Advancing Prion Science

Guidance for the National Prion Research Program

Interim Report

Rick Erdtmann and Laura Sivitz, Editors

Committee on Transmissible Spongiform Encephalopathies: Assessment of Relevant Science

Medical Follow-Up Agency

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C. www.nap.edu



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Advancing Prion Science Guidance for the National Prion Research Program Interim Report Rick Erdtmann and Laura Sivitz, Editors Committee on Transmissible Spongiform Encephalopathies: Assessment of Relevant Science Medical Follow-Up Agency INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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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 Institute 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. International Standard Book Number 0-309-08744-9 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC20055; (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 2003 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. THE 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 hemotoxylin (blue), the magnified tissue manifests microscopic holes (white circles). This report aims to guide scientists beyond histopathology toward new strategies to diagnose prion diseases non-invasively, rapidly, and early.

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"Knowing is not enough; we must apply. Willing 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 Science, 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 Academy 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 engineers. 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 engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A.Wulf is president 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 congressional 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 Council 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.national-academies.org

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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 Harvey J.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 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 Creutzfeldt-Jakob Disease Surveillance Unit; and Consultant Neurologist and Part-Time Senior Lecturer, Department of Neurosciences, Western General Hospital, Edinburgh

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Consultants Adriano Aguzzi, Professor and Associate Dean for Research, Department of Pathology, Institute of Neuropathology, 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 Pierluigi 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, Project Assistant, Medical Follow-up Agency Karen Kazmerzak, Research Associate, Medical Follow-up Agency 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

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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 comments 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: Susan L.Lindquist, Professor of Biology, Massachusetts Institute of Technology, and Director, Whitehead Institute for Biomedical Research Eugene O.Major, Senior Investigator, Molecular Medicine and Virology Section, Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health Janice M.Miller, Veterinary Medical Officer, National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture Neal Nathanson, Vice Provost for Research, University of Pennsylvania

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Kenrad Nelson, Professor, Department of Medicine, Johns Hopkins School of Medicine, and Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health 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 Morton N.Swartz, Chief, Jackson Firm of Medical Service, Department of Medicine, and Chief Emeritus, Division of Infectious Diseases, Massachusetts General Hospital. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Preface This is the interim report of the Institute of Medicine's (IOM's) Committee on Transmissible Spongiform Encephalopathies: Assessment of Relevant Science, convened to provide advice to the U.S. Department of Defense (DOD) pertaining to the newly established National Prion Research Project (NPRP). Congressional leaders saw the health and economic catastrophes caused by prion diseases elsewhere on the globe and preemptively established a new research effort that would accelerate our national capability to prevent or ameliorate prion diseases. The U.S. Congress asked DOD to administer the program. DOD, in turn, asked IOM to assist it by assembling a group of experts to assess the state of prion science and recommend the areas in which prion disease research was most needed. We can take great pride in the marvelous accomplishments achieved over the past century through the application of scientific knowledge and technology in combating diseases in humans and animals. Vaccines, improved diets, environmental engineering, and antibiotics, among other techniques and chemoprophylactic agents, have greatly reduced the rates of premature morbidity and mortality. Despite these major achievements, significant new health threats continue to emerge not only in the less developed nations but in technically advanced societies as well. A perfect example is the topic of this report: prion disease. Prions are believed to be abnormally folded proteins that can replicate by converting adjacent normal prion proteins into the altered conformation associated with disease. This

