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THE SCIENCE AND APPLICATIONS OF SYNTHETIC AND SYSTEMS BIOLOGY Workshop Summary Eileen R. Choffnes, David A. Relman, and Leslie Pray, Rapporteurs Forum on Microbial Threats Board on Global Health

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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. Financial support for this project was provided by the U.S. Department of Health and Hu - man Services: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Centers for Disease Control and Prevention, Food and Drug Administration, and the Fogarty International Center; U.S. Department of Defense, Department of the Army: Global Emerging Infections Surveillance and Response System, Medical Research and Materiel Command, and the Defense Threat Reduction Agency; U.S. Department of Veterans Affairs; U.S. Department of Homeland Security; U.S. Agency for International Development; American Society for Microbiology; sanofi pasteur; Burroughs Wellcome Fund; Pfizer, Inc.; GlaxoSmithKline; Infectious Diseases Society of America; and the Merck Company Foundation. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-21939-6 International Standard Book Number-10: 0-309-21939-6 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 2011 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Cover images: (Upper): Adapted from Mayr, E. 2004. De la bacteria la om—Evolutia lumii vii. Bucharest, Romania:Humanitas; (Lower): GloFish® fluorescent fish. Genetically modified Danio rerio. Photo courtesy of www.glofish.com. 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. Suggested citation: IOM (Institute of Medicine). 2011. The Science and Applications of Synthetic and Systems Biology. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.

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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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FORUM ON MICROBIAL THREATS1 DAVID A. RELMAN (Chair), Stanford University and Veterans Affairs Palo Alto Health Care System, Palo Alto, California JAMES M. HUGHES (Vice-Chair), Global Infectious Diseases Program, Emory University, Atlanta, Georgia LONNIE J. KING (Vice-Chair), Ohio State University, Columbus, Ohio KEVIN ANDERSON, Biological and Chemical Defense Division, Science and Technology Directorate, Department of Homeland Security, Washington, DC RUTH L. BERKELMAN, Center for Public Health Preparedness and Research, Rollins School of Public Health, Emory University, Atlanta, Georgia DAVID BLAZES,2 Armed Forces Health Surveillance Center, Division of Global Emerging Infectious Surveillance, Silver Spring, Maryland ENRIQUETA C. BOND, Burroughs Wellcome Fund (Emeritus), Marshall, Virginia ROGER G. BREEZE, Lawrence Livermore National Laboratory, Livermore, California PAULA R. BRYANT, Defense Threat Reduction Agency, Medical S&T Division, Fort Belvoir, Virginia JOHN E. BURRIS, Burroughs Wellcome Fund, Research Triangle Park, North Carolina ARTURO CASADEVALL,2 Albert Einstein College of Medicine, Bronx, New York PETER DASZAK, EcoHealth Alliance, New York, New York JEFFREY S. DUCHIN, Public Health–Seattle and King County, Seattle, Washington JONATHAN EISEN, Genome Center, University of California, Davis, California RALPH L. ERICKSON,2 Walter Reed Army Institute of Research, Silver Spring, Maryland MARK B. FEINBERG, Merck Vaccine Division, Merck & Co., West Point, Pennsylvania JACQUELINE FLETCHER, Oklahoma State University, Stillwater, Oklahoma JESSE L. GOODMAN, Food and Drug Administration, Silver Spring, Maryland EDUARDO GOTUZZO, Instituto de Medicina Tropical–Alexander von Humbolt, Universidad Peruana Cayetano Heredia, Lima, Peru 1 Institute of Medicine Forums and Roundtables do not issue, review, or approve individual docu - ments. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. 2 Forum member since September 1, 2011. v

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CAROLE A. HEILMAN, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland DAVID L. HEYMANN, Health Protection Agency, London, United Kingdom ZHI HONG,3 GlaxoSmithKline, Research Triangle Park, North Carolina PHILIP HOSBACH, sanofi pasteur, Swiftwater, Pennsylvania STEPHEN ALBERT JOHNSTON, Arizona BioDesign Institute, Arizona State University, Tempe, Arizona KENT KESTER,4 Walter Reed Army Institute of Research, Silver Spring, Maryland GERALD T. KEUSCH, Boston University School of Medicine and Boston University School of Public Health, Boston, Massachusetts RIMA F. KHABBAZ, Centers for Disease Control and Prevention, Atlanta, Georgia STANLEY M. LEMON, School of Medicine, University of North Carolina, Chapel Hill EDWARD McSWEEGAN, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland MARK A. MILLER, National Institutes of Health, Fogarty International Center, Bethesda, Maryland PAUL F. MILLER,5 Pfizer, Inc., Groton, Connecticut GEORGE POSTE, Complex Adaptive Systems Initiative, Arizona State University, Tempe, Arizona JOHN C. POTTAGE, JR.,6 ViiV Healthcare, Collegeville, Pennsylvania DAVID RIZZO,7 Department of Plant Pathology, University of California, Davis, California GARY A. ROSELLE, Veterans Health Administration, Department of Veterans Affairs, Cincinnati, Ohio ALAN S. RUDOLPH, Defense Threat Reduction Agency, Fort Belvoir, Virginia KEVIN RUSSELL, Armed Forces Health Surveillance Center, Department of Defense, Silver Spring, Maryland JANET SHOEMAKER, American Society for Microbiology, Washington, DC P. FREDERICK SPARLING, University of North Carolina, Chapel Hill, North Carolina TERENCE TAYLOR, International Council for the Life Sciences, Arlington, Virginia 3 Forum member since November 1, 2011. 4 Forum member until August 31, 2011. 5 Forum member until July 31, 2011. 6 Forum member until October 31, 2011. 7 Forum member since September 1, 2011. vi

