Sample text for Brain trust : the hidden connections between mad cow and misdiagnosed Alzheimer's disease / Colm A. Kelleher.

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Chapter 2: Kuru

A young woman sat in the corner of the mud hut. Though she was bone thin, it was the look on her face that startled her visitor. The woman's face was expressionless. Her eyes were blank. The lack of expression was so profound, in fact, that she could have been wearing a flesh-colored mask. Every few minutes, a fluttering tremor ran through her body, as if she was shivering uncontrollably from a cold wind.

Vincent Zigas observed the woman as he sweated inside the hot, humid hut. Zigas had never seen symptoms like these before. He learned that the woman had kuru. She had been bewitched, he was told. There were many women and children in the village who had been bewitched by powerful sorcerers and they would all die, or so the story went. Nobody recovered from kuru.

Zigas was a young German-Lithuanian doctor from Australia. He had arrived in the central New Guinea Highlands in 1955 on an Australian government assignment to help eradicate some of the diseases that thrived in the hot, clammy climate. Papua New Guinea presented a daunting topography for outsiders. Within an area slightly larger than California, the country combines dense, almost impenetrable, leech-infested rain forests and highlands stretching up to more than 13,000 feet. Half the island had belonged to Australia since 1910, and after the Japanese takeover during World War II, the Australian government sent several officials into the Highlands in a bid to tame the rampant lawlessness and often gory tribal conflicts among its warlike inhabitants who still used bows, arrows, and stone axes, and knew nothing of the existence of the wheel. But the term "Stone Age" fails to capture the real flavor of the place. Since Captain Cook's forays into the region in the late 1700s, New Guinea had a reputation for being home to multiple tribes of bloodthirsty cannibals and headhunters.

After his arrival in Kainantu and a nearby village called Okapa, Zigas discovered he was the only medically trained doctor in that part of New Guinea. In 1955, Kainantu, known as the "gateway to the Highlands," was a small settlement several days' hike from the Highlands, where the medical supplies from the Australian Department of Health arrived. The town was a central crossing point for people moving up and down from the Highlands and was a natural place for Zigas to set up his base. While in Kainantu he heard rumors about a mysterious disease called kuru in an obscure tribe called the Fore (pronounced FOR-ay). The Fore lived in the remote highlands and had had very little contact with the outside world.

In September 1955, accompanied by a guide, Zigas set off to investigate these increasingly persistent rumors. After two days' hiking in the high terrain the guide led him into a small hamlet with a few scattered mud huts where Zigas witnessed the woman with the strange symptoms. By the end of the year, he had seen dozens of similar cases, mostly in women and children. He first thought it was a brain disorder, maybe a virus or bacterial infection. With almost no medical facilities and no clean water or electricity in the bush, Zigas took what medical supplies he could carry on the two- or three-day hike into the Highlands. As the numbers of kuru cases multiplied, he was quickly overwhelmed.

Kuru was ripping apart the fabric of the Fore tribe, because every death from kuru demanded a death in revenge of the presumed sorcerer who had cursed the victim. The ritual murder, called tukabu, usually followed the kuru death by a few days. The deaths from kuru were predominantly women and children, but the deaths from tukabu were often men. Usually the tukabu involved the unfortunate person who was accused of sorcery, often with no evidence, being bludgeoned with rocks or hacked to death with machetes. A fiendish balance in mortality seemed to be playing out between the deaths of women and children by kuru and the deaths of men by tukabu.

In his memoirs Zigas described one of the many tragic kuru cases he witnessed. Walking past a village hut, he had encountered a Fore woman, who held "on her lap a limp figure, grossly emaciated to little more than skin and protruding bone, the shivering skeleton of a boy, looking up at me with blank crossed eyes." Zigas went on to describe how this woman's only child died the next day while her husband had just been murdered in a tukabu killing.

Zigas spent a year trying to interest the Australian health authorities in the disease and received only vaguely expressed promises in return. Sir Frank McFarlane Burnet, director of the Walter and Eliza Hall Institute in Melbourne and one of the most famous medical scientists in the world, showed curiosity about the descriptions of kuru but did not assign any of the large number of medical researchers at Walter and Eliza to help the floundering German-Lithuanian. Undeterred, Zigas began gathering samples while working virtually alone in very primitive conditions. By scrounging around among his acquaintances and by begging for funds from the Australian health authorities, Zigas began the long project of building a primitive field hospital near the airstrip at Kainantu.

