The story of Kuru, a rare neurodegenerative disorder, is, in a sense, really the story of New Guinea, as the tale of both are entwined in a beguiling, yet phantasmagoric dance that, given the circumstances, could not have occurred anywhere else on this planet. Kuru, also known as the Laughing Death, is a fascinating and tragic disease, one you will never see in your lifetime, and one that led to not one, but two Nobel Prizes in Medicine or Physiology. New Guinea, the second largest island in the world, is a wildly remote land steeped in beauty and danger. Running through the center of New Guinea and forming its spine, are rugged mountainous peaks bordering lush tropical valley’s. It is in this isolated setting that Stone-Age tribes, living as they had since the dawn of civilization, oblivious to the outside world, encountered a brave and adventurous gold prospector named Michael Leahy. It was only after this chance encounter did these people begin to emerge from isolation and darkness, having undergone a shocking introduction to the modern world.
The island of New Guinea is situated just north of the continent of Australia and separated by the Torres Strait, a 150-kilometer sea passage between isolated Cape York, Australia, and the even more remote New Guinea. New Guinea was first inhabited 50,000 years ago through the island-hopping migration of people through the Indonesian archipelago. Australia was settled next, as man migrated south across a land bridge connecting the two expanses 6000 years ago, a period resulting in low sea levels as fresh water was corralled in giant glaciers extending down from the poles.
By 10,000 years ago, these Melanesians had migrated up from the coastal areas of New Guinea into the steep mountainous jungle terrain at the center of the island, called the highlands. The tribes of New Guinea are by nature fierce and territorial, with killings and border wars still occurring even today. As a result, once these highland areas were settled, inhabitants lived within confined, isolated boundaries, due to extraordinarily precipitous cloud-capped mountains causing natural barriers between tribes, and the warrior-like behavior of nearby tribes. Migration slowed to a halt and territories became encapsulated with unfriendly,bellicose warriors.
Trade in the highlands was in food and goods, and the Kina shell, its value bolstered by their lack of contact with the coastal areas, was a popular currency. Trade items consisted of sago, taro, yams, pottery, garments, and stone tools. New Guinea was not blessed with a large animal population, and the few wild pigs in existence were nurtured for rituals, feasts, marriages, and as compensation for injury or death, rather than eaten for proteinaceous nutritional value. Rivers were steep and fast moving, not supporting large fish. Ironically, despite being on an island surrounded by huge fish densities, the highlands were cut off from the coast, and fish was generally not available for consumption. As a result, the highlanders endured a carbohydrate rich, protein poor diet. Because of these factors, cannibalism rituals may have developed as an acceptable method to add occasional protein to the diet. In addition, the highlands were also salt deficient, isolated as they were from the nearby sea. There was very little naturally iodinated salt, and intense rainfalls leached the nutrient-poor soil even further. As a result, especially in the Jimi Valley, cretinism developed, causing intellectual and physical developmental deficiencies, including small stature, a result of iodine-deficient mothers giving birth to iodine-deficient babies. It was only in the mid-to-late 20th century that iodized salt was introduced to the region through public health initiatives. Prior to this, salt was a rare but cherished commodity to be traded for.
War was engrained in the societal traditions of the New Guineans, especially in the highlands, where territorial disputes and payback killings were common. Because of the fierceness of its inhabitants and the islands extreme isolation, New Guinea was generally either ignored or given a wide berth by colonial empires, until the late 19th century, when the Dutch claimed the western half of the island, Irian Jaya, and the eastern part, named Papua New Guinea, was subdivided into British and German territories. Given the lack of mineral wealth, remoteness, and severity of malaria, the German’s soon left, and the British seeded the territory to Australia to administer. Starting in the 1920’s, although few in number, Australian patrol officers, or Kiaps, began to contact the highlanders with the agenda of trying to halt spousal abuse, war, superstition and endemic cannibalism and bring the people slowly into the fold of civilization. The patrol officers served as census takers, policeman, magistrates, peacemakers, and diplomats. The concept being a government- by-patrol method of rule. Any meaningful progress was slow and could only be measured in frustration and decades of subtle influence.
