No. 3: Prion, Schmrion?
For many clinicians and scientists who care about transmissible spongiform encephalopathies (TSEs), the idea that prions cause sheep scrapie, Creutzfeldt–Jakob disease (CJD), and bovine spongiform encephalopathy (aka mad cow disease) has largely been accepted by way of faith and capitulation. The notion is that the putative agent, normal host prion protein (PrP), causes disease by mutating into an abnormal, degradation-resistant form (PrP-res) that self-replicates without the aid of genetic material.
Now once you get beyond the utter heresy that protein replication can occur without nucleic acids, the prion theory will still require you to toss out Koch’s postulates, which have been used for more than a century to establish a causal link between microbe and infectious disease. You have to be okay with the fact that PrP-res is not invariably seen in highly infectious tissue samples, that its presence is not proportional to infectivity, and that it is not associated with reproducible infectivity—among other obstacles.
Consequently, the thought process required to embrace the prion theory (and a theory so fundamentally radical must be fully embraced, if it is to be acknowledged at all) necessitated a goodly amount of seeing a fabulous suit on a nude head of state. Nevertheless, witnessing the emperor fully clothed became a whole lot easier in 1997 when the committee for the Nobel Prize in Physiology or Medicine gave its big hug to Stanley Prusiner—professor of neurology, biochemistry, and biophysics at UCSF and chief proponent of the prion theory.
But now comes Laura Manuelidis, head of neuropathology at Yale, and her colleagues who published in the January online issue of PNAS their consistent identification of 25-nm virus-like particles in cell lines infected with a scrapie or CJD strain (EM photomicrograph). Notably, these viral particles were not observed in controls and bore no relation to the presence or production of abnormal prion protein. They were also similar to particles originally identified in 1968 in a mouse scrapie model by David-Ferreira et al, in 1971 in sheep scrapie, and in 2004 in primate and human CJD brain. Curiously enough, similar arrays of viral particles were identified by Baringer and Prusiner in 1978 in scrapie-infected brain samples, as the authors point out.
Manuelidis et al conclude that the causative agent of TSEs is most likely this 25-nm virion observed currently and historically in multiple varieties of disease but not in control cell populations (thereby fulfilling Koch’s first postulate) and that PrP-res is likely a late epiphenomenon of infection. Remaining are the large tasks of purifying the viral particles, demonstrating their infectivity, and recuperating them from inoculated host tissue.
