Sequence-Based Classification of Select Agents

A BRIGHTER LINE

Committee on Scientific Milestones for the Development of a Gene Sequence-Based Classification System for the Oversight of Select Agents

Board on Life Sciences

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

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Sequence-Based Classification of Select Agents A BRIGHTER LINE Committee on Scientific Milestones for the Development of a Gene Sequence-Based Classification System for the Oversight of Select Agents Board on Life Sciences Division on Earth and Life Studies

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street NW 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. This study was supported by Contract No. NO1-OD-4-2139 (Task Order #216) between the National Academy of Sciences and the National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the National Insti - tutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. International Standard Book Number-13: 978-0-309-15904-3 International Standard Book Number-10: 0-309-15904-0 Additional copies of this report are available from the National Academies Press, 500 Fifth Street NW, Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334- 3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. Copyright 2010 by the National Academies. All rights reserved. Printed in the United States of America.

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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. Ralph J. Cicerone 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. Charles M. Vest 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 examina - tion 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 Na - tional 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. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON SCIENTIFIC MILESTONES FOR THE DEVELOPMENT OF A GENE SEQUENCE-BASED CLASSIFICATION SYSTEM FOR THE OVERSIGHT OF SELECT AGENTS JAMES W. LEDUC (Chair), Professor, Microbiology and Immunology; Chair, Global Health; and Director, Galveston National Laboratory, The University of Texas Medical Branch at Galveston RALPH BARIC, Associate Research Professor, Microbiology and Immunology, University of North Carolina at Chapel Hill School of Public Health ROGER G. BREEZE, Chief Executive Officer, Centaur Science Group R. MARK BULLER, Professor, Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine SEAN R. EDDY, Group Leader, Janelia Farm, Howard Hughes Medical Institute STANLEY FALKOW, Robert W. and Vivian K. Cahill Professor, Microbiology and Immunology; Geographic Medicine; and Infectious Diseases, Stanford University School of Medicine RACHEL E. LEVINSON, Director, National Research Initiatives, Office of the Vice President for Research and Economic Affairs, Arizona State University JOHN MULLIGAN, Chairman and Chief Scientific Officer, Blue Heron Biotechnology ALISON D. O’BRIEN, Professor and Chair, Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences FRANCISCO OCHOA-CORONA, Assistant Professor, National Institute for Microbial Forensics & Food and Agricultural Biosecurity (NIMFFAB), Department of Entomology and Plant Pathology, Oklahoma State University JANE S. RICHARDSON, James B. Duke Professor, Department of Biochemistry, Duke University Medical Center MARGARET RILEY, Professor of Biology, Department of Biology, University of Massachusetts TOM SLEZAK, Program Leader, Global Security Program, Lawrence Livermore National Laboratory Staff INDIA HOOK-BARNARD, Study Director and Program Officer CARL-GUSTAV ANDERSON, Senior Program Assistant 

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BOARD ON LIFE SCIENCES KEITH YAMAMOTO (Chair), University of California, San Francisco, CA ANN M. ARVIN, Stanford University School of Medicine, Stanford, CA BONNIE L. BASSLER, Princeton University, Princeton, NJ VICKI L. CHANDLER, Gordon and Betty Moore Foundation, Palo Alto, CA SEAN R. EDDY, Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, VA MARK D. FITZSIMMONS, John D. and Catherine T. MacArthur Foundation, Chicago, IL DAVID R. FRANZ, Midwest Research Institute, Frederick, MD LOUIS J. GROSS, University of Tennessee, Knoxville, TN JO HANDELSMAN, University of Wisconsin, Madison, WI CATO T. LAURENCIN, University of Connecticut Health Center, Farmington, CT JONATHAN D. MORENO, University of Pennsylvania, Philadelphia, PA ROBERT M. NEREM, Georgia Institute of Technology, Atlanta, GA CAMILLE PARMESAN, University of Texas, Austin, TX MURIEL E. POSTON, Skidmore College, Saratoga Springs, NY ALISON G. POWER, Cornell University, Ithaca, NY BRUCE W. STILLMAN, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY CYNTHIA WOLBERGER, Johns Hopkins University School of Medicine, Baltimore, MD MARY WOOLLEY, Research!America, Alexandria, VA Staff FRANCES E. SHARPLES, Director JO L. HUSBANDS, Scholar, Senior Project Director KATHERINE BOWMAN, Senior Program Officer ADAM P. FAGEN, Senior Program Officer MARILEE K. SHELTON-DAVENPORT, Senior Program Officer INDIA HOOK-BARNARD, Program Officer ANNA FARRAR, Financial Associate CARL-GUSTAV ANDERSON, Senior Program Assistant AMANDA P. CLINE, Senior Program Assistant AMANDA L. MAZZAWI, Senior Program Assistant i

