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

4 The emergence of vCJD

We now turn our attention to vCJD.

Question 19

If vCJD really is 'the human form of BSE' (as it is often described), how is it likely to have crossed the species barrier from cattle to humans?

Answer

The majority of victims probably consumed food that contained cattle PrPSc protein. The cattle PrPSc protein then interacted with their own PrPC protein converting it to human PrPSc. Human PrPSc would have been much more effective than cattle PrPSc in converting more human PrPC into PrPSc, which would build up in the victims' brain cells until vCJD was eventually diagnosed.

Question 20

Which parts of cattle incubating BSE are most likely to have been the source of PrPSc?

Answer

The most infective part of cattle would probably have been brain tissue. Since other nerve cells are also likely to have been relatively rich sources of PrPSc, the spinal cord and the eye are also likely to have been hazardous.

On the basis of work on scrapie-affected sheep, various other organs were also considered to be possible sources of infection in BSE-affected cattle. In the early days of BSE, high priority was therefore given to trying to ensure that not only the head and spinal cord, but also the thymus, tonsils, spleen and intestine (and hence the lymphatic system) from any cattle that might have been incubating BSE were not incorporated into food intended for human consumption (e.g. accidentally during the recovery of as much meat as possible from the carcase) or recycled to other cattle in MBM. At the time, these banned parts were referred to as specified bovine offals (SBO). However, since technically the head is not regarded as offal, they are now referred to as specified bovine materials (SBM). In fact, only nervous tissue has been found to be infective in the case of BSE. Indeed, it has been argued that it would have been more effective to have enforced the ban on nervous tissue from cattle entering the human or cattle food chain much more rigorously than to have spread the 'safety net' as widely as was done. This is an example of how difficult it is to apply the precautionary principle in practice. [D]

Question 21

How else might vCJD victims have contracted the disease?

Answer

As in the case of iatrogenic CJD, vCJD could have been contracted through medical procedures involving the transfer of vCJD-infected tissues.

Since prions are notoriously resistant to degradation (e.g. they remained infective after the new MBM rendering process), there was concern about the effectiveness of sterilisation of re-usable surgical instruments in hospitals - particularly after they had been used for eye or tonsil operations. On the other hand, many surgeons also had reservations about the precision they could achieve using disposable instruments. Although CJD has occasionally been transmitted via surgical instruments, by mid-2004 no known cases of vCJD could be attributed to this cause. Of course, great care also has to be taken when post-mortem examinations are carried out, to ensure that pathologists and technicians are not infected.

There was also concern about whether vCJD could be transmitted through transfusion of blood from someone incubating the disease at the time of donation. As a precaution, several countries banned blood donated in the UK for transfusion. This policy appeared to have been a sensible precaution when a UK resident died of vCJD in 2003 having in 1996 received transfusion of blood that had been donated by someone who died of vCJD in 1999. It was announced almost immediately that blood donations would no longer be accepted from anyone who had themselves received a blood donation since 1980. In 2004, a patient who died from another cause was found to have been incubating vCJD at the time of their death. This patient too had received transfusion of blood donated by someone who later died of vCJD. [C R D]

Question 22

Does it follow that the recipients of the blood transfusions necessarily contracted the disease from contaminated blood?

Answer

No. It is possible that in both pairs of linked cases both the donor and the recipient of the blood contracted the disease from eating infected meat products.

However, the authorities decided even on the basis of the first pair of cases that the risk of contamination through blood transfusion was too great to ignore. The occurrence of the second pair of linked cases appears to justify this cautious approach. However, in exercising the precautionary principle, the authorities certainly went further than required by the available scientific evidence.

The death in 2004 of the second blood recipient was also significant for another reason that relates to genetics. The 142 people who had died from vCJD in the UK up until then had all been homozygous for the triplet in the PrP gene encoding the amino acid methionine at position 129 (i.e. their genotype was MM). People with this genotype make up 40% of the UK population, with about 50% being heterozygous for methionine and valine (MV) and 10% homozygous for valine (VV) at this position. It had therefore been hoped that 60% of the UK population was immune to vCJD - or at least considerably less susceptible than those who had contracted the disease thus far.

Question 23

Suggest another explanation for the pattern of vCJD in the UK until 2004.

Answer

It might simply have been that the incubation period for vCJD is longer in people with the MV and/or VV genotypes than in those with the MM genotype.

The second blood recipient who was discovered to have being incubating vCJD at the time of their death in 2004 from another cause had the genotype MV. This suggests that the majority - and possibly all - of the UK population is potentially vulnerable to vCJD, mainly following past exposure to cattle PrPSc in food.

When a UK-based research team analysed the genotypes of various ethnic groups from around the world, they found that more than 75% of Foré women over the age of 50 were heterozygous for amino acid 129 of the PrP protein (i.e. their genotype was MV). This is a much higher percentage of heterozygotes than would be expected by chance.

Question 24

In terms of natural selection, what does this suggest?

Answer

It suggests that, during the recent past, women who were heterozygous at this triplet (MV) were at a selective advantage in that many of their contemporaries who were homozygous (either MM or VV) contracted kuru and died relatively young.

Heterozygote advantage is an example of balancing selection, a mechanism that maintains two (or more) alleles in a population when one would expect that, over evolutionary time, an allele that had even the slightest advantage over the other(s) would come to predominate. Probably the best known example of heterozygote advantage in humans relates to the haemoglobin alleles HbS and HbA.

Question 25

If you have met this example of heterozygote advantage in your previous studies, try to recall how it operates. Otherwise, read the following answer.

Answer

HbSHbS homozygotes suffer severe sickle-cell anaemia and usually die before reproducing. One would therefore normally expect the HbS allele to be extremely rare in a population and that most individuals would be HbAHbA homozygotes. However, in parts of Africa where malaria is endemic, the HbS allele is far more common than would be expected if it arose only through occasional mutation of the HbA allele. The explanation is that, despite suffering mild anaemia, HbAHbS heterozygotes are resistant to malaria whereas HbAHbA homozygotes are not. Thus, balancing selection - in which many HbAHbA individuals are debilitated by malaria and HbSHbS individuals die from sickle-cell anaemia - maintains both alleles in the population.

In fact, the research team found that MV heterozygotes were relatively common in all the human populations they examined. This suggests that humans generally may have been subject to balancing selection that has maintained both alleles in the population. Controversially, the team concluded that this meant that cannibalism - one of the great taboos in modern human society - was probably widespread among our ancestors, an interpretation that was challenged by other scientists. This is an interesting example of scientific data being accepted as accurate by all parties, but with disagreement about how the data should be interpreted.

Just as it is not known whether BSE is a disease that arose spontaneously in cattle or scrapie that has crossed the species barrier, it is also not known whether kuru is a TSE that arose spontaneously in humans or one that arose in another species (most probably, pigs) and then crossed the species barrier into humans. However, because the species barrier into pigs is known to be very high, on balance it is likely that kuru originated as spontaneous CJD in humans. Either way, almost certainly kuru became more common among the Foré through their practice of cannibalism during mortuary feasts.

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