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transformation occurs in the absence of any currently detectable RNA or DNA. Every known animal and human variety of prion disease is transmissible and uniformly fatal. A prion disease of sheep called scrapie has been clinically recognized for centuries, but a new variety that recently emerged in cows in the United Kingdom has spread to continental Europe and beyond. This bovine spongiform encephalopathy (BSE) resulted in a massive outbreak in the late 1980s and mid-1990s, infecting hundreds of thousands of cattle and causing billions of dollars in economic damage. The catastrophe was further exacerbated in the mid-1990s when it became apparent that human consumption of BSE-tainted food crossed the species barrier, creating a new form of disease in humans called variant Creutzfeldt-Jakob disease (vCJD). Because of the potentially long incubation period of vCJD, the extended period of human exposure to BSE in the United Kingdom, and the absence of information on the infectious dose of BSE for humans, it is not possible to accurately predict an epidemic curve for vCJD. The upper predictions of the numbers of people affected are in the tens of thousands. This has driven an intense effort to ensure that good surveillance systems are in place for animals and humans. Surveillance, in turn, requires that good tests be available to detect the causative agent and to diagnose new cases. This is the launching point of the interim report. At present, our ability to accurately detect the putative agents that cause prion diseases is limited. In the United States, the Food and Drug Administration has not approved for use a single test that can be used to screen for the abnormal prion protein in people, although the U.S. Department of Agriculture has approved the use of a single test, from Bio-Rad Laboratories, for testing of animals. Moreover, because no validated test that can detect the abnormal prion protein in living human tissues, including blood, is available, persons who have possibly been exposed to BSE are deferred from donating blood on the basis of a theoretical risk. Tests for the detection of prions are commercially available for postmortem testing of animals in Europe, and one for the detection of chronic wasting disease in mule deer has recently been licensed for use in the United States. In addition, we have in the United States postmortem and experimental antemortem tests for the detection of prions in people and animals. The progress in developing accurate, inexpensive, and sensitive diagnostics, however, has been slow and fraught with technical challenges in need of novel research strategies. A great amount of effort and funding, particularly in Europe, but also in

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the United States, has resulted in incremental improvements. Following old patterns of progress may replicate old patterns of disappointment, however. We need strategies to leverage both new technology and new fundamental knowledge. This IOM report is intended to suggest such strategies. This interim report focuses heavily, although not exclusively, on the research needed to improve diagnostics for prion diseases. The research recommended in this interim report was carefully timed to support the programmatic review by a DOD panel of experts who will determine which of the research proposals submitted most strongly supports DOD's prion research program. This interim report briefly touches upon prion research infrastructure issues and unique risks from transmissible spongiform encephalopathies to the military. These areas and others, as noted in the committee's task statement, will be developed in even greater depth in the final report. Richard T.Johnson, M.D. Chair

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Acknowledgments The Committee on Transmissible Spongiform Encephalopathies thanks the many people who contributed to this interim report. We first thank the report's sponsor, the Medical Research and Materiel Command of the U.S. Department of Defense, for requesting advice from the Institute of Medicine regarding the National Prion Research Program. We specifically convey our thanks to COL Ken Bertram, Director of the Congressionally Directed Medical Research Program; to LTC Calvin Carpenter, our point of contact for this study; to COL Scott Severin, Deputy Director of the DOD Veterinary Service Activity; to CDR Rebecca Sparks, Deputy Director of the Armed Services Blood Program; and to LTC Ruth Sylvester, Operations Director for the Armed Services Blood Program. We greatly appreciate the expert technical advice that our six standing consultants have provided throughout the study. Their willingness to travel long distances to committee meetings without remuneration reflects their professionalism and their dedication to advancing prion science. In addition, one of the consultants, Dr. David Asher, kindly provided the photograph on the cover of this report: a histopathology slide of brain tissue from a patient with spongiform encephalopathy. We also extend our appreciation to the many invited guests who attended our meetings to share their expertise through both formal presentations and participation in committee discussions. They

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provided a significant body of information for us to draw upon as we formulated the recommendations in this report. In addition, we thank our chair, Dr. Richard Johnson, for planning meetings with the study staff and for his effective guidance and direction. The IOM's Office of Reports and Communication deserves special thanks for its assistance to the study staff. This report would not have come together as it did without Bronwyn Schrecker's help navigating the review process, Jennifer Bitticks' guidance on report production, and Michael Hayes' exceptionally detailed and thoughtful copyediting. Finally, we thank our dedicated staff at the IOM. TSE Study Director Rick Erdtmann, Research Associate Laura Sivitz, and Project Assistant Reine Homawoo have done an outstanding job planning the committee meetings, providing us with background literature, keeping the study on track, and editing this report. Their efforts were particularly impressive because this is the first IOM study they have facilitated.