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Preface Recent studies by the National Research Council have focused on the tension between the rapid advances in biotechnology that clearly benefit hu - mankind and the potential use of the same advances for nefarious purposes. The 2004 report, Biotechnology Research in an Age of Terrorism helped to focus attention on the issue, and among other recommendations called for the creation of a National Science Advisory Board for Biodefense (NSABB) to serve as a bridge between the government and scientific communities in raising awareness of the potential for misuse of biotechnology. A later report, Global- ization, Biosecurity, and the Future of the Life Sciences carried the discussion forward with a global perspective and promoted a global common culture of awareness and a shared sense of responsibility among life scientists. In 2006, the NSABB issued Addressing Biosecurity Concerns Related to the Synthesis of Select Agents, which called for expert evaluation to determine whether an alternative framework based on predicted features and properties encoded by nucleic acids, such as virulence or pathogenicity, can be developed and used in lieu of the current finite list of specific agents and taxonomic definitions. Our committee was tasked with identifying “the scientific advances that would be necessary to permit serious consideration of developing and implementing an oversight system for Select Agents that is based on predicted features and properties encoded by nucleic acids rather than a relatively static list of specific agents and taxonomic definitions.” Our committee was populated with persons who had expertise in several complementary fields. The amalgamation of scientific backgrounds allowed us to address our task from different viewpoints and to assess the potential impact of our recommendations on various sectors. We benefited by having commit- tee members who were experts in human and animal health and leaders in the ii

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iii PREFACE development of policy relevant to these fields; leaders in fundamental struc - tural, evolutionary, and computational biology and bioinformatics; scientists dedicated to the study of pathogenic viruses and bacteria; and experts from the commercial biotechnology sector. Many committee members were personally involved either directly or indirectly in research on plant or animal pathogens designated as Select Agents and thus had first-hand experience in dealing with the relevant regulations and security requirements implemented in recent years to reduce the risk of misuse. We were especially fortunate to have a senior scien- tist and executive in the biotechnology industry who was able to offer a unique perspective on the role of industry in implementation of current and future steps that might be taken to reduce the risk of misuse of synthetic biology. We were informed by the shared expertise of many professionals in syn - thetic biology, security, public health, human and animal medicine, the life sciences, informatics and several other relevant fields as we grappled with our challenging task. Specifically, Julia Kiehlbauch, Robbin Weyant, Claudia Mickelson, Edward You, and Amy Patterson helped us to understand the current structure for oversight of Select Agents. Peter Pesenti, John Mulligan, Marcus Graf, Claes Gustafsson and Stephen Maurer discussed with us the current mechanisms and criteria for screening and surveillance at the sequence level. Stanley Falkow, Jeffrey Taubenberger, Michael Katze, Ralph Baric and Ramon Felciano discussed virulence; and Sean Eddy, Jonathan Eisen, Elliot Lefkowitz, John Moult and Ian Lipkin addressed gaps, challenges and potential milestones in predicting pathogenicity from sequence information. In addition, Carol Linden, Arturo Casadevall, David Relman, Mary Groesch, Jacqueline Corrigan-Curay and James Blaine all met personally with our committee and joined in our discussions. We sincerely thank all those who took time from their busy schedules to meet with us, answer our questions, and guide us in our deliberations. Early in our discussions, it became apparent that the criteria historically used to designate a pathogen as a Select Agent included characteristics that can - not be determined by sequence alone and therefore cannot be predicted with the degree of certainty required for regulatory purposes. We soon concluded that a sequence-based prediction system for oversight of Select Agents is not now possible, nor is it likely to be feasible in the foreseeable future. We did, however, recognize that a sequence-based classification system for Select Agents focused on consideration of sequences of concern could be developed and might help to clarify taxonomic distinctions among recognized Select Agents. By focusing on “sequences of concern” and coupling that with a cautionary alert (a “yellow flag system”), one might effectively address both biosecurity and biosafety goals. Near-term milestone and long-term research objectives were defined and are discussed in our report. Throughout our deliberations, we continually tried to balance the need for safety and security, while recogniz - ing the challenges of potential dual-use applications that arise as the scientific

