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Volume 2: Science
3. The nature and cause of BSE
The investigation of the BSE epidemic
(ii) Was the source scrapie?
(iii) The effect of changes in rendering
Alternative theories for the origin and route of BSE infection
Summary

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(ii) Was the source scrapie?

3.48 Certain scientists had questioned the scrapie origin theory relatively early on. For example, in a submission to the House of Commons Agriculture Committee in 1990, Professor Richard Lacey (Professor of Clinical Microbiology, University of Leeds) and Dr Stephen Dealler (then of the Public Health Laboratory Service, Leeds), suggested that 'the evidence that BSE is due to sheep scrapie is . . . non-existent', and therefore that 'we cannot be confident that the BSE agent from bovines will still not be infectious for man'. 1 They suggested that two possibilities - that BSE was a mutant scrapie agent with an expanded host range (ie, with a greater range of animals susceptible to the disease); or that it arose from a mutation in bovines themselves - could not be excluded.

3.49 Although BSE was regarded as a scrapie-like disease because of its characteristic neuropathology, it became increasingly apparent from 1988 onwards that the two diseases were different in a number of respects:

    1. host range;
    2. transmission properties; and
    3. pathogenesis.

3.50 These differences call into question the validity of the scrapie-origin theory and are discussed in detail below.

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Host range

3.51 The first difference between scrapie and BSE to become apparent was in the range of species susceptible to the diseases. The differences became evident through both experimental studies and the observation of natural transmission (these differences are summarised in Table 3.1, below). Experimental studies showed the following:

    1. Studies in both 1987 and 1988 failed to show transmission of BSE to hamsters, a species readily susceptible to scrapie, following intracerebral inoculation of BSE material. 2
    2. The NPU had over the years developed two lines of Cheviot sheep: a 'positive' line highly susceptible to infection with scrapie, and a 'negative' line so resistant to infection with scrapie that it had never been possible to transmit the disease. Animals were inoculated intracerebrally with BSE material in June 1988, and by July 1990 animals from both lines had succumbed to disease. 3 Orally dosed animals of both lines were also found to be susceptible to BSE infection.
    3. Ten pigs were inoculated with BSE by a combination of parenteral routes (intracerebral, intravenous and intraperitoneal) in March 1989. 4 Transmission of BSE was evident when one animal succumbed to disease in August 1990. By 1993, five of the six surviving animals also had the disease (three animals died from unrelated disorders). 5 No pigs had been found to have a natural TSE previously, but this result indicated that they were susceptible to BSE. Meanwhile, oral inoculation of BSE-infected material did not result in disease in pigs over a period of seven years. We can find no record of the experimental inoculation of scrapie into pigs.
    4. Oral and intracerebral transmission of BSE to mink was undertaken in the USA and reported in 1994. 6 The transmission was successful by both routes, though it produced a TSE unlike TME. In contrast, scrapie has never been successfully transmitted to mink by the oral route. 7

3.52 An increased host range for BSE also became apparent when species previously unaffected by TSEs acquired disease following the emergence of BSE.

