The Prize:
The 1997 Nobel Prize in Physiology or Medicine went to Stanley B. Prusiner “for his discovery of prions—a new biological principle of infection.” The same prize went to Carleton Gajdusek in 1976 for his half of work on “discoveries concerning new mechanisms for the origin and dissemination of infectious diseases.”
The Science:
The field of prion disease is one rife with controversy, tales of cannibalism, and mad cows. Yet in the midst of all of these peculiarities, two Nobel prizes have been awarded to researchers in a field only 60 years old.
The discovery that many diseases are caused by micro-organisms such as bacteria, fungi, parasites, and viruses fundamentally changed the practice of medicine. Potentially life-threatening infections could be fought off with anti-microbials and anti-fungals that kill the infectious organisms. So when Stanley Prusiner proposed that some neurodegenerative diseases were caused by misfolded proteins, the medical community was baffled. At the time, it seemed impossible that an entity carrying no genetic information could cause disease.
Prusiner’s interest in neurodegenerative disease started in 1972 when he witnessed a patient die of Creutzfeldt-Jakob disease (CJD). CJD is a rare, incurable disease that can cause dementia, memory loss, and loss of motor function, eventually leading to death. CJD can be inherited genetically or acquired later in life. The brains of affected individuals slowly waste away, developing a characteristic “spongy” appearance caused by the empty pockets that once held live neurons.
Prusiner was inspired by his patient’s strange symptoms: her brain function was degrading daily but her body was unaffected and she did not display any signs of infection. This flew in the face of the hypothesis of the time that CJD, like some other documented neurodegenerative diseases, was caused by a “slow virus.” Without any symptoms of infection, Prusiner asked, how could CJD be caused by a virus?
A discovery by Carleton Gajdusek in the 1950s led to the further discoveries connecting the symptoms of CJD, the human disease “kuru,” and the disease “scrapie” in sheep. Kuru is a disease found in the Fore people of the New Guinea highlands. Like CJD, kuru slowly eats away at the brain, leading to death. Women and children of the Fore were especially prone to developing kuru symptoms. Scrapie has a similar prognosis for sheep. These and other similar diseases are now known as the spongiform encephalopathies.
Carleton Gajdusek began studying kuru in the Fore people in the 1950s. After ruling out nutritional deficiency and toxicity, he discovered that kuru was transmitted by ingesting infected human brain tissue. He showed that inoculating infected human brain tissue into chimpanzee brains caused the chimps to succumb to a kuru-like disease. For this work, Gajdusek was awarded a Nobel Prize in 1976. For the Fore people, eradication of kuru was made possible by outlawing the ritualistic cannibalism (which transferred the infectious agent from the dead to the living) that was practiced in honour of the dead. In the outlawed ritual, women and children often ate the less choice body parts, including the brain, which explained why they so often succumbed to kuru.
The chimp brain inoculation experiment was repeated with CJD-infected brain samples yielding the same results. These results allowed scientists to hypothesize that the spongiform encephalopathies were caused by a “slow virus” that had a long incubation time (it took years for the inoculated chimps to display symptoms of kuru or CJD). However, the slow virus hypothesis did not effectively explain how CJD can also be heritable, nor was it supported by the lack of infection-like symptoms such as fever or increased white blood cell counts in affected individuals. In addition, further research showed that the infectivity of diseased brain tissue was remarkably resistant: the samples remained infective after treatment with radiation, UV light, and fixatives, treatments that readily kill viruses and microbes.
Prusiner and his group began looking for the infectious agent of the spongiform encephalopathies and found it in 1982: a single protein. The result received mixed reviews. There were those who were excited by the ramifications that a protein, previously thought to be inert and innocuous, could be an infectious agent. There were others that openly mocked and refuted Prusiner’s results, some without even reading his paper.
Prusiner has said that he and his colleagues were probably the most skeptical of their “protein hypothesis,” but after 10 years of careful experimentation, the protein hypothesis was their only answer. Prusiner and his group showed that a single protein that they named “prion” (short for “proteinaceous infectious particle”) was enough to transfer spongiform encephalopathies between rodents.
The prion protein is a normal brain protein that can exist in two forms, “normal” and “scrapie.” The scrapie form of the protein is prone to aggregation and can catalyze the conversion of normal prion protein to the scrapie form. The scrapie aggregates form plaques, called amyloids, which are toxic to neurons and lead to their death. After a subject ingests a scrapie prion, the protein can migrate to the brain where a virtual domino effect is set into play, eventually converting enough prion protein to the aggregated, scrapie form to destroy neurons.
Prion diseases, however, don’t have to start with the ingestion of scrapie-form prion. The spongiform encephalopathies can also be acquired by a normal prion protein spontaneously converting to the scrapie form, or by a hereditary predisposition to the conversion of normal to scrapie prion. Thus, prion diseases can be hereditary, spontaneous, or infectiously acquired.
Strangely, the prion protein is not essential to mice. It can be “knocked-out” of the mouse genome with little effect to the mouse’s lifetime, behaviour, or health. This has brought up questions over what role the prion protein plays in normal brain function. The fact that prion protein “knock-out” mice are resistant to prion disease, supposedly because they lack the prion proteins necessary to build the toxic plaques, supports the prion hypothesis.
The Significance:
Possibly the most famous outbreak of prion disease was the “mad cow” epidemic of the 1980s and ’90s in Great Britain. Farmers unintentionally spread “mad cow” disease, or bovine spongiform encephalopathy (BSE), by feeding the remains (including brains) of infected cows to uninfected cows. The discovery led to the massive destruction of 4.4 million cattle in Britain that decimated the UK cattle industry. Unfortunately, BSE can be transferred to humans who ingest infected spinal column or brain, causing a CJD variant to develop. CJD acquired this way is thought to have caused the deaths of over 150 people in Great Britain. Media outlets all over the world picled up the “mad cow” story, first as a serious news issue, but eventually it became a running joke. Since the BSE outbreak, governments instituted stricter rules for cattle feeding practices in an effort to limit BSE transmission. Even today, blood donors in Canada and elsewhere are rejected if they spent significant amounts of time in the UK during the ’80s, as blood is also thought to carry the scrapie-form of the prion protein.
Yet the prion hypothesis remains just that, a hypothesis, and one that is hotly debated. Some scientists still hold to the slow virus theory and have some indirect evidence to support their claims. Scientists are also exploring whether exposure to heavy metals is a risk factor or causative agent of the spongiform encephalopathies.
Since the discovery of the prion protein mechanism of pathogenesis, many other diseases have been shown to involve protein amyloid formation. Amyloids made up of proteins other than prion have been implicated in causing Alzheimer’s, Parkinson’s, Type II diabetes, and Huntington’s disease. Yet for all the diseases that protein aggregation can cause, at some level, protein aggregation is actually necessary for some proteins to function normally. For instance, memory formation requires the aggregation of a specific protein within a neuron. Current research in the amyloid field aims at discovering how the body regulates acceptable levels of aggregation of proteins to ensure their proper function, and what triggers the dysregulations that cause disease.
