Farmers in Britain are commonly tenants, and so their rent can increase when profits increase (for example, due to the common agricultural policy) As a result, no matter what the potential profitability of a method being used is, there is continuous high pressure on the system to become more efficient. This led to the use of the most productive cattle for lactation; the most effective pesticides for the price; the most effective rendering plants; and any good, reasonably priced source of protein in the bovine diet. The result was that over 95% of the dairy cattle in Britain were from three breeds and the vast majority were Holstein-Friesian, and the renderers were almost all owned by two companies and used a single method for producing feed. Profits were relatively low but reliable, as long as the European Union kept the prices up and the Ministry of Agriculture, Fisheries and Food supplied technical help and help with sales.
The problem with this is that if one thing goes wrong then the mistake or risk applies to the whole system, which collapses; the individual companies and farmers have little to fall back on. As a result, the Ministry of Agriculture, Fisheries and Food believes that it must back up the farmers and bring back confidence, even when this confidence is not justified (eggs really were contaminated with Salmonella and pate with Listeria, and bovine spongiform encephalopathy infected large numbers of cattle being eaten and could not be assumed to be a low risk).
The emergence of bovine spongiform encephalopathy shows how pressure towards high efficiency leads to nationally organised, relatively fragile, single method systems that can collapse easily and may depend on the suppression or denial of information in the short term for such collapse to be avoided. What happens when a disease such as bovine spongiform encephalopathy appears that is potentially fatal to a considerable proportion of the population(2) but proof for or against this will not become available for several years? Under the current system either attempts are made to assure the consumers of the safety of the food (with inadequate justification) or the industry collapses. As McMichael states, it is the pressure on the system that leads to this, and it will happen repeatedly as the pressure increases.
STEPHEN DEALLER Consultant microbiologist
Burnley General Hospital,
Burnley BB10 2PQ
A study collecting information about folic acid supplementation by pregnant women is also collecting dietary information,(2) asking about food eaten in the past week; information is collected about 20 common foods containing varying levels of folates. During the 10 weeks 29 January to 21 April 1996, 409 pregnant women attending three hospitals in Birmingham were recruited to the study. All were attending a maternity hospital booking clinic; 294 were in the first trimester of pregnancy. The ages of the respondents ranged from 15 to 46 (mean 27.9 years). The catchment areas of the participating hospitals have varied socioeconomic and ethnic compositions.
Four hundred women (98%) completed the dietary section of the questionnaire; 105 reported that they had eaten beef during the previous week. The media coverage of the 10 cases of Creutzfeldt-Jakob disease in young people occurred in the week beginning 18 March(3) In the five weeks preceding this announcement 59 (36%) of the 163 women recruited reported that they had eaten beef at least once during the previous week (table 1).
Number (percentage) of respondents who reported having eaten beef in past week
|Had eaten beef|
|29 Jan to 17 Mar||163||104 (64)||59 (36)|
|20||18 (90)||2 (10)|
|89||73 (82)||16 (18)|
|27||24 (89)||3 (11)|
|65||50 (77)||15 (23)|
|Total||400||295 (74)||105 (26)|
In the four weeks after the media coverage the proportion of women reporting having eaten beef fell to 36 (18%) of 201 women (chi-2 = 15.6, P = 0.00008). Asians reported eating beef less frequently than other ethnic groups (4/44 (9%) versus 101/356 (28%); chi-2 = 7.52, P = 0.006). However, adjustment for weekly variation in the proportion of vegetarians (24 (6.0% of the study population)) and Asians (44 (10.8%)) recruited does not explain the observed fluctuation in consumption of beef.
Data for the most recent week (beginning 15 April) show that the rate of beef consumption had risen to 23%, which suggests that it was reverting towards former levels. Possibly, pregnant women are more health aware than the general population. These data suggest, however, that the dramatic fall in beef consumption after the heavy media coverage was short lived. This could mean either that the public has identified the scientific uncertainty or that after an initial reaction most of the public rapidly reverts to usual behaviour patterns. If the latter hypothesis is correct this may have implications for government health warnings and health education policy.
University of Birmingham,
Birmingham B15 2TT
Table 1 shows my findings.
|Table 1 - Results of survey on eating habits of random selection of doctors hand patients conducted during beef crisis. Figures are numbers (percentages)|
|Had stopped eating beef||Had stopped eating beef products||Allowed children to eat beef||Allowed children to eat beef products||Significance|
(n = 43)
|8 (19)||20 (47)||33 (77)||19 (44)||chi-2 = 7.0, P<0.01|
(n = 44)
|20 (45)||32 (73)||11 (25)||4 (9)||chi-2 = 6.2, P<005|
|Patients by occupational class:|
II, IIIN, IIIM (n = 31)
|12 (39)||21 (88)||11 (35)||4 (13)||chi-2 = 23.3, P<0.001|
|Patients by occupational class:
IV, V (n = 13)
|6 (48)||10 (77)||0||0||chi-2 = 13.7, P<0.001|
(n = 48)
|5 (16)||21 (44)||31 (65)||18 (38)|
(n = 39)
|23 (59)||31 (79)||13 (33)||5(13)|
Patients were more likely to have stopped eating beef than doctors and to have stopped eating beef products. They were more likely not to allow young children to eat beef (33 (75%)) and beef products (40 (91%)) than were doctors (10 (23%) and 24 (56%) respectively). when patients' responses were analysed by occupational class those in classes IV and V were more likely to have stopped eating beef and beef products than their counterparts in classes II and III. None of those in classes Iv or V would allow young children to eat beef or beef products. When both patients and doctors were analysed by sex women were more likely than men to have stopped eating beef and beef products and less likely than men to allow children to eat these products.
It is not surprising that doctors, with their medical knowledge, have been less worried about bovine spongiform encephalopathy and whether to eat beef than have patients. If; however, the public realised that their own doctors were continuing to eat beef then they might be less concerned. My findings show that socioeconomic status influences eating habits; this possibly reflects educational background (and thus the ability to separate facts and risks from the hype) and sources of information (for example, broadsheet rather than tabloid newspapers).
