>be postdoc >2012 in Cambridge >join Warp Drive Bio >plan to mine bacterial genomes >find macrocycles >what is a macrocycle >RAS is undruggable >everyone says so >surface is a Death Star >smooth no pockets >picomolar grip on GTP >whole field races the OFF state >bossman crazy >says hit the ON state >the active one >soil bug makes sanglifehrin >CypA just sitting in the cell >free chaperone? >what if we glue it? >macrocycle binds CypA >new surface grabs RAS >only the GTP bound state >it clamps >signal dies >pure three way complex >years of wet lab work >first compound is garbage >micromolar >aim only at conserved residues >swap phenyl for thiazole >better CypA contact >potency jumps >no bioavailability >unfixable half life >fix it anyway >chop the right side to a cyclopropyl >stick a methylpiperazine on the left >affinity explodes >811 daltons >big chungus >breaks all rules >should not be oral >it is oral >2018 buyout >molecule becomes RMC-6236 >early data looks promising >vp writes the blog post >doesn't get it >2023 need cash for phase 3 >EQRx dying with 1.1B in the bank >buy the company for the cash >sent CRO our structures to make >they like >they steal >joyo to erasca >where compound 4a >comes back as ERAS-0015 >RASolute 302 reads out >13.2 months >double chemo SoC >ASCO plenary >1 min standing ovation >presenter angry face >senator on expanded access >calls it a miracle drug >press goes wild >rash nbd >dying is worse >approval August 2026 easy >198 million in five weeks >mfw a macrocycle, from a dead startup, funded by a dead company, generational drug

🔥OK I'm editing a bunch of papers for tomorrow's ISBI deadline, and somehow everyone knows about this cool paper [1] but I didn't as I must have not been paying attention: 🔥Raut et al. found a sort of "Mexican wave" (like people standing up in a football stadium in a propagating/travelling wave) in the resting brain. A slow wave (on resting state) fMRI that is linked to arousal sweeps across cortex every so often, roughly from sensory regions to association regions (principal gradient, see the movie). 🔥SO if the standard (Yeo-7) resting state functional networks sit at different places along that path, when you average each network and compare them, you will see consistent lags between networks (even if lots of other stuff is going on and this is not the "main thing"). 🔥SO, networks far apart on the path, like visual and DMN, would show the biggest phase lags. OK so that is "Raut's wave" in the movie here from his paper, and assuming that the brain could have several, you can use dynamic mode decomposition (DMD) that includes Raut’s wave as a special case. so a puzzle... can a handful of whole-brain modes explain the 7-network lags and cross-spectra? 🔥And (my usual obsession)= how much data do we need to stably identify and estimate these components with a known accuracy? There isn't an analog of Davis Kahan (which we use in the zeta law) for DMD models as the eigenvectors of the transition operator are not normal. 🔥[1] Raut RV, Snyder AZ, Mitra A, Yellin D, Fujii N, Malach R, Raichle ME. Global waves synchronize the brain’s functional systems with fluctuating arousal. Sci Adv. 2021. 🔥[2] on DMD: Song Y, Kim PS, Philip BA, Kim T. Large-scale signal propagation modes in the human brain. Neuroimage. 2025 Sep.

This is absolutely wild. Didn’t think something like this would be in humans in my lifetime.

You can get into clinic for <$10m. I wrote a playbook on this last year shelbyann.substack.com/p/a-p…

It's fun to square these striking PRH observations w/ "neural degeneracy" findings in cogneuro, where hyperalignment / representational similarity analysis -type approaches are needed to align the seemingly-idiosyncratic encodings of subcategorical information in different brains

With many new cancer medicines, reminder that the clinical effectiveness of drug combinations is highly predictable from the clinical effectiveness of single agents 100% sensitive prediction of phase 3 trial success across all advanced cancers, 1995-2020 nature.com/articles/s43018-0…

We are finding that theta acts as a master clock that helps coordinate higher-frequency rhythms. Broschard et al (2026) Theta-based organization of information in the frontal cortex. Cell Reports, in press. Preprint: doi.org/10.64898/2026.06.03.…

MA: Most antipsychotics showed parallel dose–response curves for positive and negative symptoms, with a smaller magnitude of effect on negative symptoms academic.oup.com/schizophren…

Is [# of compounds which work in rodent models but not people] >> [# which work in people but not rodents]? Utility of rodent models in drug screening depends on that symmetry - but often the mapping itself is ambiguous. So the false negative rate can’t even be defined

“Did I do that?” Our new paper is out! In 611 participants, rumination and anhedonia were linked to distinct patterns in estimating whether effort influences outcomes. A closer look at how we learn what we can control 🧵 doi.org/10.1016/j.bpsc.2026.…

A culture clash has always simmered in biotech. Academia vs. Industry. PhDs vs. MBAs. Science vs. Business. These groups have different values and points of view. But it takes a village to develop a drug, so they had to find a way to get along But what if it doesn't take a village to develop a drug anymore? The 1-person biotech model raises the possibility of a PhD-MBA divorce I'm expecting many experiments in 1-person biotechs. I kind of love the concept and I really want it to work. Some of them will be led by MBAs and supplement the scientific expertise with Rosalind. Some of them will be led by PhDs and run the business strategy on Claude. Others, I hope, will be led by weirdos from neither of these backgrounds who approach medicine in ways we've never seen before. But navigating this transition is going to require enormous cultural sensitivity. There is a world where this is a bitter divorce - MBAs and PhDs fighting to make each other irrelevant. There is also a world where we dissolve the old cultures and re-form as a community of people who just want to build with Bio.

In 253 breast cancer survivors, sleep-related impairment tracked strongly with self-reported cognition and barely with tested cognition. Memory, attention and processing speed: no significant association. The gap is the finding. #SleepHealth pubmed.ncbi.nlm.nih.gov/4228…

.@NSF is hiring the inaugural Head of its Office of Metascience to apply the scientific method to how we fund, organize, and evaluate research. Continuous improvement will accelerate discovery. If you care about the science of science, apply:
nsf.gov/careers/openings/od/…

Sad news - Barbara did amazing work…

RT @DrAnnieHickox: Beautifully brutal.

The Unbearable Blurriness of Autism psychiatrymargins.com/p/the-…

Neural networks are already symbolic

RT @DrAnnieHickox: Rogue state.

I’ve met this team, they may well have the real thing. Great hope for the horizon of biological science thanks to tech like this

Meet Courtney and her son, Luke 💙 Stories like Courtney’s remind us who this research is for, and why it’s so urgent. We’re so grateful that she shared her story with us. At CureSHANK, one of our goals is to uplift and share the stories of families affected by Phelan-McDermid syndrome. As we accelerate life-transforming therapies for PMS, we will ensure the family voice is connected to that research. Thank you, Courtney, for sharing your family’s story. Together, we’re building the path to treatments for a better future for Luke and every person living with PMS. Are you a PMS parent or caregiver? We invite you to share your story with us! All it takes is 5-10 minutes to help shape the future of PMS research. 🔗 Click here to get started: storyprompt.com/reply/XkAW4f… Raising awareness is important every day, but especially on PMS Awareness Day this coming Thursday. Join us by sharing your story, amplifying PMS-related content, and more on October 22nd! @pmsshank3mama #PhelanMcDermidSyndrome #PMSAwarenessDay #CaregiverStories #PMSResearch #RareDiseaseResearch