CHAPTER 15

FOR THE VICTIMS OF FATAL FAMILIAL INSOMNIA THE VENETO, present day

Throughout the 1990s, members of the Italian family with fatal familial insomnia kept dying. In 1993, Pierluigi Gambetti in Cleveland developed a test for the mutation that causes the disease, and, at Lisi and Ignazio’s urging, fifty relatives went to Bologna and had their blood drawn. At last something definite was known. But in fact, the knowledge was not airtight. The test returned a considerable percentage of wrong results—as high as 15 percent in the beginning.

Some members of the family refused to take the test, worried that the stressful process would itself bring on the family disease. One such man was cousin Carlo, whose brother Flavio had died of FFI in 1974. After Flavio’s death came his brother Terenzio in 1975. Carlo tried to live a quiet life and slip past the age of onset, and at sixty-one he thought he’d succeeded. But one evening in 1996, he came to see his niece Lucia. Lucia had helped raise the children her sister Teresa had left behind and had joined forces with Ignazio and Lisi in trying to find a cure. Lucia had seen a lot of death from FFI by then: her grandfather, father, two uncles, and Teresa. She knew what it looked like. She could tell from Uncle Carlo’s shrunken pupils what his fate would be. She sent him to Ignazio, who sent him to Bologna; Lucia and Carlo’s wife accompanied him on the train ride. “I knew. He knew,” Lucia says. “Maybe his wife knew.” Carlo died shortly after.

Some branches of the family were particularly hard hit, yet, through death after death, they kept their deep faith in God. Sometimes, in fact, the onslaught sent them back to the Church. This was the case for a young man I’ll call Arturo. Arturo is intense, with Marianna’s flamingred hair and a forceful urge to question. He lost three uncles to the disease before he was thirty. In his teens he contacted the Bologna neurologist Pietro Cortelli to see if the insomnia he suffered might be a sign of the disease (Cortelli reassured him he was too young). Arturo was determined to break his family’s taboo about discussing the disease and to confront it in a modern manner. He even went to the library and pulled out a book on the subject. He saw the fateful misfolded proteins that were killing his family. In 2000, his father began to have trouble sleeping. The family tried to keep him out of Bologna. They had had enough of the institute. Instead they took him to several regional hospitals, where finally the doctors urged them to go to Cortelli and Elio Lugaresi without wasting further time. Eventually he did.

The family had been praying throughout this time, reciting the Rosary every night. Their faith deepened with their suffering. They believed and it gave them strength. As he weakened, Arturo’s father told him he was not afraid to die and reminded him to take care of his mother and his sister after he was gone—Arturo would, after all, be the new head of the family. A month later, Arturo’s father developed a soaring fever, then fell into a coma and soon after died. The doctors at Bologna hoped to be able to do an autopsy and ship the brain to Pierluigi Gambetti, as it was accustomed to do, but the family, including Arturo, did not want that. Arturo, who until now had been the family goad, had had a change of heart. His father had had a good death in the Lord. That they had prayed together every night gave him more comfort than the EEGs or the doctors. Arturo looked forward to seeing his father in heaven.

When I spoke to him a week later, his conversion was clear. He no longer wanted to be the family firebrand. His intensity had turned inward in a search for a serenity that would ward off the disease. He became the sacristan of his church and ate only holistic foods. When I asked him if he was going to take the test now to see if he had the mutation that had killed his grandmother, his father, and three uncles, he told me no. The anxiety over the test itself might bring the disease. Besides, what would he do with the information? There wasn’t a cure.

         

What happens to the Italian family in the end depends less on their own actions than on the world’s interest in prion diseases, which they cannot control. If lots of people are afraid of getting variant CJD, the family benefits. If fear of prion disease goes the way of the fear of swine flu or Ebola, then they will be orphaned again.

The mad cow years left them better positioned than before, but still a long way from safety. How do you fight a disease that remains so much a mystery? A killer protein whose function when healthy is unknown and whose method of causing cell death is obscure? Not since Pasteur’s time have researchers attempted to counter an infection knowing so little about what they are fighting.

The ideal way to defeat a pathogen is to develop an artificial molecule that can bond with it and lock it up. Unfortunately, researchers aren’t sure of the shape of the prion. Besides, to develop a drug from scratch takes a decade and costs around $750 million to $1 billion. Researchers designed some of the anti-HIV drugs this way, but millions of people have HIV. By contrast, there are roughly forty known families with FFI in the world. Add to that number the families that have related genetic prion diseases—genetic CJD or Gerstmann-Sträussler-Scheinker disease—and the number is up to three hundred. Add in all the families who have a member suffering from or who has already died of variant CJD or CJD caused by growth hormone and you are up to five hundred affected families. Five hundred families do not constitute a critical mass in the world of medical research, no matter how spectacular their symptoms or how grievous the governmental error that made some of them sick. When in 1997 the British government called a meeting to discuss cures for variant CJD, representatives of only three pharmaceutical companies showed up: there was simply not enough money in it for them.

