In the eastern highlands of Papua New Guinea, among the people of the Fore tribe, there was a disease observed and reported by Arthur Carey in 1951. The disease progressed in three stages, and the symptoms generally were tremors and muscle jerks, coordination problems, difficulty swallowing, dementia, and difficulty walking. This disease, Kuru, was mainly prevalent in the Fore tribe and their intermarried neighbours. Kuru majorly affected women and children, with a very low percentage of adult men cases. In 1953 John McArthur, a patrol officer, described the disease in his report and explained that in the Fore tribe, Kuru sorcery is practiced. Thus, he related the widely held beliefs and thoughts of the Fore people to the disease. He believed the disease to be psychological, as Fore people at that time had an extreme fear and strongly believed that sorcerers caused Kuru disease. Vincent Zigas, a medical doctor, made a provisional diagnosis of acute hysteria. Thus, in 1955, John Colman sent a case of the disease to Kainantu to be medically observed. However, medical assessments of Kuru victims made it clear that it was an organic disease. In the same year, Frank Earl, a medical practitioner, suggested the disease to be a form of encephalitis. The genetic cause was one of the hypotheses, as Kuru seemed to affect family members and relatives. Detailed analysis to test this hypothesis revealed that it was not a genetic disease. Eventually, they noticed that Fore people consume the dead bodies of their relatives. They observed that women and children eat the brain and viscera of the dead person, but men usually eat the muscles of the dead person. Thus, they supposed that the causing agent is concentrated in the brain and viscera. According to this observation, scientists regarded ritualistic cannibalism as the disease aetiology. Cannibalism was completely abandoned by the late 1950s, and Kuru disease ceased after that. Kuru disease was not seen in individuals born after 1960. However, there were still cases of Kuru disease in individuals born before 1960 for about 30-40 years because the incubation period of Kuru may be unusually long. William Hadlow, an American veterinary pathologist, mentioned the similarities between Kuru and Scrapie (a neurodegenerative disease of sheep and goats that progresses slowly) in a letter he sent to Daniel Carleton Gajdusek, a virologist who was in New Guinea at that time, in 1959. [1]
It was suggested that the causing agent of Kuru disease might be a slow, latent, and temperate virus. Although the disease was suspected to be an infectious disease, victims had no inflammatory signs. All attempts using tissue cultures to isolate the microorganism were unsuccessful. In an experiment carried out by Gajdusek, Gibbs, and Michael Alpers, brain material of the dead infected person was injected into chimpanzees, and as a result, the injected chimpanzees clinically exhibited similar presentations to Kuru disease. By doing this experiment successfully, only Daniel Carleton Gajdusek won the Nobel Prize in 1976. [1] [2]
In 1972, Stanley B. Prusiner started residency in the neurology department at the University of California San Francisco. He was surprised by a case of Creutzfeldt-Jakob disease (CJD)*, which at that time was categorized as a “slow virus” infection. After some investigation, he learned that scientists are not sure if the causative agent of the disease is a virus or not since it has unusual properties. Unusual properties of the causative agent were the ability to isolate the causing agent from formalin-fixed tissues, and compounds known to inactivate bacteria and viruses were unable to inactivate the causing agent, such as ionizing radiation, UV radiation, extreme heat, high pressure, etc. As he read more about CJD and related diseases such as Kuru of the Fore tribe of New Guinea, and Scrapie of sheep, he became more curious. He started reading every published paper about slow virus diseases. The slow, expensive assays for Scrapie’s agent in mice were an obstacle to progress, but he managed to set up a lab in 1974 to study Scrapie. His first National Institute of Health (NIH) application on Scrapie was disapproved, but later he attained modest NIH support for his study on Scrapie. He studied on sedimentation behaviour of the Scrapie agent and tried to purify the causing agent. He expected the agent to be a small virus, but the resulting data of their preparations and experiments indicated the purified agent to be a protein, not nucleic acid. He was surprised; he thought the result could be due to an artifact, and the conclusion of his study seemed to be going wrong. Howard Hughes Medical Institute (HHMI) did not renew their support to fund his study, but he managed to receive funding from the R. J Reynolds company and the Sherman Fairchild Foundation. He continued studying on Scrapie agent, and continuously the resulting data showed the absence of nucleic acid and the presence of protein. Eventually, he became more confident that the causing agent was not a virus but a protein. He decided to publish his findings in an article in 1982. In his research paper, he introduced the term Prion derived from “protein infection,” which was the causing agent. Scientists were sceptical, and the result was unbelievable; thus, investigators and other researchers started to work on the causing agent to find the nucleic acid of the slow virus, but no nucleic acid was found. It was difficult to believe that a protein is the causing agent, can be transmitted, and can propagate. The prion contraindicated the central dogma of molecular biology. Before Stanley Prusiner, Griffith was the first scientist to confidently suggest the causing agent to be a protein. Even though there were other scientists before and after Griffith suggested the agent to be a protein, Stanley Prusiner put the “protein-only hypothesis” to a new level. In 1997, Stanley B. Prusiner received the Nobel Prize in Medicine for the discovery of prion. Next, Prusiner, Leroy Hood, and Charles Weissman were able to identify the sequence of N-terminal peptides of prion protein. With further study, they concluded that DNA coding for prion peptide sequence is also expressed in healthy tissues, majorly in the brain and heart. Prusiner used proteinase K to test the difference between healthy and diseased tissue prions. He noticed that cellular prion protein (Prpc) found in healthy tissue, was fully degraded by proteinase K. In contrast, the infectious prion protein (Prpsc) found in diseased tissue was only partially degraded by proteinase K. Therefore, he concluded that the two proteins are chemically identical, but their three-dimensional folding is different. That is why misfolded prion protein (Prpsc) does not initiate an immune response because already the cellular prion protein (Prpc) is expressed. Prusiner’s finding correlated to Griffith’s hypothesis he suggested in 1967 that these diseases are caused by a misfolded protein. According to this PrpSC directly interacts with normal cellular prion protein (Prpc) and causes its misfolding. They aggregate together in the brain, leading to neurodegeneration, and increase in number, but the exact mechanism is still not known. [2] [3] [4]
What is known is that these slow-progressing, neuro-degenerative diseases (Scrapie, CJD, Kuru, etc.) are caused by a misfolded protein that is capable of misfolding the host Prpc, this causing agent is a protein, not nucleic acid or microorganism. The human cellular prion protein (Prpc) is encoded on chromosome 20. The infectious prion is chemically similar to the cellular prion, but it is misfolded. These diseases can be transmitted (infected meat products, exposure to infected tissue during a medical procedure, etc.). Till now, there has been no cure for these diseases, and yet there is much to be discovered.
* Creutzfeldt-Jacob disease (CJD) is a rare neuro-degenerative disease that causes dementia, involuntary muscle movement, loss of ability to speak, impaired thinking, and multiple other symptoms that worsen over time.
References
| [1] | G. Agata, S. Beata, L. Shirley, and P. L. Pawel, “Kuru, the First Human Prion Disease,” Viruses, vol. 11, March 2019. |
| [2] | R. Crystal and D. Z. Mark, “A brief history of prions,” Pathogens and Diseases, October 2015. |
| [3] | P. R. Graham, “The Central Region of the Cellular Prion Protein Attenuates the Intrinsic Toxicity of N-Terminus,” 2019. |
| [4] | B. P. Stanley, Madness and Memory: The Discovery of Prions- A New Biological Principle of Disease, Yale University Press, 2014, p. 343. |
