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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 or 5 adamantane units:
https://en.wikipedia.org/wiki/Diamondoid
Agreed that the Nanoputians aren't impressive. Lots of drugs are comparably complex, and they're actually designed to elicit a biological effect.
The B12 synthesis is sweet, but I'll put in a vote for the Woodward synthesis of strychnine (done using 1954 technology, no less!):
https://en.wikipedia.org/wiki/Strychnine_total_synthesis#Woodward_synthesis
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 that meristem at their base. The plant basically grows by elongating the two leaves, and they can get 4+ meters long. These things grow in the Namib desert and the wind blows the leaves all over the place and splits them at the veins (which run parallel down the leaves), so the mature plant looks like a pile of dirty green ribbon in the middle of the desert. Growing 4-meter leaves is also something of an unusual survival strategy for a desert plant. Like a lot of desert life, they grow slowly and can live a long time (possibly millennia!). The fact that it's unrelated to other desert plants like cacti or Euphorbias mean we can use it to get another data point about desert adaptation at a genome level as well.
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. Continuing to pump money into next-gen nuclear research seems like a reasonable use of money to me because the potential payoff is big enough to outweigh the low-ish probability of success. You could say the same about lots of branches of renewables research (e.g. perovskite solar cells) though.
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 non-starter. In practice, of course, there are all kinds of ways to bias your search in productive directions.
Some search-space context:
Number of possible chess games: Shannon conservatively estimated 10^120 possible games, 10^43 possible board positions.
Number of possible Go games: Wikipedia gives 10^172
Number of ways to order a standard 52-card deck: 8 x 10^67
As for why we don't see complex silicon-containing compounds in biology, here's an attempt at an answer: We do see silicates in structural roles, for example in phytoliths. However, low Si-Si bond strength relative to C-C, combined with very strong Si-O bonds mean that you tend to get Si-O-Si linkages (like in silicone polymers) rather than Si-Si bonds, and in the absence of Si-C bonds to prevent further oxidation, you form silicates pretty quickly.
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 to get that, for example directed evolution. Search in the space of amino acid sequences is possible in principle but even with several orders of magnitude increase in compute the size of the search space still seems intractable to me.
If the big pharma companies would be functional, it would be appropriate for each of them to spend a billion per year on AI.
Isn't this significantly more than DeepMind spends? I realize increased competition for ML talent would drive up salaries but I just can't see that kind of budget allocation happening for something that pharma companies don't consider to be core to their business.
Thanks again for engaging. It's been fun to see how someone in the Silicon Valley mindset looks at the biopharma landscape.
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 prediction suggests relatively little investment in the basic technology.
I actually think DeepMind is plausibly the only entity in the world who could have made AlphaFold when they did. The sheer amount of compute involved puts it out of the reach of nearly everyone else, plus pharma companies would have found it hard to hire away the caliber of ML talent DeepMind attracts. There's a case to be made that this is a nearly-ideal outcome for the pharma industry: the problem was cracked, publicly, by a company with little to no interest in making medicines. My prediction is that DeepMind either licenses the technology to pharma companies or contracts with them on specific targets (if the compute requirement is prohibitive for licensing). That seems to satisfy the incentives of DeepMind (this should be a significant money-maker, plus good publicity if and when their structures help lead to new drugs) and pharma (get structures for important targets that we can't get other ways).
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 individual patient can help identify which treatments are most likely to help.
Second, I think there's a link between the decrease in death rate from heart disease and the minimal death rate decline from cancer even with all the increased testing and new treatments. As they say, "something's gonna kill ya," and in my opinion dying from cancer at 65 instead of from a heart attack at 55 is still a win. As a comparator in a disease area where no treatments have really worked to date, see the death rates from Alzheimer's disease.
Third, I'm as bullish on cancer immunotherapy as the next guy, but it turns out that many tumors produce an immunosuppressive environment, where T cells and NK cells just don't do their thing very well. You can immunize against mutated protein fragments presented by the MHC all you want, but in an immunosuppressive microenvironment I still don't think you'll see those sweet sweet CRs.
Finally, even with all the regulatory barriers and misaligned incentives, pharma companies are still working on the best cancer therapy targets we know about. We (I work in pharma, so it's "we") certainly haven't hung up the "Mission Accomplished" banner and moved on. While I expect continued insights about basic cancer biology to come from academic labs that receive public funding, future therapies will continue to arrive primarily from the private sector. The potential pecuniary reward for even incremental increases in cancer survival rate is high enough to keep key players interested.
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 of the educational system. For college students, all the entry-level courses (general, organic, inorganic) are likely to have lab components. There are a few programs that separate the lab courses from the lectures, but they're the exception. The experiments won't be cutting-edge, but rather are designed to give students an understanding of chemical principles and what it's like to work with chemicals in a research setting.