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MURRAY TROSTLE, U.S. Agency for International Development, Washington, DC MARY E. WILSON, Harvard School of Public Health, Harvard University, Boston, Massachusetts Staff EILEEN CHOFFNES, Director LEIGHANNE OLSEN, Program Officer KATHERINE McCLURE, Senior Program Associate COLLIN WEINBERGER, Research Associate (until May 2011) REBEKAH HUTTON, Research Associate (from June 2011) ROBERT GASIOR, Senior Program Assistant (until March 2011) PAMELA BERTELSON, Senior Program Assistant (from September 2011) vii

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BOARD ON GLOBAL HEALTH1 Richard Guerrant (Chair), Thomas H. Hunter Professor of International Medicine and Director, Center for Global Health, University of Virginia School of Medicine, Charlottesville, Virginia Jo Ivey Boufford (IOM Foreign Secretary), President, New York Academy of Medicine, New York Claire V. Broome, Adjunct Professor, Division of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia Jacquelyn C. Campbell, Anna D. Wolf Chair, and Professor, Johns Hopkins University School of Nursing, Baltimore, Maryland Thomas J. Coates, Professor, David Geffen School of Medicine, University of California, Los Angeles, California Gary Darmstadt, Director, Family Health Division, Global Health Program, Bill & Melinda Gates Foundation, Seattle, Washington Valentin Fuster, Director, Wiener Cardiovascular Institute Kravis Cardiovascular Health Center, and Professor, Cardiology, Mount Sinai School of Medicine, Mount Sinai Medical Center, New York, New York James Hospedales, Coordinator, Chronic Disease Project, Health Surveillance and Disease Management Area, Pan American Health Organization and World Health Organization, Washington, DC Peter J. Hotez, Professor and Chair, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC Clarion Johnson, Global Medical Director, Medicine and Occupational Medicine Department, Exxon Mobil, Fairfax, Virginia Fitzhugh Mullan, Professor, Department of Health Policy, George Washington University, Washington, DC Guy Palmer, Regents Professor of Pathology and Infectious Diseases, Director of the School for Global Animal Health, Washington State University, Pullman, Washington Jennifer Prah-Ruger, Associate Professor, Division of Health Policy and Administration, Yale University School of Public Health, New Haven, Connecticut Staff Patrick Kelley, Director Angela Christian, Program Associate 1 Instituteof Medicine boards do not review or approve individual workshop summaries. The responsibility for the content of the workshop summary rests with the workshop rapporteurs and the institution. viii

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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 ap - proved by the National Research Council’s Report Review Committee. The pur- pose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as scientifically 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 process. We wish to thank the following individuals for their review of this report: Noubar Afeyan, Massachusetts Institute of Technology Frances Arnold, California Institute of Technology Enriqueta C. Bond, Burroughs Wellcome Fund Alan Rudolph, Defense Threat Reduction Agency Although the reviewers listed above have provided many constructive com- ments and suggestions, they were not asked to endorse the final draft of the report before its release. The review of this report was overseen by Dr. Melvin Worth. Appointed by the Institute of Medicine, Dr. Worth was responsible for ensuring 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. ix

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Acknowledgments The Forum on Emerging Infections was created by the Institute of Medicine (IOM) in 1996 in response to a request from the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH). The purpose of the Forum is to provide structured opportunities for leaders from govern- ment, academia, and industry to regularly meet and examine issues of shared concern regarding research, prevention, detection, and management of emerg - ing, reemerging, and novel infectious diseases in humans, plants, and animals. In pursuing this task, the Forum provides a venue to foster the exchange of information and ideas, identify areas in need of greater attention, clarify policy issues by enhancing knowledge and identifying points of agreement, and inform decision makers about science and policy issues. The Forum seeks to illuminate issues rather than resolve them. For this reason, it does not provide advice or recommendations on any specific policy initiative pending before any agency or organization. Its value derives instead from the diversity of its membership and from the contributions that individual members make throughout the activities of the Forum. In September 2003, the Forum changed its name to the Forum on Microbial Threats. The Forum on Microbial Threats and the IOM wish to express their warmest appreciation to the individuals and organizations who gave their valuable time to provide information and advice to the Forum through their participation in the planning and execution of this workshop. A full list of presenters, and their biographical information, may be found in Appendixes B and F, respectively. xi

