JOURNAL OF PATHOLOGY, VOL.
160: 283-285 ( 1990)
EDITORIAL BOVINE SPONGIFORM ENCEPHALOPATHY: THE NEED FOR KNOWLEDGE, BALANCE, PATIENCE, A N D ACTION In November I986 a discovery was made that was to pose one of the most serious threats to the wellbeing of the British cattle industry this century. Pathologists at the Ministry of Agriculture's Central Veterinary Laboratory at Weybridge had, as a result of the animal health surveillance activities of the State Veterinary Service. identified a scrapielike disease of cattle. a condition which previously had been confined. in food animals, to sheep and goats. They named the disease bovine spongiform encephalopathy (BSE).' That the disease. characterized by brainstem lesions of spongiform change in grey matter neuropi1 and neuronal vacuolation, was scrapie-like was supported by the clinical presentation as a sporadic. slowly progressive, fatal, neurological disorder embracing abnormalities of behaviour, sensation. posture, and gait. The findings suggested that BSE might be the latest member of the group of diseases known as the subacute. transmissible. spongiform encephalopathies (SSEs) caused by unconventional agents. The unconventionality is due to the fact that infection results in no detectable immunological response and the agents are extraordinarily resistant to heat, ultra-violet, and ionizing radiation and many common disinfectants. The SSE group consists of scrapie in sheep and goats, transmissible mink encephalopathy. chronic wasting disease of captive mule deer and elk, and in humans, kuru, Creutzfeldt-Jakob disease (CJD) and GerstmannStraussler-Scheinker (GSS)syndrome. Conclusive evidence that BSE was a new member of the group was provided by workers at Weybridge and at the Institute for Animal Health, Neuropathogenesis Unit (NPU) in Edinburgh. First. fibrils were found in detergent-treated brain extracts only of BSE-affected cattle.' These were shown to share morphological,' chemical. and immunological properties with scrapie-associated fibrils (SAFs) which are found in all other members of the disease group.' The second important study was the transmissibility of BSE from cattle brain to mice' 0022-341 7/90/040283-03 $05.00 0 1990 by John Wiley 8i Sons, Ltd
following intracerebral and intraperitoneal inoculation. This study also established mice as a suitable species for assay of infected cattle tissues and products, for identifying putative sources of BSE and strain typing of the agent responsible. Studies on the transmissibility of BSE to cattle. sheep. goats, pigs. hamsters, and marmosets are in progress and others are planned. Further studies on the post-translationally altered. host-coded fibril protein (PrP). and particularly the production of anti-PrP serum in rabbits. have enabled researchers to detect PrP by immunoblotting of brain extracts4 and immunocytochemistry in brain sections. Currently, BSE diagnosis is confirmed by conventional paraffin histology of the brain. These immunological techniques, when developed further, may, however. permit more sensitive and preclinical detection of PrP in brain tissue. and. perhaps, in extraneural sites. The current absence of any practical test for identifying infection in individuals pre-clinically is a serious deficit restricting development of measures to control the condition. Amongst the theories of unconventional agent structure is that a small nucleic acid is responsible for scrapie or BSE infectivity but which so far has evaded detection. This requires intensified research effort for success and may lead to identification of the agent pre-clinically. and in tissues. without the need for animal inoculation and assay. All disease results from the interaction of environmental or genetic factors. In the case of scrapie. we know at least 20 strains exist with differing biological and physical properties, but it is too early to say if this is true of the BSE agent. Of equal or greater importance is the genetic control of BSE disease expression in cattle. We know that in murine and ovine scrapie a single gene (Sinc in mice and Sip in sheep) exerts a large measure of control over clinical disease expression by control of the incubation period.'.' These major genes are closely associated or identical with the PrP gene. Research at NPU has enabled identification of Sip alleles in sheep by a
284
EDITORIAL
