Format
Origins & history
Where a compound came from and how the science developed.
25 articles
Origins and discoveryAOD-9604 — the human growth hormone fragment Australian biotech designed to skip the anabolic sideIn the early 1990s, a biochemist at Monash University in Melbourne named Frank Ng was working on a problem that had frustrated pharmaceutical researchers for decades: human growth hormone is a molecule that does too many things at once. It promotes fat breakdown. It drives muscle and tissue growth. It stimulates the liver to produce IGF-1, a powerful growth factor. It influences glucose metabolism. It affects bone density, skin thickness, cardiac function, and half a dozen other systems. The breadth of its activity was both its appeal and its fundamental commercial and clinical problem — because when you give someone exogenous HGH to get one of those effects, you get the others too, and some of them are effects you don't want.8 min readOrigins and discoveryThe biohacker movement — from Quantified Self to peptide stacksIn 2007, Kevin Kelly — co-founder of Wired magazine, former editor, one of the more restless and prescient minds in tech culture — started holding what he called "Show and Tell" gatherings in San Francisco. People came to talk about tracking things about themselves: steps, sleep cycles, caloric intake, mood scores, blood glucose readings taken with consumer glucometers that were really designed for diabetics. The gatherings attracted software engineers, product designers, academics, and people who were simply curious about the numbers they were generating. They were not yet calling themselves biohackers. They were calling it Quantified Self.10 min readOrigins and discoveryThe bodybuilding peptide underground — a history nobody wroteThe forum post was dated 2003. The user went by a handle that combined a number and an animal. He'd been running a protocol of GHRP-6 and CJC-1295 for twelve weeks, dosing before bed, and he was reporting on sleep quality, appetite, and recovery between sessions. He'd gotten the peptides from a research chemical company in eastern Europe. He wasn't sure about the purity. He had no bloodwork. He was dosing based on a protocol he'd assembled from three other forum threads, one of which cited a paper he hadn't read. He said it was working. He said he thought he understood why.11 min readOrigins and discoveryHow BPC-157 was found in human gastric juiceIn 1991, a gastroenterologist at the University of Zagreb was thinking about the stomach lining and asking what seemed like an obvious question that nobody had quite posed directly. The stomach is a hostile environment — hydrochloric acid, pepsin, mechanical stress, constant exposure to whatever comes down from above. And yet the gastric mucosa heals. It heals constantly, reflexively, under conditions that would destroy most tissues in the body. Predrag Sikiric thought there must be something in gastric juice itself doing that work. Not just a passive barrier, but an active signal. Something the stomach was secreting to protect itself.8 min readCompounding and complianceThe history of compounding pharmacy — from the 1990s to the modern peptide landscapeOn a Friday in September 2012, a patient in Tennessee developed what his physicians initially mistook for bacterial meningitis. By the weekend, clinicians at Vanderbilt University Medical Center were confused: the infection was not responding to antibiotics, the imaging was unusual, and the spinal fluid was not showing the bacterial pattern they expected. By the following week, they had identified the organism. It was Exserohilum rostratum, a common mold found in soil and plant matter. It had no business being in anyone's spinal cord. Tracing backward, investigators found the same fungus in patients in other states — Tennessee, Michigan, Virginia, Florida — all of whom had received epidural steroid injections for back pain in recent weeks. All of them had received the same methylprednisolone acetate preparation. All of it came from one facility in Framingham, Massachusetts: the New England Compounding Center.10 min readOrigins and discoveryEpitalon and the Khavinson school — the deeper Russian research historyIn the mid-1970s, in Leningrad — not yet St. Petersburg again — a Soviet military physician named Vladimir Khavinson began a research program that would eventually span five decades and produce a body of work that most Western scientists have never read. The institutional home was the Military Medical Academy, a prestigious institution with origins dating to the eighteenth century, where Khavinson was working in the department of pathophysiology. The question he was pursuing was not fashionable by Western standards: it was whether the aging process could be slowed through targeted peptide administration. Not reversed, not indefinitely extended — slowed. The Soviet