Mercies in Disguise Page 4
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Gajdusek still believed that he might find answers in the brains of the Fore. He sent one brain of a fifty-year-old woman with kuru to a neuropathologist at the NIH, Igor Klatzo. Like the previous brain, this one too was shot full of microscopic holes. In addition, the myelin, a fatty substance that wraps around nerves, insulating them, was ragged and thinner than normal in some places and missing entirely in others. Gajdusek sent more brains. Half of them had rough Brillo-like areas—amyloid plaques. A German doctor, Alois Alzheimer, had seen plaques like that at the turn of the twentieth century in patients with the disease that came to bear his name. To date, they were unique to that brain disease. But children did not get Alzheimer’s. And children with kuru had plaques as well.
Klatzo sent his thoughts, along with his report, to Gajdusek about the cause of the abnormalities after examining seven brains. “The closest condition I can think of is one described by Jakob and Creutzfeldt,” he explained in his letter dated September 15, 1957. It was a rare disease, abbreviated CJD, and unknown to most doctors. CJD had not been known to affect children, but the resemblance was too close to ignore. There were similar brain lesions but also a similar clinical picture, with trembling and loss of muscular control.
CJD had first been described in 1920 by a German doctor, Hans Gerhard Creutzfeldt, who published a report on “a new and unusual type of neurological disease” he’d seen in a twenty-two-year-old woman. Her illness had progressed in much the same way as kuru in the Fore: starting with tremors and an unsteady gait, moving on to involuntary eye movements, jerking limbs, and dementia. She died a year after the disease began. The next year, another German doctor, Alfons Maria Jakob, had reported four more patients with similar symptoms. The brains of CJD patients had lost nerve cells and had a characteristic spongelike appearance, the doctors wrote.
But by December 1957, Gajdusek contemplated defeat. None of his hypotheses had even a shred of evidence to support them. There could be a link to CJD—Klatzo was a brilliant scientist and it was hard to dismiss his observations—but all he had suggested was that the brains reminded him of CJD brains. It was not possible to prove that they were CJD brains.
In desperation, Gajdusek circled back to the idea that the disease was caused by a microbe, an infection. He wrote to Edward Graeme Robertson, a pathologist at the University of Melbourne who had examined some of the brains. Even though Robertson had found no evidence of a sudden or chronic infection in kuru victims, Gajdusek wrote, at this point there was nothing else left to investigate. He knew that infection was unlikely but “kuru is a highly ‘unlikely’ disease,” wrote Gajdusek, and so he wanted to return to this “wild possibility.”
All along, as he’d studied kuru, Gajdusek had photographed healthy Fore and kuru victims, publishing photos in the New England Journal of Medicine and other medical journals. Soon television crews began to arrive, asking to film him and the Fore. He rehearsed the various potential causes. His references to a cannibalism connection among a Stone Age people proved irresistible to the media. Within a year, he had become something of a celebrity in Australia, the United States, and other developed countries. But still Gajdusek had no answers.
He returned to the United States for a visit, where the cutting-edge labs at the National Institutes of Health offered him a chance to look again for evidence of an infection. The plan was to try to transmit kuru from blood or tissues of patients to laboratory animals. But again he was stymied. The animals remained healthy.
Where Gajdusek’s hard work failed, however, his fame offered an opportunity. He received a letter from an American veterinarian, William Hadlow, who happened to be doing research in England on scrapie, a peculiar disease afflicting sheep. Its name referred to the way infected sheep behaved—they scraped themselves raw against fences. Veterinarians had spent decades studying scrapie and were nearly as puzzled by it as Gajdusek was by kuru. But they did have one clue: the sheep could transmit the disease from one animal to another just as an infection would travel, although the doctors could not isolate the infectious microbe.
At the suggestion of a friend, Hadlow had visited a traveling exhibit curated by Gajdusek as part of his publicity push on the Fore. Amazingly, the slides of kuru brains and the descriptions of their victims’ symptoms were identical to those of sheep with scrapie. In both diseases there was massive brain cell death, loss of myelin, and—tellingly—the same spongelike appearance that veterinarians called “soap-bubble holes.”
