BSE and vCJD: Their biology and management
BSE and vCJD: Their biology and management

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BSE and vCJD: Their biology and management

3 The origin and spread of BSE

Question 7

In the light of the above discussion about prions, what is the most probable explanation for the spread of BSE among cattle?

Answer

The cattle presumably consumed material containing PrPSc protein.

Nevertheless, other routes of transmission could not be ruled out and therefore had to be investigated systematically. The most obvious of these are cow-to-calf transmission (either through genetic inheritance or direct contact) or cow-to-cow transmission (either through direct contact or via some aspect of their common environment such as the fields they share).

Soon after BSE was first recognised, an initial study was commenced into the pattern of BSE's spread within and between populations of cattle - that is, the disease's epidemiology. At the same time, of course, other scientists were studying the detailed biology of the disease in individual animals. Epidemiology can throw light on the cause(s) of a disease, how it is spread and ultimately on the effectiveness of various measures introduced to control it. On the basis of this initial epidemiological study, veterinary scientists had concluded by December 1987 that the BSE epidemic had been set off by the inclusion in protein-rich concentrated cattle feed (generally referred to simply as 'concentrates') of meat and bone meal (MBM) derived from scrapie-infected sheep. Concentrates are fed to dairy calves, which are taken from their mothers soon after birth so that the cows can be milked. Adult dairy cattle are also given concentrates at times when their energy demand exceeds that available from grass (e.g. during winter). Once their milk yield started to decline (at about five-and-a-half years of age), dairy cows were slaughtered and their meat used in cheaper meat products such as pies, burgers and sausages. In contrast, the calves of beef cattle are allowed to suckle from their mothers for several months (which is why they are often referred to as 'beef suckler cattle') and are seldom given concentrates. These calves are then reared for one or two years before being slaughtered for meat.

Although concentrates have always consisted mainly of plant material, for some time before BSE arose protein from almost any source was included provided it was sufficiently cheap. The feet, brains, intestines, lungs and excess fat from all animals killed in abattoirs was treated to separate the fat from the residual solid material - a process known as rendering - and the solid residue ground up and sold as MBM. It must be emphasised that, although few people unconnected with farming and the food industry would have had detailed knowledge of these procedures, they were perfectly legal at that time and were not regarded as unsafe.

It is not universally accepted that the initial source of infection was material from scrapie-infected sheep in concentrates. An alternative view is that BSE arose spontaneously in one or a small number of cattle, tissues from which ended up in MBM. Nevertheless, once BSE began to spread, increasing amounts of the MBM fed to cattle would have been derived from BSE-infected cattle. This would have enabled BSE to spread even further and faster. Thus, from an early stage the view of scientists advising the government was that BSE was caused by contamination of MBM derived from ruminant animals (ruminants include cattle, sheep and goats). However, animal tissues had been included in cattle feed for several decades prior to the mid-1980s and scrapie had been present in UK sheep for more than 200 years (whilst BSE could have arisen spontaneously in cattle at any time). Did anything occur at about this time that might explain why BSE started then? In fact, in 1980 the government allowed a relaxation in the regulations controlling rendering. Previously, it had been a batch process in which waste animal material was heated to remove water and fat, then any residual fat dissolved in a hydrocarbon solvent and finally steam at 100-120 °C was used to remove the solvent. After the change in regulations, many rendering plants went over to a continuous process in which dry heat was applied to remove water and fat from the material, with the hydrocarbon solvent extraction stage being omitted. [D]

Question 8

Summarise the main changes to the rendering process that occurred following the change in regulations.

Answer

The use of hydrocarbon solvents in a wet, low-fat environment was replaced by the application of dry heat in a high-fat environment. Furthermore, the original batch process was likely to have taken longer than the 'more efficient' continuous process that replaced it.

Probably because the market price of fat had fallen, only two of the 46 rendering plants in the UK were still using solvent extraction by 1988 (Figure 8).

Figure 8
Figure 8 Percentage of meat and bone meal produced from 1964 to 1988 by rendering plants using solvent extraction

Question 9

Cattle feed is produced in many rendering plants around the country, which supply farms in their immediate locality. Does the fact that the only two plants still using the solvent extraction process in 1988 were in Scotland relate to the geographic incidence of BSE from 1985 to 1988 shown in Figure 9?