    1. Until 1986 no TSE infections had occurred in exotic ungulates in zoological parks which had been fed commercial cattle feed. The first such case, in a nyala, was confirmed at the CVL in 1986 8 and published in 1988. 9 It was soon followed by an affected gemsbok in 1987 and thereafter by a number of other cases including an Arabian oryx (1989), greater kudu (1988) and eland (1989). 10 Since then similar reports have been described in other ungulates: moufflon (1992); 11 scimitar horned oryx (1993); 12 ankole cow, an African breed (1996); and bison (1997). 13 The last three of these species are closely related to domestic cattle, and the occurrence of the disease was therefore not regarded as particularly remarkable. Nonetheless, none of these species had been affected by a TSE before the BSE epidemic, indicating a greater host range for BSE than had been experienced with scrapie.
    2. Scrapie had never transmitted naturally to a carnivore. Consequently, when a cat was reported in May 1990 14 to have developed a scrapie-like disease, it led to considerable media interest and a public pronouncement on the safety of beef. 15 The development of a TSE in a further number of cats in the following weeks and months was cause for concern, particularly as an earlier study had failed to transmit two different strains of scrapie experimentally to cats. 16 On the other hand, CJD had been successfully transmitted to cats by intracerebral (i.c.) inoculation. 17 During 1995 strain-typing and biochemical analysis was carried out on this feline spongiform encephalopathy, and showed a similar signature to BSE. 18 In the same year, a case was seen in Norway in a cat that had been fed several imported commercial dry cat food products. 19 By mid-1998 over 80 cats were known to have developed the disease. 20
    3. Exotic carnivores in zoos are fed cattle carcass meat, and there have been a number of reports of TSE cases since 1990 including puma (1992), 21 cheetah (1992), 22 ocelot (1994), 23 tiger (1996) and lion (1998). 24 There have also been earlier anecdotal reports of cases in ostriches 25 and white tigers, 26 though these have been not been substantiated. In the latter case, six tigers from Bristol Zoo were diagnosed with brain disease or liver disease or both, between 1970 and 1977. Spongiform encephalopathy was evident in four of the tigers which, it was suggested, could have been due to infection with causative agents similar to those of scrapie and CJD. The transmission of spongiform encephalopathy to these animals may well be consistent with the theory that BSE arose early in the 1970s in the South West of England, as discussed in paragraphs 3.43-3.44 above. Cases of spongiform encephalopathy are still being confirmed in animals in zoological parks. For example, a paper published in March 1999 documented the occurrence of TSEs in lemurs (a primate species) in German zoological parks after they were fed with special mixed rations containing MBM that most likely included rendered British beef. 27

3.53 Thus, BSE seems to have occurred in a wide range of species which had not shown themselves to be susceptible to scrapie, despite ample opportunity before the emergence of BSE. Indeed, it is highly likely that all these species have in the past been given feed containing MBM derived from scrapie-infected sheep or, in the case of carnivores, been fed scrapie-infected carcasses.

Table 3.1: Host range of BSE

Table 3.1: Host range of BSE

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Transmission properties

3.54 The first demonstration of the transmissibility of BSE was in September 1988, when mice inoculated with BSE-infected brain material developed disease. This was important as it provided an animal model with which to assay BSE infectivity. However, it was found that the incubation period for BSE in mice was shorter than for known scrapie isolates. 28 While this finding was considered to demonstrate the potential of the mouse model for assaying infectivity, it also demonstrated a difference between the transmission properties of BSE and scrapie.

3.55 Similarly, the incubation periods of BSE and scrapie were found to differ in experimentally infected marmosets. Following inoculation in February 1988, it was found that animals succumbed to scrapie between two and eight months earlier than animals inoculated with BSE which died in January 1991. 29 However, the small number of animals used in the study (two each for scrapie and BSE), and problems with the comparability of infective dose, made it difficult to draw firm conclusions about differences in incubation periods.

3.56 A further difference in the transmission properties of the two diseases was the pattern of disease caused in the brains of experimental animals. Mice inoculated with scrapie material from geographically and temporally distinct sources were found to have variable brain lesions, whereas mice inoculated with BSE material similarly derived from different sources all had very similar patterns of disease. 30 These results showed that, unlike scrapie, only one strain of BSE was present in the inocula derived from different sources. As the current hypothesis suggested that scrapie had transmitted to cattle at a number of geographically separate sites, it might have been expected that several strains of BSE would have been evident, given that over 20 strains of scrapie were known. Since 1996, strain-typing studies in mice have shown that the lesion profile produced by BSE is different to all known scrapie strains. 31

