PeteFree.comMad Cows and Variant Creutzfeldt-Jakob Disease - The New Stature of the Precautionary Principle in European Law and Health Practice - Appendix
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© April 2001 Peter Free
Appendix ─ Characteristics of BSE Prions
Understanding what happened during the outbreak requires understanding the infectious protein called the prion. The prion’s story is tied to medical epidemiology. As a first step in dealing with infectious disease in people or animals, government must first identify a disease problem or outbreak. Epidemiology does this by studying the causes, and frequency and distribution of, disease in populations. [218] It assumes that effective control of infectious disease depends upon the unique characteristics of each pathogen and its specific way of operating in the environment. [219]
BSE and scrapie are transmissible spongiform encephalopathies (TSEs). [220] The neuronal degeneration in these diseases appears to be due to the accumulation of an abnormal form (called PrPSc) of a normal protein (PrP or PrPC) [221] that is associated with neural, among other, tissues. [222] The function of the normal protein is unknown, [223] but it appears to be important because evolution has conserved it in very similar form among mammals. [224] TSEs are uniformly fatal; there is no treatment. [225]
The infectious agent that causes harmful transformation of normal PrP is called a prion. [226] The amino acid structure of PrPSc is identical to the normal PrP protein. [227] This makes in vivo identification of the abnormal protein (and the infecting prion) difficult. Since prions lack nucleic acids, polymerase chain reaction (routinely used to amplify and identify nucleic acid sequences in order to make identifications) does not work. [228] However, PrPSc does have a different physical conformation than PrP. The difference alters its biochemical activity in a harmful way. [229] In vivo identification will have to be based on a method that is able to distinguish between the normal and abnormal conformations. [230] At present [April 2001], the best hope for screening lies in discovering an antibody that can distinguish between the isoforms. [231]
The delay in recognition of BSE and vCJD was a direct result of the manner in which prions operate. Absent nucleic acids, the manner in which PrPSc replicates itself is unknown. [232] Transmissible spongiform encephalopathies uniformly require long incubations, [233] so replication is either slow or does not become symptomatic until it reaches the central nervous system. Prion infection does not elicit a detectable, host immune response. Pathology is noninflammatory and confined to the central nervous system. [234] And because there is no humoral [235] immune response in the host, there are no antibodies one can detect to confirm infection. [236] Absent such a test, identification of prion infection has been done during the disease’s end-stage on the basis of pathologic changes in affected tissue. [237] Visible clinical signs of infection show up only after enough of the central nervous system has degenerated to result in behavioral change. This is too late to be medically useful.
Prions apparently disseminate through the central nervous system inside nerve cell axons; [238] how they get there from the gut or the periphery of the body is still being investigated. (Understanding the mechanics of this process might allow medical researchers to come up with ways of detecting and blocking the disease before the nervous system is damaged.) BSE investigators wondered how prions in meat and bone meal feed (made from infected cattle and fed to healthy cattle) found their way from the gut to the central nervous systems.
Significant evidence indicates that PrPSc depends on B and follicular dendritic cells, or their activity, in the host's immune system to make its way to the central nervous system. [239] Incubation time can be explained by the length of time it takes for prions to multiply in reservoirs outside the central nervous system. [240] A likely candidate reservoir is the lymphoreticular portion of the immune system, including lymph nodes and intestinal Peyer's patches. [241] Abnormal prion protein has been found in the lymphoid tissue of human and sheep tonsils. [242] This gives researchers the hope they might devise a screening test that anticipates development of clinical symptoms in the patient.
Complicating the epidemiology of prion disease (and the BSE investigation specifically) is the fact that not all prion disease is the result of infection from an external source. Prion diseases can be genetic, sporadic (de novo), or infectious. [243] Clinical presentations vary. For example, scrapie in sheep and BSE present as ataxic (lacking coordination) disorders; Creutzfeldt-Jakob disease and kuru present as a progressive dementias. [244] Investigation of prion disease has been hampered by the fact that many cases appear to come from de novo generation of the mutant protein. [245] This trait means that it is impossible to eliminate all such disease. To the extent that BSE might be sporadic, cattle will remain a potential source of infectious material. [246] Taken as a whole, these prion characteristics explain the practical, investigative difficulties government faced early in the BSE crisis.
Crossing the species barrier
A critical question early on, was whether the BSE prion could infect another species. Ordinarily, differing immune systems present a "species barrier" to cross-species prion infection. [247] For those species that do become susceptible to the infecting prion, the barrier is expressed as a longer incubation time (as compared to the source species) before the illness becomes evident. [248] Serial passages of the infecting strain of prion through the new host results in a reduced incubation time. [249] Evidence suggests that during this time the infecting prion generates different strains of new prions in the host. [250] All things being equal, the most virulent of these new strains (created in the new host) then outcompetes the less effective varieties. [251]
When BSE first appeared in cattle, concerns revolved around where it originated and whether it might jump the species barrier and infect other farm animals. Initially, investigators wondered if BSE was simply the cattle version of sheep scrapie, a disease that has been recognized for more than two centuries and to which agriculture has adapted. Evidence is now strong that BSE is not scrapie. [252] The possibility remains that sheep scrapie jumped to cattle from scrapie-infected sheep meal fed to cows. [253] The scrapie prion, passing through the immune system of a new host, might have created a new strain of prion. [254]
Observation and research slowly demonstrated that BSE could spread beyond cattle. In non-domestic animals, it was seen in zoo ungulates like eland, greater kudu, Arabian oryx, and felines like captive puma and domestic cats that had been fed with beef and cattle-based bone meal. [255] In domestic animals, pigs were experimentally infected with BSE (though they do not get it, or any other transmissible spongiform encephalopathy, under natural conditions). [256]
Sheep developed symptoms indistinguishable from sheep scrapie after being orally or intracerebrally infected with BSE under experimental conditions. [257] Importantly, one of the orally infected sheep came from a genetic line of Cheviot sheep that is not susceptible to sheep scrapie under natural conditions. [258] Fortunately, there is no sign that numbers of farm sheep exhibiting scrapie or BSE-like symptoms have increased in the United Kingdom. [259]
Initially, few people thought BSE could overcome the species barrier to infect humans. But ten years after the BSE epidemic was recognized in cows, evidence surfaced that the BSE prion had also infected people. [260] Proving that the BSE prion was the cause, however, took time.
An experimental animal model for detecting BSE and vCJD
The search for the BSE and vCJD agents was initially hampered because no dependable experimental animal model for the diseases existed. Unlike many infectious diseases, there is still no simple in vivo screening test for vCJD prion activity. [261] It is obviously difficult to combat disease, if it has a long silent incubation period and no screening test exists with which to detect the causative agent. Consequently, significant effort went into finding ways test for BSE and vCJD.
Infectious material can be experimentally inoculated into rodent models to see if infection and disease result. [262] Finding a good rodent model for BSE and vCJD took time. The best evidence that vCJD came from BSE arrived in late 1999, more than three years after vCJD was first seen and thirteen years after the visible BSE epidemic begin. [263]
Prions are exceptionally hardy
Prions are a public health danger, in part, because they are difficult to deactivate. Customary disinfecting techniques do not work to eliminate infectivity. [264] They may survive standard hospital autoclaving (121 C for 15 minutes), and they survive high doses of ionizing and ultraviolet radiation. [265] Consequently, prions may persist for long periods in the environment.
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