Over 200 years ago farmers in England, Scotland, and France noted that some sheep suffered a progressive loss of balance, shaking, wasting, and severe itching that caused them to rub their hindquarters and flanks against any upright post. The name scrapie, or tremblante in France, was given to this disorder.
Owners of healthy flocks recognized that their animals contracted scrapie only after introduction of new breeding stock later found to bear the disease. Eventually sheep exported from England infected herds in Australia, New Zealand, and South Africa.Only extermination of the affected animals stopped scrapie from spreading, but by then it was distributed widely throughout Europe, Asia, and America. A prion is a normal protein that, after modification, is associated with spongiform encephalopathic diseases like CJD and BSE.
Prions are unique foreach species so that human prions differ from cow or mouse, prions, for example. To study whether "material" in mad cow brain could modify human prions and cause disease, experiments were done in the laboratory where mice were genetically engineered to express normal human prion proteins and then given diseased cow brain.As yet, such mice have not developed any evidence of spongiform encephalopathy or CJD. However, mice as well as subhuman primates injected with similarly diseased brain tissue from cows did succumb to a CJD-like syndrome (O’Briens, 1996).
Bovine spongiform encephalopathy, or mad cow disease, is a fatal brain disease of cattle. The brain of affected animals appears sponge-like under a microscope. BSE first appeared in the United Kingdom in 1986. Since then more than 173,000 cattle in the United Kingdom have become infected.
All these cattle and the herds to which they belonged were destroyed. New cases have dropped significantly since the U. K. government enacted measures to stop its spread.
Scientists believe the disease may have first been transmitted through feeding cattle protein made from sheep carcasses infected with scrapie, the sheep form of the disease. Meat-and-bone meal made from infected animals and used as a protein source for cattle feed may also have been a causative factor and was a common practice for several decades.In the early 1980s a change in the manufacturing process that eliminated steam heat treatment may have played a role in the appearance of the disease. Although BSE has not been found in cattle in the U.
S. , spongiform encephalopathies affect other animals too, and have been found in the United States in sheep (called scrapie), mink, elk, deer, cats, and humans. The human form is Creutzfeldt-Jakob disease (CJD). It is a rare disease that occurs in approximately one person per million. A new type of CJD, new variant or nvCJD, has been linked to BSE exposure.This new variant of CJD differs from the traditional type mainly in that it affects younger people.
To date, approximately 100 cases of nvCJD have been diagnosed, all in Europe. Although scientists know little about the origin, transmission, and nature of spongiform encephalopathies, the most accepted theory is that the causative agent is a prion, a type of pathogenic protein. In 1997 Stanley B. Prusiner from the University of California, San Francisco, won the Nobel Prize for his work on prions.Infective prions are thought to be found only in the brain tissue, spinal cord, and retina of infected animals, not in meat or milk products. Gelatin and beef tallow both undergo a manufacturing process thought to produce a product free of the BSE causative agent.
In Papua New Guinea CJD is known as kuru and is believed to have been transmitted through cannibalism. Scientists were puzzled as to why kuru affected mostly women, until they discovered that during funeral ceremonies women traditionally ate the dead person’s brain, while men ate the muscle.In evolutionary terms, the animal available for experimentation that closely resembles humans is the cynomolgus macaque monkey. These monkeys have prion proteins whose structures are 96 percent identical to human prion proteins. When such monkeys were inoculated with the new CJD agent or variant, the folded structure of their prion proteins changed in the same way the prion proteins in the British youths with the new type of CJD had changed (Collinge et al. 1996).
Then, when material from a cow with BSE was injected into the brains of three cynomolgus monkeys, two adults and one newborn, all three developed progressive central nervous system disease that included such abnormal behavior as depression, loss of balance, and shaking. These symptoms began within 150 days of inoculation and progressed in severity over the next ten to twenty-three weeks (Lasmezasi et al. , 1996).After death, the autopsies of all three monkeys showed indications of spongiform encephalitis with special factors that more closely resembled brains from mad cows than brains of patients with sporadic CJD or cynomolgus monkeys given brain tissue from CJD patients.
