Kuru: the old epidemic in a new mirror

The kuru epidemic lasted almost a century; it started in 1901-1902, reached epidemic proportions in the mid-1950s, and disappeared in the 1990s. Kuru is the prototype member of a group of disorders known as transmissible spongiform encephalopathies (TSEs) or prion diseases. Recent data on the genetics and pathogenesis of TSEs contribute to a better understanding of the documented kuru phenomena, and vice versa, observations made during the kuru epidemic are immensely helpful in understanding the epidemic of variant Creutzfeldt-Jakob disease that is currently developing in Europe. The major goal of this review is to identify and illustrate these points.     

Genetic studies in relation to kuru: an overview

Kuru is a subacute neurodegenerative disease presenting with limb ataxia, dysarthria, and a shivering tremor. The disease progress to complete motor and mental incapacity and death within 6 to 24 months. Neuropathologically, a typical pattern of neuronal loss, astrocytic and microglial proliferation, characteristic "kuru-type" amyloid plaques, and PrP deposits in the cerebral cortex and cerebellum are observed. Kuru is the prototype of a group of human transmissible spongiform encephalopathies (TSEs), or "prion" diseases, that include hereditary, sporadic and infectious forms. The latest member of this group, the variant Creutzfeldt-Jakob disease (vCJD), linked to transmission of bovine spongiform encephalopathy (BSE) to humans, shows features similar to kuru. Kuru has emerged at the beginning of the 1900s in a small indigenous population of New-Guinean Eastern Highlands, reached epidemic proportions in the mid-1950s and disappeared progressively in the latter half of the century to complete absence at the end of the 1990s. Early studies made infection, the first etiologic assumption, seem unlikely and led to a hypothesis that kuru might be a genetically determined or genetically mediated illness. After transmissibility of kuru had been discovered and all major epidemiologic phenomena adequately explained by the spread of an infectious agent with long incubation period through the practice of cannibalism, the pattern of occurrence still continued to suggest a role for genetic predisposition. Recent studies indicate that individuals homozygous for Methionine at a polymorphic position 129 of the prion protein were preferentially affected during the kuru epidemic. The carriers of the alternative 129Met/Val and 129Val/Val genotypes had a longer incubation period and thus developed disease at a later age and at a later stage of the epidemic. Observations made during the kuru epidemic are helpful in the understanding of the current vCJD outbreak, and vice versa clinical and experimental data accumulated in studies of other TSE disorders contribute to better understanding of the documented kuru phenomena.     

Review. The epidemiology of kuru: monitoring the epidemic from its peak to its end

Kuru is a fatal transmissible spongiform encephalopathy restricted to the Fore people and their neighbours in a remote region of the Eastern Highlands of Papua New Guinea. When first investigated in 1957 it was found to be present in epidemic proportions, with approximately 1000 deaths in the first 5 years, 1957-1961. The changing epidemiological patterns and other significant findings such as the transmissibility of kuru are described in their historical progression. Monitoring the progress of the epidemic has been carried out by epidemiological surveillance in the field for 50 years. From its peak, the number of deaths from kuru declined to 2 in the last 5 years, indicating that the epidemic is approaching its end. The mode of transmission of the prion agent of kuru was the local mortuary practice of transumption. The prohibition of this practice in the 1950s led to the decline in the epidemic, which has been prolonged into the present century by incubation periods that may exceed 50 years. Currently, the epidemiological surveillance is being maintained and further studies on human genetics and the past mortuary practices are being conducted in the kuru-affected region and in communities beyond it.     

Review. Lessons of kuru research: background to recent studies with some personal reflections

The widespread exposure of the UK population to bovine spongiform encephalopathy prions, and the potential consequences for public health, led to a renewed interest in kuru, the principal example of epidemic human prion disease. Kuru research in Papua New Guinea was expanded to study the range of incubation periods possible in human prion infection, to investigate maternal and other possible natural routes of transmission, to characterize genetic susceptibility and resistance factors and to gain insights into the peripheral pathogenesis of orally acquired prion disease in humans. Although now essentially over, the kuru epidemic continues to provide important lessons.     

