Prion diseases are terrifying. A rare, yet aggressive and mostly fatal class of neurodegenerative maladies popularized by bovine spongiform encephalopathy (mad cow disease), but including Creutzfeldt-Jakob disease (CJD), scrapie, and wasting diseases in elk and mink, these illnesses eat away at our brains, causing dementia, motion disorders, and eventually a slow, horrid death.
Perhaps more terrifying than the symptoms is the fact that prion diseases aren't caused by your standard viral or bacterial infection. Instead, they're spread by the abnormal folding of naturally occurring and normal prion proteins in our brains. Once a misfolded prion hits a normal prion, it transforms that healthy entity into an agent of its infection. It's basically a zombie pathogen.
Fortunately, these diseases are rare in humans. They're only sometimes caused by random mutations within us. More often they stem from the consumption of the spinal tissue of creatures afflicted with a prion disorder. And that's something that we've gotten quite good at avoiding—despite paranoid claims to the contrary—since the mad cow scares of the late 80s and early 90s.
Yet there has been one major outbreak of prion disease in humans in recent history. For ages, this outbreak has served as a curiosity and a cautionary, even moralistic, tale. But some researchers have long looked at this exceptional epidemic as a means to better understand prion diseases and how to fend against them in the future. Recently, a team of British academics made a big discovery in the genetic code of the survivors of the disease: a whole new type of genetic resistance not just against the peculiar strain of illness that hit them, but potentially against every form of prion disease imaginable. Yet the means by which this resistance developed, it turns out, are unexpected and a little ghastly. Just how we can use this isolated genetic quirk to similarly protect the wider world against similar maladies remains a bit fuzzy.
The outbreak in question was kuru. In the tongue of Papua New Guinea's southern Fore people, whom it struck, kuru means "the shaking death," a reference to its symptoms. During the 50s and 60s, a massive kuru epidemic hit the Fore, at its height killing two percent of the population every year. Although initially regional investigators thought it was some kind of mass psychosomatic illness or genetic disorder, eventually they linked it to prion disease. And when they did, they discovered that the origins of kuru weren't infected cattle, sheep, or even mink.
Kuru spread through the Fore thanks to ritual cannibalism. The Fore's recently deceased were consumed, mainly by women and small children. Researchers suspect that sometime in the 1950s, a member of a Fore community contracted CJD or some variant, maybe thanks to a random mutation. Then his consumption spread the disease to others, who were themselves consumed, even after colonial officials tried to outlaw the practice.
"[An old expert] told me that… everyone who sat down to a mortuary feast where the person had died of kuru would ultimately succumb to kuru," Professor John Collinge, head of the University College London Institute of Neurology team behind the new discovery, told VICE.
Because of the compositions of the feasts, the epidemic's victims were overwhelmingly women and children. And for a time, some feared that the disease would basically wipe out all Fore of child-bearing age and capabilities, leaving the entire culture to slowly, brutally die off.
But that didn't happen. The Fore survived, for the most part presumably because the practice of cannibalism dropped off. The disease, on the other hand, faded into the realm of historical medical curiosities—and, of course, cautionary tales about the evils of cannibalism.
But a few people, like Collinge, kept boots on the ground with the Fore into the modern era. Prion diseases, it turns out, have an insane potential for dormancy, surviving for years or decades before kicking into gear and ravaging our bodies. So every now and then a new case would pop up amongst the Fore, ready for study. And even just examining the histories and remaining populations of the disease's survivors, it was thought, could teach us about how to handle another prion outbreak in the wider world if one ever were to arise.
It was while collecting such medical reference data that Collinge and his team started to realize that the old assumption about everyone who ate kuru flesh eventually dying of kuru wasn't true. In fact, they found hundreds of survivors of the epidemic who'd been exposed to kuru-tainted flesh and had not manifested any signs of the disease whatsoever. That's when Collinge realized that he might have found a population with some natural resistance to the disease worth exploring.
