In the spring of 1914, the U.S. Public Health Service sent a Hungarian-born immigrant named Joseph Goldberger to investigate a rash. The rash was not actually a rash. It was the visible part of a disease that had been killing people in the American South for a generation. The disease was called pellagra. Its symptoms came in fours, the way the doctors had taught themselves to recognise it: diarrhoea, dermatitis, dementia, death.

Between 1906 and 1940, three million Americans contracted pellagra and roughly one hundred thousand of them died. At the peak of the epidemic, fifteen southern states reported a quarter of a million new cases a year. Wards of state asylums filled with the demented stage of the illness, men and women whose bodies were rotting from the inside while their minds detached from the world around them. The cornetist Buddy Bolden, the most influential figure in early jazz, was committed to the Louisiana State Insane Asylum in 1907 with a diagnosis of dementia praecox. He never came out. By the time he died there in 1931, many historians believe his real diagnosis was pellagra.

The medical establishment of 1914 had decided pellagra was an infectious disease. The Thompson-McFadden Pellagra Commission, which had spent the previous two years walking the South Carolina cotton-mill villages with notebooks, had concluded it. It made a certain sense. Pellagra clustered in poor communities, appeared in waves, struck whole families. The bacterial revolution of the late nineteenth century had taught a generation of doctors that almost everything mysterious was eventually explained by a microbe. The microbe was their hammer.

Goldberger arrived in Mississippi with a portable microscope and a habit of asking questions the establishment had not asked. He noticed first that in every orphanage and asylum he visited, the children and the inmates were riddled with pellagra and the staff were not. If pellagra was contagious, the staff should have been the most exposed. They handled the laundry, the bedpans, the bodies. They never got it. What the staff had that the patients did not, in those buildings of the rural Deep South, was meat and milk.

In 1915, with the cooperation of the governor of Mississippi, Goldberger ran an experiment. Eleven volunteer prisoners at the Rankin Prison Farm were placed on a diet identical to that of a poor sharecropper: cornmeal, salt pork, molasses. After five months, six of the eleven had developed pellagra.

The political reaction was furious. Pellagra was a Southern disease, and the suggestion that it was a disease of poverty was understood, correctly, as an indictment of Southern agriculture and Southern wages. Senators called Goldberger a Yankee, a foreigner, a fraud. He continued. In the spring of 1916, in a final effort to silence the infectious-disease theorists for good, he held a series of dinners at his home and at his patients' bedsides. Eight times, with seventeen guests including his wife Mary, he ate or injected scabs, pus, urine, faeces and blood drawn from active pellagra patients. He called the dinners his filth parties. Six months later, none of the guests had developed pellagra. Pellagra was not contagious. Pellagra was hunger in slow motion.

Goldberger died of cancer in 1929. He never identified the specific missing nutrient. That came in 1937, when Conrad Elvehjem at the University of Wisconsin showed that nicotinic acid, soon renamed niacin, cured pellagra in dogs and then in humans. Within ten years, U.S. state laws mandated that bread and cornmeal be enriched with niacin. The 250,000 cases a year became zero. The asylum wards emptied of pellagrins. A disease that had killed a hundred thousand Americans was solved, in the end, by adding a vitamin to bread.

The arc was three steps, not one. From "we have no idea what this is" before 1914, to "we know it is something in the diet" with Goldberger, to "we know exactly which molecule" with Elvehjem. It took twenty-three years to get from the second step to the third. In between, every prescription was a guess.

*

This week, Nature Genetics published a paper led by researchers at McGill University and the Douglas Institute in Montreal. The team, working with the dorsolateral prefrontal cortex tissue of eighty-four people who had had major depression, applied single-cell genomic techniques to over two hundred thousand individual brain cells. They were looking for the cells that behave differently in a depressed brain. They found two.

The first is a class of deep-layer excitatory neurons whose stress-response transcription factor, NR4A2, binds DNA differently in people with depression than in people without. The second is a specific cluster of grey-matter microglia, the brain's resident immune cells, that loses access to genes regulating immune balance. Both cell types are present in everyone. In depressed brains they are doing different work.

For nearly seventy years, major depression has been treated through chemistry. Iproniazid in 1957. Imipramine in 1958. Fluoxetine in 1987. Esketamine in 2019. Each generation of drug has been a useful guess. The serotonin hypothesis is now widely accepted to be incomplete. We have been adding niacin to bread without knowing exactly why bread without niacin makes people sick.

The McGill paper is the equivalent of the Rankin Prison Farm experiment, not the equivalent of Elvehjem's vitamin. It identifies the cells. It does not yet identify the molecules they need to be fed. The exact nutrient, the niacin for the depressed mind, has not yet been named. It is a moment of intermediate clarity. We know the room. We do not yet know the food.

The asylum wards of the early twentieth century emptied because of a vitamin. The wards of our own century are full of people receiving treatments that work some of the time, by mechanisms that are not fully understood, for a condition whose cells we are now finally able to see.

In the spring of 1916, after the eighth filth party, none of the guests got sick.

That, in the end, is what science actually proves. Not what we think it does.