Zigas impressed everyone with his sincerity and he gradually earned trust among the Fore as well. The reward came in early 1957 when they allowed two tribal members suffering from kuru to make the long trip down to the hospital for medical observation and treatment. The Fore were humoring Zigas. They believed Zigas was wasting his time; they knew that kuru was the result of sorcery and that the only way to cure it was to find the sorcerer and persuade him to lift the curse. So it was that Zigas began the long process of medical detective work with the first two kuru patients at his makeshift medical facility.

Then, on March 14, 1957, a surprise visitor showed up at Zigas's facility in Kainantu. His now famous description of the caller appears in Zigas's posthumously published book: "At first glance he looked like a hippy, though shorn of beard and long hair, who had rebelled and run off to the Stone Age world. He wore much-worn shorts, an unbuttoned brownish plain shirt revealing a dirty T-shirt, and tattered sneakers. He was tall and lean and one of those whose age was difficult to guess, looking boyish with a soot black crew cut unevenly trimmed as if he had done it himself. He was just plain shabby. He was a well-built man with a remarkably shaped head, curiously piercing eyes and ears that stood out from his head. It gave him the surprised, alert air of taking in all aspects of new subjects with thirst....I guessed him to be from America...."

The caller, the thirty-seven-year-old D. Carleton Gajdusek, had brashly walked in on Zigas as he was preparing to take a trip to the Fore area. By any standards this tall, thin stranger who "machine gunned" people with a constant flow of questions was a remarkable individual. And Gajdusek came to the wilds of New Guinea with some very powerful connections. These connections would have a huge impact on defining the mysterious disease that ailed the Fore.

Gajdusek was a James Bond-like figure capable of slipping into any foreign country, even without permission if necessary. Combining a razor-sharp physician's intellect with fluency in nearly a dozen languages, Gajdusek moved as easily through remote tribes in obscure countries as he did in conversing with the world's best and the brightest researchers in medical science. When he arrived in New Guinea, Gajdusek was well used to spending months sleeping in flea-infested huts and primitive conditions in any number of countries around the world. But it was his very powerful backing in Washington, D.C., that Gajdusek brought to Kainantu that was to change Vincent Zigas's life.

Gajdusek had traveled extensively in South America, the Middle East, and Central and Southeast Asia under U.S. Army funding obtained by Dr. Joseph Smadel. Smadel played "M" to Gajdusek's "James Bond." Gajdusek described the formation of his relationship with Smadel in his Nobel Foundation autobiography: "In 1951 I was drafted to complete my military service from John Enders' laboratory at Harvard to Walter Reed Army Medical Service Graduate School as a young research virologist, to where I was called by Dr. Joseph Smadel. I found that he responded to my over-ambitious projects and outlandish schemes with severity and metered encouragement, teaching me more about the methods of pursuing laboratory and field research, and presenting scientific results, than any further theoretical superstructure, which he assumed I already possessed."

During the 1950s, Joe Smadel was one of the most influential and powerful men in the United States medical establishment. Not only was he director and chairman of the U.S. Armed Forces Commission on Viral and Rickettsial Diseases at Walter Reed Hospital, Smadel was also a central figure in establishing the United States military's embryonic biological warfare program.

A glance at Gajdusek's research activities for Smadel in the year prior to his arrival in New Guinea gives an idea of his ruthless global pursuit of infectious organisms. In a status report dated January 4, 1956, Gajdusek reported on blood samples with antibodies containing poliovirus, herpesvirus, mumps, panleukopenia virus (PLV), and rickettsia from children from the Río Guapay in Bolivia and the Peruvian Amazon. He had conducted seroepidemiology studies of mumps, PLV, toxoplasmosis, leptospirosis, and syphilis throughout Afghanistan, Iran, and Turkey, and had surveyed poliomyelitis and Q fever in the Middle East. He had also collected and dispatched live biological samples of tularemia, and Omsk and Crimean hemorrhagic fevers from the wilds of Central Asia to Smadel's headquarters at Walter Reed Hospital. By overcoming a series of insurmountable obstacles with unorthodox strategies, Gajdusek succeeded in grabbing whatever infectious disease prize he was assigned to capture.