So researchers work with existing drugs to try to cure prion disease. There are about a hundred significantly different compounds in use to combat all diseases. Fewer than fifteen of these can cross into the brain, where prions do most of their damage. Lab machines can automatically test variations of these compounds against material infected with prions. If a drug shows promise, the researcher can move right to a human trial—there is no need for laborious proofs that the drug is safe, since it has already been approved for other human diseases. The only question the researcher has to answer is whether it is effective.

The first drug to come down the pipeline this way was quinacrine. During World War II, malaria was a big concern for American troops. The cure—in fact, the first cure for any disease—was quinine, derived from the bark of the cinchona tree. Because the drug was so useful, over the years many governments, organizations, and scientists—the Jesuit order and Baron Liebig among them—tried to corner the supply. At the beginning of World War II, the Japanese occupied most of the Far East, where the cinchona trees grew. In response, American scientists put into wide production a synthetic replacement. American troops took millions of doses of quinacrine, and cases of malaria among them declined to nearly zero.

Quinacrine consists of very small molecules. That was its first attractive quality for prion researchers—it could get through the blood-brain barrier. By 1997, labs were trying compounds derived from quinacrine on test tubes of mouse cells infected with prions. A Japanese researcher named Katsumi Doh-Ura, working with Byron Caughey of the NIH, first published a report that the drug could reduce infectivity in 2000, but as usual Prusiner’s lab in San Francisco, which came out with similar findings a year later, got the credit.

In the summer of 2001, an Englishman named Stephen Forber was searching the Internet for a cure for his twenty-year-old daughter, Rachel, one of the hundred or so Britons who had been diagnosed with variant CJD by that time. Forber contacted Stephen Dealler, the English microbiologist who had warned early on that mad cow would cross to humans. After Dealler’s fears had come true, he began to push for a cure.

Dealler had heard that Prusiner’s lab was having some luck with quinacrine, so when Forber contacted him, he put him in touch with Prusiner’s researchers and they agreed to give Rachel quinacrine. The drug was safe at the doses necessary to prevent malaria, but those doses were too low to block a prion disease. Still, Prusiner had been promising a cure for a long time and the initial results from quinacrine—admittedly just in mouse cells—had been very encouraging. His team started Rachel on the drug. What happened next was miraculous: Rachel got better. She had arrived in San Francisco in June unable to walk or talk or recognize what was going on around her. Four weeks after that, she was nearly herself.

The British government had been stalling on funding prion cure research, but Rachel’s apparent recovery prompted it to put up £200,000 for further quinacrine trials. For Prusiner, it was sweet revenge. The government that kept him out of the mad cow drama was now beginning to understand what it had missed. Three years before, he had predicted that he could cure CJD in five years, and here he was two years ahead of schedule. Then things fell apart.

Quinacrine at high doses causes sterility, shaking, and liver damage. That was why, as soon as the military could replace quinacrine with another synthetic cure for malaria, it did. Rachel Forber was getting a very high dose of quinacrine: in the hospital, she was so yellow from liver damage that doctors called her “the lemon princess.” After her discharge, her liver began to fail. She had to stop the pills. As the quinacrine left her system, her symptoms returned. She went downhill quickly, dying in December 2001, six months after her diagnosis. By now, more than three hundred prion disease sufferers have tried quinacrine and, according to Graham Steel, the head of the CJD Alliance in the United Kingdom, “they’re all dead.”

Prusiner’s many enemies blamed the Forber fiasco on him. His lab, though, considered the treatment a success. According to them, postmortem studies of Rachel’s cells showed a great decline in prion infectivity. And what had been the alternative? “When you have someone with a fatal illness, then anything is okay,” said Fred Cohen, a biochemist who worked closely with Prusiner to treat Rachel. He is now trying to make a less toxic variation of quinacrine.

After Forber’s death, the families of most CJD sufferers put their faith in a different drug, pentosan. Derived from beechwood, pentosan is usually prescribed for infections of the lining of the bladder. In 1984, Alan Dickinson, then the irascible head of the Neuropatho-genesis Unit in Edinburgh, first tried it on mice infected with scrapie. He found that even a very low dose of pentosan delayed the onset of the disease. Over the years, various researchers tried pentosan on rats, hamsters, and dogs with similar success. Dickinson considered giving it to humans too, but he never did—he was worried about side effects. Pentosan is a blood thinner and too high a dose can cause seizures.

