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OCR for page R1
-
ADVANCING
PRION SCIENCE
Guidance for the National Prion Research Program
Committee on Transmissible Spongiform Encephalopathies:
Assessment of Relevant Science
Rick ErUtmann and Laura B. Sivitz, Editors
Medical Follow-up Agency
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu
OCR for page R2
THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001
NOTICE: The project that is the subject of this report was approved by the Governing
Board of the National Research Council, whose members are drawn from the councils of
the National Academy of Sciences, the National Academy of Engineering, and the Insti-
tute of Medicine. The members of the committee responsible for the report were chosen
for their special competences and with regard for appropriate balance.
Support for this project was provided by the U.S. Department of Defense (Contract No.
DAMD17-02-C-0094~. The views presented in this report are those of the Institute of
Medicine Committee on Transmissible Spongiform Encephalopathies: Assessment of
Relevant Science and are not necessarily those of the funding agencies.
Library of Congress Cataloging-in-Publication Data
Institute of Medicine (U.S.~. Committee on Transmissible Spongiform Encephalopa-
thies: Assessment of Relevant Science.
Advancing prion science: guidance for the national prion research program / Com-
mittee on Transmissible Spongiform Encephalopathies: Assessment of Relevant Science,
Rick Erdtmann and Laura B. Sivitz, editors.
p.; cm.
Includes bibliographical references.
ISBN 0-309-09060-1 (pbk.) ISBN 0-309-52714-7 (PDF)
1. Prion diseases. 2. Prion diseases Government policy United States.
EDNLM: 1. Prion Diseases prevention & control United States. 2. Food Supply-
standards United States. 3. Health Policy United States. 4. Prion Diseases-
diagnosis United States. WL 300 I591ad 2003] I. Erdtmann, Rick. II. Sivitz, Laura.
III. Title.
RA644.P93I55 2003
616.8'3 dc22
2003027266
Additional copies of this report are available from the National Academies Press, 500
Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-
3313 (in the Washington metropolitan area); Internet, http://www.nap.edu.
For more information about the Institute of Medicine, visit the IOM home page at:
www.iom.edu.
Copyright 2004 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America.
The serpent has been a symbol of long life, healing, and knowledge among almost all
cultures and religions since the beginning of recorded history. The serpent adopted as a
logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by
the Staatliche Museen in Berlin.
COVER: The cover photograph, provided by Dr. David Asher, is a histopathology slide
of brain tissue from a patient with a prion disease. Stained with the chemicals eosin (red)
and hematoxylin (blue), the magnified tissue manifests microscopic holes (white circles)
that illustrate why prior-infected tissue is described as spongiform. This report aims to
guide scientists beyond histopathology toward new strategies to diagnose prion diseases
noninvasively, rapidly, and early.
OCR for page R3
"~nowin,g is not enough; we finest apply.
Willtin,g is not enough; we must do."
Goethe
.......... ........
........... ........
. ::::: ::
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
Shaping the Future for Health
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THE NATIONAL ACADEMIES
Advisers to the Nation on Stienre, Engineering, and Medicine
The National Academy of Sciences is a private, nonprofit, self-perpetuating society
of distinguished scholars engaged in scientific and engineering research, dedicated
to the furtherance of science and technology and to their use for the general welfare.
Upon the authority of the charter granted to it by the Congress in 1863, the Acad-
emy has a mandate that requires it to advise the federal government on scientific and
technical matters. Dr. Bruce M. Alberts is president of the National Academy of
~ .
sciences.
The National Academy of Engineering was established in 1964, under the charter of
the National Academy of Sciences, as a parallel organization of outstanding engi-
neers. It is autonomous in its administration and in the selection of its members,
sharing with the National Academy of Sciences the responsibility for advising the
federal government. The National Academy of Engineering also sponsors engineer-
ing programs aimed at meeting national needs, encourages education and research,
and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is presi-
dent of the National Academy of Engineering.
The Institute of Medicine was established in 1970 by the National Academy of
Sciences to secure the services of eminent members of appropriate professions in the
examination of policy matters pertaining to the health of the public. The Institute
acts under the responsibility given to the National Academy of Sciences by its con-
gressional charter to be an adviser to the federal government and, upon its own
initiative, to identify issues of medical care, research, and education. Dr. Harvey V.