Throughout the 1950s Gajdusek mailed a steady stream of live biological samples back to Smadel. The full title of contract DA-49-007-MD-77 that funded Gajdusek's travels was "Field Studies on the Control of Infectious Disease of Military Importance." In a letter from Smadel to Gajdusek dated December 12, 1955, Smadel wrote: "I want the exact reference to Crimean and Omsk HF agent. I may be able to work a trade for EEE, WEE, and VEE and the two HFs through the microbiological strain center in Lucerne, Switzerland." Translating the acronym-laden scientific jargon, we can see that Smadel was casually trading on a global scale in a large number of infectious organisms of biological warfare importance, including Crimean and Omsk hemorrhagic fever, equine encephalitis virus, Venzuelan equine encephalitis virus, and many others. Thus, by the time Gajdusek's travels took him to remote Papua New Guinea, a successful multiyear relationship between two remarkable men had been established. During the mid-1950s Smadel shifted his operations to the National Institutes of Health (NIH) and maintained a rapidly expanding medical research empire based both in Bethesda and in Camp Detrick, Maryland. Camp (later Fort) Detrick quickly became the center of the U.S. biological warfare research program.

Not only was Gajdusek confident in his abilities and unorthodox methods, he probably also sensed Smadel's interest in the clandestine aspects of Soviet knowledge in the realm of infectious disease as well. "My now clear for the USSR," he wrote to Smadel on December 29, 1956. "My knowledge of the language, literature and places is better than ever. If you can think up any good reason for visiting the USSR en route home (I shall both be under its soft under-belly in Central Asia and on its European borders during the spring) please let me know. I think I would find little difficulty getting around, seeing plenty, learning much, and exchanging ideas. Not being myself aware of anything 'classified' I ought to be a 'safe' exchange ambassador with enough time to spare to learn what wisdom our Soviet colleagues will pour out."

Until his death in 1963, Joseph Smadel would have his finger directly on the pulse of all important infectious disease research conducted by the United States government after World War II. He is perhaps best known for his involvement with the polio vaccine initiative. The drive to eliminate polio from the United States took place just as Carleton Gajdusek was trotting across the globe at Smadel's behest. At that time, in the 1950s, the Sabin and Salk vaccines were in direct competition for effectiveness, and Smadel played a prominent role in judging their efficacy. Publicly, Smadel claimed that the preparations were as safe as Grade "A" pasteurized milk. But privately his sentiments were quite different.

Despite the haggling over which vaccine was superior, both shared a frightening defect not discovered until 1960. In that year, Dr. Bernice Eddy, while working in one of Smadel's many laboratories, found that extracts of the monkey kidney-cell cultures used to grow poliovirus induced malignant tumors in newborn hamsters. When Dr. Eddy had brought up her concerns to Dr. Smadel, he brushed them off, insisting that the cancers were not really cancers but merely "lumps."

But two other virologists, Dr. Benjamin Sweet and Dr. Maurice Hilleman, soon were able to pinpoint a virus, SV 40, as the cancer-causing agent. By this time, millions of children had received polio vaccines contaminated with SV 40 virus, and there was no way of knowing whether medical science had conquered polio at the risk of provoking a new affliction. "Joe Smadel couldn't believe it," recalls a Smadel colleague, Dr. Anthony Morris. "It was a frightening thing. It's still frightening. That information was held up for two years before it was made public, and I saw Joe Smadel fall apart under the pressure of keeping it quiet."

Smadel's other claim to fame was his intense interest in research on mosquitoes as efficient vectors for a family of viruses called flaviruses (including West Nile virus) that caused hemorrhagic fevers in several parts of the world. And it was his interest in arthropod (insect)-borne viruses that in part led him to commission Gajdusek to travel the world collecting samples of mosquito-borne viruses. (It is no small irony that the years 1999-2004 have seen an increase in deaths from West Nile virus in the United States as a result of the spread from mosquitoes.)

So whether it was gathering tissue or blood specimens of tularemia or West Nile virus for biological warfare development, or samples of polio serum from infected children, by 1957 the Smadel-Gajdusek team was a well-oiled machine for obtaining live infectious disease organisms from anywhere in the world.

After their initial meeting in mid-March of 1957, Gajdusek lost no time in accompanying Zigas to visit the two patients in his nearby field hospital. The two women could no longer walk and shivered uncontrollably. Their arms and legs pulsed with slow, continuous, involuntary tremors, which Gajdusek would later call "athetoid movements." Their speech was slurred, their smiles silly, and their grimaces prominent. Gajdusek would coin a phrase for this, too; he called it "pathological laughter."

Gajdusek's first letter to Smadel, dated March 15, 1957, described the excitement he felt after he first saw the mysterious kuru: "I am in one of the most remote, recently opened regions of New Guinea (in the Eastern Highlands) in the center of tribal groups of cannibals, only contacted in the last ten years -- still spearing each other as of a few days ago and cooking and feeding the children the body of a kuru case...only a few weeks ago. To see whole groups of well-nourished healthy young adults dancing about with athetoid tremors which look far more hysterical than organic is a real sight. And to see them, however regularly, progress to neurological degeneration in three to six months, usually three, and to death is another matter and cannot be shrugged off."

