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Brain Trust Chapters 8 & 9. Taylor Goldbeck. Timeline of What We Know So Far. 1700s - Farmers report sheep with scrapie -like symptoms 1913 - Creutzfeldt observes a patient with CJD 1918 - McFadyean publishes a landmark paper on scrapie

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timeline of what we know so far
Timeline of What We Know So Far
  • 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 far1
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
chapter 8 rivalry and scrapie strains
Chapter 8: Rivalry and Scrapie Strains
  • Compton vsMoredun
  • “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
Chapter 8: Dr. TikvahAlper

http://www.nature.com.proxy-um.researchport.umd.edu/nature/journal/v214/n5090/pdf/214764a0.pdf

  • Dr. TikvahAlper- 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
chapter 8 hunter and griffith
Chapter 8: Hunter and Griffith

Nature vol 215 September 2, 1967

http://www.nature.com.proxy-um.researchport.umd.edu/nature/journal/v215/n5105/pdf/2151043a0.pdf

  • 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?”
dr stanley prusiner
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
Patricia Merz

Nature vol 306 Dec 1, 1983

http://www.nature.com.proxy-um.researchport.umd.edu/nature/journal/v306/n5942/pdf/306474a0.pdf

  • 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?
merz somerville gibbs gadjusek 1984
Merz, Somerville, Gibbs, Gadjusek- 1984

http://www.jstor.org.proxy-um.researchport.umd.edu/stable/1693519

naming the infectious agent
Naming The Infectious Agent

Science-1982

http://www.jstor.org.proxy-um.researchport.umd.edu/stable/pdfplus/1687927.pdf?acceptTC=true&acceptTC=true&jpdConfirm=true

backlash
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
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
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