Fineberg is president of the Institute of Medicine.
The National Research Council was organized by the National Academy of Sciences
in 1916 to associate the broad community of science and technology with the
Academy's purposes of furthering knowledge and advising the federal government.
Functioning in accordance with general policies determined by the Academy, the
Council has become the principal operating agency of both the National Academy
of Sciences and the National Academy of Engineering in providing services to the
government, the public, and the scientific and engineering communities. The Coun-
cil is administered jointly by both Academies and the Institute of Medicine. Dr.
Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the
National Research Council.
www. nationa l-academies.org
OCR for page R5
COMMITTEE ON TRANSMISSIBLE SPONGIFORM
ENCEPHALOPATHIES: ASSESSMENT OF RELEVANT SCIENCE
Richard T. Johnson, Chair, Distinguished Service Professor of Neurology,
Microbiology, and Neuroscience, Johns Hopkins University School of
Medicine and Bloomberg School of Public Health
Harvey l. Alter, Chief of the Infectious Diseases Section and Associate
Director for Research, Department of Transfusion Medicine,
National Institutes of Health
Dean O. Cliver, Professor of Food Safety, Department of Population
Health and Reproduction, School of Veterinary Medicine, University
of California, Davis
Linda D. Cowan, George Lynn Cross Research Professor, Epidemiology,
Department of Biostatistics and Epidemiology, University of
Oklahoma Health Sciences Center, and Liaison from the Board of the
Medical Follow-up Agency
Roger Y. Dodd, Executive Director for Biomedical Safety, American Red
Cross Holland Laboratory
Frederick A. Murphy, Professor and Dean Emeritus, Department of
Pathology, Microbiology, and Immunology, School of Veterinary
Medicine. University of California. Davis
Michael B.A. Oldstone, Professor, Department of Neuropharmacology,
Division of Virology, The Scripps Research Institute
David Relman, Associate Professor of Medicine and of Microbiology and
Immunology, Stanford University
Raymond P. Roos, Marjorie and Robert E. Straus Professor in
Neurological Science, and Chairman, Department of Neurology,
University of Chicago Medical Center
David M. Taylor, SEDECON 2000 and retired Senior Scientist,
Neuropathogenesis Unit, Institute for Animal Health, Edinburgh
Reed B. Wickner, Chief, Laboratory of Biochemistry and Genetics,
National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health
Robert G. Will, Professor of Neurology, University of Edinburgh;
Director, National Creutzfel~t-Jakob Disease Surveillance Unit; and
Consultant Neurologist and Part-Time Senior Lecturer, Department
of Neurosciences, Western General Hospital, Edinburgh
v
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Consultants
Adriano Aguzzi, Professor and Associate Dean for Research, Department
of Pathology, Institute of Neuropathology, University Hospital at
Zurich
David M. Asher, Chief, Laboratory of Bacterial, Parasitic, and
Unconventional Agents, Division of Emerging and Transfusion
Transmitted Diseases, Office of Blood Research and Review, Center
for Biologics Research and Evaluation, Food and Drug
Administration
Pieriuigi Gambetti, Professor and Director, Division of Neuropathology,
Case Western Reserve University, and Director, National Prion
Disease Pathology Surveillance Center
David A. Harris, Professor, Department of Cell Biology and Physiology,
Washington University School of Medicine
Stanley B. Prusiner, Director, Institute for Neurodegenerative Diseases,
and Professor of Neurology, University of California, San Francisco
Elizabeth S. Williams, Professor, Department of Veterinary Science,
University of Wyoming
Project Staff
Rick Erdtmann, Study Director, Medical Follow-up Agency
Laura B. Sivitz, Research Associate, Medical Follow-up Agency
Reine Y. Homawoo, Senior Project Assistant, Medical Follow-up Agency
Karen Kazmerzak, Research Associate, Medical Follow-up Agency
(through December 2002)
Auxiliary Staff
Richard N. Miller, Director, Medical Follow-up Agency
Pamela Ramey-McCray, Administrative Assistant, Medical Follow-up
Agency
Andrea Cohen, Financial Associate
Mary Poos, Senior Program Officer, Food and Nutrition Board
Tina Rouse, Program Officer, Board on Agriculture and Natural
Resources, Division on Earth and Life Sciences
v'
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Reviewers
This report has been reviewed in draft form by individuals chosen for
their diverse perspectives and technical expertise, in accordance with
procedures approved by the NRC's Report Review Committee. The
purpose of this independent review is to provide candid and critical com-
ments that will assist the institution in making its published report as sound
as possible and to ensure that the report meets institutional standards for
objectivity, evidence, and responsiveness to the study charge. The review
comments and draft manuscript remain confidential to protect the integrity
of the deliberative process. We wish to thank the following individuals for
their review of this report:
Barbara Alving
Deputy Director
National Heart Lung and Blood Institute
National Institutes of Health
David C. Bolton
Head, Laboratory of Molecular Structure and Function
New York Institute for Basic Research
Bruce W. Chesebro
Chief, Laboratory of Persistent Viral Diseases
Rocky Mountain Laboratories
National Institutes of Health
v''
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~ . .
