The first prion disease to become recognized was scrapie, an acquired and sporadic disease found in sheep. In the late 1700’s British farmers began to notice their sheep undergoing drastic behavioral changes. The normally docile animals were aggressive and nervous, holding their heads stiffly and smacking their lips if tickled under the chin. Most striking, and the source of the disease’s name, the sheep constantly scraped themselves as if trying to scratch an itch. Within months, they would lie down and die.
Earlier in the century, farmers had begun to breed their sheep in-and-in (a parent bred with their offspring over and over) in order to enhance a desirable body type. Indeed, if you looked at sheep from the early 1700’s, they would be nearly unrecognizable compared to the sheep we see today. In 1710, the average weight of a sheep in market was 28lb. By 1795, it was 80lb due to the results of the breeding.
Unfortunately, inbreeding, along with bringing in superior sheep from infected Spanish flocks, transformed what was before a rare genetic disposition of protein misfolding into a prevalent problem. While breeding in-and-in was eventually ended, scrapie remained a prominent disease until the collapse of the English sheep industry in the mid 19th century. The collapse, along with the repopulation of flocks with scrapie-resistant sheep, has not completely eliminated scrapie, however the incidence is far less worldwide .
CJD & BSE
The most common human prion disease is sporadic Creutzfeldt-Jakob disease, or CJD, which occurs in one in a million people worldwide . While sporadic CJD develops due to a random folding error, there is an acquired form of CJD which results from consuming prions from cows infected with bovine spongiform encephalopathy (BSE), also known as mad cow disease. Patients of CJD suffer memory loss along with reduced coordination and balance, followed by a loss of mental function and death. Acquired CJD has killed around 150 people in Europe due to the outbreak of mad cow disease in the 1980’s, which killed over 800,000 cows .
Animals infected with BSE become aggressive, clumsy, lose their balance, and tremble as the disease sweeps through their system. The diagnosis and government response was hampered by a mess of politics and fierce scientific competition: the British kept American prion experts at a distance, refusing to share data and tissue samples and, unfortunately, fear for the cattle industry resulted in research limitations and censorship.
Eventually epidemiologists narrowed down the cause to cows being fed “cake,” a high protein concentrate of recycled dead farm animals sweetened with molasses. The companies making cake had begun using more sheep brains before the outbreak (along with decreasing the processing temperature and denaturing chemicals used to sterilize), and sheep herds still contained some scrapie. Additionally, cows that had died of BSE were likely included in the mix.
While scrapie cannot directly transfer to humans due to the species barrier, the sheep prion protein is similar enough to cows that it can cause the cow protein to misfold. Unfortunately, the species barrier between cows and humans is not as stringent, and consequently, prion diseases can morph and pass through species (the scrapie-caused BSE theory has been challenged, but no clear alternative has been agreed upon by the scientific community). An estimated 640 billion doses of BSE went into the UK diet during the time of the outbreak–luckily, the species barrier and genetic resistances to prion diseases limited the number of deaths of human acquired CJD to 150 individuals. While BSE still exists, the incidence is lower due to a mass-slaughter of infected cattle and implemented screening measures [1,2,3,4].
Fatal Familial Insomnia
While scrapie, BSE, and CJD all share some similarities in symptoms, some prion diseases are more unique. Fatal familial insomnia is a genetic prion disease that is only present in 40 families worldwide. An Italian family in Veneto has been keeping track of the disease’s progress through the family tree for over two hundred years. It is an autosomal dominant disease, meaning that there’s a 50% chance it will be passed onto an infected individual’s child. Unfortunately, as the disease doesn’t show symptoms until late middle age, there was no way for the family members to know if they had the disease before reproducing until recently. Even with modern genetic testing, many do not wish to find out if they have the disease.
At the onset, symptoms include sweating and shrunken pupils along with a stiff neck posture similar to the previous diseases. These symptoms are swiftly followed by insomnia, elevated blood pressure, exhaustion, and a loss of ability to balance. Unlike CJD, there is no cognitive impairment and it takes approximately 15 months before the patient enters an exhausted coma state and dies.
Analysis of the brain tissue from patients shows that the thalamus is almost completely destroyed in the disease. This part of the brain plays a role in stopping and starting autonomic impulses such as temperature control, sweating, and hormone release, resulting in the majority of the symptoms. The role of the thalamus in sleep is not well understood but, as the name of the disease suggests, the main symptom of the disease is insomnia. Patients lose the ability to enter deep sleep, going directly from waking into a version of REM without the usual paralysis; they physically act out their dreams. As a result of this, research has suggested that the normal prion protein plays a role in sleep, and perhaps it is the loss of the normal protein that results in this fatal insomnia .
Kuru is an acquired, human prion disease that crippled the Fore tribe in Papua New Guinea in the 20th century. As the modern world encroached upon the tribes living on the island, scientists noticed a unique disease affecting the women and children of the Fore tribe. The afflicted shivered and held their heads stiffly, and every single case was fatal.
Ritual cannibalism of the dead was part of the tribe’s culture, as an honorary ceremony of their loved ones. Indeed, cannibalism had become such an integral part of their culture that their standard greeting was “I eat you.” The connection between cannibalism and prion disease was not easy to reach, however. While prion diseases had been impacting the world for centuries, prions had yet to be identified and well known. As such, it took quite awhile before the connections between Kuru and cannibalism, as well as Kuru and CJD, were made.
What had been a rare disease spread through the community since the introduction of cannibalism, the oral consumption of the infectious agent proving disastrously effective. Looking back it seems frustratingly obvious, especially when one of the investigating scientists, the controversial Carleton Gajdusek, noted that “women and children, particularly, partake of the human flesh.” Women and children also ate the least desired parts of the body, including the brain, which is the most concentrated source of prions. Eventually, the connection was made and the ritual died out after a loss of 3,000 tribe members [2,4].
Less Well Known Prion Diseases
While Kuru has been mostly eradicated, CJD, BSE, and scrapie still persist and another prion disease, chronic wasting disease, is beginning to spread through the deer and elk in North America and South Korea. This outbreak is recent (recognized in 1978), but it has already killed thousands of deer. The disease symptoms are eerily familiar: behavioral changes, sweating, excessive urination, and a loss of balance and coordination. While not much is known about it, it is clear that direct contact is essential to the spreading and there is no research supporting a genetic source. Culling programs have been ineffective at eradicating the disease, and it is unknown if it can cross into humans . More rare and recent prion diseases include transmissible mink encephalopathy, feline spongiform encephalopathy, and, in humans, Gerstmann-Straussler-Scheinker, PrP-cerebral amyloid angiopathy, and variably protease-sensitive prionopathy .
 Hagiwara, K. et al. “Species-Barrier Phenomenon in Prion Transmissibility from a Viewpoint of Protein Science.” J. Biochem. 2013;153(2):139-145.
 Head, Mark. “Human Prion Diseases: Molecular, Cellular, and Population Biology.” Neuropathology. 2013 (Preprint).
 Iwasaki, Y. et al. “An Autopsied Case of Creutzfeldt-Jakob Disease with Mutation in the Prion Protein Gene Codon 232 and Type 1+2 Prion Protein.” Neuropathology. 2013 (Preprint).
 Max, D T. The Family That Couldn’t Sleep: A Medical Mystery. New York: Random House, 2006. Print.
 Zimowski, J et al. “Hereditary Form of Prion Disease in Poland.” Neurologia I Neurochirurgia Polska. 2012; 46, 6:509-518.