In the early 1930’s, an Irish-Australian gold prospector, Michael Leahy, was able to penetrate the highlands, making “first contact” with several tribes, including the Kukukuku and the Melpa’s. Leahy discovered a land time had forgotten, populated by tens of thousands of people still trapped in the Stone-Age. He discovered they had no system of formal education, no metal tools, wielded stone axes, and had not yet invented the wheel. The patrol officers being sparse and still making their way up towards the highlands, Leahy was literally the first white man most of the highland tribes had ever seen. In fact, initially, he was thought to be a ghost, a descendant of their dead ancestors. Once they saw these “ghosts” had human bodily functions just like they did, like the need to excrete waste, this notion was soon cast aside. The tools Leahy had with him, carried by a party of porters numbering close to one hundred, including steel machetes, bolt-action rifles, pistols, bullets, mirrors, metal cooking pots, a still camera and a movie camera, compasses, maps, altimeter’s, matches, and dynamite, reinforced that these white men, even if they were not ghosts, had indeed come from another world. Later, encounters occurring during World War 2, where massive bird-like airplanes flew overhead, and soldiers used walkie-talkie’s to call for supplies, or cargo, that would magically descend from the sky by parachute, led to what is known as the Cargo Cults. The Cargo Cults were a bizarre ritual occurrence where many Papuans tried to emulate the activities of the White Man by play-acting, including passing bits of paper back and forth to each other to simulate business activities, and simulating pretend radio requests for goods to be parachuted down to them from the skies, hoping to convince the gods they were worthy of their own cache of magical supplies, like the Leahy expeditions and the soldiers had sported.
It was the patrol officers who first noted the signs and symptoms among the Fore tribe in the Eastern Highlands region, although they had no idea what the cause was. The local inhabitants turned to sorcery and witchcraft as an explanation, and looked for those responsible. Superstition remains widely endemic in New Guinea even today, challenging the legitimacy of medical care.
The concept of “atypically slow infections” was first noted by Sigurdsson in 1954, an Icelandic veterinarian, based on documentation of a disease in sheep called Scrapie, which had long incubation periods, no evidence of inflammatory response, chronic progression, and fatal outcomes. Scrapie was initially recognized as far back as the 18th century. His paper was entitled “A Chronic Encephalitis of Sheep: With General Remarks on Infections Which Develop Slowly and Some of Their Special Characteristics, British Veterinary Journal, 1954. Sigurdsson proposed a “slow virus” as the etiology. Sigurdsson’s work was crucial in laying the conceptual framework for the pioneers that followed.
With the opening of the highlands, Dr. Carleton Gajdusek was attracted by a mysterious disorder that afflicted some members of the Fore tribe in the Eastern Highlands of New Guinea called Kuru. The name is derived from the Fore themselves and means “shaking,” or “to tremble with fear.” Dr. Gajdusek traveled to New Guinea in 1957 and met the district medical officer, Dr. Vincent Zigas, who first reported on the disease entity. At the time, Kuru was thought to be inherited, but Dr. Gajdusek ultimately proved it was transmissible, not heritable. This led to his receiving the Nobel Prize in Medicine or Physiology in 1976.
Gajdusek examining Fore boys
Gajdusek and Zigas in New Guinea
In 1959, William Hadlow noticed that the neuropathology of Kuru, which he had recently read about in Sigurdsson’s work, was similar to that of Scrapie, which was thought to be caused by a transmissible agent, yet to be found. He published his observation in Lancet, the British medical journal. This attracted Gajdusek’s attention, who building on Sigurdsson’s work and Hadlow’s observation, decided to do transmission studies in Chimpanzee’s. In 1966, after a long incubation period, the Chimp’s developed signs of Kuru. It was now known that Kuru, like Scrapie, was transmissible, but still no virus could be found.
Zigas with the Fore tribe in the Eastern Highlands of New Guinea
It was through Gajdusek’s observational insight that the funerary customs of the Fore tribe began to be suspected as the possible courier of the disease . This custom did not originate out of barbarism, but out of deep love, duty, and respect for their deceased kin. The act was called transumption, the deliberate ingestion of parts of the dead to free their spirit and a part of them within the world of the living. Burial, on the other hand, was considered barbaric by the tribe. This transumption was not symbolic. The entire body was consumed. Soon after death, the body was washed and then dismembered using stone tools and bamboo knives. After cracking the skull, the brain was lifted out of its casing, wrapped in banana leaves and roasted over a coal fire, or steamed in an earthen oven. Adult women and children participated, especially female children, ingesting the body over several meals, depending on the number of participants. Men, considered warriors, largely did not participate. The brain was the most cherished portion of the meal, as it was thought to contain the essence of life, something the tribe was trying to protect and save in the dead relative. Marrow was sucked from long bones, and the entire spinal cord eaten. Bones and hair were destroyed ritualistically as they could not be eaten, and the gallbladder discarded as too bitter.