3.57 The experiment which might have determined whether BSE and scrapie were caused by the same agent (ie, the feeding of natural scrapie to cattle) was never undertaken in the UK. It was, however, performed in the USA in 1979, when it was shown that cattle inoculated with the scrapie agent endemic in the flock of Suffolk sheep at the United States Department of Agriculture in Mission, Texas, developed a TSE quite unlike BSE. 32 The findings of the initial transmission, though not of the clinical or neurohistological examination, were communicated in October 1988 to Dr Watson, Director of the CVL, following a visit by Dr Wrathall, one of the project leaders in the Pathology Department of the CVL, to the United States Department of Agriculture. 33 The results were not published at this point, since the attempted transmission to mice from the experimental cow brain had been inconclusive. The results of the clinical and histological differences between scrapie-affected sheep and cattle were published in 1995. Similar studies in which cattle were inoculated intracerebrally with scrapie inocula derived from a number of scrapie-affected sheep of different breeds and from different States, were carried out at the US National Animal Disease Centre. 34 The results, published in 1994, showed that this source of scrapie agent, though pathogenic for cattle, did not produce the same clinical signs of brain lesions characteristic of BSE.

3.58 There are several possible reasons why the experiment was not performed in the UK. It had been recommended by Sir Richard Southwood (Chairman of the Working Party on Bovine Spongiform Encephalopathy) in his letter to the Permanent Secretary of MAFF, Mr (now Sir) Derek Andrews, on 21 June 1988, 35 though it was not specifically recommended in the Working Party Report or indeed in the Tyrrell Committee Report (details of the Southwood Working Party and the Tyrell Committee can be found in vol. 4: The Southwood Working Party, 1988-89 and vol. 11: Scientists after Southwood respectively). The direct inoculation of scrapie into calves was given low priority, because of its high cost and because it was known that it had already taken place in the USA. 36 It was also felt that the results of such an experiment would be hard to interpret. While a negative result would be informative, a positive result would need to demonstrate that when scrapie was transmitted to cattle, the disease which developed in cattle was the same as BSE. 37 Given the large number of strains of scrapie and the possibility that BSE was one of them, it would be necessary to transmit every scrapie strain to cattle separately, to test the hypothesis properly. Such an experiment would be expensive. Secondly, as measures to control the epidemic took hold, the need for the experiment from the policy viewpoint was not considered so urgent. It was felt that the results would be mainly of academic interest. 38

3.59 Nevertheless, from the first demonstration of transmissibility of BSE in 1988, the possibility of differences in the transmission properties of BSE and scrapie was clear. Scrapie was transmissible to hamsters, but by 1988 attempts to transmit BSE to hamsters had failed. Subsequent findings increased that possibility.

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Pathogenesis

3.60 In 1982, Hadlow had studied the infectivity of various tissues from sheep affected with scrapie (see paragraphs 2.162-2.163). 39 He determined that after the brain and spinal cord, tissues of the lymphoreticular system (LRS) - including spleen, lymph nodes, intestinal Peyer's patches and tonsils - were the most infective. It was on this basis that the Specified Bovine Offal (SBO) ban was introduced on 13 November 1989, to exclude tissues from the human food chain that might be most hazardous in terms of potential infectivity. However, a similar study in cattle using the mouse bioassay (see paragraph 1.43 for details on this experimental method) has shown that the spleen, lymph nodes and tonsils from BSE-affected cattle do not transmit disease. Of LRS tissues, only the distal ileum containing Peyer's patches has proved to be infective in 6-month-old calves. 40 However, infectivity has been demonstrated in the spleens of mice into which LRS tissue from BSE cases has been inoculated. Thus, infectivity can be demonstrated after the agent has first been passaged through mice, and the species barrier has been breached. 41 Nonetheless, the patterns and extent of tissue infectivity in the two species are quite different.

3.61 Although BSE is a 'scrapie-like' disease, once it had emerged in cattle, its characteristics were different, especially in terms of host range and lesion profile. At the very least such differences seem inconsistent with the original proposition that BSE was 'unmodified scrapie'. It was either modified scrapie, the modification arising from a mutation in sheep, or a new bovine TSE, again arising from a mutation in cattle (see paragraph 3.70); or, less likely, a mutation in some other species. In this regard it is worth noting that carcasses from zoos and bones from overseas were sometimes sent for rendering and could therefore have been a source of MBM in cattle feed.