Genetic susceptibility, evolution and the kuru epidemic

The acquired prion disease kuru was restricted to the Fore and neighbouring linguistic groups of the Papua New Guinea highlands and largely affected children and adult women. Oral history documents the onset of the epidemic in the early twentieth century, followed by a peak in the mid-twentieth century and subsequently a well-documented decline in frequency. In the context of these strong associations (gender, region and time), we have considered the genetic factors associated with susceptibility and resistance to kuru. Heterozygosity at codon 129 of the human prion protein gene (PRNP) is known to confer relative resistance to both sporadic and acquired prion diseases. In kuru, heterozygosity is associated with older patients and longer incubation times. Elderly survivors of the kuru epidemic, who had multiple exposures at mortuary feasts, are predominantly PRNP codon 129 heterozygotes and this group show marked Hardy-Weinberg disequilibrium. The deviation from Hardy-Weinberg equilibrium is most marked in elderly women, but is also significant in a slightly younger cohort of men, consistent with their exposure to kuru as boys. Young Fore and the elderly from populations with no history of kuru show Hardy-Weinberg equilibrium. An increasing cline in 129V allele frequency centres on the kuru region, consistent with the effect of selection in elevating the frequency of resistant genotypes in the exposed population. The genetic data are thus strikingly correlated with exposure. Considering the strong coding sequence conservation of primate prion protein genes, the number of global coding polymorphisms in man is surprising. By intronic resequencing in a European population, we have shown that haplotype diversity at PRNP comprises two major and divergent clades associated with 129M and 129V. Kuru may have imposed the strongest episode of recent human balancing selection, which may not have been an isolated episode in human history.     

The earliest cases of human immunodeficiency virus type 1 group M in Congo-Kinshasa, Rwanda and Burundi and the origin of acquired immune deficiency syndrome

The early cases of acquired immune deficiency syndrome and human immunodeficiency virus type 1 (HIV-1) infection in the 1960s and 1970s in Congo-Kinshasa (Zaire), Rwanda and Burundi are reviewed. These countries appear to be the source of the HIV-1 group M epidemic, which then spread outwards to neighbouring Tanzania and Uganda in the east, and Congo-Brazzaville in the west. Further spread to Haiti and onwards to the USA can be explained by the hundreds of single men from Haiti who participated in the UNESCO educational programme in the Congo between 1960 and 1975.     

Central and peripheral pathology of kuru: pathological analysis of a recent case and comparison with other forms of human prion disease

While the neuropathology of kuru is well defined, there are few data concerning the distribution of disease-related prion protein in peripheral tissues. Here we report the investigation of brain and peripheral tissues from a kuru patient who died in 2003. Neuropathological findings were compared with those seen in classical (sporadic and iatrogenic) Creutzfeldt-Jakob disease (CJD) and variant CJD (vCJD). The neuropathological findings of the kuru patient showed all the stereotypical changes that define kuru, with the occurrence of prominent PrP plaques throughout the brain. Lymphoreticular tissue showed no evidence of prion colonization, suggesting that the peripheral pathogenesis of kuru is similar to that seen in classical CJD rather than vCJD. These findings now strongly suggest that the characteristic peripheral pathogenesis of vCJD is determined by prion strain type alone rather than route of infection.     

Mortality from asthma: a new epidemic in New Zealand

Trends in mortality attributed to asthma in the 5-34-year age group were examined in New Zealand, Australia, England and Wales, the United States, Canada, and West Germany for the years 1959-79. An epidemic of deaths from asthma occurred in the mid-1960s in New Zealand, Australia, and England and Wales but not in the other countries. In Australia and England and Wales the death rate quickly returned to pre-epidemic levels, but in New Zealand the decline in mortality was slow, and by 1974 the death rate was still almost double the pre-epidemic level. Of great concern was an abrupt increase in reported deaths from asthma in New Zealand after 1976 with the mortality rate during 1977-9 being greater than during the previous epidemic. In contrast, asthma mortality had remained relatively stable in the other populations.The new epidemic in New Zealand was investigated and appeared to be real. It could not be explained by changes in the classification of deaths from asthma, inaccuracies in death certification, or changes in diagnostic fashions. The most likely explanation appeared to be related to the management of asthma in New Zealand, and this is being investigated.     