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xii ACKNOWLEDGMENTS The Forum gratefully acknowledges the contributions of the members of the planning committee1: James J. Collins (Boston University), Stephen A. Johnston (Arizona State University), George Poste (Arizona State University), and P. Fred - erick Sparling (University of North Carolina). The Forum is indebted to the IOM staff who tirelessly contributed throughout the planning and execution of the workshop and the production of this workshop summary report. On behalf of the Forum, we gratefully acknowledge these efforts led by Dr. Eileen Choffnes, director of the Forum; Dr. LeighAnne Olsen, program officer; Katherine McClure, senior program associate; Rebekah Hutton, research associate; Collin Weinberger, research associate; and Robert Gasior and Pamela Bertelson, senior program assistants, for dedicating much effort and time to developing this workshop’s agenda and for their thoughtful and insightful ap - proach and skill in planning for the workshop and in translating the workshop’s proceedings and discussion into this workshop summary report. We would also like to thank the following IOM staff and consultants for their valuable contribu - tions to this activity: Jill Grady, Laura Harbold, Leslie Pray, Heather Phillips, and Vilija Teel. Finally, the Forum wishes to recognize the sponsors that supported this ac- tivity. Financial support for this project was provided by the U.S. Department of Health and Human Services: NIH, National Institute of Allergy and Infectious Diseases, CDC, Food and Drug Administration, and the Fogarty International Center; U.S. Department of Defense, Department of the Army: Global Emerg- ing Infections Surveillance and Response System, Medical Research and Ma - teriel Command, and the Defense Threat Reduction Agency; U.S. Department of Veterans Affairs; U.S. Department of Homeland Security; U.S. Agency for International Development; American Society for Microbiology; sanofi pasteur; Burroughs Wellcome Fund; Pfizer, Inc.; GlaxoSmithKline; Infectious Diseases Society of America; and the Merck Company Foundation. The views presented in this workshop summary report are those of the workshop participants and rapporteurs and are not necessarily those of the Forum on Microbial Threats or its sponsors. 1 Instituteof Medicine planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution.

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Contents Workshop Overview 1 Workshop Overview References, 93 Appendixes A Contributed Manuscripts 105 A1 Commercial Applications of Synthetic Biology, 105 David A. Berry A2 Synthetic Biology: Applications Come of Age, 117 Ahmad S. Khalil and James J. Collins A3 The Genome as the Unit of Engineering, 150 Andrew D. Ellington and Jared Ellefson A4 Synthetic Biology—A New Generation of Biofilm Biosensors, 159 James Chappell and Paul S. Freemont A5 Synthetic Biology and the Art of Biosensor Design, 178 Christopher E. French, Kim de Mora, Nimisha Joshi, Alistair Elfick, James Haseloff, and James Ajioka A6 Systems Analysis of Adaptive Immunity by Utilization of High- Throughput Technologies, 202 Sai T. Reddy and George Georgiou A7 The New Science of Sociomicrobiology and the Realm of Synthetic and Systems Ecology, 213 E. Peter Greenberg xiii

