From The New England Journal of Medicine
In How the Cows Turned Mad, Maxime Schwartz recounts the history of the prion diseases, or subacute spongiform encephalopathies, as if writing a mystery. Schwartz refers to all the prion diseases under one rubric, "The Disease," as if a single criminal with many disguises were active. This story has truly been an exceptional one, with events that have dramatically and unexpectedly affected the economy, public health, and the political scene. We now know that there are a number of subacute spongiform encephalopathies of animals (e.g., scrapie and "mad cow disease," or bovine spongiform encephalopathy) and of humans (e.g., kuru and Creutzfeldt-Jakob disease) that are transmissible and that have similar pathologic features. The transmissible agent, a prion, is a misfolded protein (called PrP(sup Sc)) that has assumed a conformation different from that of the normal cellular form of the protein (called PrP(sup C)). In the presence of PrP(sup Sc), PrP(sup C) is converted into additional molecules of PrP(sup Sc), which then accumulates, resulting in the induction of disease. The prion is remarkable because it apparently contains no nucleic acid, triggers no immune response, causes a disease with an extraordinarily long incubation period, and is highly resistant to inactivation by physical and chemical agents (such as heat and formalin) that normally are expected to inactivate a pathogen. One of the attractive features of this book is its historical perspective, beginning with coverage of early records related to scrapie in 17th-century England and ending with a discussion of recent concerns in France about the spread of bovine spongiform encephalopathy and a new variant of Creutzfeldt-Jakob disease that has been strongly linked to bovine spongiform encephalopathy. The work of Pasteur is highlighted, presumably in part because Schwartz previously served as head of the Pasteur Institute. Schwartz reviews the many ways in which the prion diseases have surprised us and also covers recurrent themes that have frequently been overlooked. For example, in the 1930s scrapie was transmitted to sheep by means of inoculation with a formalin-treated vaccine against the virus that causes louping ill. The vaccine transmitted scrapie because it had been prepared from sheep that were presumed to have unrecognized scrapie and because scrapie resists formalin inactivation. This event presaged instances of iatrogenic spread of the subacute spongiform encephalopathies, such as one in which Creutzfeldt-Jakob disease was transmitted by the implantation of electrodes that had previously been used in an affected person and on which prions had been incompletely inactivated by formaldehyde vapor. The transmission of kuru after ritual cannibalistic ingestion of the tissues of relatives who had died of kuru reminds one of how bovine spongiform encephalopathy became endemic in cattle as a result of the ingestion of feed that contained contaminated cattle carcasses. Schwartz informs us that these events are reminiscent of a still earlier event recognized by Nocard, a student of Pasteur, in which anthrax was spread from fertilizer that had been prepared from carcasses of anthrax-infected animals. The subacute spongiform encephalopathies still have much to teach us, both about their pathogenesis as well as about the role of misfolded proteins in other neurodegenerative diseases. We will need to attend to the history of these diseases carefully and also be guided by current data in order to ensure that we respond appropriately in the future to the surprises of these diseases. How the Cows Turned Mad should be understandable to readers with a relatively limited scientific background; however, it would have been helpful for Schwartz to have provided some figures to show, for example, the conversion of PrP(sup C) into PrP(sup Sc). The information about these diseases is reasonably current, with only rare errors. In the interest of space, Schwartz unfortunately was selective in his discussions of prion disease and in listing references and crediting scientists who contributed to knowledge in this field. Pasteur wrote, as cited by Schwartz, "Might it not be permitted to believe . . . that the day will come when easily utilized preventive measures will end these scourges which abruptly afflict and terrify people . . . ?" In these times of outbreaks of West Nile virus infection and the severe acute respiratory syndrome, one cannot help but think of the more cautious and somber comment of Claudius in Shakespeare's Hamlet: "Diseases desperate grown / By desperate appliance are relieved, / Or not at all." Some stories that involve intrigue and human tragedy, such as Hamlet, will always challenge us and leave unanswered questions. Raymond P. Roos, M.D.
Copyright © 2003 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine is a registered trademark of the MMS.
*Starred Review* Two and a half centuries ago, sheep in England started trying to scrape their wool off; in France, to shake uncontrollably. The Brits dubbed their phenomenon scrapie; the French called theirs tremblant. Between then and now, similar conditions in cows and humans were discovered and assigned the group name transmissible spongiform encephalopathies (TSEs): diseases that fill the brain with holes as in a sponge and spread from one organism to another. Their cause eluded researchers until quite recently. SOP since Pasteur sought an invasive bacterium or virus with increasingly powerful tools, which TSE agents eluded. Eventually, evidence pointed to a genetic cause involving transformation of a normal into a deviant gene by another deviant gene introduced orally into the affected organism. You had to eat something from a sick organism to become sick, and once that became popular knowledge after the concurrence of human and bovine TSE cases in England in the 1990s, there was a panic. That reaction seems unjustified; according to Schwartz, TSEs will continue to be a very minor cause of human death. Meanwhile, there may be much to learn from TSE research about such symptomatically similar illnesses as Alzheimer's disease. Writing with immense concentration and clarity, French molecular biologist Schwartz makes the long hunt for the unexpected culprit gene utterly engrossing. Ray Olson
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