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ix PREFACE community improves its understanding of the genomic basis that leads one organism to be pathogenic, while its near neighbor is not. We were also con - cerned about the potential burden that such an oversight program might have on the day-to-day conduct of science and the biotechnology business sector, and about the opportunities that might be missed. We concluded that a gene sequence-based classification system could be developed. We did not, however, address whether such as system should be developed or whether the additional administrative structure needed to maintain such a system would be justified. Therefore, we do not specifically recommend that either the classification or yellow flag system be implemented. Rather, we provide information about what is technologically feasible, and emphasize that the potential benefits of such a system should be considered and weighed against the cost and complexity of implementation. The Nobel laureate Joshua Lederberg was quoted in Richard Preston’s 1998 article on bioweaponeers in The New Yorker as saying: “There is no technical solution to the problem of biological weapons. It needs an ethical, human, and moral solution if it’s going to happen at all. Don’t ask me what the odds are for an ethical solution, but there is no other solution. But would an ethical solution appeal to a sociopath? (Preston 1998)” We find ourselves today, more than a decade later, still searching for a technical solution to a challenge that has grown beyond biological warfare and now encompasses the threat of bioterrorism as well; a challenge that is ever more complex and threatening as biotechnology advances and access to it expands. We can attempt to harness technology to lessen risks, but we would be wise to heed Lederberg’s advice to couple this with efforts toward an “ethical, human and moral solution.” The committee wishes to express its sincere thanks and appreciation to India Hook-Barnard, our study director and program officer, for her leadership, guidance and expertise, coupled with good nature and charming personality. We benefited greatly from her dedication and creativity throughout the study. She was ably assisted by Carl-Gustav Anderson, senior program assistant, who ensured that our every need was met during our meetings and conference calls and worked diligently to coordinate schedules in what must have been a nearly impossible task. Our project was expertly guided by Fran Sharples as the direc- tor of the Board on Life Sciences. Finally, on a personal note, I would like to express my sincere apprecia - tion to the members of the committee, who generously donated their time and knowledge to make this project both extremely productive and very enjoyable. Our discussions were frank, open, and honest, and they benefited greatly from the diversity of our backgrounds and our complementary experiences. We were indeed more than the sum of our own individual contributions. It has been my pleasure and privilege to work with each of you. James W. Le Duc, Chair

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Acknowledgments 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 National Research Council’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 pos - sible and to ensure that the report meets institutional standards of 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 thank the following individuals for their review of this report: Ken Berns, Florida College of Medicine Arturo Casadevall, Yeshia Uniersity Rocco Casagrande, Gryphon Scientific David Eisenberg, Uniersity of California, Los Angeles Tanja Kortemme, Uniersity of California, San Francisco Gigi Kwik-Gronvall, Uniersity of Pittsburgh Henry Metzger, National Institutes of Health Claudia Mickelson, Massachusetts Institute of Technology Stephen Ostroff, Pennsylania Department of Health Julian Parkhill, The Sanger Institute Harvey Rubin, Uniersity of Pennsylania Janet Shoemaker, American Society for Microbiology Frederick Sparling, Uniersity of North Carolina Although the reviewers listed above have provided many constructive com- ments and suggestions, they were not asked to endorse the conclusions or rec - xi

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xii ACKNOWLEDGMENTS ommendations, nor did they see the final draft of the report before its release. The review of the report was overseen by Ronald Atlas, Uniersity of Louisille and Adel Mahmoud, Princeton Uniersity. Appointed by the National Research Council, they were responsible for making certain that an independent exami - nation 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 the report rests entirely with the authoring committee and the institution. We thank Dr. Louise Teel and Dr. Christy Ventura of the O’Brien lab; Ali - sha Prather of Galveston National Lab; and Dr. Jeremy Block of the Richardson lab, for thoughtful suggestions and contributions to the Appendices. We are grateful to those who attended and participated in the September 3, 2009, Workshop (Appendix D) and those who met with the committee during the course of this study. These individuals, named in the preface, were generous with their time, expertise, and ideas, and were helpful to the committee’s work.

