Prions: On the Trail of Killer Proteins
The Mystery of Kuru
In the 1950s, a district medical officer working in the highlands of New Guinea observed a fatal disease among the people of the Fore (FOR-ay) tribe. The Fore people called this sickness kuru, which means "trembling in fear." After intially becoming unable to walk, victims of kuru lost the ability to swallow or chew. Drastic weight loss would inevitably lead to death. Today we know that kuru is one of several diseases in humans and animals caused by prion (PREE-on) proteins.
In 1957, a virologist who had studied several infectious diseases among remote peoples, came to New Guinea to study kuru. Carleton Gajdusek wanted to uncover the cause of this unique and always fatal disease. He searched for sources of toxins in the Fore's diet and environment.
He conducted epidemiological studies and sent samples of brain tissue to the United States to be studied by a neuropathologist. Because there was no sign of inflammation in the bodies or brains of the kuru victims, and because kuru tended to appear within certain families, Gajdusek at first believed kuru was an inherited genetic disorder.
In 1976 Carleton Gajdusek became co-recipient of the Nobel Prize in Medicine for his "discoveries concerning new mechanisms for the origin and dissemination of infectious diseases."
A doctor examines a boy with kuru in New Guinea.
When you look at thin slices of kuru, classic CJD and scrapie brain tissue under the microscope, it is easy to see that they are full of holes. The holes form after misfolded prion proteins kill neurons in the brain. (Photo Credits: clockwise: Kunihiko Kobayashi; University of Iowa; Duke Medical School; University of California, Davis)
In 1959 Gajdusek's work came to the attention of William Hadlow, a research veterinarian who was studying a remarkably similar disease, called scrapie, in sheep. Like kuru, scrapie was a fatal disease that gradually destroyed the brains of sheep, leaving the brain full of holes and producing no immune response. And very importantly, scientists knew that scrapie was infectious.
The similarities between kuru and scrapie led Gajdusek to begin experiments to show that kuru could be transmitted to chimpanzees. He then went on to show that classic Creutzfeldt-Jakob disease (CJD), another spongiform disease in people, was also transmissible.
Ultimately, the rapid spread of kuru was linked to the Fore's funeral rituals: the Fore cooked and ate their dead relatives. This practice was only carried out by the Fore women and children, who lived apart from the men. This explains why men were rarely infected, and why cases appeared within families. The Fore quickly stopped eating their dead, and the spread of the disease stopped. Unfortunately, because of kuru's long incubation time, there are still a few kuru cases among the Fore each year. The people who come down with kuru today are in their 50s and 60s, which means that they have been harboring the disease ever since they ate infected tissue as young children.
What's a Prion
The History of Prions
|1730s||Earliest written record of Scrapie in English sheep; already prevalent in central Europe.|
|1950s||High levels of kuru appear among the Fore people of New Guinea.|
|1960s||Scientists experimentally transmit Kuru and CJD to chimpanzees, demonstrating the transmissible nature of these diseases.|
|1980s||60 people die from CJD after being infected by contaminated surgical instruments. 85 people die after receiving prion-infected growth hormone injections.|
|1982||Dr. Stanley Prusiner coins the term "prion" (PROteinaceous INfectious particle). Highly purified PrP-res is shown to be infectious. He goes on to win the Nobel Prize in Medicine in 1997.|
|1985||Scientists identify the PrP gene and discover that uninfected people produce a normal form of the PrP protein.|
|1986||By the year 2000, nearly 180,000 cattle will become infected. To stop the spread, thousands of cattle are killed.|
|1996||A new variant of CJD is linked to exposure to BSE from British beef. By April 2005, 155 U.K. residents are dead. Because of the long incubation period, cases of CJD due to this incident will likely surface well into the future. The mad cow story isn't over yet.|
A Survey of Spongiform Diseases
Diseases caused by prions are known as spongiform diseases, because the brain tissue in infected individuals is filled with holes, giving it a sponge-like appearance. Although prions are found throughout the brain, the symptoms of spongiform diseases vary according to the regions they are most concentrated in. There are currently no effective treatments for spongiform diseases and all are fatal.
Classic CJD or Creutzfeldt-Jakob disease (human)
- The most prevalent of the spongiform diseases
- Occurs spontaneously in 1 out of a million people
- 10% of cases are inherited mutations in the PRPN gene
- Usually strikes people age 50 to 75
- Symptoms: dementia, muscle twitching, vision problems
Fatal Familial Insomnia (human)
- All cases are inherited mutations in the PrP gene
- Usually strikes people age 36 to 61
- Disruption of sleep/wake cycle leads to coma, then death
Scrapie (goats, sheep)
- Occurs as infection in genetically susceptible sheep
- There is no evidence of spread to humans
BSE or Bovine Spongiform Encephalopathy (cattle)
- Also known as "Mad Cow Disease" because infected animals act strangely and can be aggressive
- Spread rapidly through Britain by rendering
Chronic Wasting Disease (deer, elk)
- Infectious disease in wild deer and elk primarily in the western United States
- Drooling, difficulty swallowing, weight loss
- Struck members of the Fore tribe in the 1950s and 1960s
- Muscle weakness, loss of coordination, tremors, inappropriate episodes of laughter or crying
- Transmitted by ritual cannibalism as part of funeral ceremonies
The Controversy Behind Prions
The idea that a protein alone could transmit disease has been around since the 1960s. New evidence has been stacking up to support this idea ever since.
Ever since Stanley Prusiner coined the term prion in 1982 and showed that purified prions can transmit spongiform disease, skeptics have been trying to prove him wrong. The idea that a protein can reproduce itself without going through a nucleic acid intermediate goes against everything we know about transmissible diseases. Even the simplest viruses contain genetic material, DNA or RNA, that codes for proteins necessary for function and transmission. Because prions appear to be infectious proteins that can self-replicate, the central dogma of molecular biology, (DNA to RNA to protein) seems not to apply here. So maybe these scientists are right to be skeptical. To the right are some of the reservations skeptics have about the protein-only hypothesis.
The strain phenomenon
Scrapie and other spongiform diseases come in distinct strains that differ in their incubation period, symptoms, and effects on different brain regions. Skeptics argue that these differences are due to mutations in nucleic acid and is evidence that prions do indeed have genetic material.
Information from other amyloid diseases
Alzheimer's disease, Parkinson's disease and Huntington's disease are also characterized by the formation of misfolded protein into amyloid fibers, resulting in neurodegeneration. But these diseases are not infectious, leading to the argument that misfolded protein alone is not enough to transmit disease.
Answering the skeptics
The ultimate test of the protein-only hypothesis would be to produce PrP-res in a test tube, inject it into a normal healthy brain, and show that spongiform disease results. In April 2005, scientists at the University of Texas performed this experiment successfully showing that PrP-res is indeed infectious. Questions still remain about what exactly triggers the folding of PrP-sen into PrP-res.
You Can't Kill What Isn't Alive
Prions cannot be destroyed by boiling, alcohol, acid, standard autoclaving methods, or radiation. In fact, infected brains that have been sitting in formaldehyde for decades can still transmit spongiform disease. Cooking your burger 'til it's well done won't destroy the prions!