An important issue is the power of the media to influence diet. If people in lower socioeconomic groups continue to eat less red meat, beefburgers, sausages, etc and to prevent their children from eating these then a fall in the incidence of ischaemic heart disease may result - an unexpected benefit of the saga.
House officer in general medicine
Cardiff CF64 2XX
1 Lacey RW Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. BMJ 1996;312:180-1. (20 January.)
2 Almond J W, Brown P, Gore S M, Hofnan A, Wientjens D P W M, Ridley R M, et al. Creutzfeldt-Jakob disease and bovine spongiform encephalopathy: any connection? BMJ 1995;311:1415-21. (25 November.)
3 Brown P. Bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. BMJ 1996;312:790-1. (30 March.)
4 Delamothe T. Meltdown: the media and mad cows.< BMJ 1996;312:854-5. (30 March.)
Worldwide intensive meat production is unsustainable Evidence from Britain that the agent causing bovine spongiform encephalopathy in cattle may cause neurological disease in beef eaters(1) and the consequent turmoil in the beef trade have made compelling headline news across Europe. The ecological dimensions to this public drama have, however, even wider implications for population health.
Three issues warrant discussion. Firstly, although the infective agent of bovine spongiform encephalopathy and its effects may seem exotic, this episode merely extends the long running narrative whereby changes in human culture induce new infectious diseases. Secondly, the method of cattle feeding implicated in the transmission of bovine spongiform encephalopathy seems partly to have arisen because of supply-demand pressures in the world food production system. Thirdly, the scare about bovine spongiform encephalopathy is the tip of a much larger iceberg of adverse environmental and health consequences of the mass production and consumption of meat.
Firstly, incredulity that the mysterious transmissible agent responsible for bovine spongiform encephalopathy might "jump species" and infect humans is misplaced. Microbes and their ilk are no less opportunistic than any other species and are capable of rapid genetic adaptation.(2) We humans have improved our survival prospects by widening the range of other species on which we feed. Bacteria and multicellular parasites do likewise, as do the viruses and prions that parasitise the intracellular molecular processes of animals and plants. Ever since humans made intimate contact with other animal species - by intruding on their habitats, eating them, or domesticating them - mutant strains of zoonotic agents have opportunistically become infectious agents in humans.(3)(4) Thus have we acquired smallpox from cattle, measles from ungulates or dogs. influenza from pigs, HIV from monkeys, and so on.
This endless narrative is a condition of life on earth: it is simply anthropocentrism that sees many tiny species as "pests and diseases" because they share our food supplies or parasitise us. Modern intensive methods of agriculture, animal husbandry, and aquaculture have opened up vast new ecological opportunities for microbes.(4)(5) Hence it would be surprising if transmission of the type that we think may be happening with bovine spongiform encephalopathy and Creutzfeldt-Jakob disease did not occur.(6) Recent sequencing of the prion protein in vertebrates indicates an evolutionary connection between the forms in cattle and in humans.(7)
Secondly, modern methods of intensive farming reflect increasingly the tension between food supply and demand. As populations have increased in size and affluence, so the demand for food has grown, particularly for foods such as meat that are seen as high quality. The expectation of cheap meat, helped by competition between supermarkets and government subsidy, is spreading throughout the world's middle classes. The resulting intensification in meat production requires heightened inputs of energy, chemicals, water, and protein feed.(8)
The use of protein derived from ruminants for cattle feed increased in the early l98Os, as world prices escalated for the then prevailing protein supplements, fishmeal and soybeans. The price rises reflected faltering growth in per capita production of those foods, after three decades of strong growth.(9)(10) The per capita production of soybeans tripled between 1950 and 1980 while the per capita fish catch doubled between 1950 and 1970, but neither has increased further since those peaks. From the 1980s the growth in production of these and several other foods seems to have fallen behind the growth in world population.(10)(11) We must therefore ask of our recent methods of food production: to what extent have we been depending on unsustainable resource inputs? And of the future: can we sufficiently boost production with genetically engineered plant, animal, and marine foods? The answers bear strongly on the long term prospects for human health.
Thirdly, beef production is a very environmentally damaging form of meat production.(8) If we are adequately and equitably to feed a world of 10 billion people next century, compared with today's 5.7 billion, then beef-eating Westerners cannot expect to continue dining at an elite high table. There is insufficient land and protein supplement (whether as cereal, fish, or mammalian scraps) to enable a beef enriched global diet. The supplies of fossil fuel energy and water required for intensive livestock production are huge. So is the demand for forests to be denuded to create pastoral land in Central America to produce lean beef for McDonald's burgers.(12) A unit of beef energy produced in western (and, increasingly, east Asian) factory farms requires an input of around 6-7 units of cereal grain energy.(8) Smil argues that "diets high in meat are a very recent aberration unsustainable on a global scale."(11)
Epidemiological studies indicate that vegetarians live a little longer than meat eaters.(13)(14) We should therefore expect that a world diet of modest meat content would bring widespread gains in human health - both directly and by averting the adverse social and environmental consequences of intensive meat production.(14)
These complex ecological issues portend far reaching and challenging policy decisions. Currently, however, we are preoccupied with the unsettling risks to public health from British beef already eaten. And in the political arena the findings of the parliamentary Joint Agriculture and Health Select Committee seem unlikely to go beyond the puny immediacies of economic and political face saving. We thus risk overlooking the wider ecological and public health implications of our mass produced, meat enriched diet. For over one hundred millennia food supplies and, more recently, food production methods have been central to the ecological sustainability of human societies. In the coming millennium we will need to think even more in those terms.
