Prions morphing agents of disease
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Prions are the proteins that cause deadly brain diseases. But how do they cause disease and what is their normal role in the body?
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The discovery of prion proteins as infectious agents began in the 1980s with an outbreak of mad cow disease in the United Kingdom.
Mad cow disease is a fatal condition affecting the nervous system of cattle. In an affected animal, the brain develops tiny holes. The animal loses control over its movements and its behaviour changes so it seems mad.
The tiny holes in the brain are areas where brain cells have degenerated or died. Because of all these holes, the brain of an animal with mad cow disease looks like a sponge hence the clinical name of the disease, bovine spongiform encephalopathy (BSE).
BSE was first diagnosed in Britain in 1986. It is very similar to scrapie, a well-known disease in sheep that has been recorded for more than 200 years. Scrapie is also a spongiform encephalopathy and is always fatal.
Mad cow disease started in Britain after cattle were fed meat-and-bone meal, a protein supplement made from offal from cattle and sheep. This practice had been going on for some time before BSE appeared, but in the early 1980s the way in which offal was processed changed the high temperatures and the quantities of chemical solvents used to sterilise the material were reduced slightly. This may have allowed the disease agent, which is very resistant to all forms of sterilisation, to survive. The origin of BSE is not known: It may have been a spontaneous case of BSE arising in cattle or scrapie in sheep. The most important part of the cause, however, was the use of intraspecies recycling (or cannibalism carried out as a regular practice) in the cattle industry, which allowed repeated cycles of transmission and amplification.
In 1957, D. Carleton Gajdusek (United States National Institutes
of Health) and Vincent Zigas (Australian Public Health Service)
described a strange disease among the Fore highlanders of Papua
New Guinea. Victims of the condition showed a gradual loss of
coordination, which progressed to complete motor incapacity and death. The course of the disease lasted 12 months on average and was always fatal. It affected all ages and both sexes, but it was most common in
Smart scientific detective work showed that the disease, called kuru, was caused by something that was passed on during ritual endocannibalism, when the brains of recently deceased people were eaten. This work involved inoculating chimpanzees with material from the brains of people who had died of kuru and was carried out by Caleton Gajdusek and his colleagues Joseph Gibbs and Michael Alpers. In 1976, Dr Gajdusek was awarded a Nobel prize for his work on kuru. Solving the puzzle of kuru also required detailed knowledge of the epidemiology of the disease and the mortuary practices and social behaviour of the Fore people.
Kuru began to disappear from Papua New Guinea after cannibalism was outlawed. However, it has not yet gone altogether: Remarkably, a few cases are still occurring in the early 2000s with incubation periods of up to 50 years.
Creutzfeldt-Jakob disease (CJD) is another spongiform encephalopathy that occurs in humans. It is very rare: Only about one person in a million per year is affected. Because CJD resembles kuru pathologically, Gajdusek and his colleagues tested it in chimpanzees and found that it too was transmissible. Subsequently it was discovered that when material from a CJD sufferer is transferred to another person, then that person is likely to develop the disease. Possible sources of person-to-person transmission include growth hormone and blood transfusions (Box 1: Public health issues).
But the story of contaminated human health products doesn't explain every case of CJD. The majority of cases seem to occur spontaneously, and the disease is more likely to strike in older people. About 10 to 15 per cent of cases are inherited as a result of a mutation in the DNA, which means it runs in families.
For many years no-one knew exactly what was causing the spongiform encephalopathies. A virus was presumed to be the culprit, even though biologists couldn't find anything that looked like a virus in sick animals. The agent was called a slow (or unconventional) virus because of the long incubation period between inoculation and disease – two years for kuru in chimpanzees – and the long clinical course before the inevitable fatal outcome.
In the 1970s experiments were starting to show that the mystery microbe in sheep (the scrapie agent) was remarkably resistant to many forms of sterilisation. Healthy animals could be infected even after the extract from diseased animals had been zapped with radiation or treated to destroy the genes of any bacterium or virus. It was this ability to survive normal sterilisation that enabled BSE to be passed on to cattle by meat-and-bone meal.
By 1982 an American scientist, Stanley Prusiner, following the work of the radiation biologists, had concluded that the scrapie agent seemed to have no nucleic acid, the material of which genes are made. Clearly, then, it was not a virus or any other known organism and was almost certainly not alive in any real sense. But it appeared to be able to multiply.
