Subject: Kuru history Date: Sat, 29 Jul 1995 23:32:30 +0100 (BST) (255 lines of text) From: Michael Diffin For those who are interested, and to set a few misunderstanding straight, here is an abstraction of Howell & Ford (1985) _The Ghost Disease_. You would be better advised to read the original as it is better in background information & literary style! ________________=20 Kuru and Human TSE Identification. The first transmissible spongiform encephalopathy to be identified in=20 humans was kuru, afflicting the Fore Indians in the remote highlands of Papua New Guinea. Of course, scrapie was recognised as an infectious ovine malady and Creutzfeld-Jacob disease (CJD) had been described in humans, although its aetiology was unknown, but the thorough investigation of kuru paved the way for the detailed study of TSEs and the eventual elucidation of prion transmission.=20 Discovery.=20 Papua New Guinea, the second largest island in the world, has over 450=20 peoples originally separated by geography, language and culture. Inaccessible rain forests and a virulent malarial strain discouraged exploration until this century: it was 1936 before gold prospectors discovered the Melanesian, Stone Age inhabitants of the eastern highlands. These people had a social structure so primitive that they even lacked a collective name =96the term Fore arose from a misunderstanding as the aborigines applied this word to a neighbouring tribe. The men hunted, living communally in a large hut, while the women conducted the principal business of agriculture, cohabiting with the children in smaller, satellite shelters. Some later observers detected a certain antagonism between the sexes. The isolated communities regarded strangers with suspicion and aggression; they lived in a world peopled with ghosts, where sorcery and witchcraft were rife. Relations with other tribes were distinctly unfriendly.=20 In 1949 Papua New Guinea became a trust territory of Australia, which set up as series of control posts throughout the domains often accompanied with Lutheran missions. JR McArthur, a patrol officer, moved along with a missionary in 1954 to Okapa, in the heart of Fore territory. McArthur was the first outsider to observe kuru, in this instance a young girl =93shaking violentl= y with her head jerking from side to side.=94 Soon he realised that the condition was endemic; the natives blamed sorcery while he favoured psychosomatic explanations. In some regions the malady accounted for half the female mortality. A few villages were almost wiped out. The Indian view. Kuru means to shiver and tremble, as with cold or =91flu. In Fore mythology it overtook people when a cold wind called the zona (ghost wind) blew. Gradually they came to suspect the baleful influence of witchcraft condemning the target to a slow and certain death.=20 Kuru was inflicted in a ritualised manner. First the sorcerer had to obtain something personal from the target - discarded food, hair, clothing, ornaments or excreta. Together with crumbled stone and certain plant leaves these were bound in a bundle with canes and vines, then beaten with a stick as the sorcerer intoned a curse. The bundle was buried in muddy ground: as it shook in its unsteady placement the victim shook, as it rotted and disintegrated so did the target. Should an individual fall ill, the only chance was to identify the witch. Husband and kin drew water from all the surrounding springs - anything which caused the sufferer to gag or retch indicated that the stream was close to the magician. A constant surveillance would be mounted and the Chaldean hopefully identified. Failing this, clippings of the bewitched=92 hair would be placed in a bamboo cane along with possum meat. The cane would be struck as the suspect=92s name was intoned, then heated: failure to cook the meat was proof of guilt. Alternatively, a group containing the suspect would be invited to dine. Here proof was when someone fell ill, charmed by the victim=92s ghost. Sometimes the culprit would be bribed, more usually set upon and treated to tukabo, ritual death. He would be waylaid by several men, his arms, thighs and loins crushed with heavy stones, his windpipe bitten through to prevent naming of the assassins. Then his genitals would be crushed and slivers of bamboo or thorns thrusts into his armpits and groin, the wounds being sealed with sap. Meanwhile the ensorcelled was fed on a therapeutic diet of pork, ginger and forest herbs. Aches in the limbs were ameliorated by a skin-picking ritual using tiny bows and arrows. Sometimes the patient rallied (later studies implied that these were generally cases of hysteria or some other illness) but usually the disease progressed inexorably;=20 here it was assumed that a second occultist was at work.