A J MCMICHAEL
Professor of epidemiology
Department of Epidemiology and Population Sciences,
London School of Hygiene and Tropical Medicine,
London WC1 E 7HT
A High Court judge last week held the Department of Health and the Medical Research Council to blame for the deaths of young adults from Creutzfeldt-Jakob disease (CJD) who had been treated with human growth hormone. In the first compensation claim over a pharmaceutical product to succeed in the British courts, Mr Justice Morland ruled that the two bodies were negligent in not passing on concerns raised by scientists that would probably have led to the treatment's suspension from July 1977. The decision means that only the families of patients who started the treatment after 1 July 1977 will be entitled to compensation.
The judge held, in effect, that had the Department of Health and the MRC fulfilled their duty of care, patients such as Patrick Baldwin, who was treated between October 1977 and 1980, would never have undergone the treatment and contracted CJD. He died in 1992 aged 30, leaving two daughters now aged 9 and 10, who are in line for substantial compensation, which has still to be assessed. The test case was brought by eight of the 16 families of recipients of human growth hormone who have died from CJD since 1985, and by three others who are dying from the disease. In addition, 87 claimants in whom CJD has not been diagnosed but who are claiming compensation for psychological trauma, hope to have their case heard next year.
The MRC ran the growth hormone programme as a clinical trial from 1959 until 1 July 1977, when the programme was taken over by the Department of Health. Nearly 2,000 children were treated with the hormone - extracted from the pituitaries of cadavers - between 1959 and 1985, until reports of the first deaths from CJD in the United States, after which synthetic hormone was used. The MRC retained responsibility for collecting and processing pituitaries until 1980.
In October 1976 a veterinary scientist, Dr Alan Dickinson of the Agricultural Research Council, who was working on scrapie, telephoned the MRC to alert officials to the risk of transmission of CJD through human growth hormone. In a letter in February 1977 he made four suggestions to improve the safety of the hormone. Two were never acted on, a third was only partly implemented, and the fourth - excluding the use of pituitaries from cases with dementia - was not put into force until 1980. Two virologists, Professor Cedric Mims of Guy's Hospital and Professor Peter Wildy of Cambridge University, were consulted by the MRC, but not until December 1977.
Professor Wildy replied: "Any clinician who uses growth hormone must be made aware of the gruesome possibilities and their imponderable probabilities." But while the scientific steering committee overseeing the manufacture of the hormone were told, the clinicians' committee was "deliberately kept in the dark," the judge said. Charles Brook, professor of paediatric endocrinology at University College London Hospitals and Great Ormond Street Children's Hospital and a member of the clinicians' committee, gave evidence that he had never seen the letters from Dr Dickinson and the two virologists before the trial and he was "appalled" by them.
legal correspondent, BMJ
Maternal transmission of bovine spongiform encephalopathy (BSE) does occur at low levels, according to preliminary results of research carried out by the Ministry of Agriculture, Fisheries and Food. Researchers from the epidemiology department at the central veterinary laboratory in Weybridge found that the risk of maternal transmission of BSE from cow to calf in their study was 10%. They say that outside of study conditions this would mean that 1% of calves born to cows which die of BSE will themselves die of BSE caught from their mothers.
Final results of the study, which started in 1989, are not due until the end of the year, but the Spongiform Encephalopathy Advisory Committee (SEAC) decided to break the code early and release the data. The committee decided, however, that no further action was needed to protect public health as Britain's eradication plan for BSE already recognised that maternal transmission was a possibility.
The results have received a mixed reaction from the scientific community and stirred up once again the controversial issue of maternal transmission of encephalopathies in any animal. Kenton Morgan, professor of epidemiology at Liverpool University's faculty of veterinary science, said: "Frankly I am not surprised at the results. How could anyone have thought anything else, with maternal transmission occurring in sheep, goats, and ruminants such as the kudu, an African antelope. It would have been more surprising if they did not find maternal transmission."
But Dr Rosalind Ridley, head of the Medical Research Council's comparative cognition team at Cambridge, who wrote a paper in the BMJ (311:1071) suggesting that maternal transmission of spongiform encephalopathy was a myth, remained sceptical. She said that the data do not seem to add up as similar results have not been seen in the field. "And if there is maternal transmission then why hasn't anyone found any evidence of infection in the bovine placenta?" she added.
In this latest study the researchers studied two groups of animals with over 300 cattle in each. One group consisted of offspring of mothers with confirmed cases of BSE, and in the other group were animals born in the same herd and in the same calving season whose mother had reached at least 5 years old without showing clinical signs of BSE. The animals in the two groups were kept until the age of 7 or until BSE or another disease intervened.
Of 273 animals born to mothers with BSE 42 were histologically confirmed, BSE themselves. Of 273 animals born to mothers who did not have BSE, 13 animals were confirmed as having BSE. Results are pending on a further 63 animals. The disease showed up in both groups because the cattle studied were born around the time of the ruminant feed ban in 1988, and so some at least would have been exposed to infected feed.
Four hundred and eleven of the calves were born within 13 months of the clinical onset of BSE in their mothers, and the great majority were born within five months of clinical onset. So the study does not provide a good estimate of the risk to animals born more than six months before the onset of BSE in the mother. But the Spongiform Encephalopathy Advisory Committee said that the data do provide some evidence that there is an enhanced risk of maternal transmission in the last six months of the BSE incubation period.
"The risk of maternal transmission observed in the study is likely to be greater than would be expected for the entire population of cows," the committee said. "Under field conditions, only a fraction of the BSE infected cows giving birth would be within six months of demonstrating clinical signs of BSE because of the long incubation period of the disease:'
The new research throws no light on the route of maternal transmission, which could be in utero, at birth, or soon after birth. Evidence of maternal transmission of scrapie in sheep has come from two sources. Firstly, infectivity has been detected in the uterus in a few affected sheep. Secondly, an embryo transfer experiment showed evidence of in utero transmission. The embryo from a sheep infected with scrapie was transplanted into a healthy ewe, and when that ewe gave birth the lamb went on to develop scrapie. Similar experiments are underway in cattle, but the results are not yet available. But no infectivity has been detected in bovine placenta, milk, or blood.