framing of the problem was practical, almost industrial. What compounds could preserve the functional capacity of soldiers, cosmonauts, and aging populations? The research that followed was shaped by that institutional context.10 min readCompounding and complianceFDA enforcement actions against peptide companies — what's happened and what it teachesThe warning letter arrives and the company's website goes dark. Maybe the FAQ page stays up for a few days with an explanation about "regulatory review." Maybe the domain just stops loading. Users who have been relying on that vendor for their supply find themselves scrambling, posting in forums, asking where else to go. The regulatory action that triggered it was months or years in development. For the users, it arrives as a sudden disruption. They had no warning because the vendor had no incentive to provide one.10 min readAnti-aging and cellular healthGHK-Cu — the copper peptide found in human plasma at twentyIn 1973, a biochemist named Loren Pickart was working on a specific and narrow question: why do liver cells from old rats lose the ability to synthesize proteins the way young liver cells do. He wasn't looking for an anti-aging compound. He was doing the kind of foundational molecular biology that rarely makes headlines — comparing albumin synthesis rates across tissue samples, looking for a signal that explained the difference in behavior between aged and young cells. What he found was a peptide in human plasma, tiny and overlooked, that could restore the protein-synthesis activity of old liver cells to something close to youthful function. He called it GHK. The copper-binding property came later, after he characterized the full molecule: glycyl-L-histidyl-L-lysine. Three amino acids, one copper ion, and a set of biological effects that took the better part of four decades to partially map.8 min readOrigins and discoveryThe GLP-1 discovery deeper history — Holst, Mojsov, and the science before the drugIn 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.11 min readOrigins and discoveryThe history of GLP-1 research — from Habener and Drucker to OzempicIn 1987, a paper appeared in the Proceedings of the National Academy of Sciences describing the structure of proglucagon — the precursor protein that the body cleaves into multiple peptides depending on which tissue is doing the cleaving. Joel Habener's laboratory at Massachusetts General Hospital had worked out the sequence and identified, buried inside it, two peptides that looked like distant relatives of glucagon. They called them glucagon-like peptide-1 and glucagon-like peptide-2. The paper was read by people who study pancreatic hormones. It was not a cultural event. Nobody wrote about it in a newspaper. The molecule's future wasn't legible yet from what Habener's group knew at that point.9 min readOrigins and discoveryGrowth hormone — the cadaver-extracted hormone, the CJD tragedy, and the recombinant breakthroughIn 1985, a neurologist in California diagnosed a 20-year-old with a disease that typically strikes people in their sixties. The patient presented with dementia and involuntary movements — the progressive and devastating deterioration of Creutzfeldt-Jakob disease, a prion disorder with no treatment and no survival. But this patient was not in his sixties. He had received injections of human growth hormone as a child, for a growth deficiency, through a program that had been running for two decades. He was one of the first. He would not be the last.6 min readOrigins and discoveryIGF-1 and bodybuilding — the history of an underground drugIn the mid-1980s, a certain kind of physique started appearing on competitive bodybuilding stages that hadn't been there before. The bodies were larger, yes — that trajectory had been underway since the 1950s — but the change in the 1980s was qualitative, not just quantitative. The abdomens were distended in ways that seemed to contradict the body fat percentages on stage. The internal density was different. The growth had a character that steroids alone, which the sport had used openly since the 1960s, didn't quite explain. Competitors and coaches began whispering about growth hormone, which had recently become available in synthetic recombinant form. They were right about GH. But they were, in a specific technical sense, also wrong about what was doing most of the work.8 min readOrigins and discoveryThe longevity movement — from caloric restriction in mice to Ozempic on TikTokIn 1993, a researcher named Cynthia Kenyon walked into a genetics seminar at UC San Francisco and announced that she had doubled the lifespan of a roundworm. Not extended it modestly. Doubled it. The mutation was in a single gene, daf-2, which encodes a receptor for an insulin-like growth factor. The worms lived twice as long, moved like younger worms, and showed no obvious tradeoffs. The