It was later revealed that the Kuru prion is massed predominantly in brain tissue, making consumption of the brain the fatal step. In the 1950’s, upwards of 250 Fore villagers were dying of Kuru per year. With time, and guided by public health officials, doctors, and the patrol officers, the villagers came to understand the ritual was likely to be causing the disease. After the cessation of the endocannibalism, no further cases of Kuru occurred, and the disease was extinguished, except for a few cases that appeared over 40 years later. This was confusing at first, but ultimately, these cases were not considered new, they just had exceptionally long dormant stages, with transmission having occurred before funerary practice was fully extinguished. (Clarification: endocannibalism is consuming the dead flesh of your kin. Exocannibalism is consuming the dead flesh of your enemies).
The mean incubation period of Kuru was 10-13 years, with 90% of cases occurring within 21-27 years of exposure. Incubation period was likely related to exposure dose and was shorter in women than men and shorter in older women than younger women, reflecting the likelihood of participation in cannibalistic practices (Mandell, Douglas, and Bennett’s. Principles and Practice of Infectious Diseases, sixth edition, Elsevier, Churchill, Livingstone, Volume 2, pg 2221).
Fore boy with Kuru and choreoathetoid movements
Symptoms of Kuru began with a prodromal phase of headache and arthralgia’s, knees and ankles first, followed by elbows and wrists. To the worried villagers, this was known in Pidgin (or Tok Pisin) language by the phrase “Kuru laik I-kamp nau,” or “Kuru is about to begin now.” No fevers were observed. These symptoms lasted for several months, with those affected often becoming withdrawn and depressed knowing what was about to occur. The next phase consisted of subtle ataxia progressing to incoordination of the muscles of the trunk and lower legs, often with a negative Romberg sign. A “shivering” type tremor and goose bumps commenced in the stomach muscles, and a clawing of the toes. Clonus was typical in the ankles and Babinski’s were flexor. Victims were prone to bursts of laughter; thus, Kuru was sometimes called the “laughing death.” As disease progressed, Romberg turned positive, dysmetria and dysarthria began to occur, and choreoathetoid movements and myoclonus triggered by movements, light, noise, or touch was prominent. Strangely, Zigas and Gajdusek found that a child’s shaking cerebellar tremor was found to vanish if putting the child in the fetal position on mother’s lap. A horizontal convergent strabismus and nystagmus was common.
The next stage is marked by when the patient is unable to walk without support on both sides, has marked truncal instability and leans heavily toward one side on, whether standing or sitting. Late in this stage, Zigas and Gajdusek reported “jerking clonic-type movements of the eyelids” after the patient is exposed to bright outside daylight, after being removed from a dark hut. Babinski’s remained flexor. Opsoclonus, a rare, rapid, irregular, involuntary, eye movement in which the eyes dart in all directions, was sometimes present. Cranial nerve abnormalities and motor and sensory loss are absent, or only occur in the late stages of the disease. Although labs were typically not available, they were often normal and used to exclude other diagnoses. CSF was also typically normal with no pleocytosis and a normal protein.
Fore woman with Kuru and truncal instability, being supported
In the last stage, the patient is bedridden, incontinent, demented, and with severe dysphagia. Malnutrition sets in and death occurs rapidly from resultant complications. (Liberski, Gajos, Sikorska, Lindenbaum, Kuru, the First Human Prion Disease, Viruses (Prion section), 2019. (Author’s note: this is an excellent full overview of Kuru with original but grainy pictures from Gajdusek).
Group of Kuru victims placed together for photograph
Stanley Prusiner, a neurologist and biochemist, was the first to discover the “infectious” agent in Kuru. It was neither bacterial, fungal, viral, or parasitic. It did not utilize the host cell’s DNA or RNA to replicate itself like viruses typically did. It was a novel infectious agent. His work on analyzing Scrapie and Kuru led to his important paper in 1987 entitled “The Prion Hypothesis,” detailing prions as unique proteinaceous infectious particles. He received the Nobel Prize in Medicine or Physiology in 1997 for his work proving prions were the etiologic agents behind Mad Cow Disease, Creutzfeldt-Jacob Disease, Kuru, and Scrapie. This is another cogent example of the scientific process at work. Physicians and scientists building on previously published information and applying those ideas to enhance their own work with the outcome eventually being a better understanding of an existing disease entity or the discovery of a new disease state, all over a period of decades.
