On 13 September 1848, near the Vermont town of Cavendish, a 25-year-old railway construction foreman named Phineas Gage was preparing a blast. His job was to bore holes into rock, add explosive powder and a fuse, cover it with sand, and tamp the charge down with a long iron rod. Distracted for a moment, he brought the rod down before the sand had been added. The friction sparked the powder, and the tamping iron, over a metre long, three centimetres thick, and weighing around six kilograms, shot upward like and hit his face beneath his left cheekbone, passed behind his left eye, tore through the front of his brain, and burst out through the top of his skull, landing many metres away, smeared with blood and tissue.

By every reasonable expectation, Gage should have been killed instantly - but he was not. Witnesses reported that he spoke within minutes and, with a little help, walked to a cart and sat upright for the ride back to town. When the local physician, John Martyn Harlow, arrived, Gage reportedly greeted him and reported that the iron had gone through his head. Over the following weeks he experienced infection and delirium, but under Harlow’s care he pulled through, keeping his speech, memory, movement, and the sight in his uninjured eye.

What he may not have kept, at least for a time, was himself. Harlow’s later report described a disturbing transformation: the once capable, reliable, well-balanced foreman had become impulsive, profane, capricious, and unable to stick to plans, “no longer Gage,” to those who knew him. Gage, it seemed, was living proof that the frontal lobes are the seat of personality, judgement, and social restraint, that the self has a physical home in the brain, and that damaging the tissue can alter the person. Of course, this all depends upon the definition of self.

Most descriptions of Gage’s changed character are second-hand and close to the accident. There is good evidence that he recovered a great deal over the following years, enough to hold down demanding, socially complex work as a long-distance stagecoach driver in Chile, a job requiring skill, reliability, and the daily management of horses and passengers. However, the popular myth makes a better story. He lived roughly twelve more years, dying in California in 1860 after a series of seizures, likely a delayed consequence of his injury.

His skull and the tamping iron survive in a Harvard museum, and researchers have used them, together with modern imaging techniques, to reconstruct the rod’s probable path and estimate which brain regions were destroyed. it is likely that there was damage in the ventro-medial prefrontal cortex, an area now linked to emotional regulation and decision-making. The debate goes on.

In the first half of the twentieth century, a strange and always-fatal illness spread among the Fore people of the Papua New Guinea highlands, and it spread almost entirely among women and young children.

Victims first grew unsteady on their feet, then developed tremors and lost coordination. As the disease advanced they could no longer stand, feed themselves, or control their movements. Some sufferers broke into bursts of uncontrollable laughter. The Fore called it kuru - “to shake.” Once symptoms appeared, death usually followed within a year.

For a long time the cause was a total enigma. Kuru didn’t behave like any familiar infection. It produced no fever, no inflammation, no sign of an immune response. Yet it clearly occurred in clusters, running through families and communities in a pattern that looked almost hereditary but didn’t obey the rules of inheritance. Researchers who travelled to the region in the 1950s found a society being damaged, with some villages losing so many women that the balance of the population was significantly distorted.

The breakthrough came from an unlikely direction: local funerary custom. As an act of respect and mourning, the Fore consumed the bodies of their dead. The pattern of who ate what proved informative. Women and children typically consumed the brain and internal organs - the tissues where the infectious agent was most concentrated - while adult men ate mostly muscle and were largely spared.

But what was the agent? Whatever it was contained no DNA or RNA, withstood boiling, resisted formaldehyde, and defied classification within any existing category of pathogen. It could incubate silently for years, sometimes for decades.

The answer, pieced together over a generation of research, upended biology: the culprit was a prion, a normal cellular protein folded into an abnormal shape, which then coaxes neighbouring proteins to misfold in turn - a self-propagating chain reaction that gradually turns the brain spongy and riddled with holes. The idea that a protein alone, with no genetic material, could act as an infectious agent was so radical that it met fierce resistance but eventually earned Nobel Prizes, first for demonstrating kuru’s transmissibility and later for the prion concept itself.

Once the Australian administration and changing custom brought the funerary practice to an end around the late 1950s, new infections began to dry up. But because prions can lie dormant for so long, occasional cases continued to surface decades later, the last victims carrying an exposure from childhood into old age. Scientists discovered that the epidemic had left a genetic fingerprint: a protective variant in the prion gene had become more common in the population, evidence of natural selection acting on humans within living memory.