The startling similarity of the clinical, molecular, and neuropathologic features seen in these three cynomolgus monkeys with the CJD recently seen in young adults or juveniles in Britain suggests to some that the mad cow disease agent also caused the recent outbreak in humans. For other analysts, the association between mad cow disease and the new human cases is less clear.They support an alternative hypothesis that a new variant of CJD has occurred or been newly recognized because of enhanced awareness and focus on surveillance, and it is not related to BSE. Yet the recent finding that prion proteins show a characteristic chemical pattern (specifically, a high ratio of diglycosylated to unglycosylated forms) when obtained from BSE-infected brain tissue, brains of animals inoculated with BSE, and humans with the new CJD variant (Aguzzi and Weissmann, 1996), a pattern opposite to that in sporadic CJD prions, suggests the relationship of these new human cases of CJD to BSE.No one is sure whether the BSE agent fed to monkeys will cause disease, or, if it does, what amount is required and how long the incubation period will take.
The most worrisome aspect is that, unlike spongiform encephalopathies in sheep, mice, and hamsters, for which there is no evidence for infection in humans, the similar agent in cows may well cross the species barrier and infect humans. But what would constitute definitive evidence that BSE has spread to humans?The cynomolgus monkey experiments, the picture of nerve cell disease, the younger age of this new disease in humans, the fact that no vCJD has emerged in a country that does not have BSE, and the distinct chemical pattern that vCJD has unique strain characteristics distinct from other types of CJD, but similar to BSE, all evoke suspicion that a true epidemic rather than a false alarm may be on hand. The definitive experiments are in progress.That is, the incidence of CJD disease in Britain and elsewhere that does or, just as important, does not occur over the next several years in consumers of British beef from 1985 to 1996, especially before the banning of contaminated animal feed in 1989, should answer the question. An additional dilemma is that healthy sheep, pigs, and chickens have also been fed scrapie-contaminated products. What causes these spongiform encephalopathies?Originally the agent was thought to be a virus because of its unequivocal transmission of scrapie from sheep to sheep and then from sheep to mouse.
Similarly, kuru and CJD have been transmitted to subhuman primates and spongiform encephalopathy from cow brains to mice, pigs, cats, marmosets, and healthy cattle. However, extensive scientific investigation has yet to identify the transmissible (infectious? ) material (Chesebro and Fields, 1996).Work pioneered by Stanley Prusiner (1996) argued that it was not a virus but a modified host protein that caused spongiform encephalopathies: “Based on these findings (the inability to detect nucleic acids in the infectious material, typical of viral infection], it seemed likely that the infectious pathogen capable of transmitting scrapie was neither a virus nor a viroid (viroids are small RNA nucleic acid molecules of unique structure that can replicate and cause disease (primarily of plants)).For this reason the term "prion" was introduced to distinguish the proteinaceous infectious particles that caused scrapie, CJD, GSS, and kuru from both viroids and viruses. ” Experiments by Prusiner, Bruce Chesebro, and others have shown that, in the healthy brain, the prion protein exists in a form that is easily fragmented by certain proteolytic enzymes.In contrast, during the spongiform encephalitic disease state, the prion protein resists degradation by enzymes, leading to lesions in the brain.
Consequently, many, but not all, researchers working on this problem believed that conversion from the susceptible (digested by enzyme) to the resistant (resists digestion) form of the protein is responsible for the disease (Mestel, 1996).By this means, transmissible spongiform encephalopathies are spread by an agent that lacks information programmed by nucleic acids (as required for all viruses and other microbes) but is presumably programmed by a protein structure and is therefore unlike any other known agent of disease. Further, Prusiner and his colleagues as well as other scientists have learned that patients with inherited diseases of human nerve tissues like GSS syndrome possess a different (mutated) prion protein, unlike the prion protein present in the normal population.This prion-only hypothesis as a possible cause of spongiform encephalopathies is accepted by many, but not all. Others in medical science, for example, Chesebro, are not yet totally confident that a small virus or informational nucleic acid is excluded as the transmissible agent.
At present an intense controversy rages among scientists engaged in one of the most interesting subjects in contemporary biology and biomedical research.