In addition to describing the similarities in the letter to Gajdusek, Hadlow published his observations in The Lancet, a prominent British medical journal. His conclusion: “I do not suggest that these diseases are identical or even counterparts. But in my opinion their overall resemblance is too impressive to be ignored.”
Hadlow also revealed in his letter to Gajdusek that veterinarians could give scrapie to a healthy sheep by injecting the animal with brain cells from another that was sick with the disease. The trick with scrapie, Hadlow wrote, was to wait a long time for symptoms to emerge after that injection. Hadlow called the thus far undetectable scrapie agent a “slow virus.” The disease could only be transmitted to other sheep or to goats, which are closely related to sheep. So, Hadlow suggested, the best animals for kuru transmission experiments would be primates.
Gajdusek, who had never heard of scrapie, began to obsessively study the literature. Hadlow was right: the diseases followed similar courses and had many of the same symptoms—problems walking, tremors, changes in behavior. They both ended fatally, usually within six months. And the brains of the victims of both diseases bore soap-bubble holes.
Suddenly, Gajdusek had a renewed zeal for the infectious disease hypothesis. He would use monkeys or chimpanzees instead of mice, following Hadlow’s advice, and allow a substantial amount of time for the disease to unfold. It took a while to set up a primate colony under the auspices of the NIH, but finally, on September 17, 1963, one of Gajdusek’s close colleagues, Joe Gibbs, working at the NIH lab in Maryland, near Washington, DC, anesthetized and inoculated a chimpanzee with brain tissue from a Fore child who’d died of kuru. And, nearly two years later, a lab technician observed the chimpanzee trembling and falling.
Gibbs sent a telegram to Gajdusek, who by then had returned to New Guinea. Gajdusek flew back immediately to witness the animal’s progression. By August, the animal was immobile, unable to survive without constant care. The researchers euthanized her shortly afterward. An autopsy showed that the brain had all the hallmarks of kuru, including the plaques and the holes.
It was settled. Kuru could be transmitted, though, as with scrapie, the agent remained a mystery. Gajdusek settled on using Hadlow’s term, “slow virus,” even though no one had actually isolated a virus.
Now that he knew a human neurological disease could be spread by this so-called slow virus, Gajdusek leapt at new opportunities. What other human diseases might be transmitted this way? Given Klatzo’s observation that kuru brains looked like the brains of patients with CJD, he tried to transmit CJD to monkeys in the same way he transmitted kuru. Further experiments showed that this was indeed possible. What about other diseases? Maybe degenerative brain diseases whose causes were also mysteries—Alzheimer’s, Parkinson’s, Huntington’s, multiple sclerosis, amyotrophic lateral sclerosis, or ALS—were caused by slow viruses? Maybe even chronic illnesses that did not involve the brain, like lupus and Crohn’s disease, rheumatoid arthritis, and type 1 diabetes, would fall under the slow virus umbrella.
If he was right, the kuru discovery could transform medicine. It might lead to the discovery of viruses that could be treated. Diseases thought to be random and uncontrollable might be prevented. Gajdusek’s mind raced with possibility and ambition. But his hundreds of attempts to transmit Alzheimer’s, ALS, and other such illnesses to monkeys failed.
Still, Gajdusek had made the major discovery he had sought. He had proved conclusively that some human degenerative brain diseases—specifically, ku
ru and CJD—were caused by an infectious agent and could be transmitted. The infectious agent, although termed a slow virus, was unlike anything ever seen in medicine. The brain diseases it caused had none of the hallmarks of any infection that had been studied before. And the incubation period was almost inconceivably long. Gajdusek had discovered a totally new kind of human neurological disease.
As he continued to publish papers and lecture to scientific audiences, his fame continued to grow, as did his public acclaim. In 1976, Gajdusek was awarded a Nobel Prize for his work on kuru.