Coronary heart disease (CHD)--one or several diseases? Changes in the prevalence and features of CHD

In retrospect, mortality from coronary heart disease (CHD) in the 20th century followed an epidemic pattern: mortality rates increased dramatically from 1920 until about 1960, remained roughly constant for almost a decade, and have been decreasing since the late 1960s. CHD has traditionally been conceived of as a single disease with multifactorial causality. We suggest instead that CHD cases may comprise at least two distinct populations: those associated with hypercholesterolemia, and those associated with insulin resistance. The epidemic of CHD was due primarily to changes in the incidence of the hypercholesterolemia subgroup. We propose that young adults who survived the 1918 influenza pandemic were rendered vulnerable to lipid-associated CHD and coronary thrombosis upon reinfection with influenza later in life. This vulnerability may be due to autoimmune disruption of low-density lipoprotein-receptor interactions. Historical events may affect the health of populations by affecting the susceptibility of populations to chronic diseases such as CHD. The life experiences of individuals are known to influence their susceptibility to infectious diseases; we suggest that life experiences may also influence individual susceptibility to chronic diseases.     

Review. The neuropathology of kuru and variant Creutzfeldt-Jakob disease

A comparison of the pathological profiles of two spongiform encephalopathies with a similar presumptive route of infection was performed. Archival kuru and recent variant Creutzfeldt-Jakob disease (vCJD) cases reveal distinct lesional differences, particularly with respect to prion protein, suggesting that the strain of agent is important in determining the phenotype. Genotype analysis of the polymorphism on codon 129 reveals (in conjunction with updated information from more kuru cases) that all three genotypes (VV, MV and MM (where M is methionine and V is valine)) are detected in kuru with some preference for MM homozygosity. The presence of valine does not therefore appear to determine peripheral selection of PrPCJD. vCJD remains restricted to date to MM homozygosity on codon 129. It remains to be determined whether this genotype is dictating a shorter incubation period.     

A history of scientific research at Loch Leven,Kinross, Scotland

Loch Leven is a large, shallow lake in lowland Scotland, UK. Scientific research began here almost 200 years ago. Early research characterised the biodiversity and physical characteristics of the loch, providing an important historical background for future research. In the mid-1960s, this ad hoc approach was superseded by a more structured research programme under the umbrella of the International Biological Programme. This was the beginning of the Loch Leven long-term monitoring programme. Today, the results of these studies form one of the longest and most comprehensive limnological datasets for shallow freshwater lakes in the world, comprising more than 500 physical, chemical and biological variables collected at two-weekly intervals. To celebrate the 40th anniversary of the start of the long term monitoring programme, and to highlight the scientific investigations still being conducted at Loch Leven, the NERC Centre for Ecology & Hydrology (CEH) organised a symposium entitled “Loch Leven: 40 years of scientific research” in Kinross, Scotland, UK, on 11 December 2008. This examined the role of long-term monitoring in developing our understanding of the links between pollution, climate change and ecological responses in shallow lakes. This article introduces a series of papers summarising the scientific results presented at this meeting.     

Review. Understanding kuru: the contribution of anthropology and medicine

To understand kuru and solve the problems of its cause and transmission required the integration of knowledge from both anthropological and medical research. Anthropological studies elucidated the origin and spread of kuru, the local mortuary practices of endocannibalism, the social effects of kuru, the life of women and child-rearing practices, the kinship system of the Fore and their willingness to incorporate outsiders into it, the myths, folklore and history of the Fore and their neighbours, sorcery as a powerful social phenomenon and way of explaining the causation of disease, and concepts of the treatment of disease. Many scientists from different disciplines, government officers and others have contributed to this chapter of medical history but it is the Fore people who have contributed the most, through their suffering, their cooperative and reliable witness to kuru, and their participation, in various ways, in the research process itself.     

