1700s- Farmers report sheep with scrapie-like symptoms 1913- Creutzfeldt observes a patient with CJD 1918- McFadyean publishes a landmark paper on scrapie 1921-1923- Creutzfeldt writes three papers describing 5 patients with CJD 1934/1935- Jean Cuille and Paul-Louis Chelle inject brain slurry from scrapie sheep into a sheep and observe scrapie symptoms twenty-two months later 1936- Gordon produces the louping ill vaccine 1937/1938- Sheep injected with louping ill vaccine show signs of scrapie 1947- Scrapie appears in the US TME was identified in Wisconsin by Hartsough 1955- Zigas arrives in New Guinea and observes Kuru in the Fore tribe 1957- Gajdusek arrives in New Guinea and observes Kuru Gajdusek sees the similarities between CJD and Kuru Gajdusek and Zigas write two articles about Kuru The possibility of cannibalism as the causes is considered but dismissed Timeline of What We Know So Far
1958- USDA sends Hadlow to Compton to research Scrapie 1959- Hadlow sees Gajdusek's kuru show at the Wellcome Medical Museum Hadlow sends a letter to Gajdusek describing the similarities between scrapie and kuru 1961- Lindenbaum and Glasse arrive in New Guinea Ann and John Lyle publish a paper on the possible relationship between cannibalism and kuru 1963- Gibbs and Gajdusek inject a chimp with Kuru as well as other animals. They begin working at Patuxent. A veterinarian in Idaho reports signs of a neurological disease in Mink. It became clear that rendered cows were used as feed for the mink. 1963- Hadlow shows TME is transmissible by injecting mink brain slurry into another mink 1964- Gajdusek holds a conference at NIH describing kuru, scrapie, CJD and related diseases 1965- The chimps injected with Kuru begin to show Kuru symptoms 1967- Alpers had a “ eureka ” moment about cannibalism and kuru 1968- Gibbs, Gajdusek and Alpers publish a paper in Science publish their findings 1976- Gajdusek wins Nobel Prize Timeline of What We Know So Far
Chapter 8: Rivalry and Scrapie Strains Compton vs Moredun “The Battle of Washington” Alan Dickinson with Richard Chandler at Compton Identified more than twenty scrapie “strains” Strain 22C and 22A Results and conclusions Strain 22A outcompeted strain 22C Showed scrapie strains competed with each other in the same host animal
Chapter 8: Dr. Tikvah Alper Dr. Tikvah Alper- 1967 Radiobiologist Tried to kill scrapie with ultraviolet and gamma radiation Major idea: Said scrapie was too small to be a virus and proposed scrapie could be replicated without DNA http://www.nature.com.proxy- um.researchport.umd.edu/nature/journal/v214/n5090/pdf/214764 a0.pdf
Chapter 8: Hunter and Griffith Gordon Hunter Institute for Research on Animal Diseases at Compton Tried to isolate infectious agent using enzymes so it could be purified Had more success than Dr. Alper with enzymes that break down proteins over radiation Conclusion: Proteins are essential to scrapie Mathematician J.S Griffith “Is a self-replicating protein completely out of the question?” http://www.nature.com.proxy- um.researchport.umd.edu/nature/jou rnal/v215/n5105/pdf/2151043a0.pdf Nature vol 215 September 2, 1967
Dr. Stanley Prusiner Described as very competitive and eager (“publish or perish”) Had a patient with CJD “I began to think that defining the molecular structure of this elusive agent might be a wonderful research project” Worked with Hadlow on scrapie 1968- Traveled to New Guinea and worked with Kuru patients with Gadjusek Research led him to believe infectious agent was a protein and not a virus
Patricia Merz Graduate student Wanted to try to look at the infectious agent Electron microscope “Sticks” were denser in later stages of the disease Later called scrapie- associated fibrils (SAF) Were they causing the disease or were they a cause of the disease? Nature vol 306 Dec 1, 1983 http://www.nature.com.proxy- um.researchport.umd.edu/nature/journal/v306/n5942/pdf/306474a0.pdf
Naming The Infectious Agent http://www.jstor.org.proxy- um.researchport.umd.edu/stable/pdfplus/1687927.pdf?acceptTC=true&acceptTC=true&jpdConfirm=true Science-1982
Backlash Gajdusek: “I pointed out to [Prusiner] that I would give the disease agents a proper name when we were sure what the molecular structure was… It was a clever political move on his part to jump the gun” Do you think it is fair that Prusiner named the infectious agent?
Prion Protein (PrP) Prusiner and Leroy Hood Determined sequence and structure of the prion protein PrP was found in normal cells, but with different properties. Normal: easily digested with certain enzymes Scrapie Protein: Resistant to these enzymes, different shape Prusiner receives the Nobel Prize- 1997 After all Prusiner has done with Hood, has your decision changed on whether you think he had the right to name the infectious agent?
How it works! Domino Effect Susceptibility There are different mutations in the prion protein that make individuals more or less susceptible to CJD or Kuru Mutations at position 129 Met/Met 129 lethal mutation (40% European and US population) Val/Val 129 lethal mutation (13% European and US population) Different shapes of prion protein have been found that affect susceptibility