Prions: A Mysterious Infectious Agent

By Daria Zaitseva

What could possibly link a sheep illness called scrapie, a disease associated with cannibalism called Kuru, and a neurodegenerative disease called Creutzfeldt-Jakob disease? These fatal diseases occur in different species, and yet share a chilling commonality. More mysteriously, scientists could not identify the pathogen – neither virus nor bacteria were the culprit. Human’s knowledge at that time simply could not break the mystical curse. Let’s explore the mystery and see how one of the most obscure killers was discovered.

Scrapie: Affected Sheep Uncontrollably Scratching Their Backs

We begin in 18th-century England, where sheep farming was a cornerstone of the economy. But farmers soon faced a disturbing problem: Some sheep began scratching their backs against posts uncontrollably, then stopped feeding and became lame, and eventually turned emaciated and died [1]. The only way to prevent the spread of the disease was to isolate the sick animals from the flock. Nevertheless, without the ability to investigate further, this eerie disease was soon forgotten [1].

By the middle 20th century, scientists took a closer look [1]. They tried to identify the underlying pathogen. As the first step, they succeeded in experimentally transmitting the disease by inoculating the brain or spinal cord tissue from a diseased animal to a healthy one. The onset of disease can take as long as one to two years, so it left the scientists confused about the results of the experiment at first. Then, scientists attempted to identify the pathogen by treating tissue samples with different standard inactivation methods at the time, such as using a bacterial exclusion filter to remove, if any, bacteria. They also applied a dose of ionizing radiation that could disrupt, if any, nucleic acid (including DNA and RNA) in a separate experiment. However, the tissues remained infectious, so they realized the pathogen could be unusual this time. The only clues from brain dissections are the signature vacuoles – described as “soap bubbles” – in the cytoplasm of nerve cells, and the strange holes – called spongiform – in the sheep’s brains, giving the brain a sponge-like appearance.

Kuru: A Mystical Curse Associated with Cannibalism

As scrapie returned to the limelight, two medical doctors, Daniel Gajdusek and Vincent Zigas, reported firsthand in 1957 from Papua New Guinea a mysterious disease that some believed was associated with cannibalism [1, 2]. Kuru was first discovered in the Fore tribe, with victims trembling, losing muscle control, laughing uncontrollably, and dying within months. The disease primarily affected women, with a female-male ratio of 14:1 in adults.

In 1959, William Hadlow, an American veterinarian working on scrapie, happened to visit an exhibition on kuru in a medical museum in London [3]. He was shocked to find striking similarities between the two progressive degenerative diseases, from the signature “soap-bubbles” in the nerve cells, the extensive incubation period, to the failure in isolating a microbial agent [4].

After that, Hadlow wrote a letter to the editor of The Lancet, and also reached out to Gajdusek, drawing scientists’ attention to the high resemblance of the two diseases [5]. Later, Igor Klatzo, a neuropathologist who studied the brains of 12 kuru patients received from Gajdusek, also drew parallels between kuru and another human spongiform brain disease, Creutzfeldt-Jakob disease (CJD) [6]. In the next decade, scientists were able to experimentally transmit kuru and CJD to chimpanzee by inoculating infected human brain tissue, and later to laboratory rodents [1].

For kuru, we now understand that the disease spread through cannibalism: Female relatives would consume their relatives’ bodies as a mortuary practice “to free the spirit of the dead [7, 8],” during which they ingested the infected human brain concentrated with the infectious agent.

Creutzfeldt-Jakob Disease: Lessons to Scientists

So, what was the infectious agent? Stanley Prusiner, an American neurologist and biochemist, recalled the bizarre observation in his CJD patients: There was no immune response elicited – no fever, no increase in white blood cell count, and no humoral immune response – meaning that whatever caused the disease might not be a foreign agent [9].

With his biochemistry background, Prusiner decided to approach the problem differently by attempting to purify the infectious agent from affected mice inoculated with scrapie agent [9]. After harvesting and blending the spleens and brains of the mice, the homogenate was centrifuged for different times and speeds to separate constituents with different densities. After testing the infectivity of each sample, a highly infectious fraction was recovered despite the removal of over 98% of proteins and polynucleotides. With this cleaner sample, scientists demonstrated that infectivity could be reduced by procedures that hydrolyze or modify proteins, eventually leading to the discovery that the culprit wasn’t a microbe at all, but a misfolded protein.

Prion: The Misfolded Protein

Proteins are essentially amino acid chains, which are folded into precise shapes to function properly. Despite the lack of knowledge about its precise function, prion (PRNP) gene encodes normal prion protein which is active in the brain [10]. However, the amino acid chain somehow misfolds, and these deformed proteins, usually referred to as “prions” (derived from “proteinaceous infectious particles”), can damage nerve cells [11]. Even worse, they can convert the normal prion protein into more prions, enabling them to multiply exponentially within the body and transmit among individuals through ingestion of affected tissue or direct contact of body fluid. Some prion diseases, such as fatal familial insomnia, are heritable; mutations in PRNP gene which can induce the formation of the abnormal protein were identified in those cases [12].

Prion accumulation then destroys brain tissue, creating the sponge-like holes seen in scrapie, kuru, and CJD. Unlike most other pathogens, such as bacteria or viruses, prions have no DNA – so perhaps they are not “programmed” to infect the host, but rather a tragic mistake of nature, simply a mistake in the folding process. Yet, they cause incurable, fatal diseases across species. 

Conclusion

The history of prions is a testament to the power of scientific curiosity, perseverance, and collaboration. What began as a radical and controversial idea challenged a fundamental biological dogma and ultimately reshaped the understanding of multiple fields. As scientists continue to confront new mysteries in biology and medicine, this story serves as an inspiration: Truth is not always obvious, but with rigor, collaboration, and intellectual courage, even the most unconventional ideas can shed light on the darkest of nature’s secrets.

References

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[2] Gajdusek, D. C., & Zigas, V. (1957). Degenerative Disease of the Central Nervous System in New Guinea. New England Journal of Medicine, 257(20), 974–978. https://doi.org/nejm195711142572005

[3] Hadlow, W. J. (2008). Kuru likened to scrapie: the story remembered. Philosophical Transactions of the Royal Society of London B: Biological Sciences, 363(1510), 3644. https://doi.org/10.1098/rstb.2008.4013

[4] Hadlow, W. J. (1959). Scrapie and Kuru. Lancet, 274(7097), 289–290.

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[8] Alpers M. P. (2008). The epidemiology of kuru: monitoring the epidemic from its peak to its end. Philosophical Transactions of the Royal Society of London B: Biological Sciences, 363(1510), 3707–3713. https://doi.org/10.1098/rstb.2008.0071

[9] Prusiner, S. B. (1998). Prions. Proceedings of the National Academy of Sciences of the United States of America, 95(23), 13363–13383. https://doi.org/10.1073/pnas.95.23.13363

[10] National Library of Medicine. (2024, June 28). PRNP gene: prion protein (Kanno blood group). MedlinePlus. https://medlineplus.gov/genetics/gene/prnp/

[11] Ramanan, V. K. (2025, February 14). Transmissible Spongiform Encephalopathies. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/health-information/disorders/transmissible-spongiform-encephalopathies

[12] Bernardi, L., & Bruni, A. C. (2019). Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review. International Journal of Molecular Sciences, 20(14), 3606. https://doi.org/10.3390/ijms20143606