Story of an obsession

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Prion Biology and Diseases

edited by Stanley B. Prusiner Cold Spring Harbor Laboratory Press: 1999. 710 pp. $125, £???

By my count, this is the fifth time Stanley Prusiner has edited a multi-authored book on the subject of his life-long obsession: the prion, a proteinaceous–infectious particle responsible for the transmissible spongiform encephalopathies (Creutzfeldt–Jakob disease (CJD) and kuru in humans; scrapie and bovine spongiform encephalopathy (BSE) of domesticated herbivores). Considering that more than half of the 17 chapters are actually co-authored by Prusiner, this is the closest yet to a monograph from his laboratory. And, it has to be admitted, the book is by far the most authoritative introduction and summary of the complex data that form the basis of our understanding of the molecular basis of this esoteric group of diseases. While the human forms of the diseases are rare, their economic impact, particularly in the United Kingdom, has been profound. Moreover, their occurrence is now threatening the normal operation of blood-transfusion services worldwide. Hence the need for such an authoritative book.

The prion field has been dogged by controversy, apparently the result of the long time it takes to generate reproducible scientific data, given incubation periods that can exceed 40 years. The discovery of the prion protein (designated PrPsc) in 1982 as the principal component of the infectious particle revolutionized and galvanized investigators. Prusiner recounts the background to this, and takes us through the following critical decade in which the surrogate properties of PrPsc (insolubility, resistance to proteolysis, increased β-sheet content, polymerization into amyloid fibrils) are elucidated. A certain obfuscation remains over the issue of prion rods and amyloid filaments; since the minimal infectious unit has still not been defined, and because it appears that neither rods nor filaments are required for infectivity, this issue seems to be related to attribution of discovery.

While Prusiner and his collaborators have driven the research agenda of the molecular basis of PrP infectivity, other independent groups have complemented his efforts. The nature of infectivity has been uncovered largely through the application of transgenesis to mice, including ablation studies that prove beyond reasonable doubt that PrP plays the central role in prionogenesis. Interestingly, the recent discovery of a duplicated homologue of PrP may necessitate some re-interpretation of these knockout studies, although leaving the central hypothesis intact. Studies in yeast by Reed Wickner and colleagues show that accessory chaperones (possibly the postulated ‘protein X’ of mammalian prions) may facilitate the conversion of a normal host-cell protein into a pathogen. Many enigmas remain: the topology of PrP in the cell membrane, the mechanisms underlying nerve-cell degeneration, the partial creation of de novo infectivity in overexpressing mutant PrP in mice, and the failure yet to create infectivity in vitro.

The emergence of BSE and then the threat of an epidemic in humans caused by contamination of the food chain has assured the future of intensive research of these diseases. The book closes with several helpful practical chapters on methodologies (including insights into future therapeutic strategies), antibody probes (which may prove essential for future clinical tests) and biosafety issues. The latter area is now of immediate concern, since the general levels of ignorance about the spread of CJD and BSE cause regulatory authorities to respond by containing the worst-case scenario, often with drastic financial implications.

Overall, the volume is virtually a monograph by Prusiner, and as such presents a very unified picture of the current state of research. It is the best comprehensive overview of this field and is an ideal introduction for anyone wishing to launch a career in prionology. Perhaps the major message would be that Prusiner achieved his successes through outstanding collaborators, most of whom are represented in the book.

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Masters, C. Story of an obsession. Nature 402, 581 (1999) doi:10.1038/45081

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