Prion diseases: what will be next?

In recent history there is probably no group of disease that has caused more surprises or shocks than the group of transmissible spongiform encephalopathies, or prion diseases as they have become known. Grouped together on the basis of their neuropathology, showing vacuolation of the neuropil or neurones, or both (spongiform change) (fig 1), they present a variable clinical picture; nevertheless they are all caused by aberrations of a single protein 10 (table 1). They are sporadic as well as hereditary, and in the latter two completely diVerent clinical pictures can be seen within one family (with an identical genetic abnormality in aZicted family members). For instance, in one family one can find classical Creutzfeldt-Jakob disease (CJD), with dementia, ataxia, myoclonic epilepsy, and so on, whereas other family members develop fatal familial insomnia (FFI), with sleep and autonomic disturbances, but little or no ataxia and dementia. Another shock was their transmissibility, dramatically illustrated by kuru, a spongiform encephalopathy in the Fore tribe in New Guinea, spread by cannibalism. Perhaps less exotic but no less dramatic was the demonstration of CJD in patients treated with cadaveric growth hormone, dura mater grafts, corneal transplants, or after use of contaminated surgical instruments or electrodes, 13 another reminder of the “infectious” nature of these diseases. Scientifically, however, perhaps the greatest shock or surprise was the gradual realisation that the agent causing these diseases contained no DNA or RNA, and that we are dealing here with an infectious protein, for which the term “prion”was coined by Prusiner. Here we have a protein that was apparently able to replicate without the intervention of nucleic acids. Certainly, none of the methods used to destroy nucleic acids diminished the infectivity, but the idea that some kind of virus, extremely well hidden, is involved has never been completely laid to rest. The existence of “strains” of prions—that is, diVerent inocula of prions that reproducibly cause a diVerent prion diseases (each with their own incubation time and clinical severity)—has always been a strong argument for this. Very recently, Manuelidis et al resurrected the viral hypothesis when they found that the vacuolisation of cells and nervous tissue in their experimental design preceded accumulation of the infectious protein to be described below. Though no solid evidence was produced in that paper to show that a virus was involved, perhaps there is, yet again, a surprise in store for us. Whatever the case will prove to be, this infectious protein is something else indeed...