Answer

Yes. There were no cases of BSE in central and northern Scotland during 1985 to 1988. In southern Scotland up to 1.9% of herds were affected. In some parts of England, more than 4% of herds had cases of BSE.

Figure 9
Figure 9 Incidence of BSE-affected herds from 1985 to 1988 as a percentage of the total number of herds by county/region

Question 1

At the same time as veterinary scientists investigated the geographical distribution of BSE cases in relation to the location of rendering plants that still used solvent extraction, they also examined the prevalence of BSE in different groups of cattle. In a sample of 192 cases of BSE, 190 were in female cattle and two were in male cattle. The national herd contained 3 200 000 female and 37 000 male cattle in 1987.

(a) Expressing your answers to appropriate numbers of significant figures, calculate:

  • (i) the percentage of the 192 cases of BSE that involved female cattle;

  • (ii) the percentage of the national herd that was female.

  • (iii) Is there any evidence from your answers to (i) and (ii) that either sex was more prone to BSE than the other?

(b) Using the data in Table 1, calculate to appropriate numbers of significant figures:

  • (i) the proportion of BSE cases in the national herd of beef suckler cows;

  • (ii) the proportion of BSE cases in the national herd of dairy cows.

  • (iii) Express the proportion of BSE cases in dairy cows to the proportion of BSE cases in beef suckler cows as a ratio in the form x : 1.

(c) As mentioned above, dairy calves are usually removed from their mothers soon after birth whereas beef calves suckle from their mothers for several months. On the basis of these differences in the two cattle production systems, suggest an explanation for the answer to (b)(iii).

Table 1 The number of cases of BSE in beef suckler and dairy cows from 1985 to 1988 in relation to the number in the national herd

Cow typeNumber of BSE casesNumber in national herd
beef suckler14880 000
dairy6962320 000

Answer

(a) (i) Percentage of BSE cases that involved female cattle:

Since both starting values are three-digit numbers that are known precisely, the answer should be expressed to 3 significant figures: 99.0%.

(ii) The total number of cattle in the national herd was

3200 000 + 37 000 = 3237 000.

Percentage of the national herd that was female:

Since both starting values are given to at least 2 significant figures (some of the trailing zeroes might be significant), the answer can safely be expressed to no more than 2 significant figures: 99%.

(Note: Any ambiguity about the number of significant figures to which some of the starting values are expressed could be removed by using scientific notation. Thus, expressing 3200 000 as 3.2 x 106 rather than 3.20 x 106 would make clear that the number of significant figures was 2 rather than 3. However, the use of scientific notation in this way is not the norm in all fields of study.)

(iii) Since the percentage of female cattle in the sample of 192 BSE cases is almost the same as the percentage of female cattle in the national herd, there is no evidence in these data that one sex was more prone to BSE than the other.

(b) (i) Proportion of BSE cases in beef suckler cows:

Since one of the starting values is given to 2 significant figures and the other to at least 2 significant figures, the answer is appropriately expressed to 2 significant figures.

Note: Since a proportion is defined as the size, number or amount of one object or group as compared to the size, number or amount of another, it can legitimately be expressed in a variety of ways - as a decimal fraction (0.000 016), as a decimal fraction given in scientific notation (1.6 x 10−5), as a percentage (0.0016%), as a percentage given in scientific notation (1.6 x 10−3%), as a ratio (14 : 880 000, which simplifies to 1 : 63 000) or as a conventional fraction, i.e.

(ii) Proportion of BSE cases in dairy cows:

As one of the starting values is given to 3 significant figures and the other to at least 3 significant figures, the answer is appropriately expressed to 3 significant figures.

(iii) The proportion of BSE cases in dairy cows to the proportion of BSE cases in beef suckler cows = 0.000 300 : 0.000 016 or 19 : 1 (appropriately expressed to 2 significant figures).

(c) Since dairy calves are removed from their mothers soon after birth, they have to be fed concentrates. In contrast, beef calves are seldom fed concentrates. The much higher incidence of BSE in dairy cattle compared to beef suckler cattle is therefore consistent with the cause being contaminated MBM incorporated into cattle concentrates. Given the relatively long incubation periods of TSEs, it may also be relevant that many dairy cattle were allowed to live far longer than beef suckler cattle.