audience, by several accounts, went quiet in a way that academic audiences rarely do. The implication was too large to hold comfortably: that aging itself might be a regulated process. That it might be intervened upon.10 min readOrigins and discoveryMelanotan I (afamelanotide) — from Arizona research lab to FDA-approved for EPPThe University of Arizona sits in one of the sunniest cities in North America. Tucson averages over 350 days of sunshine per year. It is the kind of place where people who move from cloudier climates take a particular pleasure in the light, and where dermatologists see, with regularity, what too much UV does to human skin over decades. It is perhaps fitting, then, that in the early 1980s a research lab at the University of Arizona began asking a question that seems obvious in retrospect but had not yet been seriously pursued: if the body already has a mechanism to protect itself from UV damage, could you turn that mechanism up pharmacologically?8 min readOrigins and discoveryMelanotan II and the bodybuilding split — how a tanning research peptide became a libido drugThere is a particular category of scientific discovery that gets described, with some frequency, as accidental. The word undersells what usually happened, which is not randomness but observation: someone noticed something unexpected and, instead of explaining it away, wrote it down and asked what it meant. The discovery that launched Melanotan II's trajectory from research compound to gray-market phenomenon falls into that category. The researchers were looking for tanning. They found something else first.8 min readSleep and recoveryMelatonin discovery — how a frog skin extract became the world's most-taken sleep aidIt was 1958, and Aaron Lerner was working with a problem that had nothing to do with sleep. The Yale dermatologist was trying to understand what caused certain skin diseases — vitiligo in particular, the condition that removes pigment from patches of skin in irregular, spreading patterns. He had a hypothesis: somewhere in the body, there was a substance that acted against melanin. Where melanin darkened the skin, this hypothetical compound would lighten it. He called it, before he'd found it, a melanocyte-lightening substance. And he believed, based on older papers suggesting the pineal gland had some relationship to skin pigmentation in frogs, that the pineal might be where it lived.10 min readOrigins and discoveryMK-677 — the oral ghrelin mimetic Merck shelved and the community kept aliveA researcher in a Merck lab in the early 1990s was thinking about a problem that sounds almost mundane: needles. Not their danger, not their cost, but their relentlessness. If you want to restore growth hormone signaling in an elderly person — someone in their seventies with a hip fracture and declining lean mass and the kind of fatigue that makes rehabilitation nearly impossible — you have to inject them. Daily. With a compound that degrades in the gut, that can't be swallowed, that requires a cold chain and a prescription and a willingness to tolerate subcutaneous injections for the foreseeable future. In a frail elderly population, that's not a clinical protocol. It's a fantasy.8 min readOrigins and discoveryMOTS-c — the peptide your mitochondria write themselvesIn 2015, a research team at the University of Southern California published a paper in Cell Metabolism that quietly changed the way biologists had to think about the mitochondrion. The paper was not loudly announced outside specialist circles. It didn't generate the cultural noise that cancer immunotherapy or CRISPR news generated that same year. But what Pinchas Cohen, Changhan Lee, and their colleagues described was a genuine reclassification — a finding that required updating a story about cellular biology that had been told, largely without revision, since the 1960s.8 min readMetabolic healthThe history of obesity drugs — from amphetamines to OzempicIn 1933, a Stanford biochemist named Maurice Tainter published results showing that dinitrophenol — a yellow industrial chemical used in explosives and pesticides — produced dramatic weight loss by uncoupling the mitochondria, turning metabolic energy into heat instead of ATP. Within a year, an estimated 100,000 Americans were taking it. By 1938, it had killed enough people from hyperthermia, cataracts, and peripheral neuropathy that the newly empowered FDA used it as a case study for why drug regulation existed. The drug was pulled. The people who had sold it moved on to other things. The demand that had driven its adoption — the urgent, intractable desire for an effective treatment for obesity — did not go anywhere.8 min readOrigins and discoveryGHRP-2, GHRP-6, Hexarelin — the older GH-releasing peptides and why newer ones replaced themIt's 1977, and a researcher at Tulane University named Cyril Bowers is trying to understand