Dr Ridley, however, is still sceptical about maternal transmission in any animal and argues that the data from sheep were derived from only a handful of animals. while agreeing that the new data have produced a striking correlation, she argues that it could be explained by genetic susceptibility in the cattle population. "If you look at a whole herd which has all been fed on the same supposedly infected feed, from the same sack, it turns out to be only one or two cows per birth cohort which go down sick. This raises the question, why not all of them?" There is some genetic variation in the PrP gene, and a small analysis has suggested that this is not associated with BSE, but Dr Ridley says that this needs to be looked at further.
Dr Ridley also added that the comparison group tended to consist of the offspring of elderly cows. "Maybe the elderly cows had some resistance to BSE - there could have been some genetic selection going on."
The Spongiform Encephalopathy Advisory Committee states categorically that there is no evidence from any of the transmissible spongiform encephalopathies that infectivity can be transmitted trough milk. Further research is, however, being undertaken.
RM Ridley, HF Baker
Department of Experimental Psychology
Cambridge CB2 3EB ... RM Ridley, head, MRC comparative cognition team ... HF Baker, senior scientific officer
Correspondence to: Dr RM Ridley,
School of Clinical Veterinary Medicine,
Cambridge CB3 OES.
It has long been accepted that the pattern of occurrence of scrapie - the form of spongiform encephalopathy associated with sheep - is determined mainly by maternal transmission, and this view has had a profound influence on policy decisions in the control of bovine spongiform encephalopathy and on public concern over the risk to human health from this disease. The occurrence of maternal transmission is, however, not predicted by modern knowledge of the aetiology of spongiform encephalopathy, and even though claims of maternal transmission have been reiterated frequently in the literature, reexamination of the source data reveals that these data are extremely scanty, unreplicated, and probably subject to ascertainment bias. The probability of maternal transmission of spongiform encephalopathy in any species should be viewed with the greatest skepticism.
In assessing the risk to human health of the epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom, the Southwood Committee accepted the view that in scrapie (the spongiform encephalopathy occurring in sheep) "there is transmission of scrapie from the infected ewe to lamb." Maternal transmission means the infection of the lamb by the dam through a mechanism which is specific to this biological relationship prenatal or perinatal transplacental transfer of infective agent or infection through milk, saliva, or the close contact of birth and suckling.
The House of Commons Agriculture Committee on BSE concluded that if maternal transmission also occurred in bovine spongiform encephalopathy then "its elimination will be much harder and its implications for humans much more uncertain" and "the policy implications would be substantial." In 1989 a long term study was initiated to monitor the possible occurrence of maternal transmission in bovine spongiform encephalopathy.
Alarm in the general public was fuelled by Professor Lacey, who promulgated the view that for bovine spongiform encephalopathy "vertical transmission should prolong the epidemic into an endemic that would be effectively permanent" and that if bovine spongiform encephalopathy were to cause spongiform encephalopathy in humans, then not only would many people succumb to this disease, but their children would also be affected. The issue of maternal transmission in spongiform encephalopathy is therefore very serious and warrants close scrutiny.
Transmission of spongiform encephalopathy in humans (kuru and iatrogenic Creutzfeldt-Jakob disease) and animals (bovine spongiform encephalopathy, for example) does occur by specific mechanisms involving food or other contamination, but the extent to which it is involved in the pattern of occurrence of natural scrapie is currently unresolved and is not the subject of this paper.
Many recent publications perpetuate the view that spongiform encephalopathy in sheep (and therefore potentially in other species) is maintained largely by maternal transmission. The source papers (see below) on which this claim is based were published in the 1960s, when nothing was known of the molecular genetics of scrapie or the molecular pathogenesis of spongiform encephalopathy and the occasional familial occurrence of the only other endemic spongiform encephalopathy (Creutzfeldt-Jakob disease in humans) was perceived but poorly understood. It is therefore appropriate to consider briefly current understanding of spongiform encephalopathy before reassessing the source data.
Pattern of occurrence of spongiform encephalopathy in species other than sheep Spongiform encephalopathy can occur as either an epidemic or endemic disease.
Epidemics consist of cohorts of cases acquired by contamination with material (usually brain) from affected cases and have occurred in humans as the result of cannibalism in Papua New Guinea (where it is known as kuru) or medical accident, or in animals as the result of consuming feedstuff containing protein derived from infected animals.
The last has occurred in cattle (bovine spongiform encephalopathy), cats, and exotic ungulates kept in zoos and fed on similar material to the cattle.
A similar disease has occurred in farmed mink, captive mule deer, and elk. There has been no evidence of maternal transmission in any of these epidemics of spongiform encephalopathy.
The incidence of kuru dropped dramatically in people born after the cessation of cannibalism in the mid-1950s, and no children born after 1959 to any of the women who had or subsequently developed kuru have themselves developed the disease. The preponderance of kuru in women and their children is adequately explained by anthropological data indicating that women and children partook of the brain and other internal organs, and the men did not.
Although there has been a single report of infectivity in placenta, blood, and colostrum from a pregnant woman with Creutzfeldt-Jakob disease, this does not establish maternal transmission since both the child in this case and two further children born to women with Creutzfeldt-Jakob disease remain well, like the offspring of the kura patients. Maternal transmission also did not occur from the mice used for transmission by Tamai et al, nor has it occurred in the progeny of a large number of primates used for the study of the transmissibility of human spongiform encephalopathy. Nationwide surveillance of bovine spongiform encephalopathy has shown no greater incidence in the offspring of dams with bovine spongiform encephalopathy than in animals in the same herd whose dam did not have the disease, the incidence in both being consistent with foodborne contamination within these herds.