OK, no towns were actually completely depopulated but the epidemic of English sweating sickness had a significant and devastating effect upon the communities it affected. The 1551 outbreak was centred around the town of Shrewsbury from where it spread, locally at first to Oswestry, Presteigne, and, a bit further, to Chester, eventually reaching London in after about three months. T the time of the outbreak, the population of Shrewsbury is thought to have been between 3,000 and 5,000. The sickness claimed 1,000 of those lives, with many more people fleeing the area. The town population fell significantly.

This pattern was to repeat throughout England.

English sweating sickness surfaced in 1485, in the weeks around Henry VII’s seizure of the English throne, and struck in a series of epidemics before disappearing for good after 1551. In between, it left a trail of sudden death and a puzzle that medicine has never solved.

Contemporaries described a horrifyingly rapid illness. A person could feel perfectly well at dinner and be dead by morning. The symptoms began with a sense of apprehension and dread, then cold shivers, aching limbs, headache and dizziness. This gave way to the phase that named the disease: a drenching, malodorous sweat, a pounding heart, breathlessness, and collapse. Survival or death was often decided within a single day. Those who lived through twenty-four hours generally recovered; many were dead before the day was out.

The sweat had odd characteristics that still baffle historians and epidemiologists. Unlike most epidemics of the era, it seemed to prefer the young, the fit, and the affluent — striking robust men in their prime rather than the old and frail. It ravaged England while largely sparing Scotland, Wales, and Ireland. And in its final major appearance in 1528, it leapt across the Channel to sweep through the German lands, Scandinavia, and the Low Countries, while curiously bypassing France and Italy almost entirely, before receding again.

Its reach touched the highest levels of Tudor society. Anne Boleyn is said to have caught and survived it in 1528, while others in Henry VIII’s circle were not so fortunate, and the king himself fled from residence to residence in fear of it. The last outbreak, in 1551, produced the one detailed medical account we have, from the physician John Caius, who set down its symptoms and course in a short treatise.

Then the sickness simply was gone.

There are many theories. Some researchers favour a hantavirus carried by rodents, pointing to the sudden respiratory collapse that hantaviruses can cause. Others have proposed a relapsing fever spread by ticks or lice, an unknown strain of influenza, or even a form of anthrax. The trouble is that no theory accounts for all the disease’s speed, social selectivity or its limited geography and, crucially, no physical trace survives.

From a modern view, the symptoms are consistent with sepsis, but what was the cause?

The sweating sickness therefore remains a genuine cold case: a lethal illness that shaped the anxieties of Tudor England, then slipped out of the historical record just before medicine developed the tools that might have caught it.

In July 1518, a woman remembered only as Frau Troffea stepped into a lane in Strasbourg and began to dance. There was no music, no festival, no evident reason — she just danced and would not stop. She danced through the day and into the night, when at last she dropped from exhaustion. After a brief rest she got up and started dancing again. Within days a handful of others had joined her. Within a month, according to the city’s chronicles, the compulsive dancers numbered in the hundreds.

Witnesses described faces contorted with distress, bodies slick with sweat, feet bloodied and bruised. Some of the dancers reportedly collapsed and died though the true death toll is impossible to verify from the surviving records.

The response of the authorities now appears naive. Strasbourg’s physicians, working from the medical theory of the day, concluded that the dancing arose from “hot blood” and that the only cure was to let the sufferers dance it out of their system. So the city cleared two guildhalls, roped in professional pipers and drummers, and even erected a wooden stage. Predictably, the intervention made everything worse: the spectacle drew in still more dancers, and the mania fed on itself.

What actually happened is still uncertain. One long-standing theory blames ergot, a psychoactive mould that grows on damp rye and can trigger convulsions and hallucinations. But ergot poisoning causes fits and tends to constrict blood flow to the limbs, causing pain and gangrene rather than sustained, coordinated dancing.

The explanation favoured by most historians today is mass psychogenic illness: a collective stress response in a population ground down by famine, disease, and the constant dread of divine judgement. Strasbourg in 1518 was perfect for this.

Locals also feared St. Vitus, a saint believed capable of cursing sinners with compulsive dancing, a belief that may have shaped the form of the affliction, the mind reaching for a template already lodged in the culture.

The episode is among the best-documented outbreaks of its kind, preserved in physician notes and municipal records. But it was not unique: similar dancing manias had rippled through the Rhine and Mosel regions for at least a century and a half, with a notable outbreak in 1374. But Strasbourg remains the most vivid and unsettling exapmle; a case study in how the mind, under sufficient pressure and given the right cultural background, can drive the body to lethal extremes we still cannot fully explain.