Epidemiology in the strategies for malaria control

A rapid overview is presented of the evolution of the main orientations of malaria control, since the discovery of mosquito transmission. Stated control objectives appear to have oscillated between expectations to eradicate the vector, or at least the disease, and more modest approaches to minimise the effects of the infection. High optimism was raised when a new control measure, or new combination of existing measures, appeared to be highly effective and was expected to have universal applicability. The implementation of large scale campaigns eventually found the limits of applicability of the proposed strategy and the exaggerated expectations soon gave way to disillusion and, eventually, to a revival of research. The longest and most impacting period of exaggerated expectations was the global malaria eradication campaign of the 1950s and 1960s, which completely disregarded the study of local epidemiology, considering that all it was needed was to know if an area was "malarious" or not. Research was practically abandoned and, even when reinstated after the recognised failure of the campaign, it has retained an almost exclusive orientation towards the development of control tools, drugs or eventually vaccines. One of the earliest victims of the eradication campaign was the study of epidemic malaria and its determinants in different epidemic prone areas. In spite of an extremely long period of disillusion, lasting for almost two decades, the reality of the malaria problem led WHO and member countries to agree on a global strategy of control, aiming at a realistic use of existing tools, to at least reduce or prevent mortality. An essential element of this strategy is the prevention or control of malaria epidemics and the selective use of vector control, both of which have to be based on a solid knowledge of local epidemiology, the study of which has to rejoin the path abandoned fifty years ago.     

Sam Karlin: A personal appreciation

In the 1960s Karlin and Bodmer established an active programme in mathematical population genetics with NIH support that, in turn, supported the work of Ewens and Feldman with Karlin. Subsequently Karlin established a similar programme in Israel. The overall contributions of Karlin to population genetics and molecular biology are briefly reviewed from a personal perspective.     

Censusing the mountain gorillas in the Virunga Volcanoes: complete sweep method versus monitoring

The mountain gorillas (Gorilla beringei beringei) of the Virunga Volcanoes Range of Rwanda, Uganda, and the Democratic Republic of Congo are one of the most endangered ape populations in the world. Following a dramatic decline during the 1960s, and relative stability in the 1970s, the population steadily increased during the 1980s. Due to political instability and war, a complete census had not been conducted since 1989. Here we compare the results of a complete census using the ‘sweep method’ conducted in 2003 with those from a monitoring program, to estimate the size and distribution of the gorilla population. A total of 360 gorillas were counted from census measurements and known habituated groups. Based on quantitative assessments of the census accuracy, we calculated that an additional 20 gorillas were not counted, leading to an estimated population of 380 individuals, and a 1.15% annual growth rate since 1989. The Ranger Based Monitoring programme yielded similar results. The encouraging results must be viewed with caution, however, because the growth was concentrated almost entirely in one section of the Virungas. Additionally, the distribution of gorilla groups was negatively correlated with the frequency of human disturbances, which highlights the need to continue strengthening conservation efforts.     

An analysis of the dysentery epidemic process in Blagoveshchensk

The retrospective analysis of dysentery morbidity in Blagoveshchensk for the period of 1960-1987 was made. The regularities linking general natural and biological factors triggering the epidemic process with dysentery morbidity among the population are emphasized. The study revealed that under the conditions of Blagoveshchensk dairy products were of major epidemic importance among factors contributing to the transmission of dysentery. Such a factor as flies also had a definite influence on the epidemic process of dysentery. Another risk factor was drinking water which influenced the epidemic process both directly and indirectly through dairy products and, probably, other foodstuffs. Reliable correlation between dysentery morbidity among the population and the quality of dairy products, tap water and the number of flies was established.     

Cytopathology in Austria

Cervical cancer screening developed rapidly during the 1970s. Today, approximately 1.5 million smears are taken annually, so 50% of the target population are screened every year, 30% are cytologically underserved (24% never had a smears, 6% only once). This figure correlates with the fact that there are still 30% deaths from cervical cancer compared with 1960. Since 1998 a voluntary quality assurance programme was introduced by the Austrian Society of Cytology, based on comparison of results reported from participating laboratories.     

Mortuary rites of the South Fore and kuru

This paper is part of a wider study to explain the historical spread and changing epidemiological patterns of kuru by analysing factors that affect the transmission of kuru. Part of the study has been to look at the mortuary feasts that were the means of transmission of the kuru agent. This paper shows the complexity of Fore eschatology, and the variations and contradictions of human behaviour in relation to mortuary rites and the transmission of kuru. It also confirms that oral ingestion was the primary route of inoculation though some cases of parenteral inoculation may have occurred. The exclusion of alternative routes of transmission is of importance owing to the dietary exposure of the UK and other populations to bovine spongiform encephalopathy prions.