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Madness and Memory

Madness and Memory: The Discovery of Prions--A New Biological Principle of Disease

Copyright Date: 2014
Published by: Yale University Press
Pages: 344
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  • Book Info
    Madness and Memory
    Book Description:

    In 1997, Stanley B. Prusiner received a Nobel Prize, the world's most prestigious award for achievement in physiology or medicine. That he was the sole recipient of the award for the year was entirely appropriate. His struggle to identify the agent responsible for ravaging the brains of animals suffering from scrapie and mad cow disease, and of humans with Creutzfeldt-Jakob disease, had been waged largely alone and in some cases in the face of strenuous disagreement.In this book, Prusiner tells the remarkable story of his discovery of prions-infectious proteins that replicate and cause disease but surprisingly contain no genetic material-and reveals how superb and meticulous science is actually practiced with talented teams of researchers who persevere. He recounts the frustrations and rewards of years of research and offers fascinating portraits of his peers as they raced to discover the causes of fatal brain diseases. Prusiner's hypothesis, once considered heresy, now stands as accepted science and the basis for developing diagnoses and eventual cures. He closes with a meditation on the legacy of his discovery: What will it take to cure Alzheimer's, Parkinson's, Lou Gehrig's and other devastating diseases of the brain?

    eISBN: 978-0-300-19926-0
    Subjects: Biological Sciences, Health Sciences, History

Table of Contents

  1. Front Matter
    (pp. i-vi)
  2. Table of Contents
    (pp. vii-viii)
  3. Preface
    (pp. ix-xii)
  4. Introduction
    (pp. xiii-xviii)

    During a trip to Buenos Aires in September 1997 to participate in the Sixteenth World Congress of Neurology, I ventured into the city one afternoon. After buying a few presents for my two daughters, I wandered into an antique store on a side street. In this small shop full of old military uniforms and decorations, I spied a brass pocketknife. On one face of the handle were raised images of hand tools—pliers, a wrench, a drill, a trowel, shears, calipers, a hammer—and on the other engraved “ABOT herramientas,” presumably the name of the tool company that produced it....

  5. Author’s Note
    (pp. xix-xxii)
  6. 1 Growing Up
    (pp. 1-15)

    That I chose an academic career seems a bit odd, for I found both grade school and high school rather boring. I could get Bs with little effort, and those always seemed good enough. My parents never pushed me to do better, even though both of them had been A students.

    My junior and senior high school was Walnut Hills High School in Cincinnati, Ohio. It was a college-preparatory public high school; you had to take a test in the sixth grade to gain admission. But Walnut Hills, as far as I could tell, was no better than elementary school:...

  7. 2 The Beginning of an Odyssey
    (pp. 16-25)

    After three years at the NIH, it was time to move on. I felt ready to build my own laboratory, but I somehow managed to grow up and take what in retrospect was a remarkably mature approach to gaining the education that I would need for studying the brain. I chose to undertake an abbreviated residency in neurology before setting up a laboratory. Most amazing, I still didn’t have a clue about what I wanted to study. My goal was to identify, during my residency, a great problem for investigation.

    In early September 1972, I was performing a lumbar puncture...

  8. 3 A Plethora of Theories
    (pp. 26-35)

    By the time I had begun contemplating a study of the scrapie agent at UCSF in the early 1970s, laboratory investigations into its naturehad been greatly enabled by transmission of the disease from sheep or goats into laboratory mice. This watershed moment was first reported in 1961, by Richard Chandler of the British Agricultural Research Council’s facility at Compton, in Berkshire, England.¹ Subsequent transmission of the scrapie agent from mouse to mouse provided the best available experimental system.

    The challenge was to apply this system to develop a scheme that would separate the scrapie agent from other substances in the...

  9. 4 The Scrapie Race
    (pp. 36-49)

    Now I found myself in a scientific race, albeit one that began at an exceedingly slow pace. Unfortunately, the lack of systematic investigations meant that I needed to start from scratch.The race would soon all but take over my life.