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(iii) The effect of changes in rendering

3.62 As described in paragraph 3.23, Mr Wilesmith's explanation of the occurrence in time and place of the BSE epidemic was largely centred on changes in the rendering processes introduced into the UK in the late 1970s and early 1980s. 42 Although Mr Wilesmith's thinking on rendering evolved during his investigations (see paragraphs 3.27-3.31), with hindsight his later conclusions regarding solvent extraction can also be questioned. Mr Wilesmith examined rendering processes in the search for an explanation of why scrapie, which had been endemic in the UK for over 200 years and had been incorporated in cattle feed since 1900 at least, had only now begun to cause disease in cattle. However, if the agent was not any of the scrapie strains which had previously existed, as we have concluded above, it is not necessary to postulate some change in animal feeding practices, feed manufacturing or rendering to explain the emergence of BSE. Moreover, an examination of the evidence on rendering suggests that abandonment of solvent extraction does not provide an explanation of the emergence of BSE which is consistent with the facts of the epidemic.

3.63 During his investigations of the changes that took place in rendering procedures, Mr Wilesmith observed a large decline in the use of solvent extraction between 1980 and 1982, which he correlated with the predicted time of onset of the effective exposure of cattle to a scrapie-like agent. 43 However, during the 1960s and 1970s, some 30 to 50 per cent of MBM was produced by methods which did not use solvent extraction; so the absence of solvent extraction was not a new factor in the early 1980s, although the proportion of MBM not solvent-extracted had increased to some 90 per cent of total output by then. 44 Furthermore, some rendering plants had never used solvent extraction, and one of the larger plants in southern England had only abandoned solvent extraction a short time before the emergence of BSE in the region. 45

3.64 Earlier work on scrapie had shown that it was exceedingly difficult to inactivate the agent completely by heat treatment and that some strains of the agent were more heat-resistant than others. Experiments to determine the effect of a variety of the more usual rendering procedures on the inactivation of BSE and scrapie were undertaken in a series of experiments in collaboration with the rendering industry by Dr David Taylor, of the NPU, starting in 1990. These experiments used pilot-scale facsimiles of industrial production methods to process raw materials spiked with the scrapie agent to determine whether infectivity could be detected in the end products.

3.65 In addition to the normal rendering processes, a solvent extraction system using heptane was tested. These procedures were initiated in the autumn of 1992, with mouse bioassays starting in December 1992 at the NPU. 46 The MBM samples produced by rendering were all infectious even when solvent extraction was carried out. Only when hyperbaric steam at 133°C was applied for 20 minutes was inactivation of the samples observed. These results were made available to the European Commission in June 1996, and published in the Veterinary Record in December 1997. 47 Further experiments, in which samples were heated to 100°C for 30 minutes and extracted with a range of solvents, showed that no solvent was significantly more effective than another in inactivating the agent. Slight inactivation (about a tenfold reduction) did occur in all treatments indicating that the heat, rather than solvents, was responsible.

3.66 Results from a 1998 study on heat inactivation suggest that the BSE agent is even more resistant to inactivation than the various strains of scrapie agent tested to date. 48 The explanation for this difference is unclear, although it may relate to specific biochemical and conformational properties of the BSE agent.

3.67 As noted in paragraph 3.29, Mr Wilesmith himself had discounted the change from batch to continuous rendering as a major factor in the emergence of BSE. The findings discussed above call into question his views that the widespread abandonment of solvent extraction was a key event in the emergence of BSE. And as paragraph 3.23 explained, changes in the regulation of the rendering industry tightened rather than relaxed controls. Thus changes in process could not have been solely responsible for the emergence of BSE, and changes in regulation were not a factor at all.

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Alternative theories for the origin and route of BSE infection

3.68 Mr Wilesmith's conclusions involved a close association between the origin of the disease (scrapie), its initial transmission to cattle (in sheep remains rendered into MBM) and its spread (in MBM incorporated into animal feed). However, if, as the foregoing sections suggest, the origin of the disease was unlikely to be unmodified scrapie and that a single point source some time in the 1970s is as likely as, and perhaps more likely than, an extended common source in the early 1980s, there is no need to postulate such a close association between the origin, initial transmission and spread of the disease.

