In movies and mythology, zombies are mindless un-dead humans, turning everyone in their path into zombies as well. Too bad they’re real – in protein form, that is.
A bit about prions
These devilish proteins are called prions (pronounced “pree-ahns”). All proteins have a very specific folding structure to give them the proper configuration for correct function. Normally, proteins that are incorrectly constructed are chewed up by the cell and recycled. Prions, however, are misfolded proteins that are able to evade this failsafe, and remain intact in the cell. Moreover, they have a devious new property: they can latch onto perfectly normal proteins and convert them into misfolded ones.
The amazing thing about this mechanism is that it’s direct protein-protein interaction. It doesn’t alter the gene that codes for the prion protein such that the next translated protein will be misfolded too; it converts pre-existing proteins instead. Because of this strange property, prions from one species can convert normal proteins from a totally different species.
While the term “prion” can be used to describe any protein with this property, the original use is for a specific protein – the normal version is called PrP and the converted version PrPsc. The normal version of the protein is actually very useful in the nervous system; it is used in myelin sheaths that coat neurons, and helps with building long-term memory.
“Symptoms of these spongiform encephalopathies include involuntary trembling and shaking of the limbs and uncontrollable bursts of laughter”
The new zombie prions, though, continue to propagate, turning more and more normal prion proteins into the misfolded version, and start to form long strands or clumps of aggregated proteins. This leads to progressive neurodegenerative diseases, like Creutzfeld–Jakob disease and kuru, causing both physical and psychological damage and ultimately leading to death. Symptoms of these spongiform encephalopathies include involuntary trembling and shaking of the limbs and uncontrollable bursts of laughter. Late stages of the disease involve loss of muscle function and loss of awareness, and morbidity is often due to a secondary infection such as pneumonia. Prion diseases are currently untreatable. And, like zombies, the infectious prions are practically impossible to kill: extreme heat, radiation, disinfectants, and sewage treatment have no effect on the proteins.
While one in a million people develop Creutzfeld–Jakob disease spontaneously, most cases have come from the consumption of prion-infected tissue. For example, the cases of “mad cow disease” in the UK a decade ago were from eating infected beef brain, most likely in the form of ground burgers. And, before it was banned, ritualistic cannibalism in the Fore tribe of Papua New Guinea caused an outbreak of kuru, killing 10% of the population.
It is among the Fore population that an amazing genetic discovery was made: evolutionary protection from prion diseases.
Genes to the rescue: our built-in zombie apocalypse kit
As with any gene, we all have two copies for the gene encoding the PrP protein. The most common variant of the gene produces a protein sequence with the amino acid methionine at position 129; however, some variants exist that place the amino acid valine at position 129 instead. The interesting thing about these variants is what happens when you take both copies of the gene into account. If a person has 2 of the same variant, he or she is susceptible to prion diseases. However, if a person has one copy of each, methionine and valine, the combination confers some protection against prion diseases! This protection most likely results because the slightly different versions of the proteins can’t pack together as well as identical versions. Because these two variants exist in nature, there are different degrees of prion disease susceptibility among humans.
Recently, a new type of protective variant was discovered, one that is even more potent in its shielding from prion diseases. This variant is at position 127, just a couple amino acids away from the other one, and seems to have been selected for in the Fore population. Whereas the normal amino acid in this spot is a glycine, valines emerged at this position 127 as well. In fact, 80% of Fore women (only women were cannibals) were found to have this protective gene. Fore women a generation or two younger, born after cannibalism was banned, were less likely to have this protective variant – presumably because the selective pressure for it no longer existed. It very neatly correlates.
“It’s fascinating that evolution came up with a way to protect us from ourselves.”
Interestingly, the protection of valine at 127 (V127) is different from position 129. While the 129 locus needed heterozygosity (2 different copies), either one or two copies of valine at 127 is protective. And, having a copy of V127 makes you completely resistant to prion diseases! While the exact mechanism isn’t known yet, the authors of the study believe V127 acts as a dominant negative allele, both resistant to conformational misshaping itself as well as preventing conversion of normal proteins even upon infection. It’s fascinating that evolution came up with a way to protect us from ourselves.
Dormant zombies among us?
People can get prions from ingesting infected meat from other species, after which prions can hang out in the lymph and spleen in a dormant state. Moreover, you can pass on the infection through donated blood, etc., and the person who receives the infectious prions could develop the disease. It is actually somewhat surprising that there are very few cases in some regions, like the UK, although based on the number of originally infected people, 1/4000 of the current population could be carriers. Is it possible that the protective genes are more common than we thought, either the known variants discussed above, or perhaps other loci?
It has been proposed that with the emergence of prion-resistant genes, new prion strains will also emerge in response to the resistance. This seems unlikely to me, since prions don’t have any of their own genetic material – unlike bacteria, viruses, and parasites, which do find ways to evade our protection against them. However, it’s something to keep in mind before chowing down on brain – human or otherwise.