Vltt
REVIEWERS
Robert Finberg
Professor and Chair of Medicine
Professor of Molecular Genetics and Microbiology
University of Massachusetts
Colin Masters
Professor of Pathology
Center for Neuroscience
University of Melbourne
James Mastrianni
Assistant Professor of Neurology
Department of Neurology
The University of Chicago Hospitals
I. Glenn Morris
Chair and Professor
Department of Epidemiology and Preventive Medicine
University of Maryland
John E. VandeF~een
Emeritus Scientist
United States Food and Drug Administration
Gerald A. H. Weds
Consultant Veterinary Pathologist
Head of Neuropathology (Retired)
Central Veterinary Laboratory, United Kingdom
Charles B. Wilson
Senior Advisor
Health Technology Center, San Francisco
Although the reviewers listed above have provided many constructive
comments and suggestions, they were not asked to endorse the conclusions
or recommendations, nor did they see the final draft of the report before its
release. The review of this report was overseen by our coordinator, Morton
N. Swartz, Chief, lackson Firm of Medical Service, and Chief Emeritus,
Infectious Disease Unit, Massachusetts General Hospital; and our monitor,
Linda Cork, Professor and Chair of Comparative Medicine, Stanford Uni-
versity School of Medicine. Appointed by the National Research Council
and the Institute of Medicine, Drs. Swartz and Cork were responsible for
making certain that an independent examination of this report was carried
out in accordance with institutional procedures and that all review com-
ments were carefully considered. Responsibility for the final content of this
report rests entirely with the authoring committee and the institution.
OCR for page R9
Preface
Why is the U.S. government concerned about prion diseases?
Known scientifically by the descriptive term transmissible
spongiform encephalopathies (TSEs), these diseases do not cur-
rently represent significant public health problems in the United States.
While it brings incalculable grief to affected families, CreutzielUt-Takob dis-
ease (CJD), the primary human prion disease, causes only 1 in 10,000 an-
nual deaths worldwide, and there is no evidence that this rate is growing.
Bovine spongiform encephalopathy (BSE), the epidemic "mad cow" disease
in Europe, has yet to be detected in the United States.
Nevertheless, several compelling reasons exist for focusing greater re-
search efforts on prion diseases. First, the sudden appearance of BSE in the
United Kingdom in the mid-1980s represented a massive and unforesee-
able contamination of the bovine and human food supplies. Hundreds of
thousands of cattle died, and the infectious agent unexpectedly crossed the
species-barrier to humans. In the past decade, more than one hundred
young adults have developed a variant of CAD from exposure to BSE. The
social, political, and economic impacts of those epidemics of cattle and
human diseases in the United Kingdom and continental Europe have been
enormous. Consequently, a number of policies have been instituted to ex-
clude BSE from the United States and to limit its spread, should it enter the
country.
iED1TORS' NOTE: After this report was completed, the first U.S. case of BSE was identi
fled in Washington State and was announced to the public on December 23, 2003.
