'The Family That Couldn't Sleep: A Medical Mystery'

Feb. 22, 2008 — -- Chapter One: The Doctor's Dilemma, Venice, 1765

In November 1765 a respected doctor from a good Venetian family died in the Campo Santi Apostoli, near the Jewish ghetto in Venice. The cause of his death was "an organic defect of the heart's sack" -- or so contemporary parish records state. In truth no one would have known for sure what he suffered from and we can't know either. But priests ordinarily only wrote detailed descriptions of diseases when what they saw was noteworthy, and it is intriguing that the description of the doctor's illness in the parish book is one of the longest of the year.

The entry records that the deceased suffered for more than a year from "intermittent difficulty in breathing" and adds that he was bedridden and "totally paralyzed for two months" before his death.

Many of the doctor's descendants would experience similar symptoms in the course of dying from fatal familial insomnia, suggesting that the Venetian doctor may have been the earliest recorded case of a disease that has gone on to torment his relatives for more than two centuries.

Mid-eighteenth-century Venice was a place of gaiety and vice. The city always had a fairy-tale aspect, but until the seventeenth century its unreality was checked by an appetite for business. Venice stood at the crossroads of east and west, Asia and Europe, and it avidly cashed in on its location. But with the colonization of the Americas, trade turned the other way -- across the Atlantic -- and Venice began spending down its inheritance. Goethe, visiting the city in 1786, noted that the Venetians' lagoon was silting up, their trade "declining, their political power dwindling ...Venice, like everything else that has a phenomenal existence, is subject to Time." The end was near, and everyone there knew it.

Venice's fall, though, was the time of its greatest opulence. This was the era of Casanova's wanton memoirs and the splendid Venetian regattas and processions painted by Canaletto and Francesco Guardi. One story may help to convey the moment: in 1709, there was a ball at the home of a Venetian noble in honor of the king of Denmark, Frederick IV. As the king danced with one of the guests, a newly married noblewoman named Caterina Quirini, his buckle caught a string of pearls that adorned the belt of her dress, scattering them on the poor. The lady paid them no mind. The king was about to bend down to retrieve the pearls, whereupon her husband stood up, walked across the dance floor, and crushed them under his feet, while his wife danced on.

Venice was a hereditary oligarchy. Its ruling class -- its doges, procurators, and ambassadors -- were drawn from two hundred families whose names, like that of the Quirini, had been inscribed in a "book of nobility" in the early fourteenth century. The Venetian doctor descended from one of these patrician families, great merchants and secretaries of state, whose surname adorned one of the central squares of the city. Though he was not himself entitled to wear the red toga that indicated patrician status, he enjoyed many of the other privileges of high birth in the republic.

The doctor had a three-story palazzo on a canal and a country home in the Veneto (both still standing today). The country house was in a town near the Piave River, a trip the doctor could make in three days, by crossing the lagoon by gondola to Portegrandi and then continuing in a carriage. In the country, on terra firma, a doctor of good family could play cards and chess with well-born friends, and supervise his gardens and the collection of rents from his tenant farmers, all the while staying clear of the infections summer brought to Venice.

If the doctor did have fatal familial insomnia -- the idea has been suggested by his descendants in their search for the origin of their mutation -- he likely would have noticed his first symptoms there in the summer of 1764. His servants, seeing his glassy eyes and sweaty forehead, might have gossiped that a witch had hexed him, but the doctor would not have entertained that idea for a moment. He was a graduate of the School of Medicine at Padua, the best in Europe. For him, sickness was not a magical but a natural process. The scientific method was blossoming in the Venetian state, of which Padua was a part. Its secular saint, Galileo, had set out the goal for all to see. "Science," he had written, could be found "in a huge book that stands always open before our eyes -- I mean the universe." To read it, though, you needed to understand the language it was written in: "the language is mathematics." A physician's job, then, was to substitute exact observation for speculation, to look with vision unclouded by metaphysics or theology.

