When cows go crazy: mad cow disease
- pietrococchiara
- Sep 30
- 5 min read
It was 1986 in the UK when for the first time the mad cow disease, also known as bovine spongiform encephalopathy (BSE) was first discovered in cattle. It took around ten years, in 1996, for BSE to make its way into humans, causing panic with this fatal disease causing rapid onset dementia. In this article, we will explore the origin of this disease and how this became a threat to humans in the past and how today this disease is still under investigation because of limited knowledge available about it.
What is the BSE and how does it originate?
BSE is an incurable and always fatal neurodegenerative disease which affects cattle, more common during the first 5 years of life. It is mostly associated with abnormal behaviour, trouble walking, and weight loss behavioural, which progressively lead to inability of functioning properly in the later stages of the disease. The name derives from the appearance of brain sections observed under the microscope, which are characterized by empty areas which remind of a sponge (from which the adjective spongiform).
BSE is taught to be caused by a prion, an infectious protein. Prions are misfolded forms of proteins normally found in the bodies of animals and people. Because of their misfolding (incorrect structure formation of these proteins), this can lead to a pathological condition, which typically takes years for symptoms to begin after an animal is infected with a prion. Indeed, once a misfolded prion protein is formed, this induces normally-folded proteins to take on the misfolded phenotype in an exponential cascade. These misfolded units can aggregate over the course of the disease and cause neuronal cell death. Inevitably, massive cell death causes the formation of lesions in the brain which lead to degeneration of physical and mental abilities and ultimately death. A similar trend is observed when this infected prions are passed to humans, in which these prions result in the variant Creutzfeldt-Jakob disease (vCJD).
About how this disease originate and spread, different hypothesis have been proposed. Some scientists believe BSE may have been caused by feeding cattle meat-and-bone meal that contained prion-infected products from cows or sheep. Although diet containing prions-infected food and contact of infected materials represent the most common causes for spreading of this disease, also a genetic predisposition has an important role in the development of BSE.
Indeed, while BSE is not directly inherited as a typical genetic disease may be, certain genetic variations which can be present in the PRNP gene, which encodes the prion protein, can influence how susceptible an animal (including humans for vCJD) is to developing BSE. However, the molecular mechanisms, as well the detailed genetic mechanisms, by which this disease can be initiated are still poorly understood and require further studies.
Methods to discriminate healthy from unhealthy prion proteins
As it may be easy to understand, it became extremely important to determine how do distinguish whether an animal has been infected with prions, in order to minimize the risks for human health (via consumption of infected meat), as well as for the animal wellbeing (since often entire herds of cows were exterminated to reduce the spreading of the disease to other animals).
Several methods in the past were developed to reach this goals, considering the poor knowledge we possess around prions and the diseases caused by their misfolding. A key method used to study transmissible prionopathies was a bioassay using transgenic bovinized mice, expressing the bovine version of the prion protein at extremely high levels which reduced the time to develop disease. This model became helpful in determining which host tissues contain BSE infectivity as well as elucidating the intricacies of BSE pathogenesis.
Another method used for detecting low levels of misfolded prion proteins are in vitro conversion assays, called real time quaking induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA). These different methods rely on the molecular principle according which the presence of a PrPSc infected sample acts as a seed to induce the conversion of native PrPC provided as a substrate in the reaction (PrPSc represents the "scrapie", so the infective prion, while PrPC represents the common one, so the healthy prion protein). Successive rounds of incubation to allow the incubation time for the prion to develop and agitation, which is needed to cause disruption of aggregates creating additional seed templates, eventually result in the accumulation of detectable levels of misfolded prion proteins in an in vitro assay. Due to the extremely high sensitivity of these methods, caution must be taken to ensure risks of contamination are minimized and replicate testing is often performed to increase confidence in the results.
Future developments: where are we now?
The current research lines have been used the in vitro system described in the previous paragraph to extend this type of assays to human studies. In facts, by using the same principle, similar test can developed and implemented to determine whether a patient is positive or negative to the vCJD. This goal is reached by collecting a sample from a potentially infected tissue (either brain-derived, or more simply, via a nasal swab) and mixed with a healthy prion protein. If the prion protein derived from the patient is a "scrapie" version, this should induce a conversion of the healthy prion proteins used in the assay into misfolded proteins. By using a fluorescence plate reader, it is possible to visualize whether the patient is positive or not by determining how close the collected values are close to the positive control (usually a "scrapie" protein used to measure that the assay worked correctly).
Although these methods are entering the common routine for screening and testing of animals and human patients with suspected prionopathies, criteria to determine the positivity of the samples tested are still under discussion for a more homogeneity in the diagnostic system used. This is made more complicated because of the restricted number of patients, as well as the limited number of labs and hospital which are able to provide this services. However, scientists are cooperating internationally for improving the early diagnosis of prionopathies and integrating these systems into common clinical practices, as these might save lives in presence of diseases characterized by a high level of lethality and very rapid onset.
References
Nathanson N, Wilesmith J, Griot C. Bovine spongiform encephalopathy (BSE): causes and consequences of a common source epidemic. Am J Epidemiol. 1997;145(11):959-969. doi:10.1093/oxfordjournals.aje.a009064
Lestari TD, Khairullah AR, Utama S, et al. Bovine spongiform encephalopathy: A review of current knowledge and challenges. Open Vet J. 2025;15(1):54-68. doi:10.5455/OVJ.2025.v15.i1.5
Bradley R. Bovine spongiform encephalopathy (BSE): the current situation and research. Eur J Epidemiol. 1991;7(5):532-544. doi:10.1007/BF00143136
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