3.69 The impact of the ruminant feed ban provides strong evidence that the disease was spread in the MBM component of feed. The epidemiology indicates that the disease was recycled, so that much of the infected MBM came from the carcasses of cattle infected earlier in the epidemic, when the disease was as yet unrecognised. But there are a number of theories about the origin of the disease, and these may have different implications for its initial transmission to cattle.

3.70 Mutations of the prion protein gene may lead to sporadic TSEs, when they occur in somatic cells, or inherited TSEs, when they occur in germ line cells (see paragraphs 1.26-1.27). Either could produce a point source for the disease and permit various means of transmission, for example:

    1. A sporadic mutation occurs in a somatic cell in an animal - cattle or sheep, or, for that matter, some other species. 49 The animal develops at least subclinical infection and is recycled in feed, spreading the infection. This possibility would be analogous to the idea that kuru started from a single case of sporadic CJD, with infection spread to others by cannibalistic or mortuary practices.
    2. A sporadic mutation occurs in one animal in a germ line cell. This mutation is inherited by its offspring, which develop a TSE, and any or all of them are recycled into feed, spreading the infection. A sporadic mutation of this kind in a bull used for artificial insemination (AI) would result in numerous offspring spread over a wide area and would lead more quickly to an epidemic than (i.) above. The attribution of the spread of BSE to an AI bull could be missed in view of the long incubation period and the fact that only 50 per cent of offspring would inherit the prion mutation. Such a possibility was considered by Professor Morris to be unlikely, as it was inconsistent with epidemiological evidence. 50 Instead, he considered it more tenable that a mutation had occurred in a single cow in the South West of England in the 1970s. 51
    3. A cow with TSE, whether sporadic as in (i.) or inherited as in (ii.), is the source of tissues used to produce veterinary medicines or hormones. These infected medicines or hormones are then injected into other cattle, spreading the disease. Those cattle are then recycled into feed, spreading the disease still further. This route of infection would be a parallel to the cases of iatrogenic CJD caused by contaminated human growth hormone. It is known that bovine pituitary growth hormone prepared from pooled pituitary glands was used to promote lactation in dairy cows on experimental farms in the 1970s and 1980s. 52 Also, pituitary gonadotrophins from sheep and pig pituitaries were used to promote fertility in embryo transfer in cattle. 53 In this technique the timing of oestrus is controlled by prostaglandins (sourced from plants or produced artificially in genetically modified bacteria) or progesterone (largely from bovine uterus, a tissue that has not been found to be infective in BSE-affected cattle). The pituitary gonadotrophins are then used to cause superovulation (the production of multiple eggs) and therefore multiple embryos after artificial insemination (see vol. 12: Livestock Farming). As well as hormones, bovine vaccines were a potential source of the BSE agent. 54
    4. Mutation of the prion gene in somatic or germ cells of sheep results in the generation of a novel scrapie strain. This possibility has been considered by Dr Hope, now at the Institute for Animal Health (IAH) in Compton. Molecular analysis has recently identified some similarity in biochemical properties (specifically glycosylation patterns - see paragraphs 3.241-3.242 for details) between BSE and a particular isolate of natural scrapie - the CH1641 strain. 55 Interestingly, this strain was isolated from a natural case of scrapie in 1970, and is hence consistent with one of the timing possibilities for the exposure of cattle proposed by Professor Morris. However, CH1641 differs from BSE in its lesion profile in experimental mice and must be regarded as distinct from BSE.

3.71 In addition to mutation of the prion gene, a toxic chemical of some description could induce the conversion of normal prion protein, PrPC, to the disease-associated form, PrPSc, in a single animal which then develops a TSE and is recycled. This theory is discussed further below in relation to organophosphate-based treatments for warble fly.