The sleepless doctor could trace his medical pedigree directly to Galileo. Galileo had taught the monk Castell, who had taught Borelli, who had taught the anatomist Malpighi, who had taught Valsalva, who had taught Morgagni, who had taught him. They had many of them learned their craft in the Acquapendente in Padua, the most beautiful autopsy theater in Europe. Its wooden balconies rose up in a narrowing series of concentric ovals -- a "high funnel," as Goethe described it -- from which the audience could look down on the human body lying in Euclidean splendor. Italian doctors were brilliant with their scalpels; seen from above, their work would have seemed to promise to the eager medical student the doctor had once been that if you studied nature hard enough, it would give up its secrets. That promise wasn't working for him now, though. He was no longer sleeping well and he did not know why. In the beginning, the feeling might not have been unpleasant -- he could stay up all night playing cards or maybe read Morgagni's famous comparisons of the body to a machine, published just a few years before. Just as any machine needed rest to prepare for the next day, so did the human. Yet the doctor's machinery seemed to be running nonstop. He was sweating more and more and his servants would by now be bringing him fresh shirts several times a day.

If the doctor had turned to contemporary authorities on insomnia, he would have found little of use. Sleep, even now a mystery in many ways to science and medicine, was utterly obscure to the doctors of his time, who were still struggling to understand what went on in plain sight in the day. Indeed, the unsleeping doctor would have had to go all the way back to Galen, the ancient Roman physician whose teachings had dominated medicine until Galileo had challenged him a century before. Galen had learned most of what he knew about sleep from Aristotle, who had pronounced condently on the question (as he had on most scientific issues). "All things that have a natural function," he wrote authoritatively in On Sleep and Dreams, "must, whenever they exceed the time for which they can do a certain thing, lose their capacity and cease from doing it, e.g., the eyes from seeing. Necessarily, everything that wakes must be capable of sleeping. For it is unable to be active at all times." Aristotle proposed that sleep was a byproduct of eating. After a person had a big meal the warm fumes from the process of digestion entered the veins, thence to the brain, and thither to the heart, the seat of consciousness, where their cooling brought about sleep. Galen, writing five centuries after him, corrected Aristotle -- the warm meal went directly to the brain, where it plugged the pores by which sensations entered and exited.

It is unlikely the Venetian doctor took either Galen or Aristotle seriously. Both would have seemed speculative to him when compared to the certainties of the Acquapendente. Still, back in Venice now, to be on the safe side, he might have ordered his cook to produce bigger meals -- roast fowls and hams and sausages from the Adriatic doused in the heavy French sauces that were newly in style. If so, the results would have confirmed his skepticism about the learnedness of anyone who had not gone to Padua. He would have sat awake in a chair, his stomach distended, waiting for the meal to warm his head. To help the process along he would have had plenty of wine, as well -- wine was particularly recommended for insomnia -- and then sat up through the night until the sun rose over the Lido.

Or maybe he got up and went out, frustrated by the noise -- the hawkers and prostitutes and gondoliers singing to one another filled the nighttime air of a city in which, as the fussy Goethe noted, "the people . . . appreciate volume more than anything else." If it was Lent, the doctor could have gone to one of the huge Carnevale masked balls in the palaces on the Grand Canal, where, as a man of noble birth, he was always welcome. There, dressed as the medico della peste, he could have kept his vigil. It was the sort of wit Venetians admired -- a doctor in the black cape, the long white nose, and the face mask of the plague. Dressed this way, the only evidence of his problem would have been the twin pinpricks of his eyes, peering from behind his mask. He'd have come home to the sound of the Marangona, the great bell in Piazza San Marco, tolling the beginning of the work day, sleep still well beyond his grasp. The doctor would have asked himself whether he had caught something. Infection was on the mind of mid-eighteenth-century Venice. The city had a public health department well versed in the subject. They burned the bedding of disease victims and left their clothes out in the sun and air for a week to help neutralize the contagion. But what were they neutralizing? Here there was less agreement. The predominant view was that infection was an invisible substance carried in the air as smell. Thus the plague doctor costume of Carnevale had a sponge at the tip of the long white nose, and workers who disinfected clothing for the Venetian authorities were also required to perfume the room and the personal effects of the deceased.