Thus, support for the hypothesis that contaminated cattle feed was responsible for the origin and spread of BSE was provided by:

  • the geographical distribution of BSE cases in the early days of the epidemic (1985-88) in relation to the number and distribution of rendering plants still using solvent extract; and

  • the relative incidence of BSE among dairy and beef suckler cattle.

By 1988, it was generally accepted by veterinary scientists that one or more of the post-1980 changes - but most probably the elimination of solvent extraction - had caused the rendering process to be less effective at deactivating any scrapie or BSE agent present in the MBM. [R]

Question 10

Of course, prions were not widely discussed at this time. But how would the above conclusions be expressed today in terms of prion biology?

Answer

The new continuous process was in some way less effective than the old batch process at deactivating PrPSc protein present in animal material sent for rendering prior to its inclusion in MBM. This material included tissue from either scrapie-infected sheep or cattle in which BSE had arisen spontaneously. However, once the BSE outbreak got underway, this material certainly included tissue from BSE-infected cattle. Cattle then consumed concentrates that incorporated MBM containing PrPSc protein. Within the cells - particularly the brain cells - of these cattle, interaction between this PrPSc protein and the 'normal' PrPC protein of these animals caused some of the latter to be converted into PrPSc protein. The increasing amounts of PrPSc protein in the brain cells of these cattle caused many of them to develop the TSE that became known as BSE. Furthermore, ever-increasing amounts of PrPSc protein became included in MBM - and hence in concentrates - which caused BSE to be transmitted to even more animals.

An important issue that has not been fully addressed so far is the cause(s) of infective TSEs, such as BSE and kuru. This is clearly relevant to the origin of vCJD in humans. However, we first need to consider the causes of some of the TSEs that are known to be inherited. Box 5 revises a few more aspects of basic molecular biology.

Box 5: Revision of basic molecular biology

As we have seen, the particular amino acid occupying each position in a protein is coded for by three consecutive nucleotides (a triplet) in the coding strand of the DNA molecule. Some amino acids are uniquely specified by one DNA triplet (e.g. methionine by TAC). Others are specified by several alternative triplets (e.g. valine by CAA, CAC, CAG and CAT). These relationships form part of the genetic code (which is usually expressed in terms of nucleotide triplets in mRNA rather than in DNA).

In the case of many genes in eukaryotes, enzymes remove triplets from newly synthesised mRNA molecules before they leave the nucleus; this is part of the process called post-transcriptional modification. The newly synthesised protein molecules also undergo processing. Post-translational modifications of newly synthesised protein molecules in the cytoplasm include the removal of certain amino acids and the attachment of sugar side-chains to others in order for the protein to become functional.

Although the human PrP gene (located on chromosome 20) comprises 253 triplets, those at positions 1-22 and 231-253 are not represented by amino acids in the 'mature' PrP protein because of post-translational processing. Some variation is possible in the triplets 23-230 without rendering the PrP protein completely inactive. However, certain mutations at particular triplets are associated with various TSEs. For instance, a mutation in triplet 102 that causes the amino acid proline to be replaced by leucine is linked to GSS. Similarly, a mutation in triplet 200 that causes glutamine to be replaced by lysine is linked to the form of CJD that is particularly prevalent among Libyan Jews. The CJD clusters reported from Slovakia, Hungary, England, the USA and Chile are also now all believed to be due to mutations at triplet 200. A combination of the triplet that codes for methionine rather than the one that codes for valine at position 129 and that which codes for asparagine rather than aspartic acid at position 178 is linked to FFI. (Some of the mutation sites in the human PrP protein are shown in Figure 6.)

The phrase 'is linked to' was used in the previous paragraph because these less common genotypes might enhance the rate of spontaneous conversion of PrPC protein to PrPSc protein or they might increase an animal's susceptibility to infection by PrPSc protein from elsewhere (e.g. in food). It would be too simplistic to say that a particular mutation 'causes' a particular TSE, because whether or not the disease develops almost always depends to some extent on the environment - both internal and external.

Question 11

Bearing in mind the above information about the genetics of some inherited TSEs, what might trigger sporadic CJD?