"We knew from some studies originally published in Nature back in 1991 that there was a common variation in the human [genetic code for the] prion protein at position 129 [that could lead to resistance to CJD]," says Collinge. This variation occurs worldwide, dating back 500,000 years ago, probably to an era when widespread cannibalism amongst early humans caused a number of kuru-like epidemics, selecting for those with this genetic booster to their defenses. So when he first examined the DNA of kuru-resistant Fore, that's what he expected to see.
But when his team looked at the results, they realized that while many of the survivors did have the protective mutation at position 129, they also displayed a totally distinct genetic anomaly at position 127 on the prion gene, unlike anything they'd seen in 20 years of research on populations all over the world. And it was most densely distributed at the very center of the kuru epidemic, where the disease had otherwise done the most damage and probably began.
"Our initial thought was that maybe… it might cause the disease," says Collinge. After all, he adds, the mutation showed up on a bit of DNA that hadn't changed for millions of years, suggesting that it served some important function. Maybe that was tamping down rogue prions.
Yet when Collinge's assistants went to collect medical histories from the families of those with this mutation, instead of finding infirmity, they found them to be in unexpectedly good shape.
If cannibalism hadn't stopped at the end of the 1950s, that population may have regenerated from the survivors and created an entirely [prion disease]-resistant population. —Professor John Collinge
"In fact," says Collinge, "there wasn't much history of kuru. Indeed, in about a dozen families that they looked at, I think there was only one person in one family that had died of kuru. In the other families, everyone had relatives that had died of kuru—multiple people."
This mutation didn't cause kuru, the team realized. It was preventing it. After a little jiggering around in genetically modified mice, they realized that while one copy of the gene offered resistance to kuru and limited resistance to mad cow disease, two copies of the gene offered total resistance against any form of prion horror the team could throw at their long-suffering vermin.
And given the distribution of the mutation, it seemed that the resistance wasn't just some complete fluke of nature. It spread through the population because of the cannibalistic outbreak.
That's not to say that kuru caused its own resistance. The mutation appears to be about ten generations (or a couple hundred years) old, whereas the oldest oral historical records of kuru only go back to the early 20th century. But under the pressure of kuru, this mutation, which elsewhere might have faded away, was favored to an insane degree, until, Collinge estimates, about 12 percent of the region at the heart of the epidemic was carrying one variant gene copy.
"If cannibalism hadn't stopped at the end of the 1950s," enthuses Collinge, "that population may have regenerated from the survivors and created an entirely [prion disease]-resistant population. It's an amazing example of human evolution—probably the most powerful example that's ever been demonstrated of resistance to lethal infection."
Yet while this genetic discovery is eye-popping for suggesting that humanity may have genetically benefitted from cannibalism, Collinge and his colleagues are still working out how to weaponize it in the fight against prion disease. (And the fight is real: While kuru has faded and mad cow is contained, the number of people exposed to prion contamination over the years, who may now be dormant carriers, suggests we're headed down a road of pain and confusion in the future for which we have few medical tools.)
"One possible thing you could do is conceive of some sort of gene therapy where you deliberately express the mutant protein in individuals as an inhibitor of prions," muses Collinge. "[But] I don't think that's a realistic approach to take. Gene therapy for brain diseases, I don't think is close to possible [at the moment]."
At the moment, when it comes to treatments, Collinge and his compatriots are focusing on an unrelated antibody, which basically sticks to healthy prions and prevents zombie monster prions from infecting and refolding them. They've even had some success in curing mice of existing disease and are on their way to developing a trial for human patients.
But even if it can't immediately translate into the premiere knock-out blow against prion disease, the kuru-bred resistance will help us in our understanding of the disease.
"I think understanding what the [mutation] does is going to be absolutely fascinating in terms of the molecular understanding of these diseases," says Collinge. "[And] these diseases are incredibly aggressive, invariably fatal. In reality it's probably going to take more than one drug working in combination to actually cure them. So although we have high hopes for our antibody, that doesn't mean that we're not looking for other things as well to knock them out."
Some of those other things could stem from the discoveries gifted to us by Fore cannibalism and the disease it triggered. But even if we don't get anything tangible out of the position 127 mutation, it's still a profound message about the speed, power, and efficiency of evolution, and the potential for human survival even against zombies. Zombie pathogens, that is.
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