In 1791, in a small town near Venice, a man named Giacomo was born. Members of his family tended to be physically impressive, powerful and broad-shouldered (and still are today), but one day in the fall of 1836, at the age of 45, Giacomo fell mysteriously ill. He began to suffer from dementia. Eventually he was confined to bed, lying awake in torment. Then he died.
Giacomo had three children who survived infancy. One of those had six in turn. Over the next century and a half, his descendants flourished. Family members would become prominent doctors and businessmen in the new state of Italy.
But running parallel with the family's affluence was an eerie record of premature death. Parish books over the decades noted oddities like "epilepsy and fever" and "nervous gastric fever." Later, family death certificates would name meningitis, Economo's disease, presenile dementia, leukoencephalitis, alcoholic encephalopathy and ictus.
In fact, the cause of death was always the same: fatal familial insomnia, a genetic disease that was not formally identified until 1986. It is vanishingly rare, and, for a time, Giacomo's descendants were the only people on the planet known to have it. About 30 other families have been found since then, in France, Germany, Northern Spain and Japan. The assumption is that more cases will appear as knowledge of the disease spreads in less affluent countries.
The course of symptoms of FFI, as the disease is known, is grim. In the typical case, one day in your early 50s, you suddenly can't sleep through the night. You try compensating with a nap in the afternoon but without luck. Your pupils become tiny. Men become impotent. Your blood pressure and pulse become elevated, and you sweat heavily as your body goes into overdrive.
Over the ensuing months, you try desperately, incessantly to sleep, sometimes closing your eyes but never succeeding in falling into more than a light stupor that provides no actual rest. Inside your brain, the traffic light that controls activity is perpetually green.
A downward progression ensues as your ability to balance, walk or speak disappears. Perhaps most tragic, your ability to think remains intact; you often know exactly what is happening. In the final phase, usually after several months, you fall into a state of exhaustion resembling a coma and, mercifully, die.
At least 30 of Giacomo's descendants have died this way in the last century -- 13 since 1973, seven in the past decade. Among the living, at least 25 more carry the gene that causes the disease.
In the mid-1980s, Italian newspapers got hold of the story of the family. They pounced. The media attention came around the same time as the first reports of another new European scourge, mad cow disease. Neighborhood children came by the home of family members and made mooing noises.
But in their cruel way, the local children had intuited something important. Their hunch that mad cow disease and fatal familial insomnia were somehow connected would turn out to be correct. Indeed, this realization would fundamentally expand our understanding of the disease.
One hundred sixty years after Giacomo's death, the king of Sweden shook hands with Stanley B. Prusiner, a professor at the University of California at San Francisco, USA, and gave him the 1997 Nobel Prize in medicine.
It is unusual for a single researcher to receive the prize, but Prusiner's work was exceptional. He had shown that under certain conditions, the body's own proteins can warp and turn against it. They can make the body devour itself.
He gave these deviant proteins an exotic name, prions (pronounced PREE-ons), and established that they cause a rare class of degenerative brain ailments: Creutzfeldt-Jakob disease, and, more important, bovine spongiform encephalopathy (BSE).
BSE, known popularly as mad cow disease, converts in humans into a variant of Creutzfeldt-Jakob disease. At the time of the award, the disease had killed two dozen people in England and one in France. It has since killed about 80 more people and spread in cattle throughout Europe.
It may kill hundreds more people, possibly thousands. No one knows for sure, because the disease has such a long incubation period. Mad cow disease put Prusiner and his prions on the map in a way that a single family in the Veneto could never do.
But how did Prusiner demonstrate that misfolded proteins could cause disease? His key experiment was simple. He took material extracted from the brains of members of the Italian family who had died of FFI. He then injected this material into mice genetically altered to produce human prions. The mice developed FFI.
He performed the same experiment with brain matter from Creutzfeldt-Jakob victims and got parallel results. Then he killed these mice and shot prions from them into new mice and again got the two diseases.
The conclusion was clear: Malignant prions can cause disease, just as viruses or parasites or bacteria can. In the years since Prusiner's historic experiment, FFI has become much more than a curio disease. It sits at the crossroads of two new and exciting areas of scientific inquiry: sleep deprivation and prion research.
The line falls
In the past two decades, Giacomo's descendants have gone from being local pariahs to a family whose genetic material is sought by scientists around the world. And those who have fallen ill have been studied in minute detail by researchers exploring the fundamentals of sleep.