In time, another father with a sick child found his way to Stephen Dealler. Donald Simms had read about pentosan on the Web. His twenty-two-year-old son Jonathan, a former star soccer player, was dying of variant CJD in Belfast. Could Dealler help Jonathan get pentosan? Dealler explained that the problem with the drug was that it was too large to cross the blood-brain barrier. It might help someone who had just been infected by prions, before the prions had had a chance to make their way into the central nervous system, but Jonathan’s was not a new infection.

Dealler also told Simms that no one in Britain was actively pursuing pentosan, but Simms, a gruff, heavy-smoking contractor who is built like a rugby player, was not easily deterred. By chance, Doh-ura, the Japanese researcher who first tested quinacrine on prions, was coming to Scotland. Don Simms found him by calling ninety hotels in Edinburgh. The researcher told him what he hoped to hear: Pentosan might be able to slow down or stop the prion infection.

The problem of how to get pentosan into Jonathan’s brain was not insurmountable, either. In recent years researchers had learned how to put shunts through the skull to deliver cancer drugs. Simms was able to find a neurosurgeon willing to carry out a similar procedure on Jonathan. Simms’s next problem was getting the British government to allow it. The Rachel Forber episode had traumatized the English medical establishment. There was worry that the young victims of variant CJD were at risk of being betrayed twice—once by the government, the second time by their own parents. Simms sued and in 2003 won his son the right to the treatment. Astonishingly, the boy had survived the seventeen-month delay.

Jonathan’s treatment has been more successful than Rachel Forber’s. Pentosan is effective because the molecule binds to a site necessary for prion proteins to convert to malignant prions. It works the way putting a dummy key into a lock prevents another key from turning the mechanism. Doctors gave Jonathan less than a year to live after his initial diagnosis in 2001. Yet he is still alive as this book goes to press, five years later, the longest-living prion disease sufferer known. He is, though, hardly well. If Rachel Forber’s story was one of improbable recovery followed by precipitous decline Jonathan Simms’s is of staving off death, perhaps even making tiny steps toward health. His blood pressure is lower, he has regained some of the weight he lost, and his ability to swallow and to sleep has returned. A year after his treatment started, he heard his favorite soccer team was playing, pointed to the TV and said the word “On”—or so it was reported in 2004. Jonathan can look at people again, but he can’t roll over in bed or feed himself and likely never will be able to. Scans have shown that his brain is continuing to atrophy, though the progress he seems to be making would suggest the opposite. “Johnny’s stable,” Donald told me when I saw him at a CJD family conference in 2005, “my boy is stable.”

Inevitably, the news of Jonathan Simms’s success reached America. The first American to be given pentosan was James Alford. In 2002, when Alford was a twenty-four-year-old Special Forces soldier serving in Iraq, he suddenly started falling apart. He seemed confused and inattentive; he went AWOL. The army suspected him of malingering. In 2003, it demoted Alford from staff sergeant and told him to carry a pen and paper with him to write down orders. The army was on the point of court-martialing Alford for insubordination when a military doctor examined him and diagnosed CJD. Alford was given a medical discharge and in April 2003 allowed to go home to die. Instead, thanks to Terry Singeltary’s efforts at getting the word out, Alford became a cause célèbre. When The O’Reilly Factor featured his story, the show’s resident military commentator called Alford’s treatment “the worst case of abuse of a soldier I’ve seen in thirty years.”

Alford believed he was a war casualty. He told others that a banquet he and other soldiers attended while on a covert mission in Oman in 2001 was not the warm welcome it seemed—someone deliberately served a scrapie-infected sheep to the Americans. Alford’s hypothesis strikes prion researchers as fanciful, because scrapie has never been shown to be contagious to humans. “We shot monkeys full of scrapie in my lab and nothing happened,” Carleton Gajdusek told me when I told him Alford’s story. “They’re still the monkeys that are there today.” All the same, the army, under media pressure, reinstated Alford at full pay and began treating him as if he were a soldier who had caught a disease or taken a bullet in a war. The army also helped Alford get access to pentosan, but the results have not been what they were for Jonathan Simms. Every month Alford’s family drives him to a hospital near his home in Karnack, Texas, where doctors mix a few drops of the drug into saline fluid and funnel it through a shunt into his head. When Alford began his treatment in March 2004, he was surviving on fluids. He did not respond to voices. He has not recovered any lost ground—his decline has continued and he is nearly comatose now—still alive, but barely. Stephen Dealler thinks the difference between Alford’s response and Jonathan Simms’s may be that Simms simultaneously received high doses of Vitamin E, but that remains to be proved. By early 2006, there were about thirty patients with variant or sporadic CJD taking pentosan around the world with all but one still living. The outlook for inherited prion disease victims is not as promising. In 2005, an American woman with an inherited form of GSS who had begun to show symptoms contacted Donald Simms, learned about pentosan, and began treatment. She died at the end of the year, one of three GSS patients to try the drug without much success, suggesting that the virulence of inherited prion diseases is greater than that of sporadic or infectious kinds.