blood test, the predictive value of which will be of value in reducing the occurrence of scrapie. Similar research is being undertaken in cattle. Recent studies' have shown that a defect (a unique amino acid substitution) occurs in the PrP gene in GSS patients but not in healthy relatives, or other individuals beyond the at-risk age, thus showing that the familial disease is inherited despite being infectious. An abnormal insertion in one allele of the PrP gene in a family of patients with CJD, but not in controls beyond the at-risk age, further demonstrates that a genetic deficit tracks with the illness.' By 23 February 1990, 10,551 cases of BSE had been confirmed in 5936 herds in Britain, of which 437 were beef suckler herds. The veterinary epidemiological investigation by Weybridge epidemiologists has been one of the most intensive ever applied to an animal disease and is continuing with the acknowledged help of the agricultural industry in its widest context. BSE is an extended common source epidemic.' Investigations of the source of the original infection point to meat and bone meal contaminated with a scrapie-like agent that survived rendering, possibly as a result of changes in the industrial processing of carcase waste.' The epidemiological study' concludes that exposure sufficient to cause clinical disease was initially established in 1981-1982 by oral exposure, predominantly of dairy calves, to a scrapie-like agent in ruminant protein-derived supplements incorporated in commercial concentrates or home-mixed rations. There is no evidence to date of cattle-to-cattle transmission either vertically (maternally, dam to offspring) or hori~ontally.~ Because of the long incubation period (age of peak incidence, 4 years) it will not be until 1992 that sufficient evidence accrues to determine whether or not cattle-to-cattle transmission occurs. The Ministry of Agriculture has set up a large experiment involving over 600 cattle (half offspring of BSE-affected dams and half controls) which will be monitored for BSE occurrence and incidence over a period of 7 years. Cattle-to-cattle transmission is the single most important issue that would influence the future course of the epidemic. This is because U.K. legislation has eliminated risks of new exposures from scrapie or BSE-contaminated ruminant-derived protein in ruminant feed since July 1988 and maternal spread of infection alone would be insufficient to sustain the epidemic. An important issue is to determine whether the bovine placenta is infective (as the sheep placenta is in scrapie) and this is under way.
Much of the advice to farmers, veterinarians, and others and the legislative control is based on our knowledge of scrapie and scrapie agent (its heat sensitivity, for example) rather than BSE. We owe a debt of gratitude particularly to William J. Hadlow, whose meticulous work",' I on the infectivity of tissues from pre-clinically and clinically affected sheep and goats with natural scrapie has given us a baseline to provide advice. There is now an urgent need to complete similar work with tissues from BSEaffected animals to provide continuing confidence in the advice or to alter it. Similarly, methods of destroying the BSE agent (including in material used for rendering) need investigation. However, patience is required, for delay in producing information is due to the long incubation period of the disease and the difficulty in interpreting the results of negative transmissions. The main issues concerning BSE at the present time are whether or not cattle-to-cattle spread occurs, whether or not there is a risk to other species including man, and if present controls are enough to reduce and possibly eliminate BSE in the cattle population. To determine the implications of BSE for human and animal health the Minister of Agriculture and Secretary of State for Health set up a Working Party in 1988. Reporting in February 1989,12 they concluded the risk to humans was remote but nevertheless, as a precautionary measure, they advised that affected animals and milk from them should be removed from the food chain. Also, that the ban on feeding ruminant protein to ruminants introduced by the Ministry should be continued indefinitely. Following consultation with the industry, from the 13 November 1989 in England and Wales and from 3 1 January 1990 in Scotland and Northern Ireland, a ban at the