Madness and Memory The Discovery of PrionsA New

Biological Principle of Disease

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To scientific investigation that
creates new knowledge,
erases ignorance,
eradicates prejudice,
prevents disease,
alleviates suffering,
and enhances well-being

To Sunnie, Helen, Leah, and William

In striving to do scientific work, the chance—even for very gifted
persons—to achieve something of real value is very small.
—Albert Einstein

Of all the services that can be rendered to science, the introduction

of new ideas is the greatest.
—J. J. Thomson

The true men of action in our time, those who transform the world,
are not the politicians and statesmen, but the scientists. Unfortu-
nately, poetry cannot celebrate them, because their deeds are
concerned with things, not persons, and are, therefore, speechless.
When I find myself in the company of scientists, I feel like a shabby
curate who has strayed by mistake into a drawing room full of dukes.
—W. H. Auden

The only good histories are those that have been written by the
persons themselves who commanded in the affairs whereof they
write.
—Michel de Montaigne

A man convinced against his will, is of the same opinion still.

—Samuel Butler
 Contents

Preface ix
Introduction xiii
Author’s Note xix
1 Growing Up 1

2 The Beginning of an Odyssey 16

3 A Plethora of Theories 26

4 The Scrapie Race 36

5 Dr. America and the Trembling Cannibals 50

6 The Battle for Tenure 65

7 What’s in a Name? 81

8 Lost in the Pacific Fog 97

9 The Amyloid Story 108

10 Finding the Gene 125

11 Jousting with the Press 143

12 Deciphering Human Prion Diseases 153

13 What’s in a Shape? 170

14 Turf Battles 184

15 Mad Cow and Other Prion Strains 193

16 Stockholm 213

17 The Third Judgment of Paris 232

Epilogue: The Quest for Therapeutics 253

Notes 261

Glossary 283

Acknowledgments 299

Illustration Credits 303

Index 305
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 Preface

“What if I’m right after all?” I said to myself as I exited an elevator on

the seventh floor of the Health Sciences East building at the University of
California, San Francisco, one morning in October 1986. Four years had
passed since my introduction of the word “prion” had elicited scorn, out-
rage, and disbelief from the scientific community. But one nugget of data
after another was supporting my hypothesis—I was beginning to con-
vince scholars that my novel perspective might have merit.
Thirty-five years after Thomas Kuhn wrote his remarkable analysis
on the structure of scientific revolutions, Clayton Christensen wrote
about the technological equivalent, which he labeled “disruptive technol-
ogies or innovations.”1 Christensen divided new technologies into two
categories: sustaining and disruptive. Sustaining technologies rely on
incremental improvements or small advances to nourish an established
technology. In contrast, disruptive technologies are transformational
and discontinuous. They create disorder by upsetting the status quo and
are often greeted with profound skepticism. Some have destroyed entire
industries—an example is digital photography, which Steven Sasson in-
vented in 1975, while working at Eastman Kodak. On November 17, 2009,
President Barack Obama awarded Sasson the National Medal of Technol-
ogy and Innovation at a ceremony in the East Room of the White House.
I had the privilege of meeting Sasson because I received the National
Medal of Science on the same occasion.
Thirty-seven years after Sasson’s disruptive innovation, Kodak filed
for bankruptcy—its executives had numerous golden opportunities to
capitalize on Sasson’s invention; they possessed neither the necessary wis-
dom nor the uncommon vision. Digital photography did not fit the Kodak
business model; how could the company survive if it were to abandon
photographic film? Chemicals, film, photographic paper, and inexpensive
cameras had become the heart and soul of a worldwide business with rev-
enues of billions of dollars annually.2 There is a strange irony to the Kodak