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Summary

3.72 It was a natural reaction among those investigating an outbreak of infectious disease to look for a source of the infection. In the case of BSE the most obvious explanation was that, as the disease shared the same changes in the brain as scrapie, the source of the outbreak was sheep scrapie, the only TSE known to be endemic among farm animals. Waste from slaughtered sheep incorporated into the MBM used in commercial cattle feed provided a route of infection to cattle. This was confirmed by the demonstration that the one common factor to all affected cattle was that they had been given commercial cattle feed. Why then had cattle not been affected before? Two possibilities presented themselves. The first was that an increase in the proportion of sheep brains in MBM might have led to an increased titre (level) of infectivity in cattle feed. The second was that recent changes in the rendering procedure might have led to a reduction in inactivation of the scrapie agent. The scrapie origin was plausible in 1988 and, indeed, was accepted by the Southwood Working Party. However, there were uncertainties, including why the outbreak was confined to the UK and why the disease could not be transmitted to hamsters. The possibility that BSE might be transmitted to humans was considered remote, since no animal TSE was known to affect humans and, in particular, epidemiological research had concluded that CJD was not caused by scrapie. The fact that scrapie does not affect humans was relied on by officials in their risk assessment from 1988 right up until March 1996, despite events in 1989 and 1990 which seriously questioned the scrapie origin theory.

3.73 With hindsight it can be appreciated that uncertainty about the scrapie origin theory increased from 1989. The role of changes in rendering became questionable, and the range of host species to which BSE could be transmitted increased. The observation of TSEs in cats in the summer of 1990, followed by the report of successful experimental transmission of BSE to a pig shortly afterwards, were key events which challenged the current theory. The agent causing BSE clearly had a wider host range than scrapie and in this respect was more virulent than scrapie. The perceived risk of transmission to humans increased.

3.74 Recent epidemiological analysis points to the importance of the recycling of cattle waste from subclinical cases of BSE in MBM, thus fuelling the epidemic. MBM was indeed the vector which led to the spread of the epidemic, but its origin is now placed much earlier, and localised to the South West of England. Several cycles of infection, initially from a single point source in Southern England in the 1970s, involving comparatively small numbers of animals, either subclinically affected or misdiagnosed, seems most consistent with the available data. Only one strain of BSE has been recognised, which is also consistent with a single point source. It is likely that the strain was a new strain of TSE, possibly from a new mutation of the prion protein gene. No conclusion can be reached about the species from which the new strain originated, although it is most likely to be a bovine strain, since cattle and related bovine species seem to be most readily infected.

3.75 The description of the investigations into other aspects of the BSE story resumes at paragraph 3.101. These investigations include experiments in transmission, infective dose and pathogenesis. Before examining them in detail, however, we consider some other theories about the nature and cause of BSE.

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1 IBD1 tab 7 pp. 19-20

2 YB87/6.9/1.3; YB88/3.00/1.6

3 Foster, J.D., Hope, J. and Fraser, H.(1993) Transmission of Bovine Spongiform Encephalopathy to Sheep and Goats, Veterinary Record, 133, 339-41

4 M40 tab 4.1

5 Dawson, M., Wells, G.A.H., Parker, B.N.J. and Scott, A.C. (1990). Primary Parenteral Transmission of Bovine Spongiform Encephalopathy to the Pig, Veterinary Record, 127, 338; Ryder, S.J., Hawkins, S.A.C., Dawson, M. and Wells, G.A.H. (2000) The neuropathology of experimental bovine spongiform encephalopathy in the pig. Journal of Comparative Pathology, 122(2-3), 131-43

6 Robinson, M., Hadlow, W., Puff, T., Wells, G., Dawson, M., Marsh, R. and Graham, J. (1994) Experimental Infection of Mink with Bovine Spongiform Encephalopathy, Journal of General Virology, 75, 2151-5