But in the lexicon of disease there was no infection that corresponded to what the doctor was feeling. He was not just hot but extraordinarily anxious, like a horse at full gallop, sweaty and prone to a shaking that seemed to come from deep within. He was exhausted, falling in and out of a light, dream-wracked sleep. His servants might have heard him knocking on his own window, thinking it was a door, or spied him preparing the leeches for use, swishing around imaginary water in the dark glass jar where he kept them. The servants would have gone into his room to waken him, followed by his distraught wife. He would not remember sleeping, nor would he feel at all rested. "I'm tired" -- "Mi so straco," he would say in Venetian. And when the servants had left the room, to his wife alone he would express his deepest horror: "Mi divento mato." Was he indeed going crazy? Was he destined for the ships of fools, those boats in the farthest parts of the lagoon where the Serenissima housed the poor souls from whom God had taken the power of reason?

By now, he would also have consulted with the experts at Venice's collegium, the learned medical society. Unfortunately, his fellow practitioners had much the same knowledge he had: they knew the structures of the body, what the major organs did, and what they looked like when examined after death. But they really knew nothing about disease in the living. Still, then (as now) doctors believed in their own judgment, in knowing when to bleed and when to salve, when to prescribe cold baths and when to recommend warm wine. They would have focused on the fact that the doctor was sweating all the time. They might have taken his temperature -- the thermometer was a recent Padovan invention -- and here things would have gotten tricky. Unlike other prion disease sufferers, FFI victims have temperatures that gyrate wildly. The doctors would not have known what to make of these huge swings but they would have treated their friend as a fever victim anyway. (Part of clinical judgment consisted in knowing when to disregard results that didn't make sense.) They would ultimately have prescribed a soak in cold water -- the servants desperately trying to hold his body so that he didn't slide under -- and when that proved useless, they would have bled their friend to cool his humors, astonished by the jerking of his legs and arms as they tried to open the vein. Had they not been men of science, his condition would have looked to them more like possession than disease, but medicine had turned a corner in the last two hundred years and modern doctors such as they would never again talk of demons and auguries.

They would have convened again soon after, dressed in the black togas and soft velvet hats of their profession, probably in the card room in the doctor's house where over dinner and wine they would have debated what to do next. Purgatives? Emetics? Diuretics? None of the doctors would have been honest and said that they had no cure for their friend, because in reality none of them ever had a cure for anyone. In fact, no eighteenth-century doctors knew how to make a patient well; they had no more success than the mountebanks who lined the Piazza San Marco. They had all suffered humiliations similar to one Casanova recounts in his memoirs. The adventurer happened to be in a gondola with a Venetian patrician -- a senator -- when the man was felled by a stroke. Casanova helped the man into his palazzo and into bed, where he waited for the arrival of the senator's physician. A Dr. Ferro, eminent in the profession, arrived and placed a poultice or mercury salve on his patient's chest and left con?dent he would ?nd him better in the morning. As he did -- only to discover that in the night Casanova, seeing the senator near death from the cure (mercury is highly toxic) had stripped off the salve and washed his body in warm water. The patrician declared Casanova his new physician, and Casanova spread the story everywhere.

