Understanding what those handles are, and what it means for a tumor to have none of them, is the only way to understand why triple-negative breast cancer is simultaneously a biology problem and, in the United States, a racial equity problem hiding in plain sight.

In 1955, a New York banker and amateur mycologist named R. Gordon Wasson talked his way into one of her ceremonies and became, by his own account, the first outsider to eat the mushrooms and write down what happened. His account ran in Life two years later under a very interesting title “Seeking the Magic Mushroom” and the name stuck to the plant for good. It cost Sabina dearly, obviously. The flood of seekers her sudden fame set off got her run out of her own village.

In a supervised, and even unsupervised session today, a person lies down, puts on an eyeshade, and listens to a curated playlist while they go on their shroom journey. What they describe afterwards…

The usual boundary between self and everything else goes soft, there’s a sense of contact with something larger than themselves, sometimes a visit from someone they’ve lost. Run that protocol on people with a life-threatening diagnosis specifically, and the numbers get hard to look away from, a single high dose, and roughly seven in ten participants later rank the night among the five most meaningful experiences of their entire life, up there with the birth of a child. In particular, the fear of dying tends not to come back the way it was.

None of it, as far as anyone can tell, was built for us. The genes a mushroom uses to make psilocybin turn up scattered across unrelated species of dung and wood-rotting fungi, the signature of genes that jumped between species. Also the leading explanation for why any fungus bothered is almost insulting. The compound looks like an insect deterrent, evolved to make the mushroom taste bad, or think badly, to the beetles that would otherwise eat it before it spread its spores.

Once swallowed, psilocybin converts within minutes to psilocin, which doesn’t stop at the receptor responsible for the visions. It walks directly into TrkB and wedges itself into a channel running through the receptor’s own membrane-spanning segment, prying the whole structure into a shape roughly a thousand times more sensitive to its natural signal than basic antidepressants medicinal chemists spent decades engineering to do exactly that job.

What the drug does next

Blocks that one pocket, and the antidepressant-like effects disappear, while the hallucinations carry on completely unbothered.

TrkA and TrkB are cousins by gene duplication, products of the same ancient tyrosine-kinase lineage, and they still show it. Line up their kinase domains and roughly six residues in every ten are identical. Their AlphaFold-predicted structures and the two practically trace each other outline for outline, especially through the transmembrane segment.

This is the exact region where a 2023 study out of Eero Castrén’s lab in Helsinki pinpointed psilocin’s binding pocket on TrkB. TrkA answers to a different growth factor, nerve growth factor rather than BDNF, but once activated it fires the identical downstream relay. Which is the same MAPK cascade, the same PI3K/Akt survival signaling, the same calcium-mobilizing PLCγ pathway that TrkB uses to build new synapses.

Structurally and functionally, TrkA is close enough to TrkB that biology has trouble telling them apart in some contexts.

Pancreatic ductal adenocarcinoma doesn’t behave like most solid tumors. Instead of waiting for a blood vessel or a lymphatic channel to hitch a ride out of the pancreas, it grows into nerves directly, a pattern called perineural invasion. This shows up in the overwhelming majority of resected specimens. Cancer cells chemotax toward the nearest nerve fascicle, breach its protective sheath, and travel inside it as a corridor

It’s also why pancreatic cancer produces some of the most severe pain in solid-tumor oncology.

And the whole process runs on the same molecular grammar as neuroplasticity — the tumor secretes nerve growth factor, activates TrkA on both itself and the adjacent nerve, and the nerve responds by sprouting toward the tumor in return. Each side is, in the most literal biochemical sense, growing toward the other.

When researchers sequenced the whole genomes of early-stage tumors in 2012, mutations in the genes that guide axons toward their targets turned out to be among the most recurrent alterations in the cancer’s genome, as fundamental to its identity as the KRAS mutations that drive nearly every case.

Trkb isn’t confined to the nerves running through the tumor’s edges. It’s expressed on the pancreatic cancer cells themselves, where it helps cancer cells let go of their epithelial identity and resist anoikis, the death a cell is normally sentenced to the moment it loses its grip on surrounding tissue.

Anoikis resistance is the property a cancer cell needs to survive the trip through the bloodstream and found a metastasis somewhere else. So the receptor that psilocin was shown to sensitize with is expressed on the tumor cells, directly relevant to how the cancer spreads.

The results described earlier (the sustained relief, the fear of dying loosening its grip) held up again in a second, independent trial published the same week in 2016, this time out of NYU. Patients with pancreatic cancer are, if anything, the population with the most to gain from that kind of intervention, carrying some of the heaviest psychological burden of any cancer diagnosis. Taking that option away from them on the basis of an untested structural argument would be its own kind of harm.

Over the Last decade

• Cancer neuroscience has been building the case that nerves are not passive bystanders in tumor growth but active participants recruited by the tumor itself.

