“‘Curious and curiouser!’ cried Alice (she was so much surprised, that for the moment she quite forgot how to speak good English).”
Lewis Carroll, Alice in Wonderland
“It is crucial for scientists to be willing to be wrong; otherwise, you might not do the most important experiments, or you may ignore your most important findings.”
Stanley B. Prusiner, M.D., American neuroscientist, biochemist, and Nobel laureate
On December 11, 2023, an article appeared in MedPage Today describing an increase in cases of classic Creutzfeldt-Jakob disease (CJD), a prion disease in humans. Then on January 4, 2024, the National Wildlife Center announced thatchronic wasting disease (CWD), a prion disease that afflicts deer and other cervids but also has the potential of infecting humans, had spread to 32 states. This news is alarming. Why? Because prion diseases are devastating infections that are uniformly fatal. In this week’s Germ Gems, I review briefly the incredible story of prions and prion-related diseases.
What are prions? The term prion stands for “proteinaceous infectious particle.” University of Californian neuroscientist Stanley Prusiner coined the term. He hypothesized that these “protein only” particles caused scrapie, a fatal neurogenerative disease in sheep. In 1997, he received the Nobel Prize for Physiology or Medicine for his discovery of prions.
The precise function of normal prion proteins in the brain is unknown. They are found in healthy brains but in a folded state. Prions are misfolded (abnormal) proteins that are found in the neurons of the central nervous system. They contain no nucleic acid, yet they behave like microbial pathogens (bacteria, archaea, viruses, fungi, and protists) in that they can be transmitted from host to host. Their main target is the nervous system where they cause severe damage (spongiform encephalopathy), progressive dementia, and ultimately kill every mammal that is infected.
What diseases are caused by prions? In the 1980s and 1990s a major outbreak in the United Kingdom of prion disease in cattle, bovine spongiform encephalopathy (BSE), aka “mad cow disease,” captured huge international attention. This was not only because of BSE’s profound impact on the beef industry but also because it was soon discovered that a human equivalent of BSE called variant Creutzfeldt-Jakob Disease (vCJD) was linked to ingestion of contaminated beef products.
This transmission across species shocked the experts who thought there was an impervious “species barrier” to transmission of prions from animals to humans. As of July 2021, 232 cases of vCJD from 12 countries have been reported—all fatal.
Far more common than humans contracting mad cow disease or vCJD is the unrelated condition known as classic or sporadic CJD, a prion disease in humans. Although there is a genetic form of CJD, no one knows why some humans develop sporadic CJD. Yet, it is responsible for 85% of all cases of prion-induced brain disease in humans. But, the overall risk of sporadic CJD remains low—only one to two cases per one million population are diagnosed in the US per year.
As was reported on December 11. 2023 in MedPage Today, there’s been an increase in the number of cases of classic CJD. The basis for this recent report was a study by Johns Hopkins researchers. These researchers used the Centers for Disease Control and Prevention (CDC) “cause-of- death data base” and found that since 1990 there’s been a steady uptick in the number of deaths due to CJD, especially in women, as well as an increase in overall incidence.
In an accompanying article in the December 11, 2023 Medscape, “Why Are Prion Diseases on the Rise,” F. Perry Wilson, M.D., a Yale University associate professor, posits three possible explanations: (1) an increase in the susceptible, or at risk, population, namely people who are 55 years of age or older; (2) implementation of better diagnostic tests; and (3) the most disconcerting, a new exposure has occurred. This leads to the question, could the increased number of cases of sporadic CJD actually be cases of vCJD acquired from contaminated beef, or has there been another zoonotic (animal) spill over into humans?
Chronic wasting disease. CWD is a contagious neurogenerative disease that affects cervids (white tailed deer, mule deer, black tailed deer, Rocky Mountain elk, and moose) and has the potential of infecting humans. This prion disease is spreading rapidly among free-range cervids and, as stated above, is now found in 32 states.
Prions are found not only in the cervid animal’s nervous system but also in the muscle of the animal. This is a major concern because people who hunt these animals often eat cervid meat.
Future considerations. In its website on “Creutzfeldt-Jakob Disease, Classic (CJD),” the CDC emphasizes that classic CJD is distinct from beef-related vCJD and that no linkages have yet been made of human cases to prions from animals with CWD. Given the CDC’s prowess in the arena of emerging infections this is reassuring. But, personally, I find the description of the University of Minnesota’s interdisciplinary prion research center in the November, 2023 CIDRAP Newsmuch more promising.
The Minnesota Center for Prion Research and Outreach (MNPRO) was founded in 2019. Scientists in the research center carry out state-of-the-art epidemiological and basic science research related to CWD and other well- characterized prion diseases. They also concentrate on other neurodegenerative disorders for which the causes are unknown.
As stated in the November CIDRAP News article, “The next stage of growth will be human research on Alzheimer’s, Parkinson’s, and ALS because what we’re learning from the animal model is applicable to humans.” Essentially, the researchers’ hypothesis is that prions (misfolded proteins) play a key role in these enormously devastating neurodegenerative diseases.
If your first reaction to this hypothesis is, “that’s really outrageous,” think again. Sometimes it takes an “outrageous” hypothesis (“thinking outside the box”) to lead to new discoveries. In the early years of Stanley Prusiner’s groundbreaking research on prions most scientists regarded his “protein only” or prion hypothesis outright heresy. It’s hard to image a more ironic moment than the 1997 ceremony when he was awarded the Nobel Prize for Physiology or Medicine.