place of slaughter on the use for human consumption of specified offals was introduced via Section 118(6) of the Food Act 1984.The specified offals are bovine brain, spinal cord, spleen, thymus, tonsils and intestines (from duodenum to rectum inclusive) from cattle over 6 months of age. Additionally, the Working Party recommended setting up an expert committee (Tyrrell Committee) to identify research in progress or planned, any further research necessary, and priorities for its initiation. To control BSE in the national cattle herd, assuming no cattle-to-cattle transmission, the ruminant feed ban (July 1988) coupled with disease notification (June 1988) is all that is required. Compulsory slaughter and disposal of affected animals (August 1988) was introduced to remove such
285
EDITORIAL
animals from the food chain. If cattle-to-cattle transmission does not occur, the incidence of BSE should reduce from 1992 and the disease should be extinct by the late 1990s. The virtue of patience is required at least until the years immediately following 1992 when the accuracy of the predictions can be ascertained. If cattle-to-cattle transmission occurred only vertically, a similar reducing incidence would occur but at a slightly slower rate. This is because five affected cattle are needed to produce one offspring that will reach adulthood and thus the epidemic could not be maintained. Horizontal transmission particularly from placenta, if it occurred, might perpetuate the epidemic. Patience is therefore necessary, not only to await the outcome of the in-progress offspring study. but also to await the infectivity studies in mice and cattle of placenta. There is no evidence whatsoever for the natural transmission of scrapie or BSE to humans. Indeed, the related human diseases are (other than kuru. which has been virtually eliminated. and a few iatrogenic CJD transmissions) more readily explained by I t has been a matter of hereditary rne~hanisms.~.' extreme prudence to remove affected cattle and specified ofTals from the human food chain. In summary. there is a need for extensive research, much of which is under way. on species transmission, tissue infectivity. agent destruction, epidemiology, clinicopathology, molecular biology, and genetics. Patience in awaiting results is essential. A balanced view of all the available and accruing evidence is needed to promote continued
confidence in existingcontrols to protect animal and human health. R. BRADLEY Central Veterinary Laborator!. Neit, Hait,, WeJ*bridgeKTIS 3 N B , U . K .
REFERENCES I . Wells G A H . Scott AC. Johnson CT. 1'1 crl. A novel progressive spongiform encephalopdlhy in cattle. L ' e r i7c.c. 1987; 121:41Y 410 -.> Hope, J. Reekie LJD. Hunter N. crul. Fihrilsfrom brainsofcows with new cattle disease contain scrapie-associated protein. Norrrrc, I 98X: 336: 39G392. 3. Fraser H. McConnell I . Wells G A H . Dawson M . Transmission 4.
5.
6.
7.
X.
9
10.
II 12
of bovine spongiform encephalopdthy to mice I'vr R r i . IYXX. 123 411. Farquhar CF. Sornervrlie RA. Ritchie L A . Po3t-mortem immunodiagnosis o f scrapie and bovine spongiform encephalopath). J i'm/ M d l , l d \ 1989: 24. 215-2??. Dickinson AG. Meikle V M H . Fraser H Identification o f a gene which controls the incubation period o f someslrains of scrapieagent in mice J Camp Pcrrhid 1968: 78: 293-299. Hunter K. Foster JD. Dickinaon AG. Hope J. Linkage of the gene for the scrapie-associated fibril protein (PrP) l o the Stp gene in Chebiot sheep. I t ' ! R w 19x9: 1 2 4 364 366 Hsiao K . Baker HF. Crou TJ. c i crl. Linkage o f a prion. protein. missense variant to Gerstmann-Striuc4er syndrome. Ncrruri, 1989: 3 x 3 4 2 345 Owen F.Poulter M.Lofthouce R.c.iu/. Insertion in p r i m proterngene in familial Creutzfeldt-Jakob disease. L c r w t . ~19x9: i:51 - 5 2 . Wilesmith JW. WellsGAH. Cranwell MP. Ryan JBM. Bovinespongiform encephalopathy: epidemiological studies. I'cv R i a ( . IYXX. 123 638-644 Hadlou WJ. Kennedy RC. Race R E Natural infection of SulTolh sheep with scrapre virus. J /n/rc i DII 19x2; 146: 657-664 Hadlow WJ. Kennedy RC. Race RE. Eklund C M . Virologic and neurohistologic findings in dairy goats afiected with natural scrapie I'c,i Pitrho/ 19x0. 17: 1x7- 199. Southwood Report-Report o f the Working Parry on Bovine Spongiform Encrphalopdthy. London. Department of Health. Ministr! of Agriculture. Fisheriesand Food. 19X9.35 pp