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Contents     EXECUTIVE SUMMARY   1 1   INTRODUCTION   17 2   PRION DISEASES AND THEIR CHALLENGES   23     Origins and Development of Prion Science,   23     The Nature of Prions and Prion Diseases,   26     The Epidemic of Bovine Spongiform Encephalopathy and the Emergence of Variant Creutzfeldt-Jakob Disease,   30     The Spread of Chronic Wasting Disease in the United States,   33     References,   35 3   DIAGNOSTICS FOR TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES   41     Clinical Diagnostics,   43     Current TSE Diagnostic Laboratory Methods,   49     Newer Laboratory Diagnostic Tests,   53     References,   58

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4   RESEARCH RECOMMENDATIONS FOR TSE DIAGNOSTICS   63     Leverage New Technology,   63     New Reagents and Detection Methods,   64     Surrogate Markers and Signatures of Prion Disease,   67     Cell Culture Systems,   69     Clinical Neuroimaging,   69     Priorities for Basic Research,   71     References,   78 5   PRION RESEARCH INFRASTRUCTURE   83     The Present U.S. Infrastructure,   83     International Collaboration,   85     Standardized Reagents and Materials,   85     References,   88 6   RISKS TO THE U.S. MILITARY   89     Risk of Exposure to BSE-Tainted Beef Products,   90     Risk of TSE Infection from Blood Products,   93     Summary of Overall Risk,   97     References,   97     APPENDIX: STUDY METHODS   99

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Figures, Tables, and Boxes FIGURES 2-1   Confirmed Cases of BSE by Month and Year of Clinical Onset,   31 TABLES ES-1   Committee Recommendations,   13-14 1-1   NPRP Award Mechanisms,   20-21 2-1   Classification of TSEs,   27-28 3-1   Clinical Differentiation of sCJD and vCJD,   44 3-2   Classification of Sporadic Prion Diseases,   46 3-3   Estimated Detection Limits of EC-Approved Postmortem Tests for BSE,   50 3-4   Diagnostic Tests for TSEs,   54-55 6-1   DOD Active Duty Personnel and Dependents in Europe,   93 6-2   Comparison of Deferral Policies,   95 BOXES 1-1   Statement of Task,   18 4-1   Priority Research on the Structural Features of Prions,   72 4-2   Priority Research on Molecular Mechanisms of Prion Replication,   74

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4-3   Priority Research on Mechanisms of TSE Pathogenesis,   75 4-4   Priority Research on Epidemiology and Natural History of TSEs,   77 4-5   Priority Research on the Physiological Function of PrPC,   78

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Abbreviations and Acronyms AAFES Army and Air Force Exchange Service ASBP Armed Services Blood Program BSE bovine spongiform encephalopathy CDMRP Congressionally Directed Medical Research Program CJD Creutzfeldt-Jakob disease CNS central nervous system CSF cerebrospinal fluid CT computed tomography CWD chronic wasting disease DOD U.S. Department of Defense EEG electroencephalography ELISA enzyme-linked immunosorbent assay FCS fluorescent correlation spectroscopy FDA Food and Drug Administration FLAIR fluid attenuated inversion recovery GAO General Accounting Office ID50 a dose that infects 50 percent of the population exposed to the infectious agent IHC immunohistochemistry IOM Institute of Medicine IU infectious unit kDa kilodaltons LCGE laser-assisted capillary gap electrophoresis MRI magnetic resonance imaging

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MRMC Medical Research and Materiel Command, U.S. Army MUFS multispectral ultraviolet fluorescence spectroscopy NaPTA sodium phosphotungstate NIH National Institutes of Health NMR nuclear magnetic resonance NPRP National Prion Research Program (DOD) and National Prion Research Project (congressional language) nvCJD new-variant Creutzfeldt-Jakob disease PCR polymerase chain reaction PK proteinase K, an enzyme that digests cellular PrP PRNP prion protein gene in humans Prnp prion protein gene in mice PrP prion protein PrPC protease-sensitive cellular protein PrPres protease-resistant protein associated with prion disease PrPSc protease-resistant protein associated with prion disease RIA radioimmunoassay sCJD sporadic Creutzfeldt-Jakob disease TSE transmissible spongiform encephalopathy USAMRMC U.S. Army Medical Research and Materiel Command vCJD variant Creutzfeldt-Jakob disease WHO World Health Organization