This text from a friend after the beginning of the new CBS drama, Watson, inspired me to share a little bit of background on the genetic disease in episode 1. When Dr. Watson visits the first patient of the show, she suspects she has FFI, or fatal familial insomnia. This isn’t your typical occasional sleepless night – it’s a rare genetic disease that affects your central nervous system (the brain and spinal cord).
FFI is classified as a prion disease. A prion is a misfolded protein, first described by Dr. Stanley Prusiner in 1982.1 Prion diseases are unusual in that they can be genetic (as in FFI), sporadic, and infectious. Many people are familiar with “mad cow disease”, or bovine spongiform encephalopathy (BSE), which is a type of prion disease that can be transmitted from cows to humans. You might have also heard of scrapie, a prion disease that affects sheep.
Almost all prions are forms of the major prion protein (PrP) which is made from the PRNP gene. This gene is highly conserved in mammals, which suggests that it has an important function – but scientists aren’t quite sure what that function is! The effects of prion disease on the nervous system suggest that it’s most important roles might be in the brain, but it probably plays a role in the immune system and in other cells of the body.
Proteins have to be folded correctly, like a piece of origami, to function properly. When proteins are incorrectly folded, they are usually degraded within the cell. In prion disease, a misfolded prion protein is present and isn’t degraded. This misfolded prion causes properly folded prions to change their shape – a bit like scrunching up a carefully folded origami figure. These scrunched up, or misfolded, prions build up in regions of the brain and destroy nerve cells.
Infectious prion diseases, like BSE, are transmitted when someone is exposed to brain or nervous system tissue, typically by ingesting animal products that contain the misfolded prion. The prion is not destroyed by heat, so typical food processing doesn’t destroy it. Canada is considered a country at negligible risk for BSE, so it’s not a major concern here.2 Some cultures which practiced ritualistic cannibalism have also shown transmission of prion diseases – this is known as kuru and is virtually extinct.3
FFI and other genetic prion diseases, such as Creutzfeldt-Jakob disease, are not caused by ingestion of a misfolded prion protein but rather by the mutation of the PRNP gene. FFI is linked to a single change in the PRNP gene, D178N.4 This indicates that the aspartic acid (D) in the protein at position 178 is replaced with an asparagine (N). These amino acids are building blocks of protein and some changes will affect the way the protein folds. This D178N mutation causes misfolding of the prion protein and results in degeneration of the brain. FFI is considered a ’dominant’ disorder because only one copy of the mutated gene is necessary to cause disease. This means there is typically a family history of FFI – if not, the mutation may have arisen spontaneously (called de novo). There is no cure for FFI to date and treatment focuses on managing symptoms.
A recent (2024) study from MIT developed a method called CHARM (Coupled Histone tail for Autoinhibition Release of Methyltransferase) which shows great promise for treating genetic prion diseases.5 This method uses DNA methylation to silence, or ‘turn off’ PrP expression. While research shows that about 50% reduction in PrP is necessary for a therapeutic effect,6 this study achieved 80% reduction in PrP. This study was performed in mice, so there is a lot of follow-up work to be done before it can benefit humans with prion diseases.
For more on the human experience of prion diseases, I encourage you to read Mercies in Disguise: A Story of Hope, a Family’s Genetic Destiny, and the Science that Rescued Them (2017). This is a powerful nonfiction account of the Baxley family uncovering the Gerstmann-Straussler-Scheinker prion disease affecting their family tree, written by New York Times science reporter, Gina Kolata.
** SPOILER ALERT ** It turns out that Dr. Watson’s patient doesn’t have FFI, and her diagnosis will be our next blog post!
1. Prusiner SB. Novel Proteinaceous Infectious Particles Cause Scrapie. Science. 1982;216(4542):136–144.
2. Canadian Food Inspection Agency. Minister Bibeau welcomes recognition that Canada is negligible risk for BSE. 2021; press release accessed February 4, 2025.
3. Liberski PP, Sikorska B, Lindenbaum S, et al. Kuru: Genes, Cannibals and Neuropathology. J. Neuropathol. Exp. Neurol. 2012;71(2):92–103.
4. Cortelli, Gambetti, Montagna, Lugaresi. Fatal familial insomnia: clinical features and molecular genetics. J. Sleep Res. 1999;8(S1):23–29.
5. Neumann EN, Bertozzi TM, Wu E, et al. Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor. Science. 2024;384(6703):ado7082.
6. Minikel EV, Zhao HT, Le J, et al. Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints. Nucleic Acids Res. 2020;48(19):10615–10631.