society is clearly told to be carefully limited and controlled.  I think Huxley's inclusion of the islands as havens for the dissatisfied greatly increases the ambiguity in how the society appears to a modern r... (read more)

I don't have any inside information about what exactly prompted the publication of these pieces, but I don't think it's unusual for practicing scientists to have some idea of what's possible if things go very, very right with their research.  They're often wrong, of course, and important discoveries are often important precisely because of unforeseen ramifications.  The Acc. Chem. Res. papers are just speculations about potentially awesome destinations for existing lines of research.

I think that the resistance to Hamming's line of questioning cam... (read more)

Thanks for this post!

To me, the early retirement option has always seemed like it was better suited to people who had unrewarding jobs that paid better than any of the jobs they would like more (for MMM, this was programming).  On the other hand, even if you like your job it's hard to see how having substantial savings in case of layoffs or unforeseen circumstances could be a bad thing (see Richard Meadows' post on this point).  Thus, like you, I've started leaning toward the "retire in your mind" option.  I also find that the parts of my jo... (read more)

2Adam Zerner
Thanks for the input! Yeah. And I think I've always underestimated how many people have a job doing exactly what they want to be doing. For me, I really, really enjoy teaching and could see myself wanting to spend my life doing that. I could also see myself at the right programming job wanting to do that forever. Well, I wouldn't go that far. There is a tradeoff in play. You could go on a lot of awesome vacations with that money you'd need to retire in your mind :) As a programmer, I see some parallels here. Mainly that you get to interact and learn from other smart people when you work at a (good) company, but also that you get to solve problems that you otherwise wouldn't get to work on alone. Caveat is that if you look hard enough you can find these things in the world of open source. Hm, I think that's a good point and that there's definitely truth here. But I also think that there are things that we can learn. Covid means people can't do certain social things with their free time, but it doesn't prevent them from doing things like art or music. So if people don't take up art or music during Covid with their excess free time, that seems like reasonably strong evidence that they also wouldn't take up art or music in a non-Covid world with excess free time.

For biochemistry, I think the Roche Biochemical Pathways chart is awesome, if a little overwhelming:

http://biochemical-pathways.com/#/map/1

I don't recommend using it to learn biochemistry but it's pretty great to see it all laid out in one place like that.

3ryan_b
I feel like it being overwhelming is a feature, rather than a bug. Why doesn't such-and-such a drug work? Because it has to go through this. A good firm smack in the face with complexity helps a lot in problem solving, in my view.

For the field of chemistry, I nominate The Periodic Table of the Elements.  I know it's old but it really does capture a surprising amount of information in a visually pleasing format.

I disagree with your assessment that structural biology is useless.  Knowing the shape of a protein can be pretty important if you want to perturb the protein's function by, say, finding or creating a small molecule that binds to it.  Crystal structures or cryo-EM structures can shed a lot of light on how a molecule binds to its target, which in turn can suggest further modifications to try and make a tighter binder.  It's not clear to me yet how easy or hard it will be to simulate ligand-protein binding using AlphaFold.  I'd lean toward 'hard' but maybe molecular dynamics simulations would dovetail well with a structure determined by AlphaFold.  

I'm very glad to see that you're learning organic chemistry!  It's a great subject for the type of exercise you've described, as it's a very visual field of study.  As you mention that visualization is a skill you're working on developing in parallel with your organic chemistry studies, I'd recommend that you get ahold of a molecular model kit.  It may sound silly, but having a physical model of a molecule in front of you can make a big difference in how long it takes to grasp why, for example, SN2 and SN1 reactions give different stereochem... (read more)

3DirectedEvolution
Haha I may take you up on that! Thank you for volunteering :D These visualization techniques are also helping with my molecular biology class. Very general purpose.

"Don't screw future self" is one that has served me well for more than a decade.