To Zigas's dogged medical investigation skills, Gajdusek brought his capacity to work continuous eighteen-hour days. The team would prove formidable. Within a couple of months, the two physicians had begun equipping the rudimentary field hospital with facilities for taking blood samples and for conducting autopsies. Zigas and Gajdusek spent much of their time trying to treat the steady stream of kuru patients in their hospital. The remainder of the time they spent hiking through the rough terrain, trying to map the epidemiology and geographical distribution of kuru.

Gajdusek accompanied Zigas on several grueling expeditions in 1957. In his book titled Laughing Death, Zigas describes Gajdusek's indomitable thirst for kuru research: "Our six day trek provided an opportunity to observe even more pictorial parables of Carleton, the crewcut maverick. His strength and endurance were outstanding. Upon our arrival in a village after the most strenuous 'thrills,' soaked to the skin, numbed and short-winded, Jack and I would have to rest for a while. Carleton, however, would immediately commence to interview the villagers and collect blood specimens. There was a smack of fanaticism in the way he collected blood from every willing person, including infants, regardless of sex or age. Although I had to go along with his 'folly' I did not dare bleed infants or toddlers."

In another display of his endurance, Gajdusek embarked on a 1,500-mile trek through some of the most dangerous travel conditions in the world in order to map the outer epidemiological limits of kuru and determine how far it extended into the Highlands. Gajdusek found that kuru stopped abruptly at the outer perimeter of the Fore domain. It appeared to be exclusively confined to the single tribal group.

In patrolling the outer limits of the kuru epidemic area, Gajdusek noticed two features that did not accord well with a nutritional cause for the disease. "Many cases develop outside the kuru region in Fore or kuru-region people who have moved into the kuru-free populace to live and work," wrote Gajdusek. "The illness progresses relentlessly even if patients are totally removed in earliest stages from the kuru region and are on a diet of the non-kuru regions." He then went on: " means that a most unusual toxin exposure is involved, one in which exposure months or even years previously is sufficient to initiate a progressive slow neurological destruction." Gajdusek was beginning to flirt with the notion of a "slow virus" as the cause of kuru.

Gajdusek's work in New Guinea continued at a frenzied pace, as did his lengthy and detailed missives to Smadel. In a letter from the remote Okapa police patrol post in New Guinea dated April 3, 1957, Gajdusek wrote: "We have now located forty-one cases of kuru, a clear cut central system degenerative disease of rather rapid course and so uniformly and progressively devastating and almost always fatal...we know of another forty cases in addition to our current forty one, who have had the disease and died...We have accumulated histories of well over a hundred other cases..."

Almost from the first days, Gajdusek's intense personality and his obvious zeal in probing the mysteries of kuru captivated the Fore people. The Fore respected his commitment to searching out new cases of kuru, even though they knew all attempts to solve the mystery were folly because "kuru was sorcery" and was immune to Western medicine. His superb linguistic skills were revealed early on and he quickly learned the basics of communication with the tribe. So it was not surprising that midway through 1957 Gajdusek had persuaded the Fore to allow them to cut into a kuru victim's brain after death.

Meanwhile, within a few weeks of Gajdusek's arrival, political tensions had exploded. McFarlane Burnet and the medical establishment at Walter and Eliza Hall Institute at Melbourne began to regret their casual attitude in not supporting the multiple pleas for help from Vincent Zigas over the previous eighteen months. Suddenly, within a few months, an American with very powerful connections had thrust himself into the middle of "their research" and threatened to hijack any fame and fortune that might result from the discovery of a brand-new neurological disease.

Almost immediately, the Australians began to send supplies and personnel to Kainantu to counteract what they saw as an attempt by the Americans to usurp their research. They also began to apply enormous pressure to protect any biological samples that were obtained from being sent to the United States. When McFarlane Burnet discovered that Gajdusek was about to perform a brain autopsy on a Fore woman who had just died of kuru, he insisted that the brain be shipped to Melbourne.

With typical derring-do, Gajdusek described this first autopsy in a letter to Smadel: "I write at the moment to tell you that we have had a kuru death with a complete autopsy. I did it at 2 am during a howling storm, in a native hut by lantern light, and sectioned the brain without a brain knife."

Copyright © 2004 by Colm A. Kelleher, Ph.D.

Library of Congress subject headings for this publication:
Prion diseases.
Alzheimer's disease.