In 1984, the first case of a new and fatal neurological disease was seen in a British cow on a farm in Sussex. The erratic behaviour and loss of co-ordination of affected cows led to the popular name of “mad cow disease”. Over the next twenty-five years almost 200,000 cases of this disease were confirmed in British cattle, mostly in older dairy cows. Millions more British cattle were slaughtered and burnt to try to eradicate this disease. The disease, named bovine spongiform encephalopathy or BSE, was shown to be one of a group of diseases collectively termed the transmissible spongiform encephalopathies (TSE) that include scrapie in sheep and goats, the rare human condition Creutzfeldt-Jakob disease (CJD) and kuru which was prevalent amongst a New Guinea tribe who practised cannibalism. These transmissible spongiform encephalopathies are so-called because of the sponge-like appearance of affected brains under a microscope and because they could be transmitted from one animal or person to another. In TSEs, transmission is not by a bacteria or virus but by an infective protein or prion; hence their designation as the prion diseases.
In 1988 all meat and milk from cattle affected by BSE was banned from sale and incinerated but there was concern that this disease might also be transmitted to people through eating beef from non-symptomatic but infected cattle. It was known from studying other TSEs that the infective protein was almost exclusively confined to a narrow range of tissues including, the brain, spinal cord, spleen, thymus and intestines. In 1989 the UK government made it mandatory to remove and incinerate these tissues, termed specified bovine offal, SBO, from all cattle, at slaughter. In hindsight, this was almost certainly the key public health measure that limited the number of people infected. Another characteristic of these diseases is that they have a very long incubation period and cases of kuru occurred sometimes two or three decades after the initial infection.
In 1996, the UK government made the sombre announcement that the first cases of a new form of Creutzfeldt-Jakob Disease had been identified and were probably caused by eating contaminated beef before the offal ban came into force. This announcement had a serious effect on the national mood that at times amounted to almost a national panic. This mood was amplified by a worldwide ban on the export of British beef by the EU which lasted for ten years and even longer in some countries; China only lifted its ban in June 2018. There were hundreds of newspaper articles and broadcasts about BSE in the decade after this 1996 announcement, with some merchants of doom predicting hospices overflowing with young people suffering a lingering and distressing death from this new disease termed variant or vCJD. Even the official inquiry into BSE predicted that deaths from vCJD could be anywhere within the range of a few hundred to 135,000. Anyone who had eaten beef prior to the 1989 offal ban was theoretically at risk and some of these merchants of doom suggested that beef and perhaps even milk produced after 1989 carried a risk. The epidemics of cattle BSE and human vCJD effectively ended almost a decade ago and there have been a total of 178 confirmed UK deaths from vCJD.
News update – just after posting this piece, news broke that a new case of BSE had been found on a Scottish farm. This is probably a spontaneous case and it may have been the inclusion of the rendered remains of such an animal(s) into animal feed that initiated the BSE crisis.
The nature of prion diseases
The infective agent
In 1997,Stanley Prusiner was awarded the Nobel prize for his work on the prion diseases and for identifying the infective agent as a protein. The prion protein is a normal brain protein that has undergone a conformation change (from largely α-helix to largely β-pleated sheet configuration) that makes it very resistant to enzymes that breakdown proteins and also to radiation and heat. This abnormal protein thus persists and accumulates in the brain and is also not destroyed when food is irradiated or cooked. When this abnormally configured prion protein comes into contact with normal prion protein it triggers this to also change shape into the abnormal form. This can trigger a chain reaction and the accumulation of large amounts of this protein in the brain leads to brain tissue destruction, the clinical symptoms of the disease and ultimately to death. It requires time for enough abnormal protein to accumulate to cause clinical symptoms so it is characteristic of prion diseases that they have a very long incubation period which in people can take several decades to manifest as overt symptomatic disease. These diseases are all inevitably fatal.
Causes of prion disease
There are three main reasons why prion diseases can develop: spontaneous, genetic or by transmission.
Some abnormal folding of prion protein can occur spontaneously in the brain and this can cause more protein to flip to the abnormal shape and accumulate. As more abnormal protein accumulates so there is destruction of brain tissue eventually leading to symptomatic and fatal disease. This is thought to be the scenario in sporadic CJD, a disease that is almost exclusively seen in elderly patients and occurs at a rate of somewhere around 1 case per million people per year in most populations.
