Cannibalism clue to brain disease

Research on a “brain-eating tribe” may hold the key to understanding and even treating mad cow disease, according to The Daily Telegraph.

A genetic study of the Fore tribe of Papua New Guinea has shown that certain members have genetic mutations that protect them from a disease called kuru, which can be contracted by eating prion proteins in brain matter. The disease, which kills tribe members who do not have the mutation, is similar to Creutzfeldt–Jakob disease (CJD), which is sometimes wrongly referred to as "mad cow disease".

The findings further our understanding of the role of inherited genes in the protection and susceptibility to diseases such as kuru and CJD, known as prion diseases. This was an informative study of the genetics of a unique population, but it does not directly improve our knowledge of the prevention or treatment of CJD in the UK.

Where did the story come from?

The research was carried out by Dr Simon Mead and colleagues from University College London Institute of Neurology, Medical Research Council Prion Unit and other medical and academic institutions in the UK, Papua New Guinea and Australia. The research was funded directly or indirectly by the Wellcome Trust, the Medical Research Council and the Department of Health’s National Institute for Health Research funding scheme.

The study was published in the peer-reviewed New England Journal of Medicine.

What kind of research was this?

This was a population genetics study on the Fore tribe of Papua New Guinea. The study included genealogy assessments and blood tests. Researchers were interested in this group because of their experiences of a fatal, progressive neurodegenerative disease called kuru. Kuru is one of a group of prion diseases that can affect humans and animals, apparently when abnormal versions of proteins damage normal proteins in the brain.

Until ritual cannibalism was outlawed in the 1950s, the Fore tribe had traditionally participated in this practice, consuming tribe members when they died. During these “mortuary feasts”, members of the tribe, particularly women and children, would be exposed to the prions that cause kuru. Some members of the Fore tribe were resistant to kuru in spite of their prion exposure, and the researchers believed that investigating the reasons for this resistance might further our understanding of this and other prion diseases.

Other prion diseases include bovine spongiform encephalopathy (BSE or “mad cow disease”) in cows and variant Creutzfeldt–Jakob disease (vCJD) in humans, which is sometimes incorrectly referred to as “mad cow disease”. People in the UK were exposed to prions of BSE through their diets, which increased their risk of getting vCJD. The authors of this study hoped their research could shed further light on prion diseases and what can be done to prevent and treat them.

What did the research involve?

The study is an expansion of a previous study, but included more samples. The earlier study found that a particular mutation was more prevalent in a small group of women from the Fore tribe who had participated in multiple mortuary feasts but had survived.

Researchers obtained information on genealogy and took blood samples (for genetic analysis) from members of the Fore tribe. These tribe members were sourced from regions exposed to the disease and regions with no recorded cases. The people who had been exposed to kuru disease were those who would have participated in multiple mortuary feasts in which deceased relatives were dismembered and consumed in ritual settings. The researchers wanted to further investigate the genetic variation that appeared to confer a survival advantage when the disease was rife.

The researchers used information on the participants’ family histories to determine what they called an “exposure index” for each of the villages in the community. This was an estimate of the relative intensity of disease in these communities in 1958. Using this, they were able to split the geographical regions of their samples into various zones: high exposure, mid-level exposure and low exposure, as well as two additional unexposed zones.

There were 557 exposed elderly survivors, 2,053 people who were currently healthy from exposed and unexposed areas, and 313 people from more distant regions in the country. The genes of these participants were analysed from blood samples and researchers determined whether there was a link between particular genetic make-ups and degree of exposure to kuru disease.

The researchers performed several well-established genetic analyses to investigate how the protective genetic variation may have spread through the population, and when it might have arisen.

The study was approved by ethics committees in the UK and Papua New Guinea and had the full support and involvement of the members of the Fore tribe.

What were the basic results?

Investigation of the participants’ genes revealed that people who were exposed to kuru but were not infected were more likely to have one copy of a particular variant (called 129V) in one of the areas of the prion protein gene. This confirmed the findings of other studies. The study also identified a previously unknown mutation (called 127V) that was more common in women from high- and medium-exposure regions. None of the people suffering from the disease had this mutation.

Both of these genetic variations were more common in people from regions that had been exposed to kuru than in people from unexposed regions. This suggests that the presence of kuru provided “selection pressure”. This means that people who carried these variants were resistant to kuru and, therefore, more likely to survive kuru and pass on their genes to future generations.

How did the researchers interpret the results?

The researchers concluded that the new genetic variation they identified (127V) increased resistance to acquired prion disease. They say that the two genetic variations they examined demonstrate that there has been a population genetic response to an epidemic of prion disease, and that this “represents a powerful episode of recent selection in humans”.

Conclusion

This study has shown that variations in two particular regions of the gene that codes for the prion protein are more common in those people who were exposed to the kuru disease but who had not become infected.

The researchers note that they cannot rule out the possibility that one of the mutations is responsible for kuru disease, but discuss several reasons why this is highly unlikely.

The study demonstrates that the kuru disease resulted in a strong selection pressure in this population. This means that any individuals with characteristics that would make them less susceptible to the disease would be more likely to survive and, therefore, to pass these genes on to successive generations. If this were true, then a kuru epidemic would be responsible for an inflated prevalence of mutations that conferred a survival advantage, and this appears to be what has happened in these groups of people.

Overall, the study adds to the understanding of how prion diseases can arise and what particular genetic factors might increase susceptibility or offer some protection. This novel study on a rare disease in a unique population does not currently have direct relevance to the prevention or treatment of CJD in the UK, but may eventually lead to research that does.