1X
OCR for page R10
x
PREFACE
In addition to concerns over the possible introduction of BSE into the
United States and the occurrence of cases of variant COD, the presence in
this country of a TSE of deer and elk, chronic wasting disease (CWD), has
caused alarm. Might this disease spread to cows or humans? There is no
evidence that it has, as yet, but European colleagues who have suffered
through the BSE crisis are astonished at the paucity of attention that the
United States has directed at CWD. They have told me, "You may be sitting
on a time-bomb."
The second rationale for expanding prion research in the United States
is that the studies may provide insights into the pathogenesis of common
neurodegenerative diseases, such as Alzheimer's, Parkinson's, and many
hereditary neurodegenerative diseases. This is because the abnormal pro-
cessing of altered neuronal proteins appears to be a feature of a variety of
brain diseases, including TSEs. Prions are believed to be abnormally folded
proteins that can replicate by converting normal prion protein into the al-
tered conformation associated with disease. This generally insoluble, patho-
genic isoform collects in the brain and spinal cord. Studies of the cellular
transport of altered proteins, such as priors, could have broad pathogenetic
. . .
Imps Cations.
All prion diseases have long incubation periods extending for years or
decades, cause progressive and uniformly fatal neurological degeneration
lasting for months, induce pathological changes limited to the nervous sys-
tem, and evoke no inflammation or immune response. The idea that a dis-
ease of this nature might be transmissible is revolutionary. Moreover, no
RNA or DNA has been implicated thus far in the process of prion replica-
tion a stunning affront to the central dogmas of biology. Unlocking the
secrets of TSEs could advance a new disease paradigm that would help
scientists develop treatments for a variety of neurological diseases that af-
flict millions of people.
The charge to the Committee on Transmissible Spongiform Encephalo-
pathies: Assessment of Relevant Science emphasized sensitive and specific
diagnostic methods. This emphasis stemmed from concerns about the safety
of blood and meat products and the wish to detect prion infections during
the incubation period of COD, BSE, or CWD. Diagnosis of infectious dis-
eases has traditionally relied on the sensitive surrogate marker of antibodies
formed by the host. As noted, however, priors, which are isoforms of a
normal host protein, usually do not evoke an antibody response. Newer,
highly sensitive tools to detect infectious agents in blood and spinal fluid
use polymerase chain reaction to amplify nucleic acids, but this method is
inapplicable to prion diseases because nucleic acid does not appear to be
involved.
Although tests are available to detect altered prion proteins in tissue
obtained at death or by biopsy, a blood or spinal fluid test is needed to
OCR for page R11
PREFACE
Xt
diagnose TSEs antemortem. Achieving the necessary level of acuity in such
a test will probably require an innovative technology, not simply incremen-
tal improvements to known methods of protein detection. More knowledge
about the structure of prions and their normal cellular counterparts, about
isoform conversion, the cellular trafficking of priors, pathogenesis, and
other basic aspects of TSEs will probably be prerequisite to devising a diag-
nostic method that increases sensitivity and specificity exponentially.
Another issue that the committee was asked to address, the infrastruc-
ture for TSE research in the United States, poses special problems. First, a
limited number of investigators and laboratories here are dedicated to study-
ing TSEs. Second, the usual investigator-initiated grants to universities or
research institutes are ill suited for supporting the quantization and charac-
terization of TSEs because this research generally involves animal hosts with
incubation periods of months or years. Initial grants usually require re-
newal and results after only 2 or 3 years, when many TSE studies are
still in a preliminary stage. Third, laboratories and animal-holding facilities
require varying degrees of complex and expensive biological containment
equipment. Fourth, few host institutions can afford to commit faculty posi-
tions and facility construction to TSE research. As a consequence of these
challenges, new funding methods or the further expansion of government
laboratories will be needed to meet the goal of increasing the number of
U.S. investigations into prion diseases.
In January 2003, our committee published an interim report that dealt
primarily with basic biomedical research on TSEs, diagnostics, research infra-
structure, and risks to the U.S. military. This final report has new chapters
and recommendations on testing blood for evidence of TSEs, on TSE sur-
veillance in the United States, and on strategies for TSE prevention and
treatment. This report also updates and expands upon the information from
the interim report. The broad array of topics discussed here will be of inter-
est not only to the scientific and medical communities, but also to a range of
readers who want to learn about the multidimensional impact of the bizarre,
fascinating, and deadly maladies collectively called prion diseases.