• Psychiatric neuroscience has discovered that its most promising new therapy works by directly rewiring a growth-factor receptor.

Whether concurrent TrkA and TrkB activation in a pancreatic tumor produces nothing worth worrying about is mostly unknown. amplifies the invasion the tumor already relies on, or actually gets in its own way, is, well, mostly unknown. All three outcomes are mechanistically defensible, and we can only hope for…

Further Reading

Wasson, R.G. (1957, May 13). Seeking the magic mushroom. Life, 42(19), 100–120.

Reynolds, H.T., Vijayakumar, V., Gluck-Thaler, E., et al. (2018). Horizontal gene cluster transfer increased hallucinogenic mushroom diversity. Evolution Letters, 2(2), 88–101. https://doi.org/10.1002/evl3.42

Moliner, R., Girych, M., Brunello, C.A., et al. (2023). Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nature Neuroscience, 26(6), 1032–1041. https://doi.org/10.1038/s41593-023-01316-5

Bapat, A.A., Hostetter, G., Von Hoff, D.D., & Han, H. (2011). Perineural invasion and associated pain in pancreatic cancer. Nature Reviews Cancer, 11, 695–707. https://doi.org/10.1038/nrc3131

Biankin, A.V., Waddell, N., Kassahn, K.S., et al. (2012). Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature, 491(7424), 399–405. https://doi.org/10.1038/nature11547

Griffiths, R.R., Johnson, M.W., Carducci, M.A., et al. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer. Journal of Psychopharmacology, 30(12), 1181–1197. https://doi.org/10.1177/0269881116675513

Ross, S., Bossis, A., Guss, J., et al. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer. Journal of Psychopharmacology, 30(12), 1165–1180. https://doi.org/10.1177/0269881116675512

Wiesmann, C., Ultsch, M.H., Bass, S.H., & de Vos, A.M. (1999). Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor. Nature, 401(6749), 184–188. https://doi.org/10.1038/43705

Notes

This post is adapted from a longer manuscript, “Convergent Neurotrophic Signaling,” proposing a preclinical framework for investigating this interface directly.

Alexander Chesler and Carsten Bönnemann began examining a handful of patients with rare, loss of function mutations in a gene called PIEZO2. When these patients were tested, their pain thresholds came back completely normal, a pinprick still felt sharp, a hot stove still hurt. What they’d actually lost wasn’t pain at all. It was the subconscious software that tells the brain where the body lives in space.

Split sensation into PIEZO2 constituent physics.

We are used to thinking of touch as a single sense, but the nervous system treats temperature, chemical irritants, and mechanical force as entirely distinct languages.

We’ve known the molecular receptors responsible for heat and cold work that earned David Julius part of the 2021 Nobel Prize in Physiology or Medicine. But the hardware responsible for sensing physical force remained elusive until Ardem Patapoutian, sharing that same Nobel Prize, identified the PIEZO family of ion channels.

PIEZO2 is a massive, three-bladed, propeller-shaped protein embedded in the membranes of our sensory neurons.

When your skin is stretched, poked, or compressed, or when a muscle spindle lengthens as you bend your elbow, the cell membrane physically pulls open the blades of the PIEZO2 channel.

Positively charged ions rush into the cell, firing an electrical signal to the brain. Force is converted into thought in microseconds.

In humans born without functional PIEZO2, the consequences reveal just how much invisible work mechanical sensation does behind the scenes.

If you ask a person with a PIEZO2 mutation to close their eyes and touch their nose with an index finger, they cannot do it.

Without visual confirmation, their brain loses track of where their hands are. If you blindfold them and gently move their foot up or down, they cannot tell you which direction it moved, or if it moved at all. They lack proprioception (the “sixth sense” generated by continuous mechanical feedback from muscle spindles and joint receptors).

To walk, they must look directly at their feet, manually substituting visual data for the automated subconscious telemetry their brain ought to be receiving from their legs. If you turn off the lights in a room, they will sway and fall, stripped of their internal coordinates in the dark.

Intriguingly, their pain sensation is almost eerily ordinary. They feel the burn of a hot stove and the sting of chili pepper at normal thresholds, because thermal and chemical nociceptors run on separate molecular machinery (like the TRPV family).

But tested against a pinprick or a blunt pressure probe, their mechanical pain thresholds come back indistinguishable from anyone else’s. This surprised even the researchers, since it meant the everyday sense of “ouch” doesn’t route through PIEZO2 at all. Somewhere in the skin, a separate circuit of pain fibers is doing that job on its own.

However, PIEZO2 doesn’t control whether touch turns into pain after an injury.

Healthy nervous systems develop tactile allodynia after a burn or a bruise. Patients without PIEZO2 never develop it. Light touch stays harmless, even on inflamed tissue, because the channel that would normally convert that touch into pain signaling simply isn’t there.