In an isolated cohort of 630 calves, half from dams with and half from dams without bovine spongiform encephalopathy, 40 animals have so far developed the disease. But all of these calves came from herds affected by the disease and many were born before 1988 (during the period of exposure to contaminated food) such that until the code is broken (in 1997) these data (supplied by the Ministry of Agriculture, Fisheries, and Food) cannot be used to support the notion of maternal transmission in cattle.
Although it might be thought that the occurrence of bovine spongiform encephalopathy in animals born after the ruminant feed ban of 1988 suggests a non foodborne mode of transmission, the dramatic drop in the incidence of bovine spongiform encephalopathy in cows born after this date' shows that food was the major source of infection. Affected animals born shortly after the ban on the production of this feed have been partly attributable to the "shelf life" of purchased material, and subsequent cases may have been due to inadvertent contamination of cattle feed with banned material.
The specified offals ban of 1990, which banned the use of certain bovine offals in all animal feed, was designed to protect other species (in which spongiform encephalopathy had not actually been seen) but would have reinforced the effectiveness of the feed ban for cattle by preventing contamination with potentially infective material.
That such contamination was occurring was shown by the geographical association between the density of pig and poultry farming and the incidence of bovine spongiform encephalopathy in cattle born after the ban. An analysis of beef suckler herds which were not fed the contaminated feed but which had "bought in" cases of bovine spongiform encephalopathy provided no evidence of horizontal transmission from animal to animal.
Spongiform encephalopathy in a kudu whose dam also had spongiform encephalopathy was initially thought to indicate maternal transmission, but the subsequent appearance of spongiform encephalopathy in several more kudus which were not the progeny of affected animals, as well as in five other species of exotic ungulates born in seven zoos in Britain suggests that a more widespread source of infection was responsible. All these other exotic ungulates had unaffected dams and were born either before the ruminant feed ban of 1988 or between that ban and the more stringent specified offals ban of 1990. No new cases have occurred since 1992. The animals born between 1988 and 1990 could have been infected by the supposed widespread, but low level, contamination of many types of animal feed, which the specified offals ban seems to have largely eliminated.
The only species apart from sheep (and possibly goats) in which spongiform encephalopathy is an endemic disease is humans, where the endemic disease is either sporadic or familial.
Familial cases occur in an autosomal dominant pattern and are associated with one of a number of point mutations or insertional mutations in the prion gene (PrP gene).
That the mutation causes the disease (rather than conferring susceptibility to an environmental agent) is indicated by the observation that transgenic mice carrying the mouse equivalent of one of these mutations spontaneously develop spongiform encephalopathy.
The great majority of sporadic cases of human spongiform encephalopathy occur in people who are homozygous for a common polymorphism in the PrP gene.
The molecular pathogenesis of spongiform encephalopathy One of the main conceptual problems in the 1960s, when the notion of maternal transmission was first propounded, was that it was believed that the "genetic" hypothesis of spongiform encephalopathy denied the possibility of the existence of a transmissible agent.
The undisputed transmissibility of spongiform encephalopathy under experimental conditions was, in that climate, a difficulty for the genetic hypothesis of natural scrapie. Our current understanding of spongiform encephalopathy is that it can be, under different circumstances, genetic, idiopathic, or acquired in origin and that cases of genetic or idiopathic origin give rise to an agent which is then transmissible. This is confirmed by transgenic experiments.
In all the spongiform encephalopathies, a normal host protein (PrP-c) undergoes a post-translational modification to an abnormal form (PrP-sc).
This abnormal form has a high beta pleated sheet conformation and spontaneously forms neurotoxic amyloid fibrils, which accumulate in the brain.
The primary structure of the PrP protein determines the probability with which it will form an amyloid polymer, so the disease is very rare when the PrP gene is "wild-type" but occurs in an autosomal dominant pattern in cases which carry certain mutations in the PrP gene.
Polymerisation can also be "seeded" by contamination with exogenous PrP-sc and this accounts for the transmissibility of the disease.
Homozygosity for polymorphisms in the PrP gene enables the protein product of both alleles to interact, making the disease more common in homozygotes.
This hypothesis is strengthened by the demonstration of the recruitment of PrP-c by PrP-sc in a cell free system. That natural sheep scrapie should be a largely recessive genetic disease determined mainly by the primary structure of the host PrP gene, but that tissues from affected cases should transmit disease, both experimentally and occasionally in the field, is wholly compatible with this current view of the spongiform encephalopathies.
The molecular genetics of scrapie Analysis of the PrP gene in sheep has shown that susceptibility to scrapie is tightly linked to polymorphisms in this gene. There are at least four polymorphic sites (codons 112, 136, 154, and 171), and association between these and the occurrence of scrapie depends largely on the breed of sheep.
Susceptible alleles are termed sA and resistant alleles are termed pA, although different combinations of the possible polymorphisms permit the occurrence of alleles of intermediate susceptibility.
Sheep with at least one sA allele are susceptible to experimental scrapie after subcutaneous injection of infectious material, and sAsA sheep sometimes show a shorter incubation than sApA sheep, depending on breed-sA is dominant or partially dominant for susceptibility to experimental, peripheral injection.
The pattern of occurrence of natural scrapie is, however, more compatible with a mainly recessive inheritance with only some involvement of heterozygotes.
In many breeds of sheep, pA alleles are known to encode alanine at codon 136 of the PrP gene and account for more than 85% of the allele frequency in unselected sheep.
The allele frequency of valine 136 is greater than 95% in sheep with natural scrapie from at least several of these breeds.
In cases of natural compared with experimentally induced scrapie, sAsA homozygosity is over represented, accounting for the largely recessive pattern of the natural disease.
In Cheviots, sheep encoding at least one valine at codon 136 show short incubations on subcutaneous challenge with the scrapie isolate SSBP/1, whereas sheep homozygous for alanine at codon 136 survive, irrespective of their genotype at codon 171; however, sheep which are homozygous for glutamine at codon 171 show greater susceptibility (than those which carry at least one arginine at codon 171) on experimental infection with another isolate, CH1641, irrespective of their codon 136 genotype.