Many questions about fatal familial insomnia remain. Although the vast majority of victims fall ill in middle age, why do a few people get sick in their teens? Why do a few who test positive for the gene not get the disease at all?
Could studying these irregularities suggest a pathway for blocking the general spread of prion diseases in humans, or for treating them before they become symptomatic? Many researchers, including Prusiner himself, think so --- guaranteeing that the family will receive more and more attention in the years to come.
Elisabetta Roiter, Giacomo's great-great-great-granddaughter, has lost her grandfather, two aunts and an uncle to the family disease. Even though the likelihood of having fatal familial insomnia is one in 33 million, in her family, it is one in two!
"She loses someone every three years or so," her husband, Ignazio, said. Elisabetta, a nurse, has also led a family effort to confront the disease over the years.
One day in 1971, her mother went in for a minor procedure at the same Venetian hospital where Pietro, Elisabetta's grandfather, died in 1944. A doctor had pulled Pietro's old chart. It said he died of encephalitis. She found something suspicious right away. Under "spinal fluid" was the notation "clear as water in a rocky stream." (Italian medicine is full of such elegant oddities.)
Elisabetta was familiar with spinal taps and thought what she read was unlikely. The fluid of encephalitis victims nearly always shows contamination from the disease. Ignazio was himself training to be a doctor and agreed to help pursue the mystery.
A few years later, one of Elisabetta's aunts came to visit. She was 48 and seemed depressed. She couldn't sleep. She asked Ignazio for a sedative. Nothing helped. The aunt began to despair over her perpetual wakefulness and to hallucinate. Ignazio and Elisabetta took her to a neurologist in Padua, who diagnosed dementia, wrongly. The aunt died soon after. In the next decade, another aunt fell prey to the disease.
In 1984, Silvano, Elisabetta's uncle, came for a visit. He was 53. His eyes were small as pinpricks, his face drawn. It was obvious what was wrong with him.
They decided to consult an expert on sleep disorders. In Bologna, Italy there was a clinic run by a professor named Elio Lugaresi. Ignazio called him. Uncle Silvano was admitted to Lugaresi's clinic in the spring of 1984. Lugaresi made tapes of his decline. In the last days of his life he lay in a twitchy, exhausted nothingness.
After his death, Silvano's brain was removed within hours, preserved in Formalin and then shipped to Pierluigi Gambetti, a former student of Lugaresi's who ran a neuropathology lab at Case Western Reserve University in Cleveland, Ohio, USA.
Gambetti's lab began to make incremental progress in understanding the disease. Meanwhile, more family members died, including Teresa, the 36-year-old sister of a distant cousin.
Separately, Gambetti and Lugaresi noted something striking about the disease. In the charts documenting Teresa's brain activity, Lugaresi saw spikes similar to those of patients with Creutzfeldt-Jakob disease. Gambetti, examining her actual brain back in America, noticed it was full of little holes: The tissue was spongiform.
They both began to suspect that what they were looking at wasn't a traditional infection. Both were aware of Stanley Prusiner's controversial theory about prions. Did prions cause FFI?
In 1992 Gambetti's research team was able to sequence the family's genetic material and pinpoint the mutation that causes FFI. Knowing the genic sequence they tested 50 reluctant members of the family. Half of the 50 relatives tested had the fatal gene.
Around this time, Gambetti called Stanley Prusiner and asked him if he wanted to use some of the family's brain tissue. Prusiner had mice with the human prion gene inserted, and Gambetti didn't -- without them he could not prove prions caused FFI.
Using the brain matter of Teresa and another relative, Prusiner in 1996 performed his key experiments. Having successfully caused FFI in the mice, Prusiner was able to confirm his theory at last. Deviant prions caused the disease. He received the Nobel Prize a year later.
For Elisabetta and her family. They continue to die. A new generation is now approaching the age of greatest risk. Some have begun to question if it made sense to go through all that work --- the blood tests, the publicity, the discrimination, the cruel jokes.
Gambetti predicts a cure for FFI within 10 years. "When I began this work," he said, "I used to think Alzheimer's was the worst disease you could get. But to see a loved one disintegrate in front of your eyes -- and for that person to know it is happening? Somehow, the fact that it is so rare makes it even worse, it seems to me. I think now even a car accident would be less cruel."