something strange. He's been working with synthetic enkephalin analogs — small opiate-like peptides — and he notices that some of them, unexpectedly, are causing growth hormone to rise in his experimental subjects. Not because they're growth hormone. Not because they mimic growth hormone-releasing hormone. For some reason, these structurally unrelated molecules are hitting a switch that growth hormone researchers hadn't known existed.6 min readOrigins and discoveryHow peptides became a drug category — from insulin to GLP-1, one hundred years of peptide pharmacologyIt is January 11, 1922, and a fourteen-year-old boy named Leonard Thompson is lying in a Toronto hospital bed. He has had type 1 diabetes for two years. He weighs sixty-five pounds. His blood sugar is five hundred milligrams per deciliter. He has been on a severe starvation diet — the only management available — which is buying him weeks. Frederick Banting and Charles Best inject him with a partially purified extract from canine pancreatic tissue. He goes into anaphylactic shock. The extract is crude, contaminated, and the dose is poorly characterized. They stop. They spend the next twelve days refining the preparation with a biochemist named James Collip. On January 23, they inject Thompson again. Within twenty-four hours his blood sugar drops to normal. The boy who was starving in a Toronto hospital lives for another thirteen years before dying, not from diabetes, of pneumonia. In those thirteen years he is the first human being to survive a disease that had been uniformly fatal in juveniles since antiquity.12 min readCompounding and compliancePeptide research fraud and questionable studies — what to know about the integrity of the literatureIn 2015, the Open Science Collaboration published the results of an effort to reproduce 100 studies from three top psychology journals. The original papers had all been published in peer-reviewed outlets, passed editorial and reviewer scrutiny, and entered the scientific record as established findings. The reproducibility project, which used the original study authors' materials and methods wherever possible, found that only 36 of the 100 studies replicated with statistical significance. The scientific community absorbed this finding with varying degrees of alarm, but the direction of the conclusion was not disputed: a substantial fraction of published research, even in prominent journals, does not reproduce when someone else tries it. This is not a peripheral problem in science. It is central to how the enterprise actually works, which is to say imperfectly, with self-correction mechanisms that operate more slowly than publication mechanisms and with significant variation in how rigorous any given piece of research actually is.10 min readOrigins and discoveryPT-141 — the peptide that was supposed to be a tanning drugIt was 1980-something in a University of Arizona lab, and a pharmacologist named Mac Hadley had a genuinely reasonable idea: if sunlight causes melanin production by triggering alpha-melanocyte-stimulating hormone, could you give people a synthetic version of that hormone and let them tan without UV exposure? Protect skin from cancer by inducing its own protection. The logic was clean. The molecule they needed — a synthetic analog of α-MSH — was the kind of thing Victor Hruby's lab was built to design.8 min readHormonal and endocrineThe isolation of testosterone — Adolf Butenandt and the 1935 NobelOn the first of June, 1889, Charles-Édouard Brown-Séquard stood before the Société de Biologie in Paris and described what he had done to himself. He was 72 years old, a neurologist of considerable distinction — he had been Jean-Martin Charcot's predecessor at the Salpêtrière, he had described the hemisensory syndrome that still bears his name — and he had spent the previous months injecting himself with a fluid he had prepared from the crushed testicles and testicular blood of dogs and guinea pigs. He reported that he felt thirty years younger. His intellectual energy had returned, his physical strength had improved, his digestion was better. He could run upstairs. He could work longer hours.10 min readOrigins and discoveryThymosin Alpha-1 — the immune modulator the US never approved but 35 countries didIn the mid-1960s, a young scientist named Allan Goldstein arrived at Albert Einstein College of Medicine with an unusual conviction: that the thymus gland — the small, butterfly-shaped organ that sits behind the sternum and had long been considered a curiosity of childhood anatomy — was doing something important that medicine had not yet named. The thymus was known to shrink with age, to be largest in early childhood and nearly invisible in adults. Most physicians considered it vestigial in adults, an organ that had done whatever it needed to do and then quietly retired. Goldstein thought otherwise.8 min read