SSBP/1 comprises a pooled sample of scrapie against which sA and pA alleles are defined and has been subject to multiple passage in sA Cheviots.
The CH1641 isolate came from a single natural case of scrapie from a "positive line" Cheviot flock which contained sAsA, sApA, and a few pApA sheep and was subsequently passaged in pApA Cheviots. Although this occurrence complicates the issue of susceptibility to scrapie, it raises the possibility that this unusual isolate represents the involvement of prion protein from a pA allele and is consistent with the extensive data that different strains of mouse sustain different experimental strains of agent, even though there is evidence that strain of agent can transcend strain of host.
Texel sheep also show a complex pattern of susceptibility, with polymorphisms at codons 136 and 171 both making a contribution while in Suffolk sheep susceptibility depends mainly on codon 171 genotype.
Embryo transfer experiments Foster et al reported embryo transfer experiments in which two sAsA and four sApA Cheviot sheep were injected subcutaneously with scrapie agent and about six months later were artificially inseminated with sApA semen. The embryos were transferred to 15 pApA sheep and one sApA sheep. Six of the 20 surviving lambs were sAsA and all these developed scrapie at about 2 years of age.
Eleven sApA lambs and three pApA lambs had not developed scrapie at the time of publication. All six donor ewes but no recipient ewes developed scrapie. The most parsimonious explanation of these data is that scrapie in the sAsA animals is genetically determined irrespective of uterine and perinatal environment.
To prove this conclusively it will be necessary to look for scrapie in the sAsA progeny of unaffected ewes and rams transferred as embryos into pApA ewes.
The only other relevant embryo transfer experiment is by Foote et al None of the progeny developed scrapie, but the genotypes of these sheep were not reported so no firm conclusions can be drawn.
Source data on the maternal transmission of scrapie in sheep Source material comprises only papers in which authors report their own data for the first time These fall into two categories: distribution of the agent in tissues, and the familial occurrence of scrapie.
DISTRIBUTION OF AGENT IN TISSUES
Detection of infectivity in tissues requires induction of spongiform encephalopathy in another animal after injection or feeding of that tissue.
Studies in which the recipients have been sheep have been hampered by the fact that if sheep resistant to scrapie are used then transmission is very difficult and if sheep susceptible to scrapie are used then they are likely to develop scrapie naturally.
Although scrapie occurred in 19 of 24 sheep susceptible to scrapie that were fed or injected intracerebrally with placental tissue from other sheep affected with scrapie, no data were given of the background level of scrapie in the recipient flock at the time.
The incubation period after which the sheep became sick varied widely but, surprisingly did not depend on the route of administration. Naturally occurring scrapie was subsequently reported in that recipient flock, which had been especially bred for high susceptibility. Thirty six goats (which were expected to be 95% susceptible to experimental infection) were also used.
In the first report, one of the goats injected intracerebrally and three dosed orally developed spongiform encephalopathy. A further four of the goats dosed orally died of intercurrent disease. The fate of the remaining 24 goats was not mentioned in the subsequent paper.
A sensible interpretation of these reports is not possible given the lack of data and the absence of knowledge of the genotype of the recipient sheep. When assessed by transmissions to mice, no infectivity was found in semen, ovary, uterus (including fetal contents), fetuses, saliva, milk, colostrum, or mammary gland of sheep affected with scrapie, nor in lambs under the age of 4 months or goats under the age of 11 months.
Hourrigan claimed transmission to mice from a small proportion of samples from reproductive organs of affected sheep, but few data were given in this short report. There is therefore no clear demonstration of the infectivity of the placenta from sheep with scrapie. In reviewing skeptically the lack of evidence for infection of the sheep placenta and its role in natural disease, Hadlow remarked of some people, "For them, it is one of the facts about scrapie." Infectivity has been detected in the lymphoreticular system of preclinical, experimentally infected mice and it has been proposed that agent is transported from there to the central nervous system by way of the splanchnic nerve and the thoracic spinal cord. Infectivity has been found in the spleen and in other lymphoreticular and intestinal tissues of Suffolk lambs (which on the basis of their parentage might have been going to develop scrapie) but only those over the age of 4 months.
However, Hadlow has pointed out that "We have no evidence supporting the notion that in the natural infection, virus moves centropetally along nerve fibres from Peyer's patches, mesenteric lymph nodes, or spleen to the the thoracic spinal cord."
Furthermore, other studies have failed to show consistent levels of infectivity in extraneural sites in some other breeds of sheep, and extensive studies in bovine spongiform encephalopathy have failed to detect infectivity in any extraneural tissue of the naturally occurring disease, including placenta (data from the Ministry of Agriculture, Fisheries, and Food), although low levels have been found in the distal ileum of a few experimentally challenged but asymptomatic calves.
Thus the involvement of extraneural mechanisms in the pathogenesis of the disease is unclear. Since the PrP gene is expressed in spleen, these findings cast little light on the mode of transmission.
FAMILIAL OCCURRENCE OF SCRAPIE
Dickinson et al compared the incidence of scrapie in the progeny of affected and unaffected sheep taken, in the first generation, from commercial flocks and subsequently mated to form another generation (see table I). The data are, however, inadequately documented since in commercial practice, as well as in some experimental matings, it is usual for a few rams to tup a large number of ewes, so that the number of lambs reported gives little indication of the number of matings and particularly the number of rams involved. Furthermore, because a few rams are used repeatedly, allele frequencies may vary greatly between groups. Dickinson et al suggested that data for the first generation should be ignored because, although the incidence of scrapie in the progeny of affected dams was 66%, the incidence in the offspring of affected sires varied from 12% to 71% per ram. This would be compatible with some of the small number of affected rams being sAsA and others being sApA. Similarly, the occurrence of some affected sApA parents could account for the apparent lack of 100% affliction rate in the progeny in some but not all studies in table I in which both parents were affected. In the second generation of Dickinson et al's study higher rates of scrapie were found in the progeny of "high risk ewes" mated with "low risk rams" (69%) than of "low risk ewes" mated with "high risk rams" (10%).