160: 283-285 ( 1990)
EDITORIAL BOVINE SPONGIFORM ENCEPHALOPATHY: THE NEED FOR KNOWLEDGE, BALANCE, PATIENCE, A N D ACTION In November I986 a discovery was made that was to pose one of the most serious threats to the wellbeing of the British cattle industry this century. Pathologists at the Ministry of Agriculture's Central Veterinary Laboratory at Weybridge had, as a result of the animal health surveillance activities of the State Veterinary Service. identified a scrapielike disease of cattle. a condition which previously had been confined. in food animals, to sheep and goats. They named the disease bovine spongiform encephalopathy (BSE).' That the disease. characterized by brainstem lesions of spongiform change in grey matter neuropi1 and neuronal vacuolation, was scrapie-like was supported by the clinical presentation as a sporadic. slowly progressive, fatal, neurological disorder embracing abnormalities of behaviour, sensation. posture, and gait. The findings suggested that BSE might be the latest member of the group of diseases known as the subacute. transmissible. spongiform encephalopathies (SSEs) caused by unconventional agents. The unconventionality is due to the fact that infection results in no detectable immunological response and the agents are extraordinarily resistant to heat, ultra-violet, and ionizing radiation and many common disinfectants. The SSE group consists of scrapie in sheep and goats, transmissible mink encephalopathy. chronic wasting disease of captive mule deer and elk, and in humans, kuru, Creutzfeldt-Jakob disease (CJD) and GerstmannStraussler-Scheinker (GSS)syndrome. Conclusive evidence that BSE was a new member of the group was provided by workers at Weybridge and at the Institute for Animal Health, Neuropathogenesis Unit (NPU) in Edinburgh. First. fibrils were found in detergent-treated brain extracts only of BSE-affected cattle.' These were shown to share morphological,' chemical. and immunological properties with scrapie-associated fibrils (SAFs) which are found in all other members of the disease group.' The second important study was the transmissibility of BSE from cattle brain to mice' 0022-341 7/90/040283-03 $05.00 0 1990 by John Wiley 8i Sons, Ltd
following intracerebral and intraperitoneal inoculation. This study also established mice as a suitable species for assay of infected cattle tissues and products, for identifying putative sources of BSE and strain typing of the agent responsible. Studies on the transmissibility of BSE to cattle. sheep. goats, pigs. hamsters, and marmosets are in progress and others are planned. Further studies on the post-translationally altered. host-coded fibril protein (PrP). and particularly the production of anti-PrP serum in rabbits. have enabled researchers to detect PrP by immunoblotting of brain extracts4 and immunocytochemistry in brain sections. Currently, BSE diagnosis is confirmed by conventional paraffin histology of the brain. These immunological techniques, when developed further, may, however. permit more sensitive and preclinical detection of PrP in brain tissue. and. perhaps, in extraneural sites. The current absence of any practical test for identifying infection in individuals pre-clinically is a serious deficit restricting development of measures to control the condition. Amongst the theories of unconventional agent structure is that a small nucleic acid is responsible for scrapie or BSE infectivity but which so far has evaded detection. This requires intensified research effort for success and may lead to identification of the agent pre-clinically. and in tissues. without the need for animal inoculation and assay. All disease results from the interaction of environmental or genetic factors. In the case of scrapie. we know at least 20 strains exist with differing biological and physical properties, but it is too early to say if this is true of the BSE agent. Of equal or greater importance is the genetic control of BSE disease expression in cattle. We know that in murine and ovine scrapie a single gene (Sinc in mice and Sip in sheep) exerts a large measure of control over clinical disease expression by control of the incubation period.'.' These major genes are closely associated or identical with the PrP gene. Research at NPU has enabled identification of Sip alleles in sheep by a
284
EDITORIAL