7 Marsh, R. F. (1979) On the Origin of Transmissible Mink Encephalopathy, Slow Transmissible Diseases of the Nervous System, vol. 1, edited by Prusiner, S.B. and Hadlow, W.J., New York, Academic Press, 451-60; Bradley, R. (1997) Animal Prion Diseases, Prion Diseases, edited by Collinge, J. and Palmer, M.S., United Kingdom, Oxford University Press, 102

8 S64 Jeffrey para. 6

9 Jeffrey, M. and Wells, G. (1988) Spongiform Encephalopathy in Nyala (Tragelaphus Angasi), Veterinary Pathology, 25, 398-9

10 Kirkwood, J. and Cunningham, A. (1994) Epidemiological Observations on Spongiform Encephalopathies in Captive Wild Animals in the British Isles, Veterinary Record, 135, 296-303

11 Bradley, R. (1997) Animal Prion Diseases, Prion Diseases, edited by Collinge, J. and Palmer, M.S., United Kingdom, Oxford University Press, 89

12 Ibid.

13 M28A tab 3 p. 61

14 Wyatt, J., Pearson, G., Smerden, T., Gruffydd-Jones, T., Wells, G., Meldrum, K., Parry-Smith, P., Isserlin, J., Auerbach, M., Bellois, E. and Loosevolt, R. (1990) Spongiform Encephalopathy in a Cat, Veterinary Record, 126, 513

15 S311 Gummer paras 147-54

16 Amyx, H., Gibbs, C. and Gajdusek, D. (1983) Experimental Creutzfeldt-Jakob Disease in Cats, Unconventional Viruses and the Central Nervous System, edited by Court, L.A. and Cathala, F., Paris, Masson, 358

17 Mitrova, E. and Mayer, V. (1977) Neurohistology of Early Preclinical Lesions in Experimental Subacute Spongiform Encephalopathy, Biologia (Bratislava), 32, 663-71

18 Collinge, J., Sidle, K.C.L, Meads, J., Ironside, J. and Hill, A.F. (1996) Molecular Analysis of Prion Strain Variation and the Aetiology of 'New Variant' CJD, Nature, 383, 685-90

19 Bratberg, B., Ueland, K. and Wells, G. (1995) Feline Spongiform Encephalopathy in a Cat in Norway, Veterinary Record, 136, 444; YB95/2.23/1.1

20 YB98/0.0/1.1

21 Willoughby, K., Kelly, D., Lyon, D. and Wells, G. (1992) Spongiform Encephalopathy in a Captive Puma (Felis Concolor), Veterinary Record, 131, 431-4

22 Peet, R. and Curran, J. (1992) Spongiform Encephalopathy in an Imported Cheetah (Acinonx Jubatus), Australian Veterinary Record, 69, 171

23 Johnson, R. and Gibbs, C. (1998) Creutzfeldt-Jakob Disease and Related Transmissible Spongiform Encephalopathies, New England Journal of Medicine, 339, 1944-2004

24 M28A tab 3 p. 61

25 Schoon, H.A., Brunckhorst, D. and Pohlenz J. (1991) Spongiform Encephalopathy in a Red-Necked Ostrich, Tierartzliche Praxis, 19, 263-5

26 Kelly, D.F, Pearson, H., Wright, A.I. and Greenham, L.W. (1980) Morbidity in Captive White Tigers, Comparative Pathology of Zoo Animals, edited by Montali, R.J. and Migaki, G., Washington DC, Smithsonian Institute Press, 183-8 (M8B tab 67)

27 Bons, N., Mestre-Frances, N., Belli, P., Cathala, F., Gajdusek, D. and Brown, P. (1999) Natural and Experimental Oral Infection of Non-Human Primates by Bovine Spongiform Encephalopathy Agents, Proceedings of The National Acedemy of Sciences of The United States of America, 96, 4046-51

28 S65 Wells para. 47

29 YB92/2.27/3.1-3.5

30 Fraser, H., Bruce, M., Chree, A., McConnell, I. and Wells, G. (1992) Transmission of Bovine Spongiform Encephalopathy and Scrapie to Mice, Journal of General Virology, 73, 1891-7; Bruce, M., Chree, A., McConnell, I., Foster, J., Pearson, G. and Fraser, H. (1994) Transmission of Bovine Spongiform Encephalopathy and Scrapie to Mice: Strain Variation and the Species Barrier, Philosophical Transactions of the Royal Society of London, Series B, Biological Sciences, 343, 405-11

