Prions: Old Dogma, New Tricks

It started with a cow in 1984 in UK. Tremors, loss of coordination and arched back, Cow 133 was dead within two months. Soon one turned to ten and ten to thousands. Autopsies of brains revealed sponge like holes and it was called Bovine spongiform encephalopathy (BSE) or as the tabloids called it, mad cow disease. 4 million cows were preemptively slaughtered to stop the disease. But something far more worrying occurred to the scientists. What if BSE had already entered the human food chain through beef food products! Their worst fears came true in 1995, when a 19-year-old teen became the first victim. Till date, 178 people have died of this disease. It causes dementia, hallucination, coordination loss and an agonising death in young people. It is a part of a family of diseases called Transmissible spongiform encephalopathies (TSE), caused by something that we still understand very little of.

A feeling, Dr. Daniel Carleton Gajdusek was very familiar with. The year was 1957 and Gajdusek had come all the way to the tropical jungles of Papua New Guinea from America in search of the Fore people. By conventional standards, the Fore were a strange people. They practiced ritualised cannibalism of their dead relatives. Stranger still was the disease plaguing them. It started with unsteady gait and tremors. As the disease progressed, intellectual functions decreased accompanied with marked emotional instability, excessive hilarity one moment and withdrawn behaviour the next. A few patients became aggressive. In the final months, speech was lost, fecal and urinary incontinence developed, chewing and swallowing became impossible, and the patient could no longer sit unaided and became unresponsive to their surroundings. No one survived the disease. As many as 200 people were dying every year in the late fifties. The natives believed it to be sorcery and called it kuru. A man undaunted by physical challenges, Gajdusek rose to the intellectual challenge presented by kuru and wanted to be the first to overcome it. He knew the symptoms suggested brain disease and observed that it selectively affected women and children more than men. But as he hiked through the jungle, collecting urine and blood samples, performing autopsies, treating patients, interviewing the Fore people and understanding their culture, the cause of the disease proved elusive. Some of these autopsied brain slices made their way to Dr. Igor Klatzo. What he saw was chaos! Degenerated neurons with distorted shapes, odd, dark plaque like deposits, dilated blood vessels, and small haemorrhages. There was extensive damage to the cerebellum, the motor control and coordination centre. He noted the similarity to “Creutzfeldt-Jakob disease (CJD)”, a new disease at that time giving the first clue to a link.

That is when serendipity, the good Samaritan of science, struck.
Some of his brain slice micrographs were displayed in a travelling exhibit that made their way to England where they were seen by Bill Hadlow in 1959. Hadlow, a veterinarian with a deep knowledge of neuropathology immediately noticed the uncanny resemblance of the kuru brain samples with that of sheep afflicted with scrapie, a disease first discovered in 1732 and with a long incubation period. Infected sheep suffered from an intolerable itch rubbing themselves against fences till they were virtually naked. It was invariably fatal. In noting the resemblances and applying existing knowledge on scrapie, Hadlow made the crucial suggestion in a letter to Gajdusek, that kuru could be experimentally induced in a laboratory primate. Gajdusek began inoculating chimpanzees with kuru-infected brain extracts in 1963 and two years later, the first symptoms appeared validating Hadlow’s claims. Eventually, it was shown that even CJD could be transmitted to primates. But the nature of the infectious agent was still unknown.

Dr. David Wilson was the first person to closely examine this agent. Among other things he discovered that it resisted destruction by a wide range of things like formalin, phenol, chloroform and even UV rays. Astounding! But he never published his results. Yet, something even more radical was brewing in the horizon.

Enter Dr.Tikvah Alper, a radiation specialist, who boldly went where no person had gone before. Through a series of brilliantly designed experiments, she showed that the scrapie causing agent had neither DNA or RNA. This was heresy! Only a few years before, Watson and Crick had shown in their “central dogma” (DNA makes RNA makes protein) that DNA was the heart of life and now, Dr. Alper was challenging not only this golden rule but was also going against the majoritarian view that scrapie, and by extension, kuru was caused by a virus. During this time, the knowledge about CJD was also increasing. It was a rare neurodegenerative disease which affected one in a million people. It affected both men and women in their fifties and sixties. But CJD also infected people in curious ways- a woman who had received a corneal implant from a man who was later diagnosed with CJD became afflicted with the same, eighteen months later. In 1976, two CJD victims were found to be infected by electrodes implanted in a CJD patient in 1974. Somehow it was bypassing rigorous sterilisation techniques in hospital!

