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Neurology Today:
doi: 10.1097/01.NT.0000449807.60016.fb

BOOKSHELF: Proteins, Prions, and Paradigm Shift — Persistence and a Little Self-Promotion Help Madness and Memory: The Discovery of Prions — A New Biological Principle of Disease. By Stanley B. Prusiner, MD. 344 Pages. Yale University Press 2014.

Filley, Christopher M. MD, FAAN

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In 1962, the science historian Thomas Kuhn published his influential The Structure of Scientific Revolutions, introducing the idea of the paradigm shift. In contrast to normal science, the paradigm shift introduces a radical change in thinking that challenges widely held scientific assumptions, and then, after validation and acceptance, exerts a lasting change in the field. Stanley Prusiner, MD, a name well known to neurologists and neuroscientists around the world, has written his own book about what he would undoubtedly regard as a paradigm shift of his own making. Whatever the reader concludes, there can be no question that what is described in this book is far indeed from normal science.

Madness and Memory is a personal account of the discovery of prions, packaged with generous autobiographical detail that expands the story to reveal much about the author's background, career, and personality. Prusiner first describes his family, upbringing, and early academic development as a prelude to the grand adventure on which he later embarked to come to his major discovery.

A neurologist with a medical degree from the University of Pennsylvania, he realized early in his training that clinical medicine was not for him, and his decision to embrace laboratory research was pivotal. His boundless enthusiasm for the opportunity offered by bench science led him away from the clinic and toward the investigation of fundamental neurobiology. Still, one finds in his prose the desire for his research to have major implications — as far-reaching as he can imagine — for the understanding and treatment of devastating human diseases he saw as a neurology resident.

The prion, as all neurologists and neuroscientists know, stands for “proteinaceous infectious particle.” The term was introduced in Prusiner's most important paper, a single-authored article in Science that appeared in 1982. Based on his work with the sheep and goat disease scrapie, Prusiner proposed the radically novel idea that the infectious agent in this disease was a particle consisting solely of protein — without the nucleic acid of conventional viruses.

In contrast to the entrenched orthodoxy regarding the structure of infectious organisms, prions were conceptualized as proteins that could transmit disease in the absence of DNA or RNA. The prion was seen as relevant to human disease, most obviously the rapidly progressive dementia Creutzfeldt-Jakob disease (CJD), as well as the cerebellar ataxia of New Guinea cannibals known as kuru. Here is the stuff of paradigm shift, breathtaking in its originality and bound to evoke strong reaction. If the concept of the prion turned out to be true, textbooks would need to be rewritten, lectures thoroughly revised, and ideas about the very nature of life itself revisited.

Just as Kuhn would predict, a robust intellectual dispute immediately erupted between the advocate of the new science and the followers of the existing paradigm. Prusiner recounts in vivid detail the opposition he faced, not only from scientists around the world but in his own department of neurology at the University of California, San Francisco, as well. The animosity he encountered was fierce indeed; he recounts being called “impulsive, presumptuous, reckless, ambitious, aggressive, callous, manipulative, and egotistical.” From his own colleagues he received “negative critiques” arising from “disbelief, disdain, and ignorance.”

Undaunted, Prusiner responded to his detractors with ceaseless energy to pursue his studies and gather the evidence needed for vindication. He reports vigorously rising to the challenges confronting him, resolutely endeavoring with competitive spirit not only to confirm the existence of prions but also to extend his findings to human diseases. An abiding self-confidence permeates his approach to investigation, steadily fueling his intense perseverance, but it is not hard to see how this seemingly enviable trait came to be seen by some as arrogant self-aggrandizement.

To some critics, the very word “prion” came to be suspect; as Prusiner points out, that objection was raised simply because the first two letters of the word are also the first two letters of his name. Was it a mere coincidence or another example of self-promotion? Obviously, the “pr” in prion applies as well to the word protein, but some viewed the double entendre of the terminology as quite deliberate.

The book at times turns to details of laboratory science, delving into aspects of basic neurovirology and related fields that may leave some readers hoping for a respite from the intricacies of polymerase chain reaction, mass spectrometry, bioluminescence, and the like. In these passages, the author's true passion for laboratory work shines through, and many insights into the creative mind are available for those who pay close attention.

But there are also more accessible moments, such as a memorable visit to New Guinea, stories about the complex life and career of Carleton Gajdusek, and an illuminating discussion of Prusiner's seeking, and eventually receiving, tenure at his medical school. At times remarkably candid, the author introduces the reader to a wide range of individuals whose personal foibles make it clear that, however brilliant they may be, scientists are still quite clearly human beings.

The highlight of the tale is Prusiner's trip to Stockholm in 1997 to receive the Nobel Prize in Physiology or Medicine. This followed soon after his receipt of the Lasker Award for Basic Medical Research in 1994. He recalls the much anticipated phone call informing him of his being the sole recipient of the Nobel Prize, and heralds the award as a “triumph of experimental science in rolling back the frontiers of our ignorance.” Once in Stockholm, even he admits to some nervousness about the award ceremony, hoping to avoid embarrassments such as dropping the medal he is to receive, or tripping in front of the King of Sweden and all the assembled dignitaries.

The book ends with a broader perspective on the possible relevance of prion biology to neurodegenerative diseases that have thus far defied satisfactory understanding. Because abnormal protein accumulations characterize Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Huntington's disease, perhaps the neuropathology resulting from the unchecked conformational change of prions will apply to these disorders as well.

Alzheimer's disease particularly attracts his attention because of the woefully limited research funding for such a common and dreaded disease. Dementia after traumatic brain injury may also be explained by the prion revolution, as progressive tauopathy has been observed after repetitive injuries, and Prusiner further speculates that post-traumatic stress disorder may ultimately implicate prions. With characteristic confidence, he suggests that the ideas that apply to rare diseases such as CJD will also prove important in elucidating more common disorders seen by neurologists and psychiatrists alike.

Madness and Memory is a fascinating account of scientific research, discovery, and controversy that will be of interest to many readers within neurology and neuroscience, as well as anyone drawn to the creative process.

With time, the idea of the prion has come to be increasingly accepted, despite a few remaining dissidents, and for the great majority of neurologists and neuroscientists the paradigm has clearly shifted. The fact that the notion of prions provoked such strong resistance may be as much due to its proponent's unstinting advocacy as to the stunning novelty of the concept, but in all proposals seeking to dislodge a widely accepted worldview, a certain degree of self-promotion may always be necessary.

Reproducible evidence is still the only way to verify the authenticity of a scientific revolution, but the forcefulness of its originator does not mean that he is not also right.

Dr. Filley is professor of neurology and psychiatry and director of the Behavioral Neurology Section at the University of Colorado-Denver School of Medicine.

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•. 1997 Nobel Prize award ceremony speech for Stanley Prusiner:

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