Given his success and discoveries based on transmitting kuru and CJD to primates—not to mention the primate colony he had developed to allow him to perform such transmission studies—doctors began to send him brains of people suspected of having CJD to confirm the diagnosis.
But another five years passed before Gajdusek stumbled upon the next major discovery. An Australian neuropathologist, ginger-haired Colin Masters, had just arrived to work with Gajdusek at his lab at the National Institutes of Health. Masters’s job was to examine the brains that doctors were sending to Gajdusek’s lab to be analyzed for CJD. In so doing, Masters discovered that many of these patients had been misdiagnosed and actually had more common diseases like Alzheimer’s.
But four of the brains were outliers. They had accumulations of amyloid, the rough hard clumps that are a hallmark of Alzheimer’s and can also be seen in kuru. But the plaque in these brains did not look like those in the brains of patients with Alzheimer’s or kuru. The pathology was somewhere between that of CJD and Alzheimer’s. There were too few plaques for Alzheimer’s and too many for CJD. And the plaques lacked the distinguishing features of both. When Masters looked at the patients’ clinical history, he discovered that each had family members who had died of a similar disease.
Masters recalled a disease he had read about in a paper published in an obscure journal decades earlier, in 1928. Entitled “A Peculiar Heredofamilial Disease of the Central Nervous System: A Contribution to the Problem of Premature Local Aging,” the paper described the pathology of a disease that is now known as Gerstmann-Sträussler-Scheinker disease, or GSS.
The author of that paper was a Viennese doctor named Josef Gerstmann. Gerstmann presented the case of a twenty-six-year-old Austrian woman, Berta H., who had an illness that was causing an odd neurological reflex. When the doctor asked Berta to hold her arms out straight in front of her and then turn her head, her arms spontaneously crossed each other so that her left arm pointed to the right and her right arm to the left. She stumbled and lost her balance when she tried to walk. As her disease progressed, she could not control her movements, her speech became slurred, she was irritable, she had a tremor, and her muscles grew weak and flaccid. Soon she could not control the muscles of her tongue or neck; she could not look up at the ceiling.
Later, in 1936, after Berta H. died, Gerstmann and two other neurologists, Ernst Sträussler and Isaac Scheinker, wrote a paper further describing the disease. Berta began showing symptoms when she was twenty-five years old, the doctors wrote, and within a year, was unable to think or reason; she was demented like someone with end-stage Alzheimer’s disease. She died six years after the disease had begun, at age thirty-one.
On autopsy, the doctors reported that the dentate nuclei in the woman’s brain had degenerated. These are neurons in the cerebellum, the brain region that controls movement. She’d lost myelin, a fatty sheath around neurons that insulates them so that signals can pass among them without interference. The doctors also saw strange-looking plaque—“peculiar inclusions of foreign substances,” they described it. Their shapes were distinctive—round or irregular, sometimes with jagged edges. They would mass together in balls or clumps. “These formations are shapes that are rarely found among senile plaque forms,” the three doctors observed, referring to plaque found in Alzheimer’s disease. In addition, there were holes in the woman’s cerebral cortex, the outer portion of the gray matter of the brain.
Gerstmann, Sträussler, and Scheinker also noted that seven other members of Berta H.’s family had suffered the same brain disorder. More than twenty years later, after four additional members of the family had died of what looked like GSS, other doctors calculated the average age of death was forty-six, the disease lasted an average of six years, and that symptoms often included dementia. Eventually, researchers traced the original family’s illness back nine generations, starting in the eighteenth century, and reported that at least twenty members of the family definitely had GSS. It seemed to be inherited, and if a parent had GSS, each child had a 50 percent chance of getting it too.
Over the years, doctors from around the world described a small number of families with the same unusual disease: it afflicts fewer than two hundred thousand people in the United States. People would lose their muscle movements, grow clumsy, develop an unsteady gait, and eventually lose the ability to walk and to speak clearly or swallow without choking. GSS remained a rare inherited disorder in the annals of medicine—a medical curiosity with no definitive explanation.
