Distillations magazine

Unexpected Stories from Science’s Past

The Strange, Gruesome Search for Substance X

John Hughes worked his way through uncounted pig brains to find the human body’s natural painkiller.


Every morning before dawn neuroscientist John Hughes biked down to the slaughterhouse with a hacksaw, hatchet, and knife in his basket. He greeted the surly men who chainsawed off the heads of pigs and began his daily plea for them to slip him a few skulls. At first Hughes secured their cooperation by expounding on the wonders of neuroscience and the nobility of his research. Think of all the people we could help manage chronic pain, he explained, if only we knew how the brain itself dulled pain using neurotransmitters. Hughes soon realized, however, that a good bottle of scotch earned the workers’ cooperation much more quickly, and he started adding some to his basket each morning.

The discovery of most neurotransmitters—chemicals that send signals from one neuron to another inside the brain—followed a repetitive pattern. Scientists would come across some new chemical in the brain while investigating cell behavior. They would isolate it and test the purified sample on neurons in the lab. If it affected the behavior of those neurons in a clear and consistent way, then the chemical probably did something similar inside the living brain. This strategy proved highly successful throughout the 20th century and helped scientists identify most of the hundred or so neurotransmitters we know of today.

But there was a major exception to this pattern: the discovery of the brain’s natural painkillers—endorphins. When it came to pain, scientists started by studying how morphine, opium, and similar drugs worked and only later started looking for chemicals in the brain. In general, neurotransmitters convey messages by locking onto the surface of cells: one neuron releases the chemical, which swims across a small junction (the synapse) and docks with receptors on another neuron. During the 1950s scientists realized that opiates also worked by docking onto neuron receptors. And if these artificial chemicals were so adept at docking, then the brain must already employ natural chemicals with a similar structure—or the receptors wouldn’t exist.

What these chemicals were, though, nobody knew. So Hughes, a brusque, young Cockney working in Aberdeen, Scotland, decided to seek them out. It ended up being one of the messiest and most nauseating projects in science history.

Hughes called the purported new neurotransmitters Substance X, and for whatever reason he decided that the best place to search for them was inside pig brains, which meant a daily visit to the slaughterhouse with his hacksaw and bottle of scotch. Fully bribed, the workers would bring Hughes 20 or so pig skulls, and while he fought off the rats, he hacked out each grapefruit-sized brain in about 10 minutes and then packed them into dry ice. Several hours later he would return to the lab, pound the brains into a gray mash, and dissolve them in acetone. (Colleagues remember the combination smelling like airplane glue and rancid fat.) Finally, he’d centrifuge the slurry and evaporate off various layers to test whether they were Substance X.

Now came the strange part. Hughes’s mentor, Hans Kosterlitz, was the world’s unchallenged expert on two extremely specific pieces of anatomy: the Cavia ileum and the murine vas deferens, better known as guinea pig intestines and mouse sperm tube. When dissected out from the rest of the body, each of these bits looks like tiny, coiled worms, and each one has a bizarre property. If you suspend it in saline solution and spark a certain nerve, it will contract over and over on its own, beating as if somehow madly alive.

Equally bizarre, somewhere along the line Kosterlitz had determined that both the Cavia ileum and the murine vas deferens were superlatively sensitive to morphine-like chemicals. That is, once these organs started contracting, even trace amounts of morphine would halt the spasms immediately. So Kosterlitz and Hughes spent months sparking the sperm tubes and intestines—producing disembodied bowel movements and orgasms in a beaker—and injecting chemical after chemical from the pig brains to see if anything interrupted these spasms. They finally found a substance—a yellow wax smelling of turned butter—that interfered with the contractions just like morphine did. Substance X had been found.

Substance X eventually became known as endorphin, a portmanteau of “endogenous morphine,” and just as Hughes had hoped, studying it provided important insights into how the body manages and even blocks out pain. So the next time you’re out for a run and you suddenly feel the swell of a runner’s high, or you smash your thumb with a hammer and notice that it doesn’t hurt nearly as much as it should, you can thank John Hughes and his mushy pile of pig brains for revealing why.

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