TAYLOR GOLDBECK

Brain Trust Chapters 8 & 9

1700s- Farmers report sheep with scrapie-like symptoms1913- Creutzfeldt observes a patient with CJD1918- McFadyean publishes a landmark paper on scrapie1921-1923- Creutzfeldt writes three papers describing 5 patients with CJD1934/1935- Jean Cuille and Paul-Louis Chelle inject brain slurry from scrapie sheep

into a sheep and observe scrapie symptoms twenty-two months later1936- Gordon produces the louping ill vaccine1937/1938- Sheep injected with louping ill vaccine show signs of scrapie1947- Scrapie appears in the US

• TME was identified in Wisconsin by Hartsough1955- Zigas arrives in New Guinea and observes Kuru in the Fore tribe1957- 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 Scrapie1959- Hadlow sees Gajdusek's kuru show at the Wellcome Medical Museum

• Hadlow sends a letter to Gajdusek describing the similarities between scrapie and kuru1961- 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 mink1964- Gajdusek holds a conference at NIH describing kuru, scrapie, CJD and related diseases1965- The chimps injected with Kuru begin to show Kuru symptoms1967- Alpers had a “eureka” moment about cannibalism and kuru1968- Gibbs, Gajdusek and Alpers publish a paper in Science publish their findings1976- 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/214764a0.pdf

Chapter 8: Hunter and GriffithGordon 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/journal/v215/n5105/pdf/2151043a0.pdf

Nature vol 215 September 2, 1967

Dr. Stanley PrusinerDescribed 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 studentWanted 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

Merz, Somerville, Gibbs, Gadjusek- 1984

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

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 EffectSusceptibility

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