Richard T. Johnson, M.D.
Chair
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xvi ABBRE VIA TIONS AND A CR ONYMS
DHHS U.S. Department of Health and Human Services
DOD U.S. Department of Defense
DOI U.S. Department of the Interior
EC European Commission
EEG electroencephalography
ELISA enzyme-linked immunosorbent assay
EU European Union
FCS fluorescent correlation spectroscopy
FDA U.S. Food and Drug Administration
FFI fatal familial insomnia
FLAIR fluid attenuated inversion recovery
FSIS Food Safety and Inspection Service, U.S. Department of
Agriculture
GAO General Accounting Office
GPI glycosy! phosphatidylinosito!
GSS Gerstmann-Straussler-Scheinker disease
HFSP Human Frontier Science Program
HIV human immunodeficiency virus
i.c. intracerebral(ly)
iC}D iatrogenic Creutzfel~t-}akob disease
ID50 a dose that infects 50 percent of the population exposed to the
. , .
infectious agent
IGIV immune globulin to be given intravenously
IHC immunohistochemistry
IMAC immobilized metal ion affinity chromatography
IOM Institute of Medicine
i.p. intraperitoneal(ly)
IU infectious unit
i.v. intravenous(ly)
kilodalton~s)
LCGE laser-assisted capillary gap electrophoresis
LD50 a dose that is lethal to 50 percent of the population exposed to
an infectious agent
,ug micrograms
MRI magnetic resonance imaging
OCR for page R17
ABBREVIATIONS AND ACRONYMS
MRMC Medical Research and Materiel Command, U.S. Army
MUFS multispectral ultraviolet fluorescence spectroscopy
NaPTA sodium phosphotungstate
NASS National Agricultural Statistics Service, U.S. Department of
Agriculture
NIH
nm
NMR
NPDPSC National Prion Disease Pathology Surveillance Center
NPRP National Prion Research Program (DOD) and National Prion
Research Project (congressional language)
National Institutes of Health
nanometer
nuclear magnetic resonance
xv't
nvC}D new variant Creutzfel~t-}akob disease
NVSL National Veterinary Services Laboratories
PCR polymerase chain reaction
pg programs
PK proteinase K, an enzyme that digests cellular PrP
PMCA protein misfolding cyclic amplification
PRNP prion protein gene in humans
Prop prion protein gene in animals other than humans
PrP prion protein
prpc pro/ease-sensitive cellular prion protein
prpsc protein associated with prion disease; has limited resistance to
proteinase K
prpres pro/ease-resistant protein associated with prion disease
PrPCwD protein associated with chronic wasting disease
RIA radioimmunoassay
sC}D sporadic Creutzfel~t-}akob disease
sFI sporadic fatal insomnia
SRM specified risk material
TME transmissible mink encephalopathy
TSE transmissible spongiform encephalopathy
USDA U.S. Department of Agriculture
vCJD variant Creutzfel~t-Jakob disease
VMRD Veterinary Medical Research and Development Inc.
WHO WorId Health Organization
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~ . .