ix
story; from its founding by George Eastman in 1889, Kodak was a “high
tech” business, yet it went broke under the burden of technological
innovation.
In this book, I describe disruptive innovation in thinking about pro-
teins and how they cause disease. I wrote this book because I feared that
neither science historians nor journalists could construct an accurate
narrative of my investigations. This is a first-person account of the think-
ing, the experiments, and the surrounding events that led to the identi-
fication of infectious proteins, or “prions” as I named them.3 I have tried
to describe what appears in retrospect to be an audacious plan to define
the composition of the agent that causes scrapie, a barnyard disease whose
etiology was a mystery at the time. On many occasions, I worried that my
data might lead me down dead-end paths. Despite my fascination with
the problem, I was haunted by a fear of failure; my anxiety was palpable
at almost every turn. Was the problem intractable? As small successes
emerged, so did a legion of naysayers who questioned both the wisdom
of my pursuit and my scientific prowess; indeed, there were times when
little but my naïveté and exuberance sustained me.
The skeptical and frequently hostile reactions to prions from many
precincts of the scientific community reflected resistance to a profound
change in thinking. Prions were seen as an anomaly: They reproduce and
infect but contain no genetic material—neither DNA nor RNA; thus they
constitute a disruptive transition in our understanding of the biological
world. The consequences of the prion discovery are immense, and they
continue to expand.4 Their causative role in Alzheimer’s and Parkinson’s
diseases has important implications for the diagnosis as well as the
treatment of these common, invariably fatal maladies.
Readers may wonder about the title Madness and Memory. Prions clog
the brain, causing neurodegeneration that often results in the diminished
cognitive and intellectual function known as dementia. The word “de-
mentia” is from the Latin demens, originally meaning “out of one’s mind”
or “madness.” The etymology of demens is a derivation from de-, “with-
out,” plus ment, the root of mens, “mind.” One of the more widely reported
prion disorders was dubbed “mad cow” disease in the popular press. The
most common form of dementia is Alzheimer’s disease, which generally
presents with memory deficits for recent events; such difficulties intensify
as cognitive and intellectual failings worsen. Hence, Madness and Mem-

x Preface
ory. The subtitle of this book, The Discovery of Prions—A New Biological
Principle of Disease, comes from the 1997 Nobel Prize citation, but with one
change that initially occurred to me during a joyous telephone call from
Stockholm. This rather challenging moment is described in Chapter 16.
I am most grateful to my loving partner, Sunnie Evers, for encourag-
ing me as I struggled to piece together a complicated story. For seven
years, she has nurtured the maturation of this book. A sabbatical at
Imperial College in London during the 2007–8 academic year provided
the time to begin writing. Professor Chris Kennard was an extraordinary
host, helping secure support from the Leverhulme Trust to defray the
cost of my lodging and the editing of this book by Sara Lippincott, who
converted my stilted prose into a readable story, for which I am very
appreciative.
If I have erred in my recollection of the circumstances or in my ana-
lysis of others’ conduct, I apologize. I hope that my attempts to describe the
foibles of human behavior as they affected scientific investigation will not
be misinterpreted as bitterness. I could have written a bland account of the
events leading to the discovery of prions, but that would not have captured
the passion with which my colleagues and I pursued our work. Nor would
it have conveyed the complex emotions that permeate laboratories as sci-
entists jockey for priority in the perennial race to be the first to discover
the unexpected.
Many people have contributed to the studies described here. Their
contributions are gratefully celebrated in the Acknowledgments. Any
omissions are unintentional, and of course, I take full responsibility for
any mistakes in the text.

Preface xi
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 Introduction

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 mili-
tary 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. This knife was a gem and I bought it for myself on the spot.
With my new pocketknife sequestered in my luggage, I left Buenos
Aires for a meeting on the “Basic Mechanism of Prion Disease” in Stock-
holm. The day after arriving, I spent a few hours with Olle Lindberg, who
had come to Stockholm by train from his farm in Dalarna. Olle and I had
become good friends thirty years earlier when, still in my fourth year at
the University of Pennsylvania’s medical school, I worked in his labora-
tory at the Wenner-Gren Institute, then at Norrtullsgatan 16, in a drab
yellow brick building with large wooden sash windows. It was during my
time with him that I began to seriously consider the possibility of becom-
ing a physician-scientist. Olle’s warm and concerned counsel, his scientific
wisdom, his gentle demeanor in the management of even the most diffi-
cult personalities, and his unwavering personal and professional ethics
impressed me. Olle retired as director of the Institute in 1980, and soon
thereafter he and his wife, Britta, moved to the farm where she had spent
her childhood. Except during the harsh, dark winter months, Olle spent
much of his time clearing underbrush from the thickly forested land, a
task that gave him great pleasure.
As we reminisced and discussed my current research in a spacious
corner room at the Diplomat Hotel with a view of the harbor, it occurred
to me to show him the little pocketknife I had acquired in Buenos Aires.
I was sure he would appreciate my purchase since he always carried one

