Volume 1: Findings and Conclusions
12. Science and research
Scientific conclusions about BSE

1122 Our analysis of the scientific knowledge occupies the major part of vol. 2: Science. We shall not attempt a summary in this volume. We shall simply set out the conclusions that we have drawn from the scientific response to BSE:

1. The vector responsible for the epidemic of BSE in cattle was MBM
   
   
The spread of BSE in cattle to the point where it became an epidemic came about from the use of meat and bone meal (MBM) in cattle feed. The MBM in question was infective because it had been made by rendering infective offal from cattle suffering from, or merely incubating, the disease. As little as 1 gram (or less) of this material could cause death if ingested by other cattle. It was so infective that accidental contamination of cattle feed with pig or poultry feed containing MBM was a significant factor in continuing to spread BSE after the ban on the use of MBM in cattle feed. Apart from MBM in feed, transmission from mother to calf is likely to have played a part. We cannot yet say whether contamination of pastures played a part. The suggestion has been made that the BSE agent may have been spread in the early stages in hormones used in veterinary preparations. This possibility cannot be discounted. But the overwhelming vector of the epidemic was MBM in cattle feed.
2. The unmodified scrapie agents were not the agents responsible for BSE
   
   
   While it was reasonable in February 1989 to accept the hypothesis that the cases of BSE being reported had come about through the rendering of carcasses of sheep infected with extant strains of scrapie established in the national flock, this theory is no longer plausible. We think it likely that the passive surveillance system failed to detect several earlier cycles of BSE in the South West of England in the 1970s and early 1980s. Each cycle was followed by more extensive contamination of MBM. Much of the recycling could not be detected because tissues from animals incubating the disease but not showing signs were involved; but it is likely that there were isolated animals which did develop signs and were slaughtered or died of the disease. BSE was unknown at the time and it seems possible that the disease in such cattle might have been ascribed to known disorders such as hypomagnesaemia or simply not explored. These early cycles began because a novel TSE agent originated in the early 1970s. The cause of this novel agent is likely to have been a new prion mutation in cattle, or possibly sheep. Moreover, other mammalian species whose carcass waste was included in MBM cannot be excluded. It is conceivable that the conversion of normal prion protein into its infective form was initiated not by a gene mutation, but by an environmental agent, such as a toxic chemical; this has not yet been achieved experimentally. Current knowledge suggests that the original agent was not the unmodified scrapie agent or agents. We have also noted a number of pointers which could have led to the conclusion by mid-1990, and certainly well before 20 March 1996, that the agent fuelling the BSE epidemic was not then (if it ever had been) the unmodified scrapie agent or agents. It is now not possible to be sure which of the hypotheses as to the origin of the novel agent is correct.

   Changes in rendering
   
   

   It is a common misconception that reduction in temperature or a failure to prescribe minimum holding times in the rendering of carcass waste led to failure of inactivation of the scrapie agent and transmission across the species barrier to cattle. Changes in the rendering process in the late 1970s and early 1980s, namely the switch from batch to continuous processing and the abandonment of solvent extraction of tallow, might have led to reduction in inactivation of the agent in MBM, but it is now known that the processes used previously were also incapable of completely inactivating TSE agents. No commercial rendering procedure has been designed capable of completely inactivating BSE in MBM before or since.

   Confirmation of the central role of prion protein
   
   

   All evidence points to the specific association of an abnormal form of the prion protein and TSEs. In its normal shape, the prion protein (PrP^C) does not cause harm. In its abnormal shape (signified by PrP^Sc - a generic term for the agents causing TSEs), it is resistant to the normal cellular processes of degradation. Contact between normally shaped and abnormally shaped proteins induces the normal to convert to the abnormal. This leads to a build-up of the abnormal form of the protein, which accumulates in, and eventually causes the death of, nerve cells. Nerve cells are particularly susceptible to PrP^Sc because they cannot regenerate. The presence of PrP^Sc can be demonstrated in the brain and spinal cord of all humans and animals affected with TSEs. Incubation times in experimental animals correlate with the infective dose of the agent, and these times are increased by treatment with agents (-sheet breaker peptides) which reverse the conformational change leading to PrP^Sc. These observations virtually eliminate other hypotheses as to the direct cause of TSEs, such as autoimmune disease of the central nervous system, because those hypotheses do not incriminate the prion protein. In both scrapie and vCJD, susceptibility and resistance to disease is associated with polymorphisms within the prion protein gene (though no such genetic susceptibility factors have yet been identified for BSE). It remains possible that environmental factors, including toxic chemicals, may additionally be implicated in susceptibility to prion disease.

   BSE is caused by a single strain of agent
   
   

   Strain-typing in mice has shown that all sources of the BSE agent so far examined produce the same lesion profile and incubation times in experimental mice. The same strain has been identified in cats, which have developed FSE since 1990, and in exotic ungulates and carnivores from zoological parks.

   Variant CJD is caused by the BSE agent
   
   

   Strain-typing studies in mice reveal that the disease patterns produced by the agents causing BSE and vCJD are identical. The glycosylation patterns of the prion protein associated with each condition are also identical and different from other TSE strains. In transgenic mice in which the mouse prion gene has been replaced by the bovine prion gene, inoculation with the BSE agent from cattle brain produces the same disease pattern and incubation period as agent derived from patients with vCJD. Following inoculation with the scrapie agent, the incubation period and disease patterns in the transgenic mice are markedly different from those produced by BSE and vCJD. In the absence of any other plausible factor, the evidence that BSE caused vCJD is so strong that all other hypotheses are now excluded.