XVIII
FIGURES, TABLES, BOXES, AND PLATES
BOXES
1-1
3-1
3-2
3-3
3-4
5-1
5-2
6-1
6-2
6-3
7-1
7-2
2-1
2-2
4-1
7-1
Statement of Task, 32
Priority Research on the Structural Features of Protons, 58
Priority Research on Molecular Mechanisms of Prion Replication, 59
Priority Research on Mechanisms of TSE Pathogenesis, 61
Priority Research on the Physiological Function of PrPC, 63
Requirements for Testing Donors of Whole Blood and Blood Components,
108
Characteristics of New Blood-Donor Screening Tests Considered by the FDA
Center for Biologics Evaluation and Research (CBER), 109
Tests that NPDPSC Performs on Suspected TSE Deaths, ~ ~ 7
Goals and Action Items for Nationwide Surveillance of CW]D, 13 ~
Priority Research on the Epidemiology and Natural History of TSEs, 133
Actions Taken by Game Processors to Minimize Contact with the Infectious
Agent of CWD, 159
Therapeutic Strategies, 175
PLATES
Cartoon of the three dimensional structure of the intact human prion
protein, PrP (23-230), 43
Hypothetical models of PrP 27-30, the pro/ease-resistant segment of PrPSc
superimposed on an electron micrograph of a two-dimensional crystal of
PrP 27-30 after image processing, 44
The results of hematoxylin & eosin (H&E) staining and of
immunohistochemistry on slides of human brain tissue from a normal
brain, the brain of a patient with sCJD, and a patient with vCJD, 74
Effects of CpG on host immune cells, 179
OCR for page R19
Contents
EXECUTIVE SUMMARY
SUMMARY
Origins of This Study, 6
Prions and PrPSc: Definitions and Usage, 8
Basic Biomedical Research, 9
TSE Diagnostics, 10
Testing Blood for Evidence of TSEs, 13
Surveillance for TSEs in the United States, 14
Assessment of Strategies to Prevent and Treat TSEs, 17
Research Infrastructure, 22
The Risk of TSEs to the U.S. Military, 24
Conclusion, 25
References, 29
1 INTRODUCTION
Charge to the Committee, 35
Organization of the Report, 35
References, 38
2 PRION DISEASES: AN OVERVIEW
Origins and Development of Prion Science, 40
The Nature of Prions and Prion Protein, 43
The Epidemic of BSE and the Emergence of vCJD, 49
Global Impact of BSE and vC}D, 52
XtX
1
33
39
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xx
The Spread of Chronic Wasting Disease in the
United States, 53
Unique Challenges in Conducting TSE Research, 54
References, 55
3 BASIC BIOMEDICAL RESEARCH ON TRANSMISSIBLE
SPONGIFORM ENCEPHALOPATHIES
Structural Features of Prions, 61
Molecular Mechanisms of Prion Replication, 62
Mechanisms of TSE Pathogenesis, 63
Physiological Function of PrPC, 67
References, 68
4 DIAGNOSTICS FOR TRANSMISSIBLE SPONGIFORM
ENCEPHALOPATHIES
Clinical Diagnostics, 74
Current Laboratory Diagnostics, 79
Newer, Experimental Diagnostics for Laboratory Use, 89
Research Recommendations for TSE Diagnostics, 94
References, 101
CONTENTS
60
72
5 TESTING BLOOD FOR EVIDENCE OF THE AGENTS OF
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES 108
Animal Studies to Assess TSE Infectivity of Blood, 109
Risk of Human-to-Human Transmission of TSE Agents by
Transfusion and Transplant, 112
Blood Tests for TSE Agents, 114
References, 122
6 SURVEILLANCE FOR TRANSMISSIBLE SPONGIFORM
ENCEPHALOPATHIES IN THE UNITED STATES
U.S. Surveillance for Human TSEs, 126
U.S. Surveillance for TSEs in Animals, 137
Essential Research to Improve U.S. Capabilities to Conduct
Surveillance for TSEs, 150
References, 154
7 ASSESSMENT OF STRATEGIES TO PREVENT AND TREAT
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Measures to Prevent the BSE Agent from Entering the U.S.
Food Chain, 160
Measures to Prevent the CWD Agent from Entering the U.S.