xiii
himself. Removing the knife from my toiletry kit, I proudly showed it to
Olle, who admired it with a sparkle in his eyes and began thanking me.
Though taken aback, I finally managed a few words, “Olle, I am so sorry!
I didn’t mean to give you the impression that it was a gift. I bought this in
Buenos Aires for myself—it’s a memento of the trip.” As these awkward
moments passed, Olle responded with his usual grace, but I was morti-
fied. Each time I recall that episode, I marvel at how my brain continues
to evoke the same feelings of surprise, confusion, embarrassment, and
remorse.
Despite advances in unraveling the molecular basis of ner vous sys-
tem activity, our knowledge of the brain is still rudimentary. We have
little understanding of the molecular events that occur when we experi-
ence events like the one I have just described—nor of what happens later
when we remember the details with clarity. How did this little knife con-
tretemps arouse such powerful feelings and stimulate my brain for years
afterward with an intense cascade of recollected emotions?
Looking back, I think my fascination with the human ner vous sys-
tem began during a rotation on the neurology ser vice as a third-year
medical student at Penn. My teachers were distinguished and unforget-
table: The chairman of the department was Milton Shy, who discovered
what for many years was called Shy-Drager syndrome and is now re-
ferred to as multiple system atrophy (or MSA).1 I would argue that the
Shy-Drager eponym is a more evocative term than the nonspecific string
of words “multiple system atrophy.”2 Ironically, Shy-Drager is a prion
disease. Another remarkable teacher was a visiting professor, E. A. Carmi-
chael, the former head of the National Hospital for Neurology and
Neurosurgery at Queen’s Square in London and a master clinician.
My next experience with neurology remains somewhat of a blur.
During my medical internship at the University of California, San Fran-
cisco (UCSF), in the late 1960s, I spent a month on the neurology ser vice,
and while I remember the chief resident, I cannot recall the attending
professor. I attribute this amnesia to the every-other-night call schedule.
I was often so exhausted that it was nearly impossible to enjoy the flower-
child culture of nearby Haight-Ashbury. I was envious of the relaxed
lifestyle the hippies brought to the Bay Area, and I dreamed of having a
house in Big Sur on a cliff overlooking the Pacific Ocean. I saw myself
as an artisan of some sort, spending each late afternoon watching the

xiv Introduction
sunset while reclining in a large, cast-iron, antique bathtub perched on
the lawn. These restless thoughts were not new. A year earlier, during my
stay in Stockholm with Olle, I had visited Morocco and fallen in love
with the wonderfully preserved small town of Asilah, on the Atlantic
coast about twenty miles southwest of Tangiers. Many of its stone ram-
parts and gateworks date back to the 1500s, when it was occupied by the
Portuguese. After spending two nights in a magnificent old stone house
at the edge of the Kasbah, I was ready to spend the next several years
there, the romantic sound of waves breaking on the rocks as I drifted off
to sleep only enhancing these impractical dreams.
But sanity, guilt, and lucid thinking prevailed, and I returned to
Stockholm, where I continued my studies with Olle on the oxidative me-
tabolism of brown fat cells. I was trying to figure out how these special-
ized fat cells could rapidly burn fat and generate lots of heat; normally, our
bodies try to conserve energy and generate as little wasted energy in the
form of heat as possible. After another two months of captivating research,
I went back to Philadelphia to complete medical school, but I had become
bedazzled by the “science bug.” I was astonished that people actually got
paid to solve puzzles every day—what a fantastic way to make a living!
Although I wanted to return to Stockholm, this was not an option. The
Vietnam War was raging in Southeast Asia, and I had two choices: become
a U.S. Army hospital administrator or “suck-it-up” and do an internship
before going to the National Institutes of Health (NIH). I briefly toyed with
a third possibility—leaving the United States permanently—but in the end
I was not prepared to constrict my future choices in who knows how
many unforeseen ways.
While the grueling schedule of my UCSF internship is now a foot-
note, it left me with little energy or enthusiasm for clinical medicine. For-
tunately, the next three years at the NIH working on enzymes in bacteria
rekindled my interest in the study of human disease. One of my NIH col-
leagues, Mike Brown, would periodically ask me, “What are you going to
do next, Stan? You’re a physician; you need to figure out what you’re going
to do with your life. You’ve learned enough about enzyme regulation in
bacteria and you’re wasting time here.” His advice was golden.
Once I decided to study the brain, I began to feel less adrift. With its
billions of neurons, its ability to direct all aspects of human activity and
its endless mysteries, the brain seemed a perfect subject for research, but