    During the previous decade, Bill Hadlow and his Montana colleague Carl Eklund had performed a large number of experiments on the pathogenesis of scrapie in sheep and goats, as well as some studies on experimental scrapie in mice. While neither of them had tried to define the molecular structure of the scrapie agent, Eklund, a virologist who thought like a...

  10. 5 Dr. America and the Trembling Cannibals
    (pp. 50-64)

    Player number one in the competition I had joined was undoubtedly Carleton Gajdusek of the NIH, guru of kuru and proponent of the “unconventional virus.” His and Joe Gibbs’s successful transmission of CJD to a chimpanzee in 1968, demonstrating that it was an infectious disease, had its origins in the Eastern Highlands of New Guinea, where he eventually set up camp in longer and longer hegiras from the NIH, and where I was to have an enlightening visit with him. Gajdusek, who died in 2008, was an engaging, forceful, insecure individual whose rambunctious personality remained unaltered throughout the thirty-four years...

  11. 6 The Battle for Tenure
    (pp. 65-80)

    Back home at UCSF, I had become frustrated. My collaborative work with Bill Hadlow was proceeding much too slowly. We had managed to publish only three papers on the behavior of the scrapie agent during centrifugation. I was beginning to realize that my approach to understanding its composition was not realistic. Something better had to happen or my grant support would disappear. My fantasies of success were fading, my productivity was unimpressive, and my chances of tenure were declining.

    I was tired of waiting for answers while the biological sciences were exploding with new technologies, including gene cloning. I wanted...

  12. 7 What’s in a Name?
    (pp. 81-96)

    With academic politics behind me, at least for the moment, I could once again focus all my energy on the science. As I drew nearer to unlocking the mysteries of the scrapie agent, however, I would run head on into another kind of politics: the politics of just how you present your discovery to the larger scientific community.

    In the meantime, though, while I tracked down the artifacts in the viroid story of Marsh and his collaborators, it dawned on me that we could not afford to concentrate solely on purification. I began to realize that my earlier idea of...

  13. 8 Lost in the Pacific Fog
    (pp. 97-107)

    One of the most satisfying parts of my work was identifying the scrapie agent’s essential protein. Around the time of publication of my paper introducing the word “prion,” we succeeded in identifying the scrapie protein. With the discovery of what I called the prion protein or PrP, all the tools of modern biology became available. Once we made antibodies, we could perform a limitless number of experiments in several days or at most a few weeks. My research took on an entirely new flavor—no longer were our studies governed by what was possible. Rather, we now had to decide...

  14. 9 The Amyloid Story
    (pp. 108-124)

    Our discovery that prions form amyloid fibrils that coalesce into plaques would foreshadow by several decades a series of discoveries eventually showing that prions cause a wide array of neurodegenerative diseases. The idea that prions could form amyloid unleashed another maelstrom of controversy. For me, the amyloid discovery was a remarkable finding that created a kaleidoscope full of unimaginable, future, unanticipated findings.

    The combined funds from the NIH and R. J. Reynolds had provided adequate support for our efforts in the late 1970s, but more money was needed if we were to scale up our efforts, which I had been...

  15. 10 Finding the Gene
    (pp. 125-142)

    Secure with the evidence that PrP 27–30 was an essential component of the infectious prion, we needed to learn its genetic origin. By now, I had entered into two collaborations that would help carry the prion work forward on just that front.

    Initially, we considered the possibility that PrP 27–30 was synthesized from a subset of amino acids by a process not utilizing genes. Once we found that PrP contained all twenty amino acids, the likelihood of a synthetic process not involving a gene became small. Assuming a gene encoded PrP, we needed to identify the gene and...

  16. 11 Jousting with the Press
    (pp. 143-152)

    Although I had already had more than my share of publicity, I considered it my duty to speak to interested reporters. How else would the public learn about our work, and more important, about scientific research in general? It is a widely held belief that the more informed the public is through newspaper and popular magazine articles, the more supportive they will be of scientific research. But sometimes these attempts backfire.¹

    A couple of years before David Perlman’s original story about prions appeared in theSan Francisco Chronicle, a reporter fromOmni magazinecame to see me. He was enthusiastic...