=20 Presentation. Kuru has an insidious onset, beginning with a minor disorder or gait becoming more pronounced when the victim was tired. The patient, generally female, would exile herself from the community, becoming secretive and uncommunicative, believing herself enchanted by an acquaintance. Headaches and leg pains followed. Very occasionally there was no further progression, more usually the patient was helpless within a few months and, resigned to her status, returned to the community. Loss of balance was the most important indication as the disease progressed. Eventually standing was impossible, then unsupported sitting. The voice grew weak then disappeared along with other motor functions. Double incontinence paved the way for a then merciful death, often by bronchopneumonia. Overall the illness would have lasted between 18 months and two years. Males rarely developed kuru. Those who did could not accept it, possibly regarding it as a female condition, and often capitulated totally perhaps starving themselves to death or committing suicide before the full clinical picture developed. Children and adolescents, who suffered less than women but much more frequently than men, were favoured with a more rapid onset and progression. The old, in contrast, endured a much more protracted degeneration where dementia was the most prominent feature. Significantly, women who married into the Fore, and Fore women who moved away, were subject to the affliction.=20 Medical Investigation.=20 Official study began in 1955 when Vincent Zigas, a district medical officer, remarked on the prevalence of kuru. In 1956 he devoted himself to a thorough clinical examination - blood tests, virus studies and tissue samples were dispatched to the mainland for thorough analysis. Within a few months the negativity or normality of all the tests forced Zigas to admit defeat. Serendipitously, a young researcher from Harvard, D Carleton Gajdusek, was just finishing a period at the Hall Institute, Melbourne, under Macfarlane Burnet. When he heard of kuru, he set off for Papua New Guinea and, overcoming some initial scepticism of his own and considerable official opposition, set up a study centre in Okapa with links to Australia and the USA.=20 By July 1957 over 500 cases had been identified and 100 more were residing in the new hospital. Gajdusek began a serious study, realising that kuru may have implications for other chronic degenerative diseases. Enquiries were not helped by the natives=92 indigenous spiritualism (they would often suggest that an ophthalmoscope could bare a person=92s soul, or that a photograph must surely display the guilty as the victim=92s ghost would lurk behind them) nor by endemic disease, especially malaria which resulted in about one third of the population having hepatomegaly.=20 Gajdusek originally thought that kuru was a viral meningoencephalitis, or possibly delayed encephalitis from a previous viral infection, as in SSPE. Yet there were absolutely no symptoms or signs of acute illness, no CSF or blood signs, no trace of virus in tissue or animal culture. Neither was there statistical correlation between childhood illnesses like mumps, chicken pox, measles and whooping cough (which the team treated anyway) and later kuru development. Next Gajdusek considered an environmental poison, organic or heavy metal. Diet, soil, cooking methods and other factors were analysed with negative results. Moreover no toxins were found in blood, urine, faeces or CSF. Similarly he discounted vitamin deficiency: the Fore diet was excellent, better than many other tribes, and anyway it was standardised in the hospital. Even the possibility of rare pasture syndromes like =91phalaris staggers=92 were considered and eliminated. Duri= ng the investigation some effort at treatment was made. Large doses of antibiotics and sulphonamides to counter occult bacterial infection; vitamin injections, cod liver oil concentrate and liver extract for unrecognised vitamin deficiency; steroids and anti- histamines to suppress any immunopathology; hormones; chelating agents; even aspirin were tried with no success. As the natives had begun to suspect, the doctors=92 sortilege was no more powerful than their own.=20 Next Gajdusek concentrated on epidemiology, travelling hundreds of miles among the Melanesians charting, geographically and temporally, every known case of kuru facilitated by an excellent tribal memory . The disease was confined to an area approximately 35 by 25 miles across, and surprisingly had only reached plague proportions in living memory (although Gajdusek initially suspected this data). Fore women who married into adjacent tribes carried the disease with them: generally they or their children would succumb first. Such information drew Gajdusek to genetics, although such a high incidence would be remarkable at least and the predilection for women and children difficult to explain. A genetic hypothesis caused official concern, particularly as the high male:female sex ratio encouraged many men to move away. For the first time in history, Australia passed a genetic law in 1960 quarantining the Fore. At a dead end, Gajdusek had returned to America, leaving a permanent and fully-staffed hospital and laboratories.