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Dr David Brown, University of Bath, on 28 June 2002
People fear v-CJD (variant Creuzfeld-Jacob Disease) because of its debilitating effects and long slow death, especially as there is no known cure. BSE (bovine spongiform encephalopathy), or mad cow disease, has appeared among our cattle in large numbers, but is now on the decline. Since these seem to have come on the scene at about the same time, it is natural to ask whether there is any relationship between them.
These two diseases are both TSEs (i.e. transmissible spongiform encephalopathies), which means they can be transmitted to experimental animals by injecting infected brain tissue into primates or rodents, and the recipient can develop the disease. However, there is currently no firm evidence that they can be transmitted between animals under normal conditions.
The diseases are characterised by vacuoles forming in the brain and the incubation periods are very long. For cows, this is 3-5 years, and death follows about 6 months after symptoms appear. For humans with v-CJD, the corresponding figures are possibly 20 years and 18 months. Thus if an epidemic is possible, we may not know for 20 or more years.
Placental mammals have in their brains a harmless protein called the prion protein. When, by an unknown process, this protein is converted to an abnormal form it is possibly the infectious agent of the disease. This abnormal protein was called a prion by Stanley Prusiner (Prusiner SB, 1998, Proc. Natl. Acad Sci. USA, 95, 13363-13383), but so far attempts to infect another animal by injecting the abnormal form of the protein have failed. It seems that there must be another mechanism at work that causes the disease to be passed from infected brain tissue. The normal proteins (not the abnormal form in diseases like BSE and v-CJD) are antioxidants and have a site on them which combines with copper in normal use, but the abnormal form is folded differently and has a different shape.
There are inherited conditions of a similar nature to v-CJD (Gerstmann-Straeussleer-Scheinker Syndrome and Inherited Familial Insomnia) and these are associated with mutations in the gene which codes for this protein, again implicating this protein in some, as yet undefined, way.
But almost all prion diseases are sporadic. The sporadic form of CJD typically occurs in older people (average age 62 years) and accounts of 1 death in a million around the world, and was first described in 1920, but there is evidence of it from the 1700s. Scrapie in sheep is similar and has been known since 1300, but was first described in 1788 in the Bath Agricultural Journal. In Colorado, chronic wasting disease in elk and deer has been known since 1950. In mink there is a similar condition that uniquely appears to be infectious between individuals, although it is not understood how it is transferred.
An interesting case is that of kuru, a disease of some tribes in Papua/New Guinea which ritually ate the brains of deceased relatives. After this practice was stopped, the instances dropped off sharply, but has recently seen a resurgence 40 years later, which may indicate a 40 year incubation period from when the victims had been infected as children.
BSE possibly appeared in the 1960s first and was noticed in older animals of 18 years or more. But it was then found in younger animals after it became common practice to put recycled offal into the feed. After this was banned, the occurrence has decreased and is currently at about 500-1000 per year and steady.
The variant form of CJD has a different distribution. It causes death at an average age of 27 years, but the sufferers range up to 74 years of age and include at least one vegetarian, although she converted late in life. The numbers have been increasing, but it is not clear how much of this is due to a higher awareness of the disease leading to better diagnosis.
So, is there a link between BSE and v-CJD? There is little evidence that the disease could cross from cows to humans, and attempts to infect other mammals have largely failed. Primates can get it but only after ingesting large quantities of infected brains directly, but even this is inconclusive as lemurs succumbed but macaques did not.
v-CJD was detected after BSE, but with an incubation period of at least 15 years, this may or may not be meaningful. If there was a causal connection, we would have expected more cases of v-CJD than in fact occurred in view of the number of cases of BSE.
The two are similar, but there are noticeable differences. However, when transgenic mice are injected with brain extracts, the differences seem to disappear, with again ambiguous results.
Recently, attention has been drawn to the possibility that both of them might be caused by another agent and in particular something in the environment. This idea is strengthened by the clustering apparent in the cases of chronic wasting disease in Colorado, scrapie in Iceland, where certain farms are more susceptible than others, and some areas of Crete and Slovakia where CJD occurs. BSE started in localised areas, but then rapidly spread to the whole of the UK. After the introduction of changed methods of feed, the numbers dropped and is now fairly uniform across the country. It is known from laboratory work that the prion can bind to manganese instead of copper and that this can cause them to become abnormal. Also, there have been reports of elevated levels of manganese in infected brains. Mark Purdey (Purdey, 2000, Med. Hypothesis. 54, 278-306.) has examined the regions where clusters occur and found that these regions have a relative high ratio of manganese to copper in their soils, and so evidence is building that there is a common environmental factor rather than a direct relationship between these two diseases.
Dr Brown then left us with some personal speculation by asking whether these diseases are symptoms of our ostracism from nature and inattention to the complexities of our environment. An understanding of molecular biology cannot solve these ills, but perhaps we need to step back and look at what we are doing to our fellow beasts and even ourselves.