"Who is it that says there is a great difference between a good physician and a bad one; yet very little between a good one and none at all?" asked Arthur Young, the English agricultural journalist, in 1787, on a tour of the Continent. Still, faced with a sleepless, thrashing colleague, urged on by his terrified wife, the doctors would have taken action. In a case this grave, the best option was to prescribe the most powerful drug in their repertoire: triaca, or teriaca, or theriaca ex Galena. Or, in English, Venetian treacle. Triaca was a typical Venetian story. Galen himself was said to have concocted the original version of the drug, and the recipe had then followed the Roman armies into Europe. With the collapse of the empire, its formula had survived in the monasteries: for the next fourteen hundred years, it remained the wonder drug of Europe. Triaca was reputed to cure fever and even the plague, and to counteract all poisons. The exact recipe varied depending on the ingredients available in the region and the druggist's tastes.

The Venetians had begun manufacturing triaca in the Middle Ages, taking advantage of their window on the east to ?ll it with ingredients to which other European countries didn't have access. By law, members of the magistrato alla sanita, the department of public health, had to be present when the apothecary ground and mixed these ingredients. The public was sometimes invited to attend too, the apothecary's shop with its impressive jars on burnished wood shelves an appealing locale for a show. Once the health department had certified the treacle as authentic, the druggist was allowed to hang the Venetian stag, the lion of Saint Mark the Evangelist, outside to alert the world that a new batch of treacle was on sale. The hocus-pocus of government certification turned treacle into a patented brand that Venice could ship to the rest of Europe at a good profit.

Treacle's most important ingredient was viper's flesh -- "the base and foundation . . . without which you can absolutely not concoct it," as the great sixteenth-century Bolognese physician Aldrovandi wrote. The theory, enshrined in the work of Galen himself, was that it took a poison to counteract a poison. Since fever was a poison in the body, you needed an equally potent venom to stop it. The best (and most expensive) viper's flesh happened to come from the Euganean Hills near Padua, on Venetian territory.

The doctor's colleagues would have been able to negotiate a good price for the expensive drug because doctors licensed pharmacists in Venice. They would have carried the concoction back to their friend's house, where he now lay confined to his bed. They would have had to put the treacle paste directly on his tongue, bidding him to swallow it, or, if he was too weak to do so, they might have dissolved a small amount of the treacle in rose water to hide its bitter taste, and dripped it down his throat.

Treacle is a diaphoretic, which means it makes the recipient sweat, the last thing a sufferer of fatal familial insomnia needs. And while the viper flesh likely had no effect, the opium with which treacle was laced certainly would have. The phrase "treacle sleep" appears in several European languages to mean a deep, dreamless sleep, but the opium in the doctor's brain would not have brought about that result. He would no longer have had the capacity in his brain for sleep, because prions had eaten it away. The opium would have eased his pain for a period, dulling the horror of what he experienced, but his eyes would have remained open.

After the treacle passed from his system, he would have been worse off than before, his servants having to hold his arms and legs down to keep him from twitching and jerking out of bed. Perhaps his wife would have given them permission to tie him down. Mutely, the doctor would have watched them do it.

All the same his colleagues would have declared themselves satisfied; the treacle had helped reduce their friend's phlegm: you had only to look at how sweaty he was. And from a professional point of view, who could fault them if the patient died, as he surely would soon? They had encountered a challenging case and devised a therapy, the best one available to them. And while medicine had progressed in the past century and would progress in the next, they were just men. Now it was the priests' turn. In 1770, a man named Giuseppe was born in the Veneto. It is not clear exactly how he was related to the doctor; the family name was common by the eighteenth century, and citizens bearing it were "spread all over Venice," according to a contemporary document, but he may have been his nephew.