Answer

An individual's PrP gene might code for PrPC protein that (1) spontaneously converts to PrPSc protein particularly easily or (2) is particularly susceptible to conversion to PrPSc through interaction with PrPSc from an external source.

So, the human PrP gene certainly displays some genetic variation (see Box 6 for a brief revision of basic genetics terminology). The various genotypes give rise to several phenotypes with respect to the PrP protein. These phenotypes appear to differ mainly in the ease with which the PrP protein changes from being comparatively rich in α-helices (PrPC) to being comparatively rich in β-sheets (PrPSc), either spontaneously or as a result of coming into contact with PrPSc protein from elsewhere. Given this variation within a single species, it is reasonable to expect there to be some systematic differences in the PrP gene - and hence the PrP protein - between different species of mammal. If there are such differences in the amino acids sequences of typical PrPs in sheep, cattle and humans, a number of important questions arise. Can sheep PrPSc effect the conversion of cattle PrPC into cattle PrPSc and, if so, how easily? Similarly, can sheep and/or cattle PrPSc effect the conversion of human PrPC into human PrPSc and, if so, how easily? These questions relate to the existence of possible species barriers between the current host species of a prion disease and potential new host species.

Box 6: Revision of basic genetics terminology

In the context of genetics, the appearance (and also internal anatomy, biochemistry, behaviour, etc.) of an organism is referred to as its phenotype. Thus, blue and brown are alternative phenotypes for human eye colour. Many phenotypes are determined partly by an organism's environment and partly by its genetic make-up or genotype. Diploid sexually reproducing species have two sets of chromosomes - and therefore two sets of genes (except for those on the sex chromosomes, i.e. X and Y in humans) - one set derived from the mother and one set from the father. Many genes exist as several alternative alleles. For instance, there are three common alleles (A, B and O) of the main blood group gene. An individual possesses two copies of each gene - one maternal and one paternal. Where these copies are identical, the individual is described as being a homozygote or homozygous (e.g. the genotypes AA, BB and OO that give rise to the blood group phenotypes A, B and O respectively). Where the copies are not identical, the individual is described as being a heterozygote or heterozygous (e.g. the genotypes AO, BO and AB that give rise to the blood groups phenotypes A, B and AB respectively).

If a protein can have two alternative amino acids at a particular position along its length (i.e. different phenotypes are possible with respect to this protein), then the two genes coding for that protein present in an individual can either be different alleles or the same allele. In other words, the individual can be heterozygous or it can be homozygous for either one allele or the other.

Question 12

Cite an example - discussed earlier in this course - in which a prion disease definitely crosses between different species of mammal.

Answer

Prusiner worked with scrapie-infected rodents. Since scrapie is a disease of sheep, this is an example of a prion disease crossing between different species - albeit as the result of a human-induced experiment.

Differences in the amino acid sequence of the PrP protein of one species and that of another might make it impossible for any PrPSc of the first species to interact with PrPC of the second species so as to convert the latter into PrPSc. In such a case, the species barrier must be regarded as insurmountable. Alternatively, the PrP proteins of two species might be sufficiently similar for PrPSc of the first species to convert PrPC of the second species into PrPSc, but not as easily as PrPC can be converted into PrPSc within the first species.

Question 13

Suggest three ways in which relative 'ease of conversion' of PrPC to PrPSc might vary.

Answer

Relative 'ease of conversion' might be reflected in variation in (1) the length of the incubation period of a TSE (i.e. the time from infection with PrPSc to the first appearance of symptoms of the TSE), (2) the amount of PrPSc required to trigger development of the TSE, or (3) the ways in which an animal can become infected with PrPSc (e.g. absorption of PrPSc from food might be sufficient, infection might require injection of PrPSc into the bloodstream or the only possible route of infection might be injection of PrPSc directly into the brain).

Question 14

How would you expect the incubation periods to compare between an animal infected with PrPSc derived from a member of its own species and an animal infected with PrPSc derived from a member of another species?

Answer

The incubation period might well be shorter when a species is infected with PrPSc derived from a member of its own species than when it is infected with PrPSc derived from another species.

Question 15

Explain this possible difference in incubation period in terms of prion biology.