Some people inherit a rare variant form of the normal prion protein that is more prone to adopting the abnormal configuration. These people often develop symptoms in their early fifties and in the period 1990 to 2018 just over 200 UK deaths have been attributed to this genetic form of CJD i.e. an average of about 7 deaths per year.
The third possible cause is the introduction into the body of abnormal prion protein from an external source. In Papua New Guinea, a CJD-like condition was endemic amongst the Fore tribe and was caused by eating human brain tissue as part of cannibalistic rituals. Kuru affected mainly women because children and women usually ate victims’ brain whilst men ate the muscle. The likely scenario is that consumption of a single person’s brain with developing CJD infected several other people who would then serve as a source of infection if eventually eaten or themselves develop and die of the disease. Cases of kuru were still occurring three decades after cannibalism was prohibited and the average incubation period was around twenty years.
Cases of iatrogenic (physician-induced) CJD have been caused by the introduction of infected material as part of a medical or surgical procedure. The biggest group of such cases were caused by the use of human pituitary hormones particularly human growth hormone to increase growth in people with growth limiting conditions. Many pituitary glands were removed from the brains of people at autopsy and some of these glands were from people with the abnormal prion protein which then contaminated that whole batch of growth hormone. Note that animal growth hormone is not effective in people so human derived hormone was the only source before genetically engineered hormone became available. Patients received multiple injections of growth hormone, some of which may have contained the abnormal prion. Between 1990 and 2018 just over 80 UK deaths have been attributed to iatrogenic CJD i.e. an average of around 3 deaths per year.
Eating infected tissue from cattle with developing BSE resulted in the new form of vCJD that had slightly different symptoms, different EEG pattern and different microscopic appearance of brain tissue compared to spontaneous CJD; it also occurred in much younger people. Since 1995, there have been 178 UK deaths attributed to vCJD. In 2004, the first case of a person developing vCJD as a result of a blood transfusion was reported. Blood donors who are infected with the prion but asymptomatic can donate blood and pass on the prion to recipients of their blood. There have been four known UK cases of people developing vCJD as a result of a blood transfusion.
The cattle epidemic of BSE
Time course of the epidemic
Figure 1 shows the rise and fall of the BSE epidemic in British cattle. There have been no confirmed British cases of BSE in the last five years. Cases of BSE have occurred in other countries but rates were just a fraction of those recorded in the UK e.g. around 1000 total cases in France, 800 in Spain, 400 in Germany and just over 100 in Italy.
What caused the cattle epidemic?
Since the 1920s, cattle had been fed with a protein supplement made from the rendered remains of other animals including other cattle. There seems no doubt that this feed became contaminated with the abnormal prion protein and was the source of infection. It is not clear, however, how the feed became contaminated in the first place. One theory, that was initially popular, was that a change in the rendering process allowed some abnormal protein from the remains of scrapie infected sheep to remain intact after rendering. This theory also offered reassurance about its likely impact upon human health because scrapie had been endemic in the British flock for centuries with no measurable impact upon CJD incidence. This theory was eventually abandoned as untenable and the most likely explanation is that the origin was from a cow or cows with a genetic or spontaneous form of BSE that was rendered and infected other cattle and then recycling of their rendered remains amplified the epidemic.
Measures taken to limit vCJD and eliminate BSE
In 1988, milk and meat from clearly infected animals was ordered to be destroyed. From November 1989, the UK government ordered that all specified bovine offal should be removed from the human food chain, the SBO ban. This measure went further than scientific advisers had recommended; they had only recommended the banning of SBO from baby foods. In hindsight this seems to be the key measure that limited the size of the human vCJD epidemic and at the time of writing there have been no cases of vCJD confirmed in anyone born after 1989. From 1996-2005 only meat from cattle under 30 months of age was permitted to be sold for human consumption (with a few specific exceptions). Almost no cases of BSE were ever recorded in cattle younger than 30 months and most cases were in older dairy cows. For a few years, the sale of “beef on the bone” was banned just in case it was contaminated with neural tissue. As can be seen from figure 1, by the time these extra measures (including the worldwide ban on British beef exports) were introduced, the cattle epidemic was almost over. In 2004, when the first case of vCJD caused by a blood transfusion was identified, the UK government banned people who had had a blood transfusion after 1980 from donating blood; this excluded around 50,000 of the UK’s approximately 1.7million regular donors. Blood transfusion had been recognised earlier as a potential route for CJD transmission and white blood cells would be the most likely component for this transmission. In November 1999 it was made mandatory to filter all blood for transfusion to remove almost all of the white cells (leukodepletion).