Giuseppe grew up in the doctor's country villa and may have inherited it at some point, though later he moved to a nearby town. He was a rural noble, a sir, a man of property. He did not get to enjoy his privileged life for long, though. When he was in his late twenties, revolutionary France invaded Venice. Napoleon declared the Venetian Republic a meritocracy and suddenly everyone -- patrician, doctor, lawyer, gondolier -- became simply "cittadino." No sooner however had Venice accepted "Liberta Virtu Eguaglianza" than Napoleon traded the city to the Austrians for Belgium and Lombardy. Again the Venetians adjusted. "A Venetian law lasts but a week," one noble famously noted. Quickly the Venetians exchanged their red leggings, collars, and gloves (red was the color of the revolution) for black ones (the color of piety) and met the Austrians in the Piazza San Marco to celebrate mass for the Catholic emperor. Nine years later, Napoleon, now an emperor himself, was back; the Venetians put up his statue and a gilded "N" in Piazza San Marco, only to pull both down after his defeat at Waterloo in 1815. The victors of that battle, Austria, Britain, and Prussia, gave Venice back to Austria, which ruled it for another fifty years -- except during a liberal insurrection in 1848 -- until it was absorbed by the new nation of Italy.

The days when a Venetian would crush his wife's pearls sooner than appear to bow before a foreign king were over. The great powers fought constantly on Venice's doorstep, carried off its grain, and blockaded its ports. Venice, bereft of its territories, suffered an economic collapse so severe it took a hundred years to recover.

The small towns that dotted the countryside of the Veneto, like the one Giuseppe lived in, were hit especially hard. The early Venetians had never cared about terra firma. Only in the fifteenth century did the Republic change its mind and, to protect itself, acquire possessions in territorial Italy. Not surprisingly, over time they learned to make quite a bit of money off their holdings. Not only did the towns serve the defense of the Republic, but they also functioned as an economic colony for the rich in their fantasy city across the lagoon. The peasants in the Veneto grew corn and ground it at mills along the rivers to ship to the capital, and raised silk worms whose cocoons the artisans in Venice could weave into the beautiful clothes of the Venetian rich. When those clothes were dirty, they were sent by boat back to the Veneto, where the locals washed and ironed them. A patrician could sit on the balcony of his country house in the Veneto and watch his clean laundry, his food, and his firewood go past on their way to his palazzo in the city.

When the fortunes of the aristocratic class fell, so did those of their support industries in the Veneto. The Veneto suffered further when, in an effort to satisfy their need for transportation across the countryside, the Venetians and then the Austrians began rerouting the shallow, winding network of rivers that carried water from the nearby mountains into the lagoon. This bit of hubris turned the Veneto into a swamp for much of the year. The swamp brought mosquitoes and the mosquitoes brought malaria; an 1849 Austrian military report stated that one quarter of the residents of Giuseppe's town had the debilitating, occasionally fatal disease. Malaria prevented peasants from farming, which in turn led to outbreaks of pellagra, a disease of malnutrition. One of the prime symptoms of pellagra was insanity and one of the prime symptoms of malaria is delirium and intermittent fever. As a result, the Veneto in the mid-nineteenth century was full of people who had symptoms that resembled fatal familial insomnia.

Of Giuseppe's eight children, five died before reaching their first birthday. So much infant death was in line with the norms of country life, even among the wealthy, and Giuseppe would have accepted it. He would, however, have been surprised when, in about 1827, his teenaged son Costante became ill. At first the boy's fever would have come and gone, but within a few months he would have begun hallucinating and maybe claiming he was possessed. The local witch, an old spinster who lived on the edge of town, would have been brought in. Her solution would have been to shine light in every corner of Costante's sleeping quarters, in order to repel the massari -- l, the malicious elf who liked to surprise sleepers in the middle of the night by sitting on their chests, making them gasp for air. Or she might have taken Costante into the countryside and swung him three times under a chestnut tree, a cure-all. When Costante didn't get better, Giuseppe would have tried a local priest -- there were priests in the Veneto reputed to be able to return the mad to their senses. At the altar of the town church, beneath swirling frescoes of the baptism of Christ executed by one of Tiepolo's sons, the priest would have sprinkled holy water on Costante and had him touch the cross. When that didn't work, he would have locked the boy in the church with him and performed an exorcism. Exorcism was back-breaking labor, but no matter how much the priest sweated to remove this devil, Costante would have sweated more.

The boy died in 1828. The parish priest recorded his cause of death as pellagra, although the assertion makes no sense --