  17. 12 Deciphering Human Prion Diseases
    (pp. 153-169)

    Over the next two years, our discoveries would create a new paradigm of the human prion diseases that represented a major leap forward. From our data and those of others, we developed a unique understanding of how prion disorders in people can be manifest as sporadic, infectious, and genetic illnesses. Gene sequencing, transgenic mice, genetic linkage, and epidemiology would all conspire to help unravel the conundrum of human prion diseases. These studies proved to be a wonderful example of the interplay between the basic and clinical sciences—biomedical science at its best, using patients to disentangle complex biological phenomena.


  18. 13 What’s in a Shape?
    (pp. 170-183)

    Just what exactly turns the harmless form of the prion protein into its evil twin? This was the great, still-unanswered question. From transgenic mice, we learned that new prions were generated when the good twin danced with the evil one. We surmised that good guys needed to come in contact with the bad ones as new prions formed. Although prion studies driven by molecular biological and genetic investigations had created a legion of supporters, the utility of that approach waned in the early 1990s, and protein structure research soon assumed a predominant role.

    We had begun by searching for a...

  19. 14 Turf Battles
    (pp. 184-192)

    By now, the opposition among my colleagues to the prion had all but collapsed, and our work was about to begin to receive significant public recognition. There were a couple of drawbacks to my newfound fame: The less serious was the attention of the press, which I had managed to keep at bay for the past eight years. The other, considerably more disturbing to me, was the steady encroachment—or perhaps I should say poaching—on my territory by the formidable Carleton Gajdusek.

    But first, to the press: In June 1994, I was in Paris for a monthlong appointment at...

  20. 15 Mad Cow and Other Prion Strains
    (pp. 193-212)

    The need for a better understanding of the prion’s molecular structure was dramatically apparent during the third week of March 1996. The British scientist Robert G. Will and several of his colleagues in the United Kingdom’s National Creutzfeldt-Jakob Disease Surveillance Unit (NCJDSU) were suddenly summoned back to London from a prion meeting in Paris. They had written a paper describing ten young patients with CJD that was about to be published in theLancet, and the government felt compelled to acknowledge the possibility that these patients had contracted prion disease from eating tainted British beef.¹

    The NCJDSU had been founded...

  21. 16 Stockholm
    (pp. 213-231)

    As the concept of infectious proteins became accepted, more and more people, both inside and outside science, began speculating about whether (or when) there would be a Nobel Prize for the work. I was never sure how to handle such comments. I viewed them as idle chatter, given all the negative press I’d engendered. The very people who had been contemptuous of the prion concept were beginning to realize that their scorn had served only to elevate the achievements of my colleagues and me. But others still did not understand the evidence, and their continued skepticism burnished my image as...

  22. 17 The Third Judgment of Paris
    (pp. 232-252)

    In the 1860s, an imaginative group of mostly French painters began a revolution in their Parisian studios. These Impressionists, as they were later called, were subjected to years of harsh judgment and ignorant ridicule by the French artistic establishment. Impressionism would profoundly change art and artists forever. In 1874, the Impressionists held their first exhibition in Paris on their way to achieving worldwide acclaim.

    One hundred and two years later, a second Judgment of Paris would be offered by a group of French oenophiles, who ranked both a cabernet and a chardonnay from California as number 1 over some exalted...

  23. Epilogue: The Quest for Therapeutics
    (pp. 253-260)

    You have to give people some hope. Tell them that they can do something to prevent Alzheimer’s. Why can’t they take vitamins and supplements or do brain exercises that will help prevent dementia?” I had just finished speaking at the Aspen Institute; my host and friend, Kenneth Adelman, was admonishing me about being too set in my ways. “Stan, you need to give them some reason to believe that Alzheimer’s is not hopeless—otherwise, they won’t be interested in supporting your research.”

    I told Ken that I believed biomedical science would eventually come up with effective medications but that it...

  24. Notes
    (pp. 261-282)
  25. Glossary
    (pp. 283-298)
  26. Acknowledgments
    (pp. 299-302)
  27. Illustration Credits
    (pp. 303-304)
  28. Index
    (pp. 305-320)