Introduction xv
I had to pick a doable problem. I needed a focus with achievable goals for
the next several decades—the more I thought about the brain, the more
worthwhile my pursuit seemed. Before setting up a laboratory to study
some aspect of the brain, I had to learn about the ner vous system and
define a research problem. As it happened, studies of the ner vous system
had reached a propitious point; the Society for Neuroscience had just
been founded and was to grow over the next four decades to have more
than forty thousand members worldwide.
After a few visits to laboratories studying the chemistry and physiol-
ogy of the brain, I decided to pursue an abbreviated residency in neurology
to gain the training I needed to become an effective physician-scientist.
It was during my residency at UCSF that I encountered a patient with a
rare, progressively debilitating illness called Creutzfeldt-Jakob disease
(or CJD), and the mysteries surrounding this illness launched my scien-
tific studies for the next four decades.
Neurologists have a vibrant, colorful, and almost endless vocabulary to
describe normal functions and pathological states of the human nervous
system. They are fond of words beginning with the negative prefix “a” from
the Greek, such as “akinetic” to indicate that some motor functions that
have become impaired; other such “a” terms include “anomia,” “anosmia,”
“agnosia,” “anosognosia,” “aphasia,” “apraxia,” and “ataxia,” and the parade
of these wondrous words marches on. And then there is the “dys” prefix,
meaning bad or abnormal; such words include “dysaesthesia,” “dysautono-
mia,” “dysphasia,” “dysphemia,” “dysmetria,” “dysphonia,” and “dystonia.”
Some neurologists seem to enjoy the cadence and rhythm that such terms
as “perseveration,” “dysdiadokokinesia,” “dentatorubral-pallidoluysian at-
rophy,” and “palatopharyngolaryngo-oculodiaphragmatic myoclonus”
summon forth.
I was unprepared for the resistance of the scientific community to
the discovery of prions—this created a rather harrowing and arduous
journey for more than a decade. In the chapters that follow, I describe my
thinking and that of others in elucidating new principles of disease that
underlie many if not all neurodegenerative illnesses. Besides CJD, these
disorders include Alzheimer’s, Parkinson’s, Lou Gehrig’s (ALS), and
Huntington’s diseases, as well as the frontotemporal dementias (FTDs),
including posttraumatic forms called dementia pugilistica and chronic
traumatic encephalopathy (CTE). This book is a first-person account

xvi Introduction
written by a scientist who had a leading role in these studies. As such, it
must be considered a retelling of a scientific odyssey from my perspective
that took me from pariah to prophet.
The current state of prion research, which continues to evolve and
expand with unexpected discoveries, might best be described by quoting
Winston Churchill. In late 1942, Churchill spoke at a Lord Mayor’s lun-
cheon in London, where he described recent British military success in
North Africa but cautioned, “Now this is not the end. It is not even the
beginning of the end. But it is, perhaps, the end of the beginning.”
As one after another mysterious property of the prion began revealing
itself, I was forced to think in ways that were often counterintuitive. Such
reasoning is generally wrong, but occasionally it heralds a groundbreaking
discovery of the sort epitomized by prions. My ideas contradicted the
scientific body of knowledge: All biological entities, from viruses to people,
have DNA or RNA, the genetic material that directs the synthesis of their
progeny. Many argued that I was spewing heresy and I had to be wrong.
The incredulity of my colleagues only strengthened my conviction that
scientists have a responsibility to convince their skeptics of the validity
and importance of discoveries that run counter to prevailing opinions,
and that they can do so only by performing experiments that challenge
their own hypotheses.3 Sometimes the road of testing and retesting is
long and arduous—such was the case for me.
Any commentary on scientific discoveries must include a discussion
of luck. Extremely intelligent men and women can toil for years in the
vineyards of science and never be fortunate enough to make a great dis-
covery. And then there are a few people (I include myself ) who are the
recipients of a mammoth dose of good luck. The infectious pathogen that
we now call a prion might well have turned out to be an atypical virus—
not nearly as interesting as an infectious protein. Alternatively, prions
might well have been much rarer than they are, and all but impossible to
isolate; had that been so, we might have been unable to identify the pro-
tein of the prion. Or another group instead of mine might have discov-
ered prions; that sort of preemption happens all the time in science—and
unlike sporting events, there are no rematches. A discovery is made only
once; there are no silver medals, no runner-up awards. Another champi-
onship game may be contested in twelve months, another Olympics in
four years, but the race to a particular discovery is run only once.

Introduction xvii
 Thirty years after the discovery of prions, we have come to appreci-
ate their wide implications and the new challenges they pose. All neuro-
degenerative diseases are fatal; moreover, diagnostic tests are poor and
effective therapeutics nonexistent for all of them. The discovery of prions
has given us an entirely new approach to the development of drugs for
treating these devastating maladies.
So how exactly did the story begin?

xviii Introduction
 Author’s Note

The book that you are reading contains a true story. The conver-
sations in the book all come from my clear recollection of them, though
they are not written to represent word-for-word transcripts. Rather, I have
retold them in a way that evokes the feeling and meaning of what was
said. In all instances, the essence of the dialogue is accurate.

xix