I’ve been busy recently due to moving, so I needed an easier topic that would require a little less research on my part. A topic such as prion diseases, one that I researched during graduate school and remember finding interesting. Fortunately (for literally no one besides myself), prion disease has been in the news recently in the form of “zombie deer disease” spreading through parts of North America, Scandinavia, and South Korea. It’s a scary name for a viscerally terrifying illness, but one I hope I can shed some light on.
The Disease
Prion disease (also known as transmissible spongiform encephalopathy or TSE) is a neurodegenerative disease caused by the misfolding of the Major Prion Protein (PrP). The exact function of PrP is currently unknown, but it is primarily expressed in nervous system tissue and there is evidence to suggest it is involved in regulating circadian rhythm. Normal PrP proteins are free-floating inside nerve cells and are easily broken down by the cellular enzymes that recycle old and unneeded proteins. Problems occur when PrP becomes misfolded. Remember, a protein is a chain of amino acids, a family of 20 organic molecules that each have slightly different molecular properties. These properties determine what shape the protein will take once it's folded up. A good way of picturing this would be with origami. Imagine that one could create a sheet of paper where different sections had unique properties; a line that would naturally crease itself in one direction, a square that would glue itself to another square if the two ever came into contact. One wouldn’t need to deliberately fold such a piece of paper into a crane or swan, you could throw the sheet in a box and shake it for a bit and it would naturally fold itself. A protein is a chain of molecules whose most easy-to-fold-itself-into shape happens to be the right shape to serve as a useful tool for the cell.
But this unconscious folding mechanism can occasionally err. Perhaps there’s a second most easy-to-fold-itself-into shape that isn’t as useful a tool, one that could be harmful. The most easy shape will still be the most common, but the second-most easy shape might crop up from time to time. PrP has one such second-most easy shape, one that is very resistant to being broken down and recycled and one that can attach itself to other PrP proteins. When a misfolded PrP protein attaches itself to a healthy PrP, the healthy protein will become misfolded in the same way. Other healthy PrP proteins can now attach themselves to the newly misfolded PrP, lengthening the chain. More and more PrP proteins attach themselves to either side of this rigid, insoluble filament of corrupted proteins until the filament becomes longer than the nerve cell it’s inside, ripping through the cell membrane and tearing it apart from within. Once outside, fragments of the filament can be taken in by surrounding nerve cells and the process begins anew. The rate of cell death accelerates exponentially as the number of misfolded proteins in the brain double with each ‘generation.’
The first symptoms of prion disease in humans are neurological symptoms such as memory loss, changes in personality, and loss of vision and coordination. As it progresses, patients experience rapidly developing dementia and, depending on the specific disease, hallucinations, muscle stiffness, trouble walking, slurred speech, fatigue, coma, and eventually death. In all prion diseases, there is usually between 6 to 12 months between the first symptoms and death. Depending on the specific disease, there could be a latency period between initial infection and the first symptoms of a few years to four or more decades. Currently, the only way to definitively confirm a prion infection is with a post mortem brain biopsy. Very little is currently known about how the initial misfolding occurs and there are currently no effective treatments against prion diseases or methods to detect them in the latency period.
Fortunately, prion diseases are exceedingly rare in most circumstances. The most common way to become infected is for one PrP protein in a person’s brain to become randomly misfolded. The chance of this happening is roughly one in a million; you’re 65 times more likely to be struck by lightning than randomly get prion disease. There are variants of the PrP gene that can make misfolding more likely, but these variants are even less common. And then of course, there are acquired cases where prions enter the body from the outside. This can only occur from coming into direct contact with infected tissues and fluids, particularly brain and nervous system tissue. For human-to-human spread in developed nations, this is limited to healthcare-associated infections, such as transplanting corneas from infected donors or transferred via infected surgical implements. Prions are incredibly difficult to sterilize since they aren’t living things and because they are so resistant to degradation, and there have been cases of instruments used on prion disease patients transferring prions to new hosts years after the fact.* In nature, the majority of acquired infections are caused by eating infected meat (particularly brain tissue) with cannibalism being the most effective way to transmit prions due to the shared host species. Other bodily fluids have been observed to be infection vectors in animals, but this has not been observed in humans.
If you were familiar with any prion diseases before now, it might be the outbreak of bovine spongiform encephalopathy (mad cow disease) in the United Kingdom in the eighties and nineties. Before the outbreak, the British beef industry had made it standard practice to feed their cows meat-and-bone meal, a high-protein dietary supplement made from the otherwise unusable parts of ruminant animals such as cows and pigs. This meant that any cow that had a prion infection could spread it to those that ate its remains, who would spread it to those that ate that cow’s remains. In 1986, the first cows tested positive for mad cow disease, with this number rising to 180,000 infected in total. Organ meat was banned for human consumption in 1989 as a precaution, but the British government assured consumers that British beef was safe to eat, claiming the disease couldn’t jump between species. This was disproven in 1990 when a cat was diagnosed with the disease, with the first human cases appearing in 1994. To date, a total of 178 people have died of the disease, with experts believing a second wave of cases will come in the future due to an unknown number of latent infections. The European Union would ban British beef for ten years, causing strife between the UK and the rest of Europe, and the United States only recently lifted a ban on blood donation from anyone who’d spent more than three months in the UK between 1980 and 1996.