When Prusiner discovered that he could make extracts of infectious scrapie that seemed to be pure protein, he concluded that the scrapie agent was definitely composed only of some sort of protein and coined the word prion to describe it. He later found that the scrapie prion consisted of just one protein chain, folded in an abnormal way that made it remarkably strong and resistant to digestion.
Prusiner suggested that, rather like a game of tag, an infectious prion can affect a normal prion protein. Whenever a prion comes in contact with a normal prion protein, it somehow causes the normal protein to 'flip' into the abnormal shape, thereby becoming a prion (ie, the rogue form of the protein). Any other normal prion protein that a rogue prion touches will also be converted, creating a domino effect.
A protein-only infectious agent was a revolutionary idea because of what was known about living organisms. All known organisms, however small and simple, have both protein and nucleic acid. One cannot exist without the other in a living system. A protein doesn't just appear: Something must be making it, so it must have access to a nucleic acid that carries the information for its construction.
Recent research shows that instructions for making prion protein are on a gene that all mammals have and is mainly active in nerve cells. This gene normally produces a protein that causes no harm. But a slight change in the gene, or in the environment in the cell where the protein assumes its final shape, and the protein produced may flip into a different shape, converting it to a prion. So prions can be produced by a chance alteration in their shape (which explains the origin of sporadic CJD), a genetic change (which explains familial CJD) or when a normal prion protein comes in contact with a prion (which explains transmission through the consumption or injection of infected brain material).
As far as we can tell, these abnormal proteins are useless proteins. They are not fully broken down, and accumulate in the brain as an insoluble complex of proteins called an amyloid. Nor do we know what, if anything, normal prion proteins do, except that they are found in the outer membrane of neurones, the nerve cells of the brain. In ways not yet understood, the interaction of prions with the normal cellular prion proteins damages the cell and leads to its slow degeneration and death. This releases prions, which can then induce more prions on the surface of surrounding cells, causing more degeneration and death of cells.
This process of spreading cell death accounts for the holes in the brain. The current idea is that other tissues are not much affected because prion protein is mainly produced in nerve cells. Lymphoid cells also have a lot of prion protein and they are important in spreading the infection to nerve cells. However, lymphoid cells are readily replaced, whereas a process that destroys neurones, even a slowly progressive one, will lead to disease, since nerve cells cannot normally be replaced.
All spongiform encephalopathies, including CJD, are caused by prions. A new variant form of CJD (vCJD), first described in 1996, is the human form of mad cow disease: This was transmitted by eating infected beef products.
Since prions exist mainly in nervous tissue, you would need to eat nervous tissue to become infected; so why was there such a worry about beef, which is simply muscle tissue?
It is because during the slaughtering and butchering of animals, muscle tissue may be contaminated by the other organs of the animal and this is the meat that goes into sausages and hamburgers. Good steaks were probably quite safe. All beef in the United Kingdom is now considered safe because the BSE epidemic was brought under control by excluding meat-and-bone meal from cattle feed, and because it is now prohibited to put any risk material from the carcass into the human food supply.
Theory suggests that prions from one mammal cannot readily infect another mammal species, unless the normal prion proteins of the two species are quite similar in their shape. If not, they can't be altered by contact with the prion of the other species. However, this whole theory is based on probability, and even an event with very low probability can occasionally occur. Moreover, this probability is hard to predict from genetics. For example, it was assumed that because sheep scrapie does not transmit to humans, neither would BSE. Unfortunately, this assumption proved to be wrong.
Australia is currently free of scrapie and BSE. Since 1988 the Australian Quarantine Inspection Service has prohibited the importation of live animals and bovine products from the United Kingdom and from any other country that is not BSE-free, in an attempt to keep these diseases out of Australia (Box 2: The Australian Quarantine Inspection Service and the need for quarantine). Researchers in Australia are working on different aspects of prion proteins and CJD (Box 3: Australian researchers looking at prion proteins and CJD).
Though the individual risk of getting human BSE is low, the consequences of doing so are devastating. With as yet no blood test, no cure, and no certain means of decontamination, prions and prion diseases raise many complex practical, public health and ethical issues.
Related Academy Material
Interviews with Australian Scientists
Professor Jenny Graves (Genetics)
Safeguarding Australia - Being prepared – from a diagnostic laboratory perspective
Dr Martyn Jeggo, 4 March 2008
Safeguarding Australia - Emerging viral diseases: what are the threats and how should we respond?
Professor John Mackenzie, 4 September 2007
Safeguarding Australia - From mad cows to disappearing bees: safeguarding Australia from emerging diseases of animals
Dr Mike Nunn, 7 August 2007
Page updated December 2011.