Background to Mad Cow Disease in Humans

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Background to Mad Cow Disease in Humans
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The Beginnings

• Hans Gerhard Creutzfeldt
• Worked with Alois Alzheimer in Germany
• In 1920 he published a paper describing a new
  neurological disease, some of the symptoms
  included
• Difficultly walking
• Tremors, uncontrollable muscle movement
• Incoherent speech, disorientation
• Strange behavioral changes
• Eventual paralysis and death
• Autopsy revealed holes in the brain tissue which
  make the brain look like a sponge, hence the
  classification of this disease as a
• Spongiform encephalopathy

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The Disease is Named

• Alfons Maria Jakob
• A well known German professor of neurology
• In 1921-23 he published three articles describing
  5 different cases that showed similar symptoms to
  what Creutzfeldt had described
• Gradual impairment of motor function
• Problems with speech
• Loss of emotional control and personality changes
• Eventual paralysis and death
• From first symptoms to death takes, on average,
  five months.
• A colleague of both Creutzfeldt and Jakob
  referred to the condition as Creutzfeldt-Jakob
  disease, or CJD.

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Kuru and the Fore People of Papua New Guinea

• In the 1950s Australia administered Papua New
  Guinea and wanted to gain control over its
  primitive tribal people to reduce
• The constant tribal warfare
• The practice of cannibalism
• A young doctor, Vincent Zigas, on an early
  pacification mission became aware of a disease of
  the Fore tribe
• I observed a small girl sitting down beside a
  fire. She was shivering violently, and her head
  was jerking spasmodically from side to side. I
  was told that she was a victim of sorcery, and
  would continue this shivering unable to eat until
  death claimed her within a few weeks.
• The disease was called Kuru, a Fore word meaning
  to tremble.

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Carl Gajdusek Makes a Series of Important
Observations

• In 1957, Carl Gajdusek (Guy-doo-shek), an
  American physician on his way home from a
  fellowship in Australia, stopped in Papua New
  Guinea and discovered his lifes work.
• Observations/Evidence
• The victims brains were sent to NIH and
  recognized to be similar to the brains of CJD
  victims.
• The incidence of Kuru was greatest in women and
  young children- not adult males.
• The Fore were cannibals- they ate their dead
  relatives as an act of homage.
• Men ate the muscle, woman and children ate the
  brains.

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Gajduseks Nobel Prize Winning Discovery

• Through a series of experiments he established
  that Kuru was an infectious disease, transmitted
  through the cannibalistic practices of the Fore.
• He was able to get the Fore to stop cannibalism
• Incidence of Kuru peaked in the 1960s and has
  been decreasing ever since.
• However, symptoms of the disease may not appear
  for decades.
• Last year a person died of Kuru, even though
  cannibalism has been discontinued for over 40
  years!
• Gajdusek won the Nobel Prize in 1976 for
  demonstrating for the first time in the history
  of medicine that human diseases causing central
  nervous system degeneration could be infectious.
• A new category of disease was identified
• Transmissible spongiform encephalopathies (TSE)
• Title of his Paper Unconventional Viruses and
  the Origin and Disappearance of Kuru
• First sentence Kuru was the first chronic
  degenerative disease of man shown to be a slow
  virus infection, with incubation periods measured
  in years with a progressive accumulative
  pathology always leading to death.

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Is TSE Caused By A Virus?

• In the 1960s most scientists studying TSEs,
  which included Kuru and a similar disease in
  sheep, called scrapie, believed viruses were
  responsible.
• A number of experimental results caused them to
  begin to question the viral hypothesis
• The agent remained infective after being exposed
  to temperatures of 6000 C which was highly
  unusual for viruses.
• Using a high energy beam of electrons the agent
  was shown to be smaller, by a factor of 10, than
  any known virus.
• UV treatment to destroy nucleic acids did not
  affect the infectivity of the agent.
• Problems still existed for researchers studying
  TSEs
• No good model animal existed on which to research
  TSEs
• Scrapie in sheep was hard to study because it
  took several years for them to come down with the
  disease, etc.

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Stanley Pruisners Breakthrough

• Finally by the early 1980s Stanley Pruisner of
  UCSF made a huge breakthrough
• He was able to cause hamsters to come down with
  scrapie
• This shortened the disease incubation time
• Easier to raise hamsters
• Experimental results
• It was impossible to destroy the infectivity
  using sophisticated compounds that destroyed
  nucleic acids (nucleases, etc.)
• Chemicals that denatured or digested protein
  inactivated the infective agent
• The size of the agent was determined to be about
  250 amino acids long!
• 1982 Publication in Science
• Because the dominant characteristics of the
  scrapie agent resemble those of a protein, an
  acronym is introduced to emphasize this feature.
  In place of such terms as unconventional virus
  or unusual slow virus like agent, the term
  prion (pronounced pree-on) is suggested.
• Prion is derived from Proteinaceous Infectious
  Particle

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1997 Nobel Prize

• Pruisner won the 1997 Nobel Prize for his
  discovering a new biological principle of
  infection
• How Might a Protein Infect?
• The current theory was proposed in 1967 by J.S.
  Griffith an English mathematician who was
  speculating how scrapie might be transmitted!
• He proposed that proteins could replicate
  without nucleic acid (RNA or DNA) .
• It was suggested that the scrapie agent could be
  a malformed version of a normal protein existing
  in healthy hosts.
• The agent was thought to act as a template that
  created malformed versions of the hosts protein
  and hence lead to disease.

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Current Status of TSE Disease in Humans

• It is now known that we all have normal prion
  proteins
• The incidence of CJD in human populations is 1 in
  a million.
• This is called sporadic CJD and spontaneously
  arises in humans
• Perhaps it is due to some change in the human
  prion protein
• Mad Cow Disease and Humans
• Prions are the cause of mad cow disease
• The name of the disease is Bovine Spongiform
  Encephalophathy (BSE)
• It probably first appeared spontaneously, just as
  CJD appears spontaneously in human populations,
  and then was spread widely in cattle populations
  by cow cannibalism ( just as Kuru was spread in
  the Fore by human cannibalism).
• It jumped the species barrier to humans by human
  ingestion of infected beef
• Humans who catch the disease from cows have a
  disease which is similar to CJD and is called
  variant CJD (vCJD)
• As of December 1, 2003 153 people have been
  diagnosed with vCJD
• Almost all cases are from England due to their
  outbreak of mad cow disease in the 1980s
• It is a fatal disease with no known cure

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