A breakthrough was needed to bring these disparate ideas together. That was provided by Dr. Stanley Prusiner in 1982 who corroborated Alver’s claim that it was indeed proteins that was the infectious agent causing scrapie, kuru, CJD, and BSE. He called them prions. Along with other scientists, he discovered that there was indeed a gene coding for the prion protein, thus validating the central dogma once more. He also showed that these protein particles- prions, existed in two forms- a good, normal form and a bad, disease causing form and it was this bad protein form moving from cell to cell causing diseases. This radically changed what people knew about proteins then- that they could fold and form one shape only. These bad prions formed clusters and when they encountered the good prions in brain cells (neurons), they turned it into a bad prion and prevented them from carrying out myriad functions, like regulating cell death, long term memory formation, immune system functioning etc. For his contribution towards prion science, he was awarded the Nobel Prize in 1997.

We are still far from understanding the disease-causing mechanism or curing prion diseases in humans but hope is on the horizon. Scientists have discovered that decreasing prion protein production either through switching the gene off or blocking the RNA that produce it can reverse prion disease in mice. Furthermore, prions have revolutionized our knowledge of disease transmission and increased our understanding of diseases like Alzheimer’s and Parkinson’s. It has opened frontiers in science and biology.

References:

  1. Gajdusek, D. C., & Zigas, V. (1957). Degenerative disease of the central nervous system in New Guinea: the endemic occurrence of kuru in the native population. New England Journal of Medicine, 257(20), 974-978.
  2. Gajdusek, D. C., & Zigas, V. (1959). Kuru: clinical, pathological and epidemiological study of an acute progressive degenerative disease of the central nervous system among natives of the Eastern Highlands of New Guinea. The American journal of medicine, 26(3), 442-469.
  3. Gibbs, C. J., Gajdusek, D. C., Asher, D. M., Alpers, M. P., Beck, E., Daniel, P. M., & Matthews, W. B. (1968). Creutzfeldt-Jakob disease (spongiform encephalopathy): transmission to the chimpanzee. Science, 161(3839), 388-389.
  4. Hadlow WJ. Scrapie and kuru. Lancet 1959;2:289–90
  5. Ingram, J. (2013). Fatal flaws: how a misfolded protein baffled scientists and changed the way we look at the brain. Yale University Press.
  6. Alper, T., Haig, D. A., & Clarke, M. C. (1966). The exceptionally small size of the scrapie agent. Biochemical and biophysical research communications, 22, 278-284.
  7. Alper, T., Cramp, W. A., Haig, D. A., & Clarke, M. C. (1967). Does the agent of scrapie replicate without nucleic acid?. Nature, 214(5090), 764-766.
  8. Zabel, M. D., & Reid, C. (2015). A brief history of prions. Pathogens and disease, 73(9).
  9. Prusiner, S. B. (1982). Novel proteinaceous infectious particles cause scrapie. Science, 216(4542), 136-144.
  10. Prusiner, S. B., Groth, D., Serban, A., Koehler, R., Foster, D., Torchia, M., … & DeArmond, S. J. (1993). Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies. Proceedings of the National Academy of Sciences, 90(22), 10608-10612.
  11. Prusiner, S. B., McKinley, M. P., Bowman, K. A., Bolton, D. C., Bendheim, P. E., Groth, D. F., & Glenner, G. G. (1983). Scrapie prions aggregate to form amyloid-like birefringent rods. Cell, 35(2), 349-358.
  12. Minikel, Eric Vallabh, Hien T. Zhao, Jason Le, Jill O’Moore, Rose Pitstick, Samantha Graffam, George A. Carlson et al. “Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints.” Nucleic acids research 48, no. 19 (2020): 10615- 10631.
  13. https://www.iatp.org/news/human-deaths-from-mad-cow-disease-rising-by-a-third-inbritain
  14. https://www.nytimes.com/1999/01/26/science/britain-details-the-start-of-its-mad-cowoutbreak.html

Written by Rohan Sarkar

Ph.D student in Ethology

IISER Kolkata

Twitter: https://twitter.com/SarkarRohan1

Instagram: https://www.instagram.com/mandrax100/

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