My personal blog, mainly focusing on issues of chemistry and metascience, unified by trying to answer the question 'how can we make science better'?
If you’re wondering “is this a joke,” the answer is both yes and no. This post is certainly a joke in the sense of "something that I'm intentionally doing because I thought it would be funny." I picked up Feser’s Scholastic Metaphysics: A Contemporary Introduction after reading a First Things article by Mary Harrington , and whilst reading the book I thought of the title of this post and started…
TW: profanity, sarcasm, misuse of theological concepts. Hosea and Gomer, from the Bible Historiale (1372) There’s something special about “Venice Bitch,” the nine-minute-long song from Lana Del Rey’s 2019 album Norman Fucking Rockwell . Wikipedia writes that the song earned “unanimous praise from music critics” and “was ranked by numerous publications amongst the best songs of the year and…
Something I’ve been thinking about recently is the information content of different biomolecules. While small molecules, peptides, antibodies, and oligonucleotides can all be valuable therapeutic assets in various contexts, they’re strikingly different to synthesize, develop, and simulate. There are well-known reasons for many of these differences—oligonucleotide synthesis can be highly automated,…
The Rebuilding of the Temple is Begun , Gustave Doré (1866) As AI systems get more powerful and better at scientific tasks, what will the new research ecosystem look like? One perspective, which is rarely stated explicitly but comes up implicitly or in conversation, is that AIs will render much of conventional theory and modeling obsolete: either AI will write its own scientific tools and…
Yesterday, an interesting paper was released by Prescient Design (Genentech), “Evaluating the Progression of Large Language Model Capabilities for Small-Molecule Drug Design.” The authors formulate a variety of problems in small-molecule drug design as reinforcement-learning (RL) problems and use RL-based post-training to improve the performance of a 30B-parameter Qwen model (specifically,…
Martin Luther in the Circle of Reformers (1600s) TW: stridently anti–Roman Catholic rhetoric, medieval realist metaphysics Popular histories of the Reformation typically emphasize the discontinuity between medieval theology and the Reformers. In its simplest form, an account of church history through the Reformation might go like this: During (and shortly after) the events of the New Testament,…
Long ago, there were no software companies. In the age of System/360, vertically integrated companies like IBM were responsible for virtually all aspects of the end product they sold, from hardware to operating system to end-user applications. Then, the value chain started to diversify: Microsoft allowed software and hardware to become decoupled, and then a variety of application-specific…
(Previously: 2022 , 2023 , 2024 .) #1. Andrew Roberts, Napoleon: A Life Strangely, Roberts’ Napoleon reminded me a lot of Elon Musk—incredible drive and energy, mind-melting attention to detail, and a culture of micromanagement and direct control which perhaps more than anything else drove him to ruin. (I hope Elon’s story has a happier ending.) #2. Magda Szabo, The Door #3. Marc Benioff, Behind…
The Vision of The Valley of The Dry Bones , Gustave Doré (1866) Last week I had the privilege of attending the 2025 Progress Conference , which brought together a diverse cadre of people working on progress, metascience, artificial intelligence, and related fields. I was surprised by how optimistic the median attendee was about AI for science. While some people inside science have been excited…
I don’t write about my non-working life much on the Internet; my online presence has been pretty closely tied to Rowan and I try to adhere to some level of what Mary Harrington calls “digital modesty” regarding my family. Still, some basic demographics are helpful for context. I have two kids (aged 2 and 4) and one more due in December. My children have many and varied interests: they like playing…
The Astronomer , Johannes Vermeer (c. 1668) I’ve been sitting on this post for well over a year. This is the sort of thing I might consider turning into a proper review if I had more time—but I’m quite busy with other tasks, I don’t feel like this is quite comprehensive or impersonal enough to be a great review, and I’ve become pretty ambivalent about mainstream scientific publishing anyway .…
The Moneylender and his Wife , Quentin Matsys (1514) Inspired by related writings from Scott Alexander, who is funnier than me. TW: fiction, but barely. AlphaProteinStructure-2 is a deep learning model that can predict the structure of mesoscale protein complexes like amyloid fibrils. AlphaProteinStructure-2 is free for academic usage. Typically this means researchers at universities can use the…