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Contents SUMMARY 1 1 THE SELECT AGENT REGULATIONS 9 Charge to the Committee, 9 Organization of the Report, 11 Context of the Select Agent Regulations, 11 Biological Weapons, 13 Biosafety (and Categorization of Microorganisms), 14 Biosecurity and the Select Agent Regulations, 18 Current Status of the Select Agent Program, 21 The Select Agent Program—Beyond Biosafety, 21 The Select Agent Regulations—Focus on Known Biothreat Agents, 23 Unclear Boundaries, 25 Gene Synthesis Industry, 26 Impact of Select Agent Regulations on Research, 28 Criteria for Select Agent Designation, 30 Non-Biological Criteria, 33 Biological Criteria, 35 2 CHALLENGES OF PREDICTING PATHOGENICITY FROM SEQUENCE 37 Introduction, 37 The Art of Sequence-Based Prediction, 38 Predicting Biological Function from Sequence, 40 Protein Structure Prediction, 42 Gene Regulation, 45 xiii

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xi CONTENTS The Nature of Infectious Disease and the Art of Predicting Pathogenicity, 47 What Is the Origin of Bacterial Pathogenicity? What Makes a Pathogen?, 50 The Evolution of Bacterial Host Specificity, 55 The Parallels in the Evolution of Pathogenicity in the Large Viruses, 57 Evolution of Plant Pathogens in Human-Managed Ecosystems, 59 Interactions of Infectious Agents with the Host, 60 The Special Case of Synthetic Biology, 63 Top-Down Approach, 65 Bottom-Up Approach, 68 Synthetic Biology—Summary, 69 What Can Currently Be Predicted from Sequence about the Identification of Pathogenic Microorganisms, Including Select Agents?, 69 3 A PROPOSAL FOR CONSIDERATION: SEQUENCE-BASED CLASSIFICATION OF SELECT AGENTS 73 Novel Agents: Synthetic Genomics and the Select Agent Regulations, 75 Classification Is Distinct from Prediction, 81 Synthetic Genome Classification under the Current Select Agent Regulations, 85 Classification Depends on Both Gene Content and Genetic Distance, 88 Using “Parts Lists” to Define Gene Content, 88 Sequence Analysis of Individual “Parts,” 90 Methods for Sequence Subfamily Classification, 93 Outline of a Possible System for Profile-Based Classification of Select Agents, 96 Considerations for Implementation of a Profile-Based Classification System, 99 Role of Prediction and Classification in Biosafety, 101 Raising a Yellow Flag for “Sequences of Concern,” 102 Should Such a System Be Built?, 104 4 COMMITTEE FINDINGS AND CONCLUSIONS 107 Findings and Conclusions, 107 The Yellow Flag System, 117 Near-Term Milestones for Sequence-Based Classification, 118 Long-Term Milestones for Genome Sequence-Based Select Agent Regulations, 121 Conclusion, 126

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x CONTENTS REFERENCES 129 APPENDIXES A Statement of Task 135 B Committee and Staff Biographies 137 C HHS and USDA Select Agents and Toxins 145 D 2009 Workshop Agenda 147 E Applicability of the Select Agent Regulations to Issues of Synthetic Genomics 151 F Summary of Relevant Legislation, Regulation, and Guidance 157 G Influenza A and SARS-CoV 161 H Virus-Host Interactions 163 I Botulinum Neurotoxin, B. anthracis, and Variola Virus 165 J Pathogenicity Acquisition 181 K Interactions of Infectious Agents with the Host 193 L Near-Term Milestones for Consideration 207 M Executive Order: Optimizing the Security of biological Select Agents and Toxins in the United States 215

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