Answer

Initially, PrPSc from one species with a particular amino acid sequence has to interact with PrPC of another species which is likely to have a slightly different amino acid sequence. However, once some PrPSc with the second species' amino acid sequence has been produced, this PrPSc will probably more readily be able to convert more of the second species' identical PrPC (i.e. with the same amino acid sequence) into PrPSc.

Question 16

How might the amount of PrPSc required to trigger a TSE differ before and after a species barrier has been breached?

Answer

A higher dose of PrPSc might be required to breach a species barrier than to transmit a TSE within a species.

Similarly, once the species barrier has been breached it might be possible to transmit a TSE within a species simply through the presence of that species' PrPSc in food. However, to breach a species barrier in the first place it might be necessary to inject 'foreign' PrPSc into a second species' blood or even directly into its brain.

It has been suggested that there are no impenetrable species barriers. Any barriers that appear to be impenetrable do so simply because the incubation period is longer than the normal lifespan of the potential new host species.

Question 17

How could this be demonstrated experimentally?

Answer

PrPSc of the first species might be injected into the brain of a member of a second species. After some time, some brain tissue from the latter animal might be injected into the brain of another member of the second species. This procedure might then be repeated several more times before a member of the second species finally displays symptoms of the TSE. (Note: this experiment has been done.)

As we have seen, the veterinary scientists who carried out the initial epidemiological study of BSE concluded that BSE is effectively scrapie that has crossed the species barrier between sheep and cattle because changes in the rendering process allowed still-infective PrPSc protein from sheep to be consumed by cattle. In fact, in its final report published in October 2000, the official BSE Inquiry (chaired by Lord Justice Phillips) came down in favour of the disease originating in cattle in South-West England during the 1970s or early 1980s. A further review (chaired by Professor Gabriel Horn), specifically into the origin of BSE, considered this suggestion to be plausible but necessarily speculative and concluded that scrapie could not be ruled out as the source of BSE. We will consider these official inquiries in more detail later in the course. [C D]

There is now some concern that BSE might somehow cross back over the species barrier between cattle and sheep. Indeed, it is possible that scrapie may already be masking the presence of BSE in sheep. A major problem is that we don't know what BSE in sheep would look like - BSE, scrapie or something else? In early 2005, it was reported for the first time that BSE had been detected in a goat in France (where these animals - which are quite closely related to sheep - are commonly kept to provide milk for cheese-making) and another in Scotland.

The possibility that BSE might have been triggered by the mandatory use of an organophosphate pesticide to eliminate warble fly in cattle, as suggested by organic farmer Mark Purdey and others, was also considered by the BSE Inquiry. Although the Inquiry ultimately rejected this idea, there are intriguing suggestions in Purdey's data that an imbalance between copper and manganese in nerve cells - whether reflecting the local natural environment or caused by pesticide treatment or industrial pollution - might make humans and other animals more likely to develop TSE diseases. A particularly interesting aspect of this 'story' is the great difficulty Purdey initially experienced in getting his hypothesis taken sufficiently seriously by the scientific 'establishment' to obtain research funding, etc. Effectively, he became a self-trained scientist and eventually persuaded some university-based researchers to work with him, resulting in the publication of several peer-reviewed papers. [C D]

Question 18

Does Purdey's experience bring to mind the treatment of another TSE researcher?

Answer

There are some parallels with the treatment of Stanley Prusiner, whose ideas were initially rejected by many of his peers. However, Prusiner was already an established scientist with a well-equipped university laboratory, which enabled him to pursue his research interests anyway. Ultimately, of course, he was able to convince (most of) his critics and became an 'establishment' figure himself when awarded the Nobel Prize.

Prusiner's prion hypothesis may eventually be rejected or refined beyond recognition as more is learned about TSEs or the nervous system generally. However, it is currently the most convincing explanation for the cause of TSEs and the one most widely accepted by the scientific community because it has provided a very effective foundation for further research. On the other hand, Purdey's (rather less all-embracing) hypothesis appears to be languishing on the sidelines. This contrast epitomises a difficult dilemma for science. On the one hand, there is the danger of accepting as valid an ill-founded hypothesis with all that this might entail in terms of wasted time and resources. On the other hand, there is the danger of rejecting a truly prescient hypothesis because minds are not sufficiently receptive to it. This dilemma clearly impinges on both communication and decision making. [C D]

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