Where things get really interesting from a lab perspective is if you can convince a professor to let you into their research lab as an undergraduate assistant. It's helpful if you're at a research university rather than a small liberal arts college because the lab facilities will be more conducive to cutting-edge research, and there will be grad students and postdocs who relish the opportunity to teach a curious undergrad how to do chemistry. You likely won't be designing your own project, but will have the opportunity to use modern equipment to do novel research under supervision. My undergraduate research experience was formative and a huge reason why I do what I do today. I was also lucky enough to get to pay it forward and mentor undergraduates when I was a grad student and a postdoc.
Graduate school in chemistry has a (somewhat deserved) reputation as a potentially miserable time. You get lots of great experience and training, but the hours are brutal and the rewards can be sparse. Synthesis in particular is a field where no matter how brilliant you are, lots of time in the lab is still essential for success. At this point you will work with your advisor to design and execute research projects, and success depends on your insight and work ethic. You can mitigate a lot of the problems with grad school by being careful about which lab you choose and being willing to set boundaries on your work time. It's also worth noting that I know a lot of really good chemists who started working in industry immediately after their bachelor's, or after a master's degree.
For the adult who has completed their education and wants to start doing chemistry at a level other than "fun home experiments", I don't have great suggestions. Maybe this is just a lack of imagination on my part as someone inside "the system" but the hurdles I talked about above are pretty daunting.
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 second problem is that chemical reactions typically generate waste in addition to the products you want. And it's not the kind of waste that most municipal garbage collectors are willing to accept. Third, the hard part of organic chemistry isn't running reactions, it's purifying and characterizing your products. Purifications might be tractable, depending on what you're doing (recrystallization, anyone?) but modern characterization techniques like NMR or mass spectrometry require hardware that's beyond most people's side-project budgets. A fourth problem, at least in the US, is that buying certain types of chemicals, including some common and useful reagents, will get you on the DEA's radar unless you're buying through an academic or industrial research institution (thanks, wannabe Walter Whites!).
There are examples of chemistry experiments that are safe and fun to do at home. As Mary says, you can illustrate many principles with safe DIY experiments but unfortunately I just don't know how to mitigate these very real hurdles to at-home micro-projects in organic chemistry.
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.
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 some fundamentals (what a chemical bond is, ionic vs. covalent bonding, electronegativity, bond dissociation energies, etc.) so if organic is really what you're after, feel free to give that a try. You can always pause that and go back to the general chemistry textbook if you feel like you're lacking foundation.
If memory serves, the Best Textbooks list has Clayden et al, which is the one that all the UK universities seem to use. It's a good textbook but if you're looking for an alternative suggestion, I used and liked Wade. Again, I'll put in a plug for OCW: 5.12 is the intro semester, with 5.13 following on.
Can I ask what the end goal for studying organic chemistry is? MCAT prep, learning biochemistry, and preparing to work in a synthesis lab all benefit from somewhat different approaches.
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.
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. Merlin Sheldrake's Entangled Life is also fun if you want an intro to the crazy stuff that happens in the fungal kingdom.
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 reader.
Thanks for the pointer to your blog post. You've clearly thought a lot about this. As you predicted, I find your conclusion repugnant and dystopian, but I don't have a knock-down argument against your train of thought.
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 came about because (a) the criticism was coming from an outsider, and (b) it's kind of a bait-and-switch to ask someone what the most important problem in their field is and then laugh at them when they don't immediately say "the thing I'm working on right now". I'd be ticked off if someone did that to me, especially if I didn't know them well beforehand.
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 job I like the most require physical infrastructure that is effectively only accessible within institutions, so I favor a path that lets me retain access to that while not worrying about the periodic layoffs endemic to my chosen industry.
I don't think we can learn too much about what people want to do with large amounts of free time from what they have done during Covid. The pandemic has brought a new set of unpleasant constraints. Inability to travel or see friends and loved ones without inducing lots of worry and guilt might make you pine for office politics!
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.
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 stereochemical outcomes.
Organic chemistry can be a playful subject if you approach it with the right mentality (don't believe what the pre-meds tell you, and don't try to memorize your way through the first semester!). If you're looking for ways to see how it impacts your life, try looking up the chemical structures of over-the-counter medications like aspirin, dietary supplements like vitamin B12 or taurine, or polymers like polyethylene terephthalate. Relating a structure to basic sensory data (the feel of a plastic bottle in your hand, the aftertaste of aspirin) can help the subject matter feel more relevant.
Please feel free to reach out to me if you have questions about learning organic chemistry! It's good to see someone posting on LW about a subject I feel qualified to comment on, for once!
"Don't screw future self" is one that has served me well for more than a decade.