Gustave Doré, illustration for Paradise Lost (1866) In center-right tech-adjacent circles, it’s common to reference René Girard. This is in part owing to the influence of Girard’s student Peter Thiel. Thiel is one of the undisputed titans of Silicon Valley—founder of PayPal, Palantir, and Founders Fund; early investor and board member at Facebook; creator of the Thiel Fellowship; and mentor to…
(This post is copied from some notes I gave to our summer interns at Rowan almost without modification. Hopefully people outside Rowan find this useful too!) This is a brief and opinionated guide on how to give a research talk to an external audience. Some initial points of clarification—this guide is for a research talk, not a sales call or a VC pitch. Research talks have their own culture and…
The past is powerful evidence for arguments about the present. Since the time of Livy and Tacitus, it’s been common to cite history to advance some ideological, cultural, or political idea. While there’s nothing wrong with this in principle, these lines of discourse often break down because (1) people know very little history and (2) what little history they do know is usually wrong. Popular…
Expanded from a post on X , which I felt didn’t do a good job expressing all of what I meant. The past few years of “AI for life science” has been all about the models: AlphaFold 3, neural-network potentials, protein language models, binder generation, docking, co-folding, ADME/tox prediction, and so on. But Chai-2 (and lots of related work) shows us that the vibes are shifting. Models themselves…
“You dropped a hundred and fifty grand on a f***** education you coulda' got for a dollar fifty in late charges at the public library.” — Good Will Hunting I was a user of computational chemistry for years, but one with relatively little understanding of how things actually worked below the input-file level. As I became more interested in computation in graduate school, I realized that I needed to…
Recently, Kelsey Piper shared that o3 (at time of writing, one of the latest reasoning models from OpenAI) could guess where outdoor images were taken with almost perfect accuracy. Scott Alexander and others have since verified this claim. I’ve been playing around with this too: with the prompt linked in Scott’s post, o3 can guess where my photos were taken almost every time, even when I…
A traditional iconographic depiction of Abraham's visitors. I did not enjoy John Mark Comer’s book The Ruthless Elimination of Hurry . Comer’s book is written to people trying to find meaning in a world that feels rushed, distracted, and isolated. At the time of writing, Comer was a Protestant pastor in Portland, Oregon, but he’s since stepped back to focus on creating resources for spiritual…
In scientific computation, where I principally reside these days, there’s a cultural and philosophical divide between physics-based and machine-learning-based approaches. Physics-based approaches to scientific problems typically start with defining a simplified model or theory for the system. For instance, a scientist attempting to simulate protein dynamics might start by defining how the energy…
With apologies to Andrew Marvell. If you haven’t read “To His Coy Mistress” , I fear this won’t make much sense. * * * Had we but funding enough and time, This coyness, founder, were no crime. We would sit down, and think which way To build, and pass our slow run-rate’s day. Thou by the Potomac’s side Shouldst SBIRs find; I by the tide Of El Segundo would complain. I may Fund you ten years before…
In 2007, John Van Drie wrote a perspective on what the next two decades of progress in computer-assisted drug design (CADD) might entail. Ash Jogalekar recently looked back at this list, and rated the progress towards each of Van Drie’s goals on a scale from one to ten. There’s a lot in Jogalekar’s piece that’s interesting and worth discussing, but I was particularly intrigued by the sixth item on…
This post is an attempt to capture some thoughts I have about ML models for predicting protein–ligand binding affinity, sequence- and structure-based approaches to protein modeling, and what the interplay between generative models and simulation may look like in the future. I have a lot of open questions about this space, and Abhishaike Mahajan’s recent Socratic dialogue on DNA foundation models…
(This is a bit of a departure from my usual chemistry-focused writing.) Fasting is an important part of many religious traditions, but modern Protestant Christians don’t really have a unified stance on fasting ( and have opposed systematic fasts for a while ). That’s not to say that Protestants don’t fast, though: over just the past few years, I’ve met people doing water-only fasts, juice fasts,…
(Previously: 2022 , 2023 .) #1. Baldassar Castiglione, The Book of the Courier This book gets cited from time to time as a sort of historical guide to "being cool," since the characters spend some time discussing the idea of sprezzatura , basically grace or effortlessness. More interesting to me was the differences between Renaissance conceptions of virtue, character, & masculinity / femininity…
