The Prion Puzzle
ZURICH – The outbreak of mad cow disease in the United Kingdom, which ultimately led to the slaughter of 3.7 million cows and severely damaged the British cattle industry, began insidiously. In 1986, a UK cow developed an unknown brain disease. The following year, tests revealed that the brain had been eroded by a myriad of small vacuoles, producing the sponge-like appearance that inspired the disease’s scientific name: bovine spongiform encephalopathy. Within a few months, cases began appearing throughout the country.
A similar disease, called scrapie, was common in sheep, but had not previously been diagnosed in cows. And a nearly identical, invariably lethal disease, kuru, had ravaged the aboriginal people in Papua New Guinea throughout the twentieth century. Both kuru and scrapie are infectious.
Kuru was transmitted through cannibalistic rituals that were commonplace in Papua New Guinea until the 1950’s. Similarly, in the UK and elsewhere, healthy cattle were fed meat and bone meal made from infected cattle. The resulting epizootic (animal epidemic) affected more than 280,000 cows. At its peak in 1992, mad cow disease was claiming nearly 1,000 head of cattle weekly.
Faced with a rapidly growing health crisis, the British authorities – equipped with little scientific understanding of the disease, and under pressure from a powerful industrial lobby – made a fatal mistake. Because scrapie had never been definitively linked to human disease, they assumed that infected cows were also innocuous.
This assumption not only ignored the kuru tragedy; it also overlooked the hundreds of young people who had died of spongiform encephalopathy after receiving growth hormones extracted from human corpses. This mixture of hubris, ignorance, and subservience to commercial interests reached peak toxicity in 1990, when the UK’s agriculture minister, John Gummer, televised his daughter eating a hamburger, declaring that British beef was safe.
But British beef was not safe. In late 1995, two young people were diagnosed with Creutzfeldt-Jakob disease – a rare disease typically seen in elderly patients. Post-mortem examinations of their brains revealed deposits of prions – the infectious agents that cause scrapie, kuru, and mad cow disease. But these were not the prions of classic Creutzfeldt-Jakob disease. Since then, “new variant” Creutzfeltdt-Jakob disease has claimed roughly 300 lives.
As the tragedy unfolded, however, scientists gained a greater understanding of the disease. Prions seem to defy all conventional wisdom, surviving pressure-cooking, irradiation, and even incineration at 340°C for four hours – treatments that are routinely and reliably used to deactivate all known viruses and bacteria.
Furthermore, prions lack their own genes. The prion gene is provided by the infected individual, in whom it resides in an innocuous state. The infectious prion then hijacks the body’s machinery, reprogramming it into a willing executioner of prion replication. Since the disease’s outbreak, it has been revealed that many common ailments – including Alzheimer’s disease and Parkinson’s disease – have similar properties.
While no cure has been found, some progress has been made, particularly on early detection of prions, which had been a daunting problem. Sensitive detection of pathogens, such as HIV, typically relies on the presence of nucleic acids (DNA or RNA), which are absent in prions. Recently, however, effective methods for amplifying prions have been developed, which could enable detection of the pathogen before it can damage its host.
Moreover, there is hope that an effective vaccination can be developed. Introducing an innocuous version of a pathogen into the body causes the immune system to produce antibodies, which will neutralize the “wild” pathogen if it enters the body later. A decade ago, my laboratory showed that an anti-prion antibody could significantly delay – and, in some cases, prevent – infection in mice that had been exposed to prions.
But several problems have emerged. The host’s body produces its own version of the prion protein, and it is difficult to create a high-quality antibody against a body’s own components. As a result, rather than trying to induce immunity, researchers must develop prefabricated anti-prion antibodies that can be delivered directly to patients.
This solution might work for related diseases like Alzheimer’s, but it has its own array of problems, including the difficulty of driving such antibodies from the injection site to the brain. Severe side effects in animals, meanwhile, may prohibit the antibodies’ use in humans altogether.
Another possibility could be to eradicate prion diseases in livestock by removing the host’s prion gene. The Swiss scientist Charles Weissmann demonstrated this using mice in a series of experiments two decades ago. Using recently developed “zinc finger nuclease” technology, any given gene can be removed from an animal’s DNA.
In fact, prion-free sheep and cows have already been created. These animals cannot host infectious prions. While the quality of their meat remains to be assessed, they can provide a safe source of biological agents – such as therapeutic antibodies and growth factors – for use in human medicine.
Adriano Aguzzi is Professor of Neuropathology at the Institute of Neuropathology, University Hospital, Zürich.
Copyright: Project Syndicate, 2012.