To what extent is strain variation evidence for an independent genome in the agent of the transmissible spongiform encephalopathies?

The apparent existence of multiple strains of the 'transmissible agent' associated with spongiform encephalopathy (prion disease) has been used to support the argument that these diseases are caused by an independent, replicating agent with its own genome. However, the length of the incubation period (time from injection of infected material to onset of clinical signs) and the lesion profile (regional distribution of neuropathology), which are the key features used to define the strain of agent, have been shown to be influenced by the prion protein of the host and the donor, such that it is only the variance in these measures which remains after variation due to all other factors has been taken into account, which can be used as evidence for the existence of different strains of agent. The donor is the animal from which infectious material is prepared for injection into the host. Almost all aspects of pathogenesis, including most of the variance in incubation time, can be explained in terms of interactions between donor and host prion protein. We argue that the number of separate strains of agent may be more limited than is usually represented. It is important to distinguish between the hypothesis that the prion protein of the host 'permits' the selection of mutated strains and the hypothesis that it 'induces' changes in the agent. The former is consistent with the concept of an agent with an independent genome while the latter is consistent with the concept that 'strain of agent' is another expression of the involvement of prion protein in the pathogenesis of transmissible spongiform encephalopathy.