=20 The break came in 1959 when a veterinary surgeon named WJ Hallow wrote to the Lancet remarking on the similarities between kuru and scrapie in sheep. Scrapie was known as an infectious disorder In the 1940s 18 000 Scottish sheep had been vaccinated against louping-ill, an ovine encephalomyelitis, using a formalin-treated sheep brain preparation. The donors had scrapie, as did 1500 of the vaccinated after two years. Gajdusek returned to Okapa in 1962, sending necropsy samples to Bethesda where they were intracranially inoculated into chimpanzees. As controls, more chimpanzees were inoculated with preparations from patients who had died from other central degenerative disorders. In 1965, the first batch of chimpanzees developed symptoms and signs similar to kuru.=20 Meanwhile two anthropologists, Robert & Shirley Glasse, repeated Gajdusek=92s anthropological studies and confirmed that kuru was only 50 years old. Also cannibalism, although frequent among other tribes in Papua New Guinea, was uncommon with the Fore until about 1915 when they enjoyed human flesh at a Kamano feast. With almost unbelievable rapidity, cannibalism was syncretised with the funeral rituals. Customarily the body was left to putrefy for three or four days, then baked and totally consumed. Division of parts was strictly formalised (the mother=92s brother=92s wife got the brain) and the men generally forewent the fare believing that it would hamper fighting ability. The Australians had tried to suppress cannibalism but Gajdusek suspected that secret ceremonies were performed during his tenure.=20 At about the same time, chimpanzees which had been inoculated with CJD material started to fall ill: this was recognised as the second =93slow virus=94 disease of humans. The agent was so-designa= ted almost by exclusion as, although filterable, it could not be seen under the microscope or cultured outside animals but could survive rigorous chemical assault. Gajdusek thought it might be related to viroids, plant pathogens consisting of naked nucleic acid, and that a sporadic case of CJD may have initiated the epidemic facilitated by the Fore obsequies. As Western influence took effect cannibalism and then kuru gradually died out, along with sorcery, bark skirts, body adornments and the rest of Fore culture.=20 The Infectious Agent.=20 Once the pathological similarity between scrapie, kuru and CJD had been noted the search was on for an agent. Scrapie has been the paradigm for the group, although there are differences, both genetic (see ***) and in host susceptibility. What is remarkable about the agent is its remarkable resistance to inactivation by physical, chemical and enzymatic procedures which normally destroy proteins and nucleic acid. It resists 90 C for 30 minutes, exposure to acid (pH 2), some proteases, Dnases, Rnase, X and uv irradiation and formaldehyde and =DF-propiolactone (alkylating agents which destroy practically all viruses). This has led to endless speculation, notably that viroids are involved, a class of pathogen so-far only identified in plants, or that the agent is a polysaccharide with the ability to replicate. =20 More recently experiments indicated that a protein was central to the pathogenic activity, perhaps wholly responsible (see section 3). Evidence includes inactivation by proteinase K and trypsin, by the denaturing agents sodium dodecyl sulphate (SDS) and urea, and by chaotropic salts like guanidium thiocyanate which disrupt hydrogen bonds in proteins. The protein is hydrophobic and recent evidence indicates that it is a membrane protein. The real surprise is inability to demonstrate any r=F4le for nucleic acid in pathogenesis. Nuclease digestion, uv irradiation at 254 nm, hydrolysis by divalent cations (Zn2+), modification by hydroxylamine and reactions with psoralens have no effect. So, if nucleic acid is present, it must be in a different form from other known viruses, which are susceptible to such changes. Filtering suggests that the infective particle is about 60kDa, smaller than any known virus or viroid but about the same as a simple monomeric protein like albumin.=20 Soemthing this size, even if a nucleic acid, could only encode 32 bases at most - not nearly enough for the smallest protein. The term prion, for proteinaceous infectious agent, is now generally accepted for this pathogen -the polysaccharide hypothesis has been discarded, although some investigators still believe that a virus is involved somewhere (rrr). Similarities in prions underpin the pathological semblance between the animal and human conditions.=20 __________________ An Australian disease of sheep. Phalaris is a grass lacking cobalt; if this is not supplemented the animals develop a neurological disorder.=20 The Fore had no concept of age or dates (close to the equator there are no seasons) but could consistently recall birth orders. By relating these to estimated age (particularly children) and external events such as patrol post foundation a good timescale was developed.=20 Because of the height (6000 feet above sea level) water boiled at 95 C, and meat was never fully cooked.=20