However, when what seem to be the same high risk rams were mated with high risk ewes the incidence in the offspring was only 41%. Although 75% of high risk ewes in the first group eventually developed scrapie, only 48% of those in the second group did so.
Furthermore, only 40% of the high risk rams (two animals) actually developed scrapie.
This small number of rams with scrapie makes these data essentially uninterpretable.
Furthermore, Dickinson et al reported that it was relatively easy to find lambs with affected dams because they run together in the flock, whereas the sire may have been sold or culled-but in this sort of analysis the status of both parents is equally important. Without rigorous assessment, lambs with affected dams are more likely to have an unknown, affected sire than vice versa. Since the incidence of scrapie where both parents are affected is extremely high any such ascertainment bias would profoundly affect the perceived incidence.
It can be seen from table I that the bias towards maternal transmission is much reduced when experimental matings are assessed and is also much reduced in more recent publications. This secular change, along with the current demonstration of the dependence of scrapie on an autosomal gene, makes maternal transmission unsupported by the evidence. Parry classified his sheep into three risk categories -"black" sheep, which were either affected or had both parents affected; "white" sheep, which came from a scrapie free line and which had already produced many progeny without scrapie; and "grey" sheep, which were of less certain status.
The data were drawn from 25 years of stock records of more than 2500 sheep. Thus although the number of sheep reported is still small their choice has been extremely rigorous. Table II shows the proportion of affected offspring in each type of mating. There is no suggestion of maternal transmission in these data.
|Table 1-Progeny of sheep of differing scrapie status affected with scrapie. Values are percentages (numbers)|
|Dam x sire||Dam x sire||Dam x sire||Dam x sire|
|Dickinson et al (1965)||High risk x High risk||High risk x low risk||Low risk x High risk||Low risk x low risk|
|Suffolk||41(19/46)||69 (48/69)||10 (4/38)||18 (5/27)|
|Dickinson et al (1965)||Scrapie x Scrapie||Scrapie x No scrapie||No scrapie x Scrapie||No scrapie x No scrapie|
|Commercial flocks, Suffolk||Not reported||66 (38/57)||12-71 (7-40/56)||Not reported|
|Experimental mating, Suffolk||95(20/21)||81(25/31)||Not clear||18 (5/27)|
|Dickinson et al (1974)||Scrapie x Scrapie||Scrapie x No scrapie||No scrapie x Scrapie||No scrapie x No scrapie|
|Suffolk/Blackface F1*||100 (8/8)||62 (20/32)||33 (14/43)||30 (38/125)|
|Hourrigan et al(1979)||Scrapie x Scrapie||Scrapie x No scrapie||No scrapie x Scrapie||No scrapie x No scrapie|
|Suffolk||78 (14/18)||42 (13/31)||39 (50/129)||25 (26/105)|
|Foster and Dickinson (1988)||Scrapie x Scrapie||Scrapie x No scrapie||No scrapie x scrapie||No scrapie x No scrapie|
|Suffolk||99 (274/277)||Not reported||56 (37/66)||Not reported|
|High risk of developing scrapie was assessed from affected parents; low risk
was assessed from unaffected parents.|
*F1 progeny of matings of Suffolk x Blackface breeds; F2=progeny of matings of F1.
Conclusion Familial patterns of occurrence of spongiform encephalopathy is seen only in the endemic form of the disease, and this occurs only in sheep and humans. With the exception of kuru and iatrogenic Creutzfeldt-Jakob disease (the epidemic forms in humans), spongiform encephalopathy in humans can be regarded as idiopathic, the primary pathogenic event being the spontaneous post-translational modification of prion protein.
In sporadic cases, the occurrence of this event is largely confined (with extremely low penetrance) to people who are homozygous for a common polymorphism in the PrP gene; in familial cases, this event is almost inevitable in those with dominant mutations in the PrP gene.
In those breeds of sheep in which it has been assessed, it is clear that natural scrapie is tightly linked to polymorphisms in the PrP gene in patterns which are either recessive or show partial dominance.
Thus the familial pattern of scrapie is explicable largely or totally by genetics, and embryo transfer experiments suggest that the perinatal environment is unlikely to be relevant to the pattern of occurrence of natural scrapie. The debate between the role of genetics and perinatal infection in natural scrapie which took place in the 1960s could not be resolved because the genotype of the sheep could only be partially inferred from the eventual occurrence of scrapie in any particular animal, and transmission studies were hampered by the fact that sheep of unknown susceptibility to natural scrapie were the recipients in transmission experiments. The independent determination of susceptibility to scrapie by sheep genotyping now removes this difficulty and points to natural scrapie being a recessive or partial dominant disease in different breeds of sheep.
Belief in maternal transmission as the main mode of acquisition of natural scrapie has held sway for 30 years on the basis of poorly reported data on the occurrence of scrapie in a handful of sheep of unknown genotype. The genetic basis of spongiform encephalopathy in familial cases in humans, the absence of maternal transmission in any other form of spongiform encephalopathy and the results of embryo transfer experiments all suggest that a genetic basis for natural sheep scrapie is compatible with our current understanding of spongiform encephalopathy. The onus should now be on those who wish to maintain the importance of maternal transmission of spongiform encephalopathy in any species to provide convincing data.
|Table 2 - Progeny of Suffolk sheep of differing scrapie status affected with scrapie found by Parry. Values are percentages (numbers) of sheep aged 4-5 years|
|"Black"||86 (48/56)||46 (57/124)||0(0/156)|
|"White"||0 (0/39)||0 (0/7)||0 (0/159)|
|"Black"=sheep with scrapie or with both parents affected |
"grey"=sheep without scrapie but with one first degree relative affected
"white"=sheep without scrapie and no affected relatives.