Aside from mad cow disease, other prion diseases include Scrapie in sheep as well as Kuru and Creutzfeldt-Jakob disease in humans. For each disease, the misfolded prions have slightly different shapes and can give them different preferred species, latency periods, presence in other bodily tissues, and infectiousness. There are also researchers who argue that Alzheimer’s disease should be regarded as a prion-like disease. Alzheimer’s is also a disease where misfolded proteins damage the brain, and there are studies showing that the amyloid plaques and tau tangles in patients with early-onset Alzheimer’s had self-propagating properties. This wouldn’t make Alzheimer’s a literal prion disease since the PrP protein isn’t involved, but research into the two diseases might overlap.
Chronic Wasting Disease
Zombie deer disease, more accurately called Chronic Wasting Disease, is a prion disease which affects Cervid species such as deer, elk, caribou, and moose. Symptoms include difficulty moving, weight loss, lethargy, tremors, self-isolation, repetitive walking in set patterns, excessive drinking, salivation, and urination, nervousness and confusion, and ultimately death. Initial onset of symptoms can take between 18-24 months with death taking only a few weeks. CWD prions can concentrate more highly in non-neural tissue and fluids, making the disease much easier to be spread than other prion diseases. The most common vectors of transmission are believed to be contact with an infected animal’s bodily fluids (such as feces, urine, or saliva) or eating vegetation that grew in areas contaminated by said bodily fluids or decomposed bodies. CWD prions are so stable and resistant to destruction that they can remain infectious in the soil for years. All these factors together make CWD one of the most transmissible known prion diseases. CWD has been known about since 1967, but its spread has been rising steadily for the past few decades. Cases have been reported in 29 US states, four Canadian provinces, Norway, Finland, Sweden, and South Korea. In a few of these regions, up to 12% of tested animals had CWD.
The reason why zombie deer disease has been in the news is because of an uptick in research into the possibility of CWD being transmitted to humans. The disease has been growing in prevalence in recent decades, making the likelihood of a species-jumping event more likely if it is at all possible. To date, there have been no confirmed cases of humans becoming infected with CWD prions. But given that other prion diseases can jump species, researchers aren’t comfortable ruling out the possibility. In vitro studies found that CWD prions could convert human PrP, but did so far less efficiently than they did for deer and other cervids. Studies have found that CWD prions can infect primate species such as squirrel monkeys by feeding them infected food, but studies on macaques (which are more closely related to humans) were less conclusive. Making matters more difficult for researchers is that prion infection is highly dependent on several conditions, such as the manner of transmission, disease strains, species of animal, and which variant of the PrP gene one carries. Determining exactly how likely it is for CWD to infect a human is more complicated than just the protein interactions. The other big concern scientists have is the possibility of CWD jumping to cattle, since bovines are much more closely related to cervids and they’re much more susceptible to cervid transmission channels (i.e., grazing where an infected animal urinated or salivated). If there were to be a mass spread of CWD to livestock, it could cause a worse version of the mad cow disease outbreak, with mass quarantining of herds and entire industries shut down to eliminate the risk of the disease jumping to humans. Fortunately, there are no known cases of CWD infections in cattle and researchers have found there to be low interactivity between CWD prions and cow PrP.
Regardless of how terrifying prions diseases are, they are still incredibly rare. Prions can only be transferred by direct tissue or fluid exchange, with even this being a less effective vector than consuming brain tissue. Based on current research, the likelihood of CWD jumping species to humans or our farm animals seems incredibly unlikely. Even if it were to happen, it almost certainly won’t be nearly as infectious as it is in deer, making it less likely to spread. The fact that prion diseases are incurable and undetectable during latency means that even small risks of infection are treated seriously by researchers and medical professionals, but the vectors of infection are well-documented and monitored. As it stands, if a human were to become infected with CWD, it would most likely be from eating deer meat or handling a deer’s carcass, both of which are rather avoidable activities. The CDC has advised hunters to not handle or eat an animal that is acting strangely, to wear rubber gloves while dressing a carcass, to avoid contact with the animal’s brain and spinal cord, and to disinfect all utensils and surfaces with bleach after the fact. They are also advising hunters to have all meat tested before consuming (this does require sending it to a lab and can take weeks, so it is admittedly a big ask) and to check with state wildlife and public health authorities before hunting a particular animal. This is certainly a risk worth managing and studying, but not the one you’d picture from the name ‘zombie deer disease.’ Regardless of how scary prions are, they are not the most dangerous disease that I have written about for this blog in terms of the risk they pose to the average person.
For More Details
*It should be noted that these cases were from the seventies, when our understanding of prions wasn’t as developed. The risk of these medical infections today are far lower.
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