In 2021, I was traveling around the U.S. with my two friends, Slava and Marty, renting a new place in a new city every month or so. I was free to be nomadic thanks to working remotely as a machine learning consultant in cloud-based development. It was engaging work that paid well, but I knew I didn’t want to be doing it forever.
Outside of work, I read about neuropharmacology and molecular biology, my fondest extracurricular interests acquired in college. After graduating, I grew increasingly enchanted by the multilayered mechanics of how drugs work at the molecular level to modulate biological systems at higher levels, from cells to organs to Coachella. But this kind of science didn’t strike me as an area where I could make any serious contribution; in my mind, that world was for people in lab coats, not software engineers.
My Stanford Psychedelic Society T-shirt. The emergence of the still-ongoing "psychedelic renaissance" in the late 2010s coincided with my time as an undergraduate student, shaping and deepening my early curiosity about pharmacology.
One night in NYC, we put on a new episode of the TV show Hamilton’s Pharmacopeia, titled “Ultra LSD”. Chemist & journalist Hamilton Morris was tracing the scientific legacy of LSD, from its accidental discovery and notorious cultural impact to its later role in shaping the study of receptor pharmacology, particularly the serotonin receptors responsible for the drug’s psychedelic effects.
Two researchers featured prominently in the episode: David Nichols and Bryan Roth, both legendary figures in neuropharmacology and medicinal chemistry. Roth had just recently solved the structure of the LSD-bound 5HT2A serotonin receptor and was using it to computationally screen billions of molecules in search of new antipsychotics and antidepressants. They called this methodology ultra-large-scale docking (ultra-LSD). It was the first time I’d seen drug discovery framed as a computational problem rather than a heroic feat requiring immense manual labor, perpetual trial-and-error, and a good dose of serendipity. To be succinct, this was perhaps the most intriguing application of computers I’d ever come across. Put another way, it was the coolest shit I’d ever seen.
Professor Roth explaining the significance of his lab producing the first cryo-EM structure of the LSD-bound 5HT2A receptor. With this snapshot of the hallucinogen at the moment of activating the receptor, computational methods like molecular docking can find new compounds likely to be active as well—even ones never synthesized before.
I was enthralled. I immediately emailed my résumé to Nichols and Roth, eagerly asking whether they had any use for someone with my skill set. I was willing to get involved in any capacity, even as an unpaid volunteer. To my surprise, both replied that their collaborator Brian Shoichet was the one I should really talk to, as he’s the one who did all the computation. I still find it curious that the apparent mastermind behind ultra-LSD somehow goes unmentioned in “Ultra LSD”.
So, I sent Shoichet an email. I said I’d watched the episode, read some of his group’s papers, and asked if he thought I could contribute. He and his co-PI, John Irwin, wrote back offering to meet on Zoom. On the call, I told them what I’d been working on and what I wanted to learn. They told me they were looking for someone like me and explained how they thought my skills could help their research. I’d cold-emailed a world-class lab, and somehow, it had actually worked! I left the call with a strange sense that I was stumbling in the right direction.
By the end of the year, I had joined the Shoichet Lab at UCSF as a Bioinformatics Programmer, my first step in the world of science. I spent the early weeks sifting through decades of accumulated code, learning the intricacies of molecular docking, and trying not to break anything too important. Eventually, I started writing software to streamline and automate the docking protocols powering active drug discovery projects in the lab. It was the first time my technical and scientific interests came together in a single, coherent pursuit.
UCSF Shoichet Lab, December 2021. That’s me under the red arrow.
[To be continued…]