Gajdusek, like most neurologists, knew almost nothing about GSS. But once Masters made that connection, he immediately performed his go-to experiment, trying to transmit the illness to monkeys using brains from GSS patients. He discovered he had found yet another slow-virus brain disease. But it was puzzling.
GSS seemed to be inherited because it only occurred in people related to others who had it—a parent, for example, or a sister. Infectious diseases such as kuru would not spread in such a way. While CJD was also often inherited, showing up in generation after generation of afflicted families in the same way as GSS, it too sometimes cropped up at random in a person who had no contacts with other CJD patients and no family history of the disease. It was hard to see how one slow virus could explain all the variations.
And, most curious of all, even though the infectious agent was being called a virus, it had resisted all attempts to isolate it. That raised questions about what the agent was—and why Gajdusek and his colleagues could transmit GSS and CJD to monkeys; yet at the same time, these ailments were also inherited diseases and, in the case of GSS, seemed to be only inherited.
As Gajdusek struggled to resolve these conundrums, unbeknown to him, a young and very ambitious scientist was on his trail. Stanley Prusiner would not rest until he had claimed these diseases for his own.
3
Revelation
Tim had always felt his life was shaped—or perhaps something more like overshadowed—by his exemplary older brothers Billy, Buddy, and Mike. Each had been a stellar student, an honor society member. Each was popular and handsome. Their parents had high expectations for all of their sons and kept them under a tight rein: Buddy later told his wife that leaving for college felt like being let out of prison. Growing up, the brothers bonded in quiet resistance, wrestling in the basement in utter silence so Merle would not come to the top of the steps and ask what was going on; they were always slightly pushing the limits, testing what minor infractions they could get away with without alerting their parents.
In the end, Billy, Buddy, and Mike fulfilled their parents’ expectations, growing up to be a dentist, a doctor, and a lawyer, respectively—about as prestigious a group of professions as one could imagine. Only Tim had resisted the pressure to excel. If each of his brothers was going to strive in school, to be at the center of attention, at the top of his class and then his career, Tim decided to take on an opposite role. It was his way of rebelling, assuming what a psychologist once told him was a “negative identity.” He did not try to be an exemplary student or an athlete or anything special. He wanted to seem laid back, like someone who didn’t care about what was expected of a Baxley. He was the dude who delivered medicines for a local drugstore, driving the business car, a yellow Pinto. He got the job when he was fifteen, the same year he got his driver’s license, and kept it throughout high school and through his first year of college. In a continuing effort at rebellion, Tim decide
d to become a chiropractor after college, a route that won no praise from Buddy, ten years his senior and already established as Hartsville’s beloved family doctor. Buddy even asked a revered surgeon in town, Pickens Moyd, to try to dissuade Tim from what Buddy thought was a ridiculous career—to no avail.
Tim’s parents, though, were happy to see him find direction, even if it wasn’t one they would have chosen for him. They read up on chiropractic practices and did not disparage him.
So Tim got his degree and began practicing chiropractic, enjoying his profession and the close contact he had with his patients. But then, one spring day in 1987, before Bill became ill, when the family was gathered at the family house after church, Tim was struck by a revelation, one that overtook him in a way that he still cannot explain.
Buddy had challenged Tim to a run. They often got into scrappy competitions, even as grown men, still jockeying for position. The two brothers sped along the neighborhood streets lined with tall laurel oaks and headed for a route around the golf course—Buddy, as always, a bit ahead—when suddenly Tim realized something with such certainty, such conviction, that it felt like a blow. It was as though he were being given an order: he was going to go to medical school and he was going to become a neurologist. He’d never before thought about becoming a medical doctor, let alone a neurologist. Yet he now knew that it was his destiny. Nothing like that had ever happened to him before and he was both shaken and exhilarated as he continued to run, awestruck, barely noticing the road beneath his feet.
The brothers sprinted to their parents’ house, panting with the exertion, then collapsed into hammocks in the backyard, Tim still tingling from his epiphany. Looking up at the sky he addressed his brother, trying to sound casual. “Buddy, I decided right now that I want to go to medical school.”