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6 plain-language articles on origins and discovery — the physiology, the compounds, and what the evidence actually shows.
6 articles
The David Sinclair NAD+ story — hype, evidence, honest assessment
In the late 1990s, a graduate student named David Sinclair was working in Lenny Guarente's lab at MIT, trying to understand why yeast cells age. The answer his experiments pointed toward involved a protein called Sir2 — Silent Information Regulator 2. In yeast, Sir2 controlled whether certain genomic regions were transcriptionally active or silenced, and its activity appeared to be linked to lifespan. When you increased Sir2 expression in yeast, the cells lived longer. When you inhibited it, they lived less long. Sinclair went on to characterize Sir2 and its mammalian cousins, the sirtuins, as what he would eventually describe as a master regulatory system of aging — a set of molecular sensors that respond to cellular stress and energy status and govern whether cells survive, repair themselves, or succumb to aging-associated dysfunction.
Exenatide and the gila monster — how the GLP-1 family started
The gila monster doesn't eat much. A large meal — a bird's egg, a small mammal, a clutch of nestlings — can sustain it for weeks. It lives in the Sonoran Desert and the Mojave, in rocky terrain where food is scarce and unpredictable, and its metabolism has spent millions of years adapting to this reality. When it does eat, its blood glucose management has to be precise: a spike of glucose into a system that isn't continuously calibrated for meals would be dangerous. And yet the gila monster manages this without a meal plan, without continuous glucose monitoring, without insulin injections. It manages it with chemistry that its body produces and that, it turns out, looks remarkably like a hormone humans also produce — just improved. Sturdier. Built for the long intervals between meals.
The GLP-1 discovery deeper history — Holst, Mojsov, and the science before the drug
In 1982, Jens Juul Holst was working in a basement laboratory at the University of Copenhagen, trying to understand what the gut did with glucose. Not what happened in the bloodstream afterward. Not what the pancreas produced. What the gut itself was doing — the biochemical signaling that happened in the intestinal wall in the seconds and minutes after food arrived. It was methodical, unglamorous work: isolating intestinal tissue from pigs and dogs, running extracts through high-performance liquid chromatography, measuring immunoreactive peptide fractions that no one had fully characterized. One of those fractions kept showing up in a way that suggested it was derived from the glucagon gene but wasn't glucagon. It behaved differently. It appeared in the intestine rather than the pancreas. And it seemed, in preliminary experiments, to do something interesting to insulin secretion.
Insulin in Toronto, 1921 — the discovery that started peptide pharmacology
It was past two in the morning when Frederick Banting read the paper. November 1920, in his rented room in London, Ontario, where he'd opened a small surgical practice that wasn't filling up. Banting was 29, trained as a surgeon, failing at attracting patients in a city that had no shortage of them, and moonlighting as a part-time lecturer in physiology at the University of Western Ontario to cover rent. The paper was by Moses Barron, published in Surgery, Gynecology and Obstetrics, describing the pancreatic duct and what happened when it was ligated. The acinar cells — the cells responsible for digestive enzymes — degenerated. The islets of Langerhans, packed into the pancreas like small islands, survived. Banting underlined something and wrote in the margin. Then he wrote in his notebook: "Diabetus. Ligate pancreatic ducts of dog. Keep dogs alive till acini degenerate leaving Islets. Try to isolate the internal secretion of these to relieve glycosurea."
Peptide drug conjugates — the targeted delivery revolution underway
A chemotherapy drug administered conventionally travels everywhere. It enters the bloodstream, circulates, and kills cells that are dividing rapidly — which is most of what makes cancer cells vulnerable and most of what makes conventional chemotherapy brutal. The cells lining the gut divide rapidly. Hair follicle cells divide rapidly. Bone marrow produces new blood cells through rapid division. Chemotherapy doesn't distinguish. The drug is poison delivered systemically, and the art of chemotherapy dosing has always been the art of finding the highest dose the patient can survive while hoping the tumor can't.
The Amazon rainforest, snake venom, and the discovery of ACE inhibitors
The workers in rural Brazil who were bitten by the Bothrops jararaca, the lancehead pit viper, did not die from blood pressure. They died from hemorrhage — the snake's venom is hemotoxic and causes catastrophic disruption to the coagulation cascade. What the surviving bite victims noticed, and what eventually caught a pharmacologist's attention in the early 1960s, was a different effect: profound, sudden hypotension. Their blood pressure dropped dramatically after envenomation. Something in the venom was doing something specific to the vasculature. The question of what that something was, pursued through a series of unglamorous and painstaking biochemical extractions over the following years, produced one of the most consequential drug classes in the history of cardiovascular medicine.