Chronic pain remains one of the most stubborn failures of modern pharmacology, largely because targeting broad pain pathways often numbs the entire nervous system or carries high addiction liabilities. PIEZO2 selectively encodes mechanical force and opens up hyper-targeted therapeutic possibilities, drugs that selectively dampen mechanical hypersensitivity in conditions like fibromyalgia or neuropathic pain without wiping out a patient’s ability to feel thermal danger or basic touch.

PIEZO2 is actively guiding how our bodies assemble themselves. Patients with PIEZO2 deficiency frequently develop severe scoliosis, joint hypermobility, and skeletal deformities. During development, the spine and joints rely on mechanical feedback from movement to align correctly. Without the constant tension readings supplied by PIEZO2, the body grows without knowing its own geometry.

Which brings us back to what sensory perception actually is.

We tend to view our senses as external tools, cameras and microphones taking in an outside world. But it’s also about defining the internal self. Literally It is the molecular architecture of presence, constantly anchoring your mind inside a physical structure.

Stripped of that single protein, the brain is simply left floating in space.

Further Reading

Chesler, A.T., Szczot, M., Bharucha-Goebel, D., et al. (2016). The Role of PIEZO2 in Human Mechanosensation. The New England Journal of Medicine, 375(14), 1355–1364. https://doi.org/10.1056/NEJMoa1602812

Nagi, S.S., Marshall, A.G., Makdani, A., et al. (2019). An ultrafast system for signaling mechanical pain in human skin. Science Advances, 5(7), eaaw1297. https://doi.org/10.1126/sciadv.aaw1297

Szczot, M., Liljencrantz, J., Ghitani, N., et al. (2018). PIEZO2 mediates injury-induced tactile pain in mice and humans. Science Translational Medicine, 10(462), eaat9892. https://doi.org/10.1126/scitranslmed.aat9892

Coste, B., Mathur, J., Schmidt, M., et al. (2010). Piezo1 and Piezo2 are essential components of distinct mechanically-activated cation channels. Science, 330(6000), 55–60. https://doi.org/10.1126/science.1193270

Woo, S.H., Lukacs, V., de Nooij, J.C., et al. (2015). PIEZO2 is the principal mechanotransducer of proprioception in mice. Nature Neuroscience, 18(12), 1756–1762. https://doi.org/10.1038/nn.4162

Notes

Banner photo: Cultured dorsal root ganglion (DRG) sensory neuron explant showing axonal outgrowth. Image via Wikimedia Commons, CC BY-SA 3.0.

The setup is called DishBrain, built by a team at Cortical Labs led by neuroscientist Brett Kagan. The neurons were a mix of mouse cortical cells and human neurons derived from stem cells. They were cultured directly onto a high-density array of electrodes, a grid dense enough to both listen to the electrical activity of individual neurons and deliver precise electrical stimulation to them cell by cell.

The team wired this array into a simulated version of Pong. The position of the ball was converted into a stimulation pattern delivered to one region of the dish. The neurons’ own resulting activity in another region was read out and converted into paddle movement.

This is much stranger than a standard reinforcement learning setup because, what were the neurons were working with when they got something wrong?

A game-playing AI is normally trained by maximizing reward, like points for winning or a number going up. Neurons in a dish don’t have access to anything like a dopamine signal you can just hand them. So the team, working with theoretical neuroscientist Karl Friston, a co-author on the paper, built the feedback around Friston’s free energy principle instead, the idea that biological systems act, fundamentally, to minimize surprise about their environment rather than to chase reward directly.

• When the dish hit the ball, it received predictable, structured stimulation.

• When it missed, it received unstructured electrical noise.

Instead of earning a prize laying well earned a more orderly, a less chaotic world to be stimulated by.

Within about five minutes of gameplay, the culture’s rallies got longer. The neurons weren’t just twitching randomly or occasionally connecting with the ball by chance, their hit rate improved over the course of play, in a way the researchers could track and reproduce.

Interestingly, the human-derived neurons sustained longer rallies than the mouse-derived ones, though the team has been careful not to lean too hard on that difference given how early this work still is.

Kagan himself ALSO stressed that DishBrain shows no evidence of consciousness, and the original paper’s use of the word “sentience” in its title, meaning simply the capacity to sense and respond to an environment, drew real pushback from other neuroscientists who felt it invited exactly the kind of overclaiming Kagan says he wanted to avoid.

A system can behave adaptively, in a measurable, repeatable way, without that behavior implying anything about what it’s like, if anything, to be that system.

Deep reinforcement learning agents typically need enormous numbers of training episodes to master something as simple as Pong. A follow-up study directly comparing biological neuron cultures with deep RL agents on the same task found the neurons could reach comparable performance using far less experience, a property researchers call sample efficiency.