Food Chain, 178
125
160
OCR for page R21
CONTENTS
Preventing TSE Transmission Through Blood, Blood Derivatives, and
Transplanted Tissues, 184
Inactivation of Prions on Surfaces and in the Environment, 188
Vaccination as a Preventive Strategy, 195
Progress in Therapy for TSEs, 196
References, 205
8 INFRASTRUCTURE FOR RESEARCH ON TRANSMISSIBLE
SPONGIFORM ENCEPHALOPATHIES
Present U.S. Infrastructure, 214
Need for Consistent, Science-Based Standards for Biological Safety
Levels in TSE Laboratories, 216
Need for Standardized Reagents and Materials, 217
Opportunities for International Collaboration, 220
References, 221
9 RISKS OF TRANSMISSIBLE SPONGIFORM
ENCEPHALOPATHIES TO THE U.S. MILITARY
Risk of Exposure to Beef Products Containing BSE Infectivity, 224
Risk of TSE Infection from Blood Products, 227
Summary of Overall Risk, 228
References, 229
APPENDIXES
xxt
214
223
A AGENDAS OF OPEN SESSIONS OF COMMITTEE MEETINGS 233
B BIOGRAPHICAL SKETCHES
GLOSSARY
243
250
OCR for page R22
Figures, Tables, Boxes, and Plates
FIGURES
2-1 Diagram of the primary structure of normal human prion protein
PrPC, 46
2-2 Mode! of PrPSc formation and deposition in a neuron infected with
the agent of TSE, 47
2-3 Confirmed cases of BSE by month and year of clinical onset, 50
2-4 The best-fit curve for the observed quarterly incidence of vC.ID
onsets in the United Kingdom through December 2002 is quadratic,
52
4-1
Electron micrograph of negatively stained fibrils composed of PrP
27-30 from scrapie-infected Syrian hamster brains, 81
6-1 The relative occurrence of sporadic, genetic, and iatrogenic forms of
human TSEs in the United States, 1997-2002, 127
Percent distribution of vCID cases in the United Kingdom anal sCID
cases in the United States by age group at death, 1995-2001, 128
Locations of 375 of 379 confirmed cases of scrapie reported to
USDA APHIS's Veterinary Services during the 2002 fiscal year, 139
Number of cattle brains tested for BSE per year in the United States,
143
North American locations where CW1) had been diagnosed as of
May 2003, 146
6-2
6-3
6-4
6-5
The 36.75 million U.S. cattle slaughtered in 2002, 169
. .
XXtt
OCR for page R23
FIGURES, TABLES, BOXES, AND PLATES
. . .
XXtt!
7-2 The path of the Canadian forward trace of rendered tissue from the
BSE-positive cow found in Alberta, 176
7-3 Commercial processing of cervid tissues in the United States, 181
7-4 Paths taken by hunter-harvested cervid tissues during processing in
the United States, 181
TABLES
S-1 Committee Recommendations by Functional Area and Priority for
the National Prion Research Program, 26
1-1 NPRP Award Mechanisms, 36
2-1 Classification of TSEs, 44
4-1 Clinical Differentiation of sC}D and vC}D, 75
4-2 Classification of Sporadic Prion Diseases, 76
4-3 Estimated Detection Limits of the First Three EC-Approved Post-
mortem Tests for BSE, 82
4-4 Results of Field Trial Evaluations of Two New Rapid Postmortem
Tests for BSE, 84
4-5 Diagnostic Tests for TSEs, 90
5-1 Studies of the Infectivity of Blood Components Transmitted Intrave-
nously, 110
Risk of Transmitting Human TSE Agents Through Blood, Trans-
planted Tissues, or Surgical Instruments, 113
5-3 The Predictive Value of a Positive Test Relative to the Prevalence of
a Disease in a Population, 117
6-1 Annual Referrals and Diagnoses of Human TSE Cases in the United
States, 1997-May 2003, 132
6-2 Actual and Expected Numbers of U.S. Cases of Human TSEs Con-
firmed in 2001 and 2002, 133
6-3 Comparison of National Surveillance and Epidemiology Programs
for Human TSEs in the United States with Those in the United
Kingdom and Canada, 136
7-1 Measures Taken by the United States to Prevent the Introduction,
Spread, and Consumption of the Infectious Agent of BSE, 164
7-2 Measures Taken in Response to Concern That TSE Agents May Be
Transmissible via Human Blood Products, 185
7-3 Agents Used to Deactivate Prions, 190
OCR for page R24
xxtv
FIGURES, TABLES, BOXES, AND PLATES
7-4 Drug Classes and Agents Used Experimentally to Treat TSEs, 199
9-1 DOD Active Duty Personnel and Dependents in Europe, 226
9-2 Comparison of Deferral Policies, 229
BOXES
1 -1
Statement of Task, 34
Priority Research on the Structural Features of Prions, 61
Priority Research on Molecular Mechanisms of Prion
Replication, 62
3-3 Priority Research on Mechanisms of TSE Pathogenesis, 64
3-4 Priority Research on the Physiological Function of PrPC, 67