A group of children with Kuru
Prions are proteinaceous particles that lack nucleic acids and that occur in normal human brain tissue. Disease occurs when the normal isoform is transformed into the pathologic isoform, by unclear mechanisms. This abnormal folding of the prion protein appears to be a post-translational event and leads to a decrease in alpha helical content and an increase in the percentage of Beta-pleated sheet, causing the prion to go from a monomer to a polymer. According to Mandel et al, “Human prion diseases share many fundamental properties. First, their major pathologic manifestations are confined almost exclusively to the central nervous system. Second, the disease typically has long incubation times that, at least in the case of Kuru, may exceed 30 years. Third, the diseases seem to be inexorably similar (neuropathologically), although not identical, and often include reactive astrocystosis, minimal inflammatory response, and neuronal degeneration, but not invariably, accompanied by vacuoles within cells and in the surrounding neuropil (spongioform degeneration). Finally, each of these diseases seem to be associated with aberrant accumulation of a pathologic isoform of the prion protein (Mandell et al, sixth edition, Elsevier, pg 2219).
Group of Fore women with Kuru
Genetically, according to Mandell et al, “Kuru cases show…a higher than expected incidence of methionine/methionine (M/M) homozygosity at polymorphic codon 129, of the PRNP gene(gene encoding the normal prion protein) …..It has been suggested that, not without controversy, that the wide geographic prevalence of codon 129 heterozygosity is indirect evidence that cannibalism may have been more widespread among ancient human populations than previously believed…(Mandell et al, Principles and Practice of Infectious Disease, 6th edition, pge 2222). In other words, codon 129 heterozygosity may confer some immunity to developing Kuru.
A vacuolated “moth-eaten” neuron. Courtesy of D. Carleton Gajdusek. (Liberski et al, Viruses,(Prion section), 2019)
Figure 16. (a) Typical kuru plaque stained silver. Courtesy of D. Carleton Gajdusek; (b) a linear row of kuru plaques probably attached to a neurite; (c) a kuru plaque stained with Alzian blue (41-93-2a-alcian-20-17-alcian). Courtesy of D. Carleton Gajdusek; (d) A kuru plaque and PrPSc deposits surrounded by glial cells in the human cerebellum. Confocal laser microscopy, prion protein (clone 12F10, Alexa Fluor 488)—green, GFAP (polyclonal rabbit, AlexaFluor 546)—red, magnification 600×, digital zoom 2.1×. Three-dimensional reconstruction with surface rendering. (e) Electron microscopic image of the kuru plaque, material reversed from paraffin, 13,000×; (f); higher magnification to show bundles of kuru plaque-fibrils, 50,000×.
(Liberski, Gajos, Sikorska, Lindenbaum, Kuru, the First Human Prion Disease, Viruses (Prion section), 2019)
Interestingly, prions do not replicate. They have no DNA or RNA. They misfold and cause other adjacent prions to misfold, a sort of domino effect, with eventual aggregation into amyloid fibrils and plaques, which disrupt normal cellular function and trigger neuronal death and spongioform degeneration. Once they do misfold, they have been found to be remarkably resistant to heat, enzyme degradation, and even radiation. Rather than infections, they may be better described as transmissible proteinopathies. Prions may be natures perfect weapon of warfare.
In summary, the devastating neurodegenerative disease Kuru could not have occurred anywhere else on Earth, in modern times at least, except in the highlands of New Guinea. Just the right mixture of unusual ingredients was required for Kuru to emerge from the witch’s cauldron, the first being the geographic remoteness of New Guinea itself on the world map. The second, the isolation of the highlanders themselves in relation to the coastal peoples, due to being, practically speaking, trapped within the confines of impenetrable jungle and steep mountainous terrain, resulting in a persistent Stone-Age society. Third, the unusually bellicose nature of the New Guineans themselves, resulting in further isolation from other tribes and virtually no travel opportunities, due to the risks involved. And lastly, the extreme protein-deficient environment endured by the highlanders, which likely led to their endo-cannibalistic practices. All these conditions had to be met for Kuru to surface during modern times. Because of the extraordinary efforts of doctors like Sigurdsson, Hadlow, Gajdusek, Zigas, and Prusiner, Kuru is a disease that was finally solved and one the world will never see again, at least by the same mechanisms. New Guinea is, and remains, a truly tantalizing land that befuddles the mind.
