The Prion Challenge to the `Central Dogma' of Molecular Biology, 1965–1991: Part II: The Problem with Prions

Abstract

Since the 1930s, scientists studying the neurological disease scrapie had assumed that the infectious agent was a virus. By the mid 1960s, however, several unconventional properties had arisen that were difficult to reconcile with the standard viral model. Evidence for nucleic acid within the pathogen was lacking, and some researchers considered the possibility that the infectious agent consisted solely of protein. In 1982, Stanley Prusiner coined the term `prion' to emphasize the agent's proteinaceous nature. This infectious protein hypothesis was denounced by many scientists as `heretical'. This two-part essay asks why the concept of an infectious protein was considered controversial. Some biologists justified their evaluation of this hypothesis on the grounds that an infectious protein contradicted the `central dogma of molecular biology'. Others referred to vague theoretical constraints such as molecular biology's `theoretical structure' or `framework'. Examination of the objections raised by researchers reveals exactly what generalizations were being challenged by a protein model of infection. This two-part survey of scrapie and prion research reaches several conclusions: (1) A theoretical framework is present in molecular biology, exerting its influence in hypothesis formation and evaluation; (2) This framework consists of several related, yet separable, generalizations or `elements', including Francis Crick's Central Dogma and Sequence Hypothesis, plus notions concerning infection, replication, protein synthesis, and protein folding; (3) The term `central dogma' has stretched beyond Crick's original 1958 definition to encompass at least two other `framework elements': replication and protein synthesis; and (4) From the study of scrapie and related diseases, biological information has been delineated into at least two classes: sequential and what I call `conformational'. In Part I of this essay, a brief review of the central dogma was given, and the developments in scrapie research from 1965 to 1972 were traced. This section summarized many of the puzzling, non-virus-like properties of the scrapie agent. Alternative hypotheses to the viral explanation were presented, including early versions of a protein-only hypothesis. Part II of this essay will follow the developments in scrapie and prion research from the mid-1970s through 1991. The growing prominence of a protein-only model of infection will be countered by continued objections from many researchers to a pathogen devoid of nucleic acid. These objections will help illuminate those generalizations in molecular biology that were indeed challenged by a protein-only model of infection.