         

The Italian family watches all this activity. Ignazio reads English well and checks the CJD websites for updates, but neither he nor Lisi nor anyone else in the family is a Donald Simms or a Stephen Forber, willing to go to any length for a cure. Nearly every month there is news about a new drug that blocks prion malformation, but it is always in cell cultures or maybe mice, never people. The developments both excite them and increase their desire to stay on the sidelines. They have seen experts who have sent them to other experts, who have only delivered more expertise. Living with FFI has made them tired. And wary. They know that for all that has been learned about their disease, deliverance is still a long way off.

At the first family reunion in 2001, the talk was of America. The family wanted to have a foundation there. “America,” they said, “is where the money and the research are.” Lo zio d’America, the rich emigrant uncle, is a stock figure in Italians’ minds, this family’s as well. America had saved Italy many times. America could save Italy again. And in America, some reasoned at the reunion, the family would also be anonymous. They could have both the privacy and the money.

But then they thought about it some more. Prusiner loves prions more than people, they told me. And the prospect of pentosan filled them with horror. Having, as USCF chemist Fred Cohen puts it, “a bolt put in your head” so a technician can “squirt something into your brain” is a high price to pay for a few more years of life.

The family knows that it has value to researchers. People with prion diseases are not easy to come by; large families with a hereditary prion disease even rarer. I was once in Pierluigi Gambetti’s office in Cleveland and heard him talking on the phone about some tissue he was expecting. His end of the conversation, in his careful, accented English, went like this: “Do you have a way to keep it frozen?…Do you know if it will last un-teel tom-or-row?…You have a refrigerator or freeeez-er? Can you add dry ice?…We can’t get Fed-er-al Ex-press after six pee-em. There is no way to get in…. Well, see if it fits in the freeeez-er.”

And FFI is a disease of sleeplessness in an era when insomnia affects about 10 percent of the Western world, or some one hundred twenty million people. “If I were the director of the NIH, I would pour money into FFI research,” William Dement, the founder of sleep medicine, told me. “You might get a cure for insomnia. At the very least we could make our sleeping pills infinitely safer and more practical.” Still the family evaluates its options cautiously, shadowboxing with its past. Recently it teamed up with a prestigious institute for protein research in Milan. The difficult goal of the alliance will be to find a drug that can turn off prion production in skin cells and then get it to do the same thing in the brain.

In the meantime, to raise money and to reach out to other sufferers of FFI, the family launched a website for their association (www.afiff.org/). Its home page features a drawing of Hypnos, the Greek god of sleep, above an inert man. A ticker on the margin of the page scrolls through the latest prion disease research and therapies from around the world. Hypnos looks close enough to it that if he were to just put down his useless trumpet and reach a long arm out, he could pluck a cure that would finally make the figure beneath him wake.

In early 2003, another member of the Italian family got sick. Vittorino lived at the southern end of the Venetian lagoon. He was from a distant branch of the family; its point of intersection with Lisi’s branch is so remote that until Ignazio received a call from Vittorino’s two daughters, he did not know it existed. The daughters, Maria and Roberta, had seen a recent article on the new fatal familial insomnia association in an Italian newspaper and they wanted to know if the disease their father had might, in fact, be FFI. Vittorino had already been to three hospitals, Sottomarina—where he had been diagnosed as alcoholic—Piove, and Padua, whose neurologists had long since forgotten the mystery of Assunta and Pierina. Ignazio explained the condition to Maria and Roberta and tests given to Vittorino confirmed he had the disease. Before this time, no one in his family had ever heard of FFI.

Vittorino turned out to be a direct descendant of Giuseppe, whose fourteen-year-old son, Costante, was the first certain victim of the disease, in 1828. Maria and Roberta’s grandmother and great-grandmother both died of the disease, which their older relatives long referred to as the family curse. No one had ever been willing to talk to the sisters about it.

When, shortly after Vittorino’s death, I met Roberta and Maria—modern, cultured Italians, with stylish hair and eyewear—they were still awestruck by what they had seen. Vittorino, an athletic man, had been reduced to a wraith in months. In the grip of the disease, he mimed happily fishing in the Adriatic. The death itself was terrible to see—the myoclonic jerks, the stupor, the gasping for breath—and yet they were grateful that they were not alone in their suffering, that dozens of distant relatives had been wrestling with the same disease for centuries and that there was even a writer interested in the subject. They told me that after their father died, they made sure that his body was available to researchers. They talked about what had happened with friends. And then they did something else no member of the family had ever done before in two centuries. They placed an offering jar outside the church where the funeral mass was said, with the words “For the victims of fatal familial insomnia” on it for everyone to see.