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xiv CONTENTS A8 Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome, 222 Daniel G. Gibson, John I. Glass, Carole Lartigue, Vladimir N. Noskov, Ray-Yuan Chuang, Mikkel A. Algire, Gwynedd A. Bend- ers, Michael G. Montague, Li Ma, Monzia M. Moodie, Chuck Merryman, Sanjay Vashee, Radha Krishnakumar, Nacyra Assad- Garcia,Cynthia Andrews-Pfannkoch, Evgeniya A. Denisova, Lei Young, Zhi-Qing Qi, Thomas H. Segall-Shapiro, Christopher H. Calvey, Prashanth P. Parmar, Clyde A. Hutchison III, Hamilton O. Smith, and J. Craig Venter A9 Synthetic Biology “From Scratch,” 236 Gerald F. Joyce A10 Manufacturing Molecules Through Metabolic Engineering, 243 Jay D. Keasling A11 Novel Approaches to Combat Biofilm Drug Tolerance, 254 Kim Lewis A12 Next-Generation Synthetic Gene Networks, 278 Timothy K. Lu, Ahmad S. Khalil, and James J. Collins A13 Engineering Scalable Biological Systems, 310 Timothy K. Lu A14 Metabolic Systems Biology, 325 Bernhard Palsson A15 Systems Vaccinology, 336 Bali Pulendran, Shuzhao Li, and Helder I. Nakaya A16 Solving Vaccine Mysteries: A Systems Biology Perspective, 365 Lydie Trautmann and Rafick-Pierre Sekaly A17 Systems Biology of Vaccination for Seasonal Influenza in Humans, 370 Helder I. Nakaya, Jens Wrammert, Eva K. Lee, Luigi Racioppi, Stephanie Marie-Kunze, W. Nicholas Haining, Anthony R. Means, Sudhir P. Kasturi, Nooruddin Khan, Gui-Mei Li, Megan McCausland, Vibhu Kanchan, Kenneth E. Kokko, Shuzhao Li, Rivka Elbein, Aneesh K. Mehta, Alan Aderem, Kanta Subbarao, Rafi Ahmed, and Bali Pulendran A18 Synthetic Systems as Microbial Threats: Predictability of Loss-of- Function Mutations in Engineered Systems, 394 Sean C. Sleight, Bryan A. Bartley, and Herbert M. Sauro A19 Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli, 417 Parayil Kumaran Ajikumar, Wen-Hai Xiao, Keith E. J. Tyo, Yong Wang, Fritz Simeon, Effendi Leonard, Oliver Mucha, Too Heng Phon, Blaine Pfeifer, and Gregory Stephanopoulos A20 Programming Cells: Towards an Automated ‘Genetic Compiler,’ 429 Kevin Clancy and Christopher A. Voigt

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xv CONTENTS A21 Prokaryotic Gene Clusters: A Rich Toolbox for Synthetic Biology, 449 Michael Fischbach and Christopher A. Voigt A22 The Silicon Trypanosome, 480 Barbara M. Bakker, R. Luise Krauth-Siegel, Christine Clayton, Keith Matthews, Mark Girolami, Hans V. Westerhoff, Paul A. M. Michels, Ranier Breitling, and Michael P. Barrett B Agenda 495 C Acronyms 499 D Glossary 501 E Forum Member Biographies 511 F Speaker Biographies 539

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Tables, Figures, and Boxes TABLES A4-1 The Most Common Causes of Nosocomial Infections, 161 A5-1 Reporter Genes Commonly Used in Whole-Cell Biosensors, 180 A6-1 High-throughput technologies used to study adaptive immunity and the scale of information generated, 204 A8-1 Genomes that have been assembled from 11 pieces and successfully transplanted, 230 A15-1 Methods to Measure Antibody Correlates of Protection, 341 A18-1 Evolutionary Half-Life of T9002 and Reengineered T9002 Genetic Circuits, 402 FIGURES WO-1 This figure illustrates the synthetic biology concept that complex biological systems can be broken down into their component parts in a similar way as more traditional engineering disciplines, 5 WO-2 Construction of bacteria that are capable of light-dark edge detection, 10 WO-3 Biosynthetic pathways with increasing complexity, 11 WO-4 Improving mutational robustness in a genetic circuit, 14 xvii

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xviii TABLES, FIGURES, AND BOXES WO-5 General conceptual framework for incorporating top-down and bottom-up perspectives in the synthetic biology design process, 16 WO-6 Cost per base of DNA synthesis and sequencing, 19 WO-7 Schematic presentation of directed evolution studies, 22 WO-8 Breeding by DNA shuffling, 23 WO-9 Principles of evolution, 25 WO-10 Self-sustained amplification of a population of cross-replicating RNA enzymes, resulting in selection of the fittest replicators, 28 WO-11 Is it alive? (no), 31 WO-12 Type III secretion system, 34 WO-13 “Refactoring” gene clusters, 35 WO-14 Phases and data used to generate a metabolic reconstruction, 39 WO-15 XBP-1 target genes correlated to the maximum HAI response, 43 WO-16 Schematic for theoretical construction of a generic vaccine chip, 44 WO-17 CAMK4 expression on postvaccination day 3, 45 WO-18 A framework for systems vaccinology, 46 WO-19 Adoptive T-cell immunotherapy, 48 WO-20 Clinical trial timeline on patient 5, 49 WO-21 The effectiveness of T-cells based upon their functionality is reflected in this analogy, 50 WO-22 Data showing the persistence of the population of engineered MART-1 antigen-specific CD8+ T-cells and the evolving functional performance of those cells, 52 WO-23 Gyrase inhibitors induce an oxidative damage cellular death pathway, 55 WO-24 A common mechanism induced by bactericidal antibiotics, 56 WO-25 “Hello World” was the first image taken by the team at the University of Texas at Austin/UCSF with their photosensitive bacterial photographic “film” (this is a later, more polished version), 60 WO-26 Overview of steps in making a