5-1 Requirements for Testing Donors of Whole Blood and Blood
Components, 121
5-2 Characteristics of New Blood-Donor Screening Tests Considered by
the FDA Center for Biologics Evaluation and Research (CBER), 121
6-1 Tests That NPDPSC Performs on Suspected TSE Deaths, 129
6-2 Goals and Action Items for Nationwide Surveillance of CWD, 149
6-3 Priority Research on the Epidemiology and Natural History of
TSEs, 151
7-1
7-2
Actions Taken by Game Processors to Minimize Contact with the
Infectious Agent of CWD, 182
Therapeutic Strategies for TSEs, 198
COLOR PLATES
Depiction of the three-dimensional structure of the intact human
prion protein, PrP (23-230)
Hypothetical models of PrP 27-30, the pro/ease-resistant segment of
prpsc
4-1 The results of hematoxylin and eosin (HOE) staining and of immu-
nohistochemistry staining (IHC) of PrP are visible in microphoto-
graphs of human brain tissue from a normal brain, the brain of a
patient with sC}D, and the brain of a patient with vC}D
7-1 Effects of CpG on host immune cells
OCR for page R25
ADVANCING
PRION SCIENCE
OCR for page R26
XXVI
PrPC: Normal cellular prion protein digestible by proteinase K.
GLOSSARY
PrPCwD: Abnormally folded prion protein associated with a TSE called chronic wasting disease
(CEDE, which is kno~m to occur in elk, mule deer, and white-tailed deer. The disease's name
derives from the observation that infected animals at the clinical stage lose muscle mass and
appear wasted.
PrPreS: Abnormally foldeUprion protein that is highly resistant to proteinase K digestion and is
strongly associated with prion disease. It is sometimes used synonymously with PrPSC
.
PrPSc: Abnormally foldeUprion protein that has a gradient of resistance to proteinase K
digestion. It is associated with infectious potential and with prion disease even in circumstances
where it may be sensitive to proteinase K digestion.
PrPSen: Prion protein that is sensitive to proteinase K digestion. Sometimes used synonymously
with PrPC.
rational drug design: The development of a drug based on foreknowledge of the three-
dimensional structure and behavior of a specific molecule involved in a disease process. With this
knowledge, drug developers can target a specific binding site on the molecule to disrupt, enhance,
or redirect its normal activity, thus interrupting the disease process. By contrast, traditional drug
development typically begins with a range of potentially therapeutic chemical compounds that are
narrowed down to the best candidates through empirical observation of their effects. Applying
rational drug design to transmissible spongiform encephalopathies (TSEs) would begin with the
knowledge of differences between the tertiary structures of cellular prion protein (PrPC) and its
misfolded isoform (PrPsC) as well as the identification of one or more epitomes on these proteins.
Blocking or activating the epitope(~s) could potentially disrupt an essential step in TSE
pathogenesis, such as the conversion of prpc to PrPSc.
scrapie: A TSE of sheep and goats. The TSE was first described by Scottish veterinarians in the
1 700s, centuries before prions were first recognized. The modes of transmission are thought to be
contact with infected sheep or goats or their placentas, contact with a scrapie-contaminated
environment, or oral intake of scrapie agent-contaminated material. The "Sc" in the term PrPSC
refers to scrapie. PrPSc is used to refer to the abnormal isoform of prPc associated with TSEs.
species barrier: The genetic, metabolic, physiological, and physical differences among species
that result in variable susceptibility to an infectious agent.
--a -a
sporadic Creutzleldt-]akob disease (sCJD): The most common variety of CAD. The cause is
unknown. sCID appears to occur worldwide at a rate of approximately ~ case per ~ million
population. Most cases involve older adults.
transgene: A gene from one organism that has been transferred and integrated into the DNA of
another organism of the same or different species such that the transferred gene is expressed in
_ ~ ~ ~
.. . . . ~ .. . . .. . . . . . .. .
the host organism. Investigators conducting prion transmission studies use transgenes to convey
unnatural molecular characteristics to experimental animals so as to circumvent the species
barrier. For example, it is easier to transmit BSE to a transgenic mouse with a bovine transgene