Whatever the neurons are doing to organize themselves around this task, they’re doing it with less data and drastically less power than a GPU cluster needs.

Real translational pull: a living, adaptable neural system on a dish is a plausible platform for testing how drugs, or conditions like epilepsy, alter learned behavior directly, without ever needing an animal model in the loop.

What this suggests, I think, is the capacity to act so as to make your surroundings more predictable isn’t something that waits around for a full brain, a body, or a nervous system shaped by millions of years of evolution to show up. Whatever learning fundamentally is, it may be running on much simpler hardware than we’ve been assuming.

Further reading

Kagan, B.J., Kitchen, A.C., Tran, N.T., et al. (2022). In vitro neurons learn and exhibit sentience when embodied in a simulated game-world. Neuron. https://doi.org/10.1016/j.neuron.2022.09.001

Friston, K. (2010). The free-energy principle: a unified brain theory? Nature Reviews Neuroscience, 11, 127–138.

Biological Neurons Compete with Deep Reinforcement Learning in Sample Efficiency in a Simulated Gameworld (2024). arXiv:2405.16946.

Some spend up to five hours a day underwater.

Divers routinely descend past 60 metres and hold their breath for several minutes at a time, in a range most people could never approach even with training.

That has always been treated as a story about skill and lifestyle. Then, in 2018, a team led by geneticist Melissa Ilardo set out to test whether any of it was written into the Bajau’s biology itself, rather than just trained into it.

The team compared the Bajau to a nearby population, the Saluan, who share a similar environment but don’t dive for a living. The finding was striking. Bajau spleens were significantly larger than the Saluan’s, and the difference held even among Bajau who don’t dive. That detail matters because it meant this wasn’t a body adapting to a lifestyle through training. It was something the Bajau were already carrying, genetically, before they ever entered the water.

The spleen turns out to be the key organ here.

In diving mammals, it contracts during a dive, releasing a reserve of oxygen-rich red blood cells into circulation, buying extra time underwater. The researchers traced the Bajau’s enlarged spleens to variation in a gene called PDE10A, which appears to influence thyroid hormone levels known to regulate spleen size.

They also found evidence of selection on a second gene, BDKRB2, linked to the body’s diving reflex, the automatic narrowing of blood vessels in the limbs that redirects oxygen toward vital organs during breath holding. Put together, the Bajau seem to carry a genuine, inherited physiological toolkit for life underwater.

Both of those genes point toward the same organ, even though, well, neither one sits inside it. The dive reflex exists to protect the two structures that can least afford to run out of oxygen, the heart and the brain.

When BDKRB2 tightens blood vessels in the arms and legs, it’s rerouting blood toward the brain specifically, the organ most vulnerable to hypoxia and the one whose damage is hardest to reverse. The reflex itself is coordinated by circuits in the brainstem, which means the apparatus doing the redirecting sits inside the very organ it evolved to protect.

It’s one of the clearest documented cases we have of a population evolving a specific, measurable adaptation to a specific way of life, and it has real medical relevance.

Beyond Curiosity

Understanding how the body naturally tolerates low oxygen has direct implications for treating acute hypoxia in emergency and critical care medicine, including the neuroprotective strategies used when the brain itself is starved of oxygen after a stroke or cardiac arrest, situations where every minute of unprotected hypoxia costs measurable brain tissue.

A population that has spent a thousand years surviving repeated, voluntary bouts of exactly that stress is, in effect, a natural experiment in the same question critical care medicine is still trying to solve artificially.

Many stories like this never get found

The Bajau’s variant was only discoverable because someone chose to sequence their genomes in the first place. Most of the world hasn’t had that chance.

The GWAS Catalog, one of the largest public repositories of genomic association data, is still roughly 95 percent European ancestry, even though people of European ancestry make up less than 9 percent of the world’s population.

It means population-specific variants, protective or otherwise, in African, Asian, Latin American, and Indigenous populations are largely invisible to the reference data modern medicine is built on. Simply because the sequencing was never done.

Most of the world still waiting for a desicion to be made about them. Inclusion

Further reading

Ilardo, M.A., Moltke, I., Korneliussen, T.S., et al. (2018). Physiological and Genetic Adaptations to Diving in Sea Nomads. Cell, 173(3), 569–580. https://doi.org/10.1016/j.cell.2018.03.054

Petrovski, S. & Goldstein, D.B. (2016). Unequal representation of genetic variation across ancestry groups creates healthcare inequality in the application of precision medicine. Genome Biology, 17, 157.

Notes

Banner photo: A Sama-Bajau village in Pulau Omadal, Sabah, Malaysia, by Tom Gunnar Hoogervorst (2012), CC BY 3.0, via Wikimedia Commons.