ore than 167 000 cases of bovine spongiform en- cephalopathy (BSE) have been reported in Great Britain since the disease was first recognized in 1986, and it is estimated that over one million cattle have been in- fected 1. The epidemic has affected over 40 000 cattle holdings, with more than half of these experi- encing just a single case, a most un- usual pattern for an infectious dis- ease. Following the introduction of the ruminant feed ban in July 1988, the incidence of BSE is now declining rapidly, with 7417 cases (less than one in a thousand animals) occur- ring in 1996. Understanding the BSE epidemic poses a considerable chal- lenge, not least because of past re- strictions on access to the available epidemiological data and the paucity of good experimental studies of BSE transmission and pathogenesis. Aetiology BSE is a transmissible spongiform encephalopathy (TSE), a group that includes scrapie in sheep and kuru in humans. The nature of the aetio- logical agent is controversial. Cur- rent opinion favours the 'prion hy- pothesis', which suggests that TSEs are caused by a conformationally abnormal, protease-resistant form of the prion protein (PrP) (Ref. 2). Although the prion hypothesis re- mains unproven, it is consistent with two epidemiologically important observations: (1) the agent is not inactivated by treatments that de- stroy most viruses and bacteria and (2) no host immune response to the agent has been detected. The main challenge to the prion hypothesis is that for some TSEs, notably scrapie, there are several distinct strains (al- though for others, including BSE, only one strain is known). Multiple strains would require numerous conformational forms, which is con- sidered unlikely 3. Molecular chaper- ones may act as cofactors by affect- ing PrP conformation 4, but these would appear as host factors rather than strain-determining factors. An interesting suggestion is that strain characteristics may be determined by different forms of PrP aggregates 4. Incubation period All TSEs have a long incubation pe- riod: from approximately one year for scrapie in mice to several dec- ades for kuru in humans. For scrapie in mice, the incubation period is remarkably constant for a given mouse genotype, strain of agent and infective dose 5. For BSE in cattle, most of the variation in incubation period results from variation in the infective dose. For example, ten cat- tle exposed to three 100 g doses of infective brain tissue (given orally) had incubation periods varying from 3 to 3.5 years, whereas none of ten cattle given I g doses had incubation periods less than 4 years ]. The dis- tribution of infectivity in cattle feed, and thus the range of doses to which cattle were exposed, is completely unknown. However, the available data are consistent with a mean incubation period of 5 years, and backcalculation, using the BSE case data, has suggested a range of 2- 10 years 1. Despite the fall in the age of confirmed cases during the early stages of the epidemic, there is no evidence that the BSE agent has