31 Bruce, M., Will, R., Ironside, J., McConell, I., Drummond, D., Suttie, A., McCordie, L., Chree, A., Hope, J., Birkett, C., Cousens, S., Fraser, H. and Bostock, C. (1997) Transmissions to Mice Indicate that 'New Variant' CJD is Caused by the BSE Agent, Nature, 389, 498-501

32 Clark, W., Hourrigan, J. and Hadlow, W. (1995) Encephalopathy in Cattle Experimentally Infected with the Scrapie Agent, American Journal of Veterinary Research, 56, 606-12

33 YB88/10.00/1.1

34 Cutlip, R., Miller, J., Race, R., Jenny, A., Katz, J., Lehmkuhl, H., Debey, B. and Robinson, M. (1994) Intracerebral Transmission of Scrapie to Cattle, Journal of Infectious Diseases, 169, 814-20

35 YB88/6.21/1.2

36 YB88/11.17/2.4

37 S71D Bradley para. 26

38 S100B MacOwan Annex B para.11

39 Hadlow, W., Kennedy, R. and Race, R. (1982) Natural Infection of Suffolk Sheep with Scrapie Virus, Journal of Infectious Diseases, 146, 657-64

40 Wells, G. (1994) Short Communications: Infectivity in the Ileum of Cattle Challenged Orally with Bovine Spongiform Encephalopathy, Veterinary Record, 135, 40

41 Middleton, D. and Barlow, R. (1993) Failure to Transmit Bovine Spongiform Encephalopathy to Mice by Feeding Them With Extraneural Tissues of Affected Cattle, Veterinary Record, 132, 545-7

42 Wilesmith, J., Wells, G., Cranwell, M. and Ryan, J. (1988) Bovine Spongiform Encephalopathy: Epidemiological Studies, Veterinary Record, 123, 638-44

43 Wilesmith, J., Ryan, J. and Atkinson, M. (1991) Bovine Spongiform Encephalopathy: Epidemiological Studies on the Origin, Veterinary Record, 128, 199-203

44 Ibid.

45 M14 tab 1 pp. 1-2; M14 tab 2 pp. 160-1; M14 tab 3 p. 281; and M14 tab 4 pp. 365-7

46 S150 Taylor para. A15

47 Taylor, D., Woodgate, S., Cawthorne, R. and Fleetwood, A. (1997) Effect of Rendering Procedures on the Scrapie Agent, Veterinary Record, 141, 643-9

48 Schreuder, B., Geetsma, R., Van Keulen, L., Van Asten, J., Enthoven, P., Koeijer, A. and Osterhaus, A. (1998) Studies on the Efficacy of Hyperbaric Rendering Procedures in Inactivating Bovine Spongiform Encephalopathy (BSE) and Scrapie Agents, Veterinary Record, 142, 474-80

49 Among other possibilities, the white tiger noted at paragraph 3.52 (iii) above may have entered the animal feed chain in the early 1970s consistent with Professor Morris's theories

50 T111, 76

51 Ibid.

52 Hart, I.C., Blake, L.A., Chadwick, P.M., Payne, G.A. and Simmonds, A.D. (1984) The Heterogeneity of Bovine Growth Hormone. Extraction from the Pituitary of Components with Different Biological and Immunological Properties, Biochemical Journal, 218, 573-81

53 S537 Coulthard para. 4

54 YB89/2.22/11.3

55 Hope, J., Wood, S., Birkett, C., Chong, A., Bruce, M., Cairns, D., Goldmann, W., Hunter, N. and Bostock, C. (1999) Molecular Analysis of Ovine Prion Protein Identifies Similarities Between BSE and an Experimental Isolate of Natural Scrapie, Journal of General Virology, 80, 1-4

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