This post assumes some knowledge of molecular dynamics and forcefields/molecular mechanics. For readers unfamiliar with these topics, Abhishaike Mahajan has a great guide to these topics on his blog. Although forcefields are commonplace in all sorts of biomolecular simulation today, there’s a growing body of evidence showing that they often give unreliable results. For instance, here’s Geoff…
Abhishaike Mahajan recently wrote an excellent piece on how generative ML in chemistry is bottlenecked by synthesis ( disclaimer: I gave some comments on the piece, so I may be biased ). One of the common reactions to this piece has been that self-driving labs and robotics will soon solve this problem—this is a pretty common sentiment, and one that I’ve heard a lot. Unfortunately, I think that the…
I've been playing around with generating non-equilibrium conformations by molecular dynamics recently, and I've been thinking about how to best parse the outputs of a dynamics simulation. A technique I've seen quite often in the literature is "choose a dissimilar subset of conformers by RMSD"—for instance, here's what the SPICE paper says: For each of the 677 molecules, the dataset includes 50…
Scientific software can be confusing, particularly when you're doing something that the software isn't primarily intended for. I often find myself wanting to run quick-and-dirty molecular dynamics simulations on small organic molecules, but I've struggled to find an easy way to do this using open-source tools like OpenMM. This is particularly frustrating since I feel like I should be equipped to…
Update: As of October 2024, you can now run DiffLinker calculations through Rowan , my computational chemistry startup. Read more about this in our newsletter ! Much molecular design today can be boiled down to “put the right functional groups in exactly the right places.” In catalysis, proper positioning of functional groups to complement developing charge or engage in other stabilizing…
Pure mathematics has all sorts of unexpected connections to other fields, and chemistry is no exception. One example of this is group theory: while I never delved deeply enough into math to actually study group theory as its own field, I've had to learn how to assign point groups to three-dimensional objects for several inorganic chemistry classes. This process, demonstrated below for water,…
Apologies for the long hiatus: we've had some health issues in the family, and startup life has been particularly overwhelming. With any luck, I'll be able to return to a more regular posting frequency soon. What’s the right relationship between theory, computation, and experiment? Much has been written on this. In this piece, I want to put forward an answer that I think is underrated in the life…
In Wednesday’s post , I wrote that “traditional physical organic chemistry is barely practiced today,” which attracted some controversy on X . Here are some responses: “POC has evolved in many directions and its concepts are widely used, e.g., in host-guest chem, org syn, materials sci, drug discovery.” - Bill Jorgensen “There is still a lot of absolutely gorgeous classical phys org done with…
In this post, I’m trying something new and embedding calculations on Rowan alongside the text. You can view the structures and energies right in the page, or you can follow a link and view the full data in a new tab. While PDFs and printed journals are limited to displaying 2D renditions of 3D structures, there’s no reason why websites should follow suit—and now that all my calculations are…
(Previously: 2022 ) #1. Tony Fadell, Build #2. Giff Constable, Talking To Humans #3. Ben Horowitz, The Hard Thing About Doing Hard Things #4. Dale Carnegie, How To Win Friends And Influence People Sounds Machiavellian, but actually quite wholesome: a “dad book,” as my friend called it. #5. Ben Patrick, Knee Ability Zero . #6. Neal Stephenson, The Diamond Age Snow Crash was much worse upon…
“And I took the little scroll from the hand of the angel and ate it. It was sweet as honey in my mouth, but when I had eaten it my stomach was made bitter.” –Revelation 10:10 As machine learning becomes more and more important to chemistry, it’s worth reflecting on Richard Sutton’s 2019 blog post about the “bitter lesson.” In this now-famous post , Sutton argues that “the biggest lesson that can…
I took a pistol course in undergrad, and while I was a poor marksman I enjoyed the experience. In particular, I was surprised by how meditative the act of shooting was. As our instructor explained, much of good shooting comes down to not doing anything when you pull the trigger. When you’re not firing, it’s easy to point a gun at a target and line up the sights, but as you pull the trigger you…