Feeding rendered ruminant protein to other ruminants but not to pigs and poultry was banned in 1988. Ruminant feed was probably being cross-contaminated by other animal feeds during this period after 1988 and in 1996 a total ban on the use of rendered ruminant protein in animal feeds was introduced. In order to speed up the eradication of the disease in the British herd, a program of selective culling and burning of cattle at increased risk of being infected (especially older dairy cows) was introduced. Millions of apparently healthy cattle were culled and their carcasses burnt during the BSE crisis.
The human vCJD epidemic
Figure 2 shows the rise and fall of the vCJD epidemic; there have been a total of 178 UK deaths. The rate peaked in 2000, declined to less than ten annually in 2004 and reached zero for the first time in 2012. Since the start of 2012 there have been only 2 recorded deaths from vCJD. This epidemic has been at the extreme low-end of earlier predictions. There have been a total of just over 50 recorded vCJD deaths from all countries other than the UK. There have been 27 deaths in France, 5 in Spain and four each in Ireland and Canada.
At position 129 on the human prion protein there can be either of the amino acids methionine or valine. There are thus three genetic variations:
- About 38% of the population are homozygous for methionine at position 129 i.e. both copies of their prion gene code for methionine at this position (double MET) and all of the prion they produce will have methionine at this position.
- The majority of the population (51%) have one methionine and one valine gene (MET/VAL) and so they produce both types of protein.
- The remaining population has 2 valine genes (double VAL).
Prior to 2017, all known cases of vCJD across the world were in people who were in the double MET category above. Routine testing of tonsil tissue has suggested that perhaps one in 2000 people in the UK carry the infective prion protein which should have led to about 6000 cases of vCJD if all infected double MET people had developed the disease; only a small proportion of those infected with the protein go on to develop the disease. If the person produces only prion protein with valine at position 129, it does not undergo the conformational change that leads to vCJD so the double VAL group are essentially immune from vCJD. People who are VAL/MET produce both types of prion protein although they produce less of the MET protein than the double MET group. In theory this VAL/MET group are susceptible to vCJD and so some scientists have predicted that there might be a second wave of vCJD cases amongst this group. As they have less of the MET protein then one would expect the incubation period to be longer than for the double MET group and probably for fewer of them to develop vCJD if infected with the prion. In early 2017, it was announced that a 36-year-old man from the MET/VAL group had died of vCJD. His symptoms were similar to sporadic CJD but his protein was tested because of his young age. It is possible that there may have already been more vCJD cases in the MET/VAL group who have been misclassified as sporadic CJD.
The New Scientist published a useful timeline of the BSE/vCJD crisis.
The costs of this crisis
To date, 178 young people have suffered a lingering and unpleasant death from vCJD. Fear of the disease caused considerable anxiety amongst much of the population who had consumed beef or fed it to their children.
Millions of British cattle have been slaughtered and their meat burnt in order to protect public health or speed up the eradication of the disease from the British national herd. For many years cattle older than 30 months could not be sold for meat. All specified bovine offal has been and continues to be removed and incinerated and for some years all beef had to be boned prior to sale. Millions of tons of meat, requiring the input of even more millions of tons of animal feed have been wasted at a time when there was widespread starvation in some parts of the world.
British farmers were unable to sell their beef outside of the UK for around a decade and it has taken a considerable amount of time for some countries to relax this ban and for sales to recover. Even within the UK, beef sales declined substantially during the peak of this crisis and took some time to recover. There was a general loss of confidence in the safety of British food, especially meat, and a loss of confidence in the ability or willingness of government agencies to ensure the safety of the food supply.
There were political repercussions as well as economic ones. The Ministry of Agriculture Fisheries and Food (MAFF) was widely criticised for its role in this affair (and a subsequent outbreak of foot and mouth disease); it was dissolved in 2002 and replaced by The Department for Environment, Food and Rural Affairs (Defra). A non-ministerial government department, The Food Standards Agency FSA, was formed to take over responsibility for ensuring food safety and food hygiene and for generally overseeing consumer interests with respect to food. There have even been suggestions that dissatisfaction with government handling of the BSE crisis was a factor in their defeat in the 1997 general election.