Source of funding: MRC Programme Grant. Conflict of interest: None.
Scrapie is a naturally occurring disease of sheep, which has become the subject of increased scientific and media interest as scrapie contamination of feed was the probable origin of bovine spongiform encephalopathy. Despite research over the past 30 years the mechanism of transmission of natural scrapie remains uncertain.
The literature on natural and experimental scrapie is extensive and at times confusing with some authors arguing that scrapie is a purely genetic disorder while others maintain that it is an infectious disease.
The advances in molecular biology in recent years have provided new information on scrapie, and Ridley and Baker provide a timely review, concluding that maternal transmission of scrapie and other spongiform encephalopathies is a myth.
There is no good evidence of maternal transmission in any of the human spongiform encephalopathies, in experimental spongiform encephalopathy in laboratory species, or in transmissible mink encephalopathy.
The occurrence of bovine spongiform encephalopathy in cattle born after the feed ban in 1988 has led to speculation regarding maternal transmission of this disease, but epidemiological evidence provides little support for this hypothesis and concern about possible continuing contamination of cattle feed has led to new legislative measures. Maternal transmission in kudu, a breed of captive zoo ungulate, was originally suspected but is now uncertain.
Only with natural scrapie is there evidence of maternal transmission.
However, Ridley and Baker question the evidence that shows infectivity in the placenta of sheep with scrapie, and they provide alternative interpretations of embryo transfer experiments and the important breeding experiments carried out by Dickinson and colleagues.1 There are therefore cogent reasons for reconsidering the importance of maternal transmission in natural scrapie, although as Kimberlin has pointed out maternal transmission may be masked if there is a high level of lateral contagion.' In scrapie, and other spongiform encephalopathies, the occurrence and phenotype of disease is influenced by host genetics and agent characteristics and by the level of infectious challenge and route of exposure. In scrapie, analysis of the prion protein (PrP) gene in sheep has shown that susceptibility to disease is linked to polymorphisms of the PrP gene.
The genetics of scrapie susceptibility, summarised by Ridley and Baker, are complex, with the type of inheritance (dominant, partially dominant, or recessive) varying by breed of sheep.
Crucially, there is also evidence of an interaction between host genotype and strain of scrapie agent, indicating that selective breeding for resistance to scrapie may be problematic and that regarding scrapie as a simple genetic disease may be an oversimplification.
One of the peculiarities of the epidemiology of scrapie is that the large sheep population in New Zealand has been scrapie free for decades. If scrapie is primarily genetically determined, the current analysis of genotypes of sheep in New Zealand may provide important data - for example, it might be predicted hat all tested sheep will be of resistant genotype.
However, in 1979 Hourrigan and colleagues reported he development of scrapie in two out of 20 sheep imported from New Zealand following contact with locks known to be affected by scrapie, and 39% of he progeny of the inbred New Zealand flock also developed scrapie.
Despite molecular biological research, the mechanism of transmission of natural scrapie remains unclear, and control of this important endemic disease cannot currently be based solely on genetic manipulation. Even if maternal transmission is a myth, the complexities of the interaction between host genetics and agent train, together with the evidence for lateral transmission, indicate that eradication of scrapie may be difficult to achieve.
One important implication of the paper by Ridley and Baker is that previous assumptions about scrapie may have to be reevaluated, and further research on the epidemiology and transmission characteristics of the natural disease will be necessary if scrapie is to be eradicated.
Even if the epidemic of bovine spongiform encephalopathy declines and disappears early in the next century as predicted, scrapie will remain as a potential source of animal zoonoses in many countries where it is endemic.
The rise in the number of cases of Creutzfeldt-Jakob disease (CJD), the human form of bovine spongiform encephalopathy, is more likely to reflect increased awareness among healthcare professionals than a true rise in the number of new cases, according to Austrian researchers.
Although the incidence of CJD cases reached a peak in the United Kingdom in 1994, with 59 definite or probable deaths reported to the CJD Surveillance Unit in Edinburgh, the UK figure remained only 62% of the number of cases confirmed by postmortem examination in Austria in the same year. The number of neurologically confirmed cases in 1995 totalled 1.25 per million of the Austrian population, a figure which was considerably higher than any other European country, including the UK, according to researchers writing in the Journal of Neurology, Neurosurgery, and Psychiatry (1996;61:139-42).
"Since our figures for the first half of 1996 are comparable to those of 1995, we are confident that we are missing very few cases of CJD," said Herbert Budka, professor of neuropathology at the University of Vienna, one of the study's authors. "However, in many other parts of Europe, including the UK, there may still be a considerable degree of underreporting." Between 1985 and 1994 the total number of reported UK cases more than doubled, from 28 to 59 cases, which the researchers attribute to better reporting.
However, the researchers exclude the 10 cases of a new CJD variant in people under the age of 42 (average age 27), described in March by the UK's CJD Surveillance Unit. Although two of the 79 patients diagnosed as having CJD in Austria between 1969 and 1995 were 27 and 30 years old, both had classic features of CJD. "The new CJD variant appears to be evidence of increased incidence, rather than a reporting artefact. Furthermore, it appears to be unique to Britain at this time," Professor Budka said.
Not a single case of bovine spongiform encephalopathy has been reported in Austria, so CJD is unlikely to be linked to consumption of contaminated beef products there. Austria does have many more neurologists and a higher rate of routine necropsy than Britain. "We autopsy 70% of suspected CJD cases, but we could still improve on this figure," said Dr James Ironside, senior lecturer in pathology at the University of Edinburgh. "While the unit is willing to help as much as it can, and we frequently perform autopsies or examine neural tissue of suspected CJD cases, we still depend on initial notification," he added.
ALISON BOULTON, BMJ medical journalist