“Like arrows in the hand of a warrior are the children of one's youth.” –Psalm 127:4 Mata Mua , by Paul Gaugain (1892), another Westerner looking for enlightenment among “venerable cultures.” What if our most fundamental assumptions about parenting were wrong? That’s the question that Michaeleen Doucleff’s 2021 book Hunt, Gather, Parent tries to tackle. Hunt, Gather, Parent (henceforth HGP )…
Quantum computing gets a lot of attention these days. In this post, I want to examine the application of quantum computing to quantum chemistry, with a focus on determining whether there are any business-viable applications today. My conclusion is that while quantum computing is a very exciting scientific direction for chemistry, it’s still very much a realm where basic research and development is…
In 2019, ChemistryWorld published a “wish list” of reactions for organic chemistry, describing five hypothetical reactions which were particularly desirable for medicinal chemistry. A few recent papers brought this back to my mind, so I revisited the list with the aim of seeing what progress had been made. (Note that I am judging these based solely by memory, and accordingly I will certainly omit…
"Hi, would you like to connect on LinkedIn?" (in the spirit of Dale Carnegie and post-rat etiquette guides ) Scientists, engineers, and other technical people often make fun of networking. Until a few years ago, I did this too: I thought networking was some dumb activity done by business students who didn’t have actual work to do, or something exploitative focused on pure self-advancement. But…
“A cord of three strands is not easily broken.” —Ecclesiastes 4:12 Abu Simbel relief of Ramesses II shooting a composite bow at the Battle of Kadesh. Computational chemistry, like all attempts to simulate reality, is defined by tradeoffs. Reality is far too complex to simulate perfectly, and so scientists have developed a plethora of approximations, each of which reduces both the cost (i.e. time)…
ICYMI: Ari and I announced our new company, Rowan ! We wrote an article about what we're hoping to build, which you can read here . Also, this blog is now listed on The Rogue Scholar , meaning that posts have DOIs and can be easily cited. Conventional quantum chemical computations operate on a collection of atoms and create a single wavefunction for the entire system, with an associated energy and…
Recently in off-blog content: I coauthored an article with Eric Gilliam on how LLMs can assist in hypothesis generation and help us all become more like Sharpless. Check it out! The Pauling model for enzymatic catalysis states that enzymes are “antibodies for the transition state”—in other words, they preferentially bind to the transition state of a given reaction, rather than the reactants or…
Since the ostensible purpose of organic methodology is to develop reactions that are useful in the real world, the utility of a method is in large part dictated by the accessibility of the starting materials. If a compound is difficult to synthesize or hazardous to work with, then it’s difficult to convince people to use it in a reaction (e.g. most diazoalkanes). Organic chemists are pragmatic,…
TW: stereotypes about molecular dynamics. In his fantastic essay “ The Two Cultures ,” C. P. Snow observed that there was (in 1950s England) a growing divide between the academic cultures of science and the humanities: Literary intellectuals at one pole—at the other scientists, and as the most representative, the physical scientists. Between the two a gulf of mutual incomprehension—sometimes…
An important problem with simulating chemical reactions is that reactions generally take place in solvent, but most simulations are run without solvent molecules. This is a big deal, since much of the inaccuracy associated with simulation actually stems from poor treatment of solvation: when gas phase experimental data is compared to computations, the results are often quite good. Why don’t…
TW: sarcasm. Today, most research is done by academic labs funded mainly by the government. Many articles have been written on the shortcomings with academic research: Sam Rodriques recently had a nice post about how academia is ultimately an educational institution, and how this limits the quality of academic research. (It’s worth a read; I’ve written about these issues from a few angles , and…
The concept of p K a is introduced so early in the organic chemistry curriculum that it’s easy to overlook what a remarkable idea it is. Briefly, for the non-chemists reading this: p K a is defined as the negative base-10 logarithm of the acidity constant of a given acid H–A: p K a := -log 10 ([HA]/[A-][H+]) Unlike pH, which describes the acidity of a bulk solution, p K a describes the intrinsic…
You are a scientist, not a lab monkey. You ought not to view your degree as “six years of hard labor in the chemistry mines.” Always make time to go to interesting seminars, talk with other people about their research, and read the literature. Otherwise, what’s the point of being a scientist? Only one person is really looking out for your best interests: you. Your advisor, your classmates, and…