In March 2009, after a long night on duty at the hospital, Emmeline Lagrange took a deep breath and prepared to place a devastating phone call. Lagrange, a neurologist, had diagnosed a 42-year-old woman with amyotrophic lateral sclerosis, or ALS. The woman lived in a small village in the French Alps, an hour and a half drive away from Lagrange’s office in Grenoble Alpes University Hospital. Because ALS is rare, Lagrange expected that the patient’s general practitioner, Valerie Foucault, had never seen a case before.

Snow fell outside Lagrange’s window as she got ready to describe how ALS inevitably paralyzes and kills its victims. But to her surprise, as soon as she shared the diagnosis, Foucault responded, “I know this disease very well, because she is the fourth in my village.”

ALS, also known as Lou Gehrig’s disease, occurs in roughly two to three people out of every 100,000 in Europe. (The rate is slightly higher in the United States.) But every so often, hot spots emerge. Elevated ALS rates have been observed around a lagoon in France, surrounding a lake in New Hampshire, within a single apartment building in Montreal, and on the eastern—but not western—flank of Italy’s Mount Etna. Such patterns have confounded scientists, who have spent 150 years searching for what causes the disease. Much of the recent research has focused on the genetics of ALS, but clusters provocatively suggest that environmental factors have a leading role. And each new cluster offers scientists a rare chance to clarify what those environmental influences may be—if they can study it fast enough. Many clusters fade away as mysteriously as they once appeared.

After the call, Lagrange was uneasy; she had a hunch about how much work lay ahead of her. For the next decade, she and a team of scientists investigated the cluster in the Alps, which eventually grew to include 16 people—a total 10 times higher than the area’s small population should have produced. Even during that first call, when Lagrange knew about only four cases of ALS, she felt dazed by the implications, and by Foucault’s desperate plea for help. If something in the village was behind the disturbing numbers, Foucault had no idea what it was. “She was really upset,” Lagrange remembers. “She said to me, ‘This is impossible; you must stop this.’”

For some people, the trouble begins in the throat. As their muscles waste, swallowing liquids becomes a strenuous activity. Others may first notice difficulty moving an arm or a leg. “Every day, we see that they lose something,” Foucault said of her patients. “You lose a finger, or you lose your laugh.” Eventually, enough motor neurons in the brain or spinal cord die that people simply cannot breathe. Lou Gehrig died two years after his diagnosis, when he was just 37. Stephen Hawking, an anomaly, lived with ALS until he was 76.

Five to 10 percent of people with ALS have a family member with the disease. In the 2000s, advancements in DNA sequencing led to a swell of genetic research that found that about two-thirds of those familial cases are connected to a handful of genetic mutations. But only one in 10 cases of ALS in which patients have no family history of the disease can be connected to genetic abnormalities. “What we have to then explain is how, in the absence of genetic mutation, you get to the same destination,” Neil Shneider, the director of Columbia’s Eleanor and Lou Gehrig ALS Center, told me.

Scientists have come up with several hypotheses for how ALS develops, each more complicated and harder to study than genetics alone. One suggests that ALS is caused by a combination of genetic disposition and environmental exposures throughout a lifetime. Another suggests that the disease develops after one person receives six cumulative “hits,” which can be genetic mutations, exposures to toxins, and perhaps even lifestyle factors such as smoking.

Each time a cluster appears, researchers have tried to pin down the exact environmental hazards, professions, and activities that might be linked to it. After World War II, a neurodegenerative disease that looked just like ALS—though some patients also showed features of Parkinson’s and dementia—surged in Guam, predominantly among the native Chamorro people. “Imagine walking into a village where 25 percent of the people are dying from ALS,” says Paul Alan Cox, an ethnobotanist who studied the outbreak. “It was like an Agatha Christie novel: Who’s the murderer?”

Early research tried to pin the deaths on an unlikely culprit: the highly toxic cycad plant and its seeds, which locals ground into flour to make tortillas. Cox and his colleagues hypothesize that human cells mistake a compound called BMAA found in the plant for another amino acid, leading to misfolded proteins in the brain. Peter Spencer, an environmental neuroscientist at Oregon Health & Science University, has argued for a different explanation: The body converts cycasin, a compound also found in the plant’s seeds, into a toxic chemical that can cause DNA damage and, eventually, neurodegeneration. Each theory faced its own criticism, and a consensus was never reached—except for perhaps an overarching tacit agreement that the environment was somehow integral to the story. By the end of the 20th century, the Guam cluster had all but vanished.

Genetic mutations are precise; the world is messy. This is partly why ALS research still focuses on genes, Evelyn Talbott, an environmental epidemiologist at the University of Pittsburgh, told me. It’s also why clusters, muddled as they might be, are so valuable: They give scientists the chance to find what’s lurking in the mess.

Montchavin was a mining town until 1886, when the mine closed, leaving the village largely