blood test, the predictive value of which will be of value in reducing the occurrence of scrapie. Similar research is being undertaken in cattle. Recent studies' have shown that a defect (a unique amino acid substitution) occurs in the PrP gene in GSS patients but not in healthy relatives, or other individuals beyond the at-risk age, thus showing that the familial disease is inherited despite being infectious. An abnormal insertion in one allele of the PrP gene in a family of patients with CJD, but not in controls beyond the at-risk age, further demonstrates that a genetic deficit tracks with the illness.' By 23 February 1990, 10,551 cases of BSE had been confirmed in 5936 herds in Britain, of which 437 were beef suckler herds. The veterinary epidemiological investigation by Weybridge epidemiologists has been one of the most intensive ever applied to an animal disease and is continuing with the acknowledged help of the agricultural industry in its widest context. BSE is an extended common source epidemic.' Investigations of the source of the original infection point to meat and bone meal contaminated with a scrapie-like agent that survived rendering, possibly as a result of changes in the industrial processing of carcase waste.' The epidemiological study' concludes that exposure sufficient to cause clinical disease was initially established in 1981-1982 by oral exposure, predominantly of dairy calves, to a scrapie-like agent in ruminant protein-derived supplements incorporated in commercial concentrates or home-mixed rations. There is no evidence to date of cattle-to-cattle transmission either vertically (maternally, dam to offspring) or hori~ontally.~ Because of the long incubation period (age of peak incidence, 4 years) it will not be until 1992 that sufficient evidence accrues to determine whether or not cattle-to-cattle transmission occurs. The Ministry of Agriculture has set up a large experiment involving over 600 cattle (half offspring of BSE-affected dams and half controls) which will be monitored for BSE occurrence and incidence over a period of 7 years. Cattle-to-cattle transmission is the single most important issue that would influence the future course of the epidemic. This is because U.K. legislation has eliminated risks of new exposures from scrapie or BSE-contaminated ruminant-derived protein in ruminant feed since July 1988 and maternal spread of infection alone would be insufficient to sustain the epidemic. An important issue is to determine whether the bovine placenta is infective (as the sheep placenta is in scrapie) and this is under way.
Much of the advice to farmers, veterinarians, and others and the legislative control is based on our knowledge of scrapie and scrapie agent (its heat sensitivity, for example) rather than BSE. We owe a debt of gratitude particularly to William J. Hadlow, whose meticulous work",' I on the infectivity of tissues from pre-clinically and clinically affected sheep and goats with natural scrapie has given us a baseline to provide advice. There is now an urgent need to complete similar work with tissues from BSEaffected animals to provide continuing confidence in the advice or to alter it. Similarly, methods of destroying the BSE agent (including in material used for rendering) need investigation. However, patience is required, for delay in producing information is due to the long incubation period of the disease and the difficulty in interpreting the results of negative transmissions. The main issues concerning BSE at the present time are whether or not cattle-to-cattle spread occurs, whether or not there is a risk to other species including man, and if present controls are enough to reduce and possibly eliminate BSE in the cattle population. To determine the implications of BSE for human and animal health the Minister of Agriculture and Secretary of State for Health set up a Working Party in 1988. Reporting in February 1989,12 they concluded the risk to humans was remote but nevertheless, as a precautionary measure, they advised that affected animals and milk from them should be removed from the food chain. Also, that the ban on feeding ruminant protein to ruminants introduced by the Ministry should be continued indefinitely. Following consultation with the industry, from the 13 November 1989 in England and Wales and from 3 1 January 1990 in Scotland and Northern Ireland, a ban at the place of slaughter on the use for human consumption of specified offals was introduced via Section 118(6) of the Food Act 1984.The specified offals are bovine brain, spinal cord, spleen, thymus, tonsils and intestines (from duodenum to rectum inclusive) from cattle over 6 months of age. Additionally, the Working Party recommended setting up an expert committee (Tyrrell Committee) to identify research in progress or planned, any further research necessary, and priorities for its initiation. To control BSE in the national cattle herd, assuming no cattle-to-cattle transmission, the ruminant feed ban (July 1988) coupled with disease notification (June 1988) is all that is required. Compulsory slaughter and disposal of affected animals (August 1988) was introduced to remove such
285
EDITORIAL
animals from the food chain. If cattle-to-cattle transmission does not occur, the incidence of BSE should reduce from 1992 and the disease should be extinct by the late 1990s. The virtue of patience is required at least until the years immediately following 1992 when the accuracy of the predictions can be ascertained. If cattle-to-cattle transmission occurred only vertically, a similar reducing incidence would occur but at a slightly slower rate. This is because five affected cattle are needed to produce one offspring that will reach adulthood and thus the epidemic could not be maintained. Horizontal transmission particularly from placenta, if it occurred, might perpetuate the epidemic. Patience is therefore necessary, not only to await the outcome of the in-progress offspring study. but also to await the infectivity studies in mice and cattle of placenta. There is no evidence whatsoever for the natural transmission of scrapie or BSE to humans. Indeed, the related human diseases are (other than kuru. which has been virtually eliminated. and a few iatrogenic CJD transmissions) more readily explained by I t has been a matter of hereditary rne~hanisms.~.' extreme prudence to remove affected cattle and specified ofTals from the human food chain. In summary. there is a need for extensive research, much of which is under way. on species transmission, tissue infectivity. agent destruction, epidemiology, clinicopathology, molecular biology, and genetics. Patience in awaiting results is essential. A balanced view of all the available and accruing evidence is needed to promote continued
confidence in existingcontrols to protect animal and human health. R. BRADLEY Central Veterinary Laborator!. Neit, Hait,, WeJ*bridgeKTIS 3 N B , U . K .
REFERENCES I . Wells G A H . Scott AC. Johnson CT. 1'1 crl. A novel progressive spongiform encephalopdlhy in cattle. L ' e r i7c.c. 1987; 121:41Y 410 -.> Hope, J. Reekie LJD. Hunter N. crul. Fihrilsfrom brainsofcows with new cattle disease contain scrapie-associated protein. Norrrrc, I 98X: 336: 39G392. 3. Fraser H. McConnell I . Wells G A H . Dawson M . Transmission 4.
5.
6.
7.
X.
9
10.
II 12
of bovine spongiform encephalopdthy to mice I'vr R r i . IYXX. 123 411. Farquhar CF. Sornervrlie RA. Ritchie L A . Po3t-mortem immunodiagnosis o f scrapie and bovine spongiform encephalopath). J i'm/ M d l , l d \ 1989: 24. 215-2??. Dickinson AG. Meikle V M H . Fraser H Identification o f a gene which controls the incubation period o f someslrains of scrapieagent in mice J Camp Pcrrhid 1968: 78: 293-299. Hunter K. Foster JD. Dickinaon AG. Hope J. Linkage of the gene for the scrapie-associated fibril protein (PrP) l o the Stp gene in Chebiot sheep. I t ' ! R w 19x9: 1 2 4 364 366 Hsiao K . Baker HF. Crou TJ. c i crl. Linkage o f a prion. protein. missense variant to Gerstmann-Striuc4er syndrome. Ncrruri, 1989: 3 x 3 4 2 345 Owen F.Poulter M.Lofthouce R.c.iu/. Insertion in p r i m proterngene in familial Creutzfeldt-Jakob disease. L c r w t . ~19x9: i:51 - 5 2 . Wilesmith JW. WellsGAH. Cranwell MP. Ryan JBM. Bovinespongiform encephalopathy: epidemiological studies. I'cv R i a ( . IYXX. 123 638-644 Hadlou WJ. Kennedy RC. Race R E Natural infection of SulTolh sheep with scrapre virus. J /n/rc i DII 19x2; 146: 657-664 Hadlow WJ. Kennedy RC. Race RE. Eklund C M . Virologic and neurohistologic findings in dairy goats afiected with natural scrapie I'c,i Pitrho/ 19x0. 17: 1x7- 199. Southwood Report-Report o f the Working Parry on Bovine Spongiform Encrphalopdthy. London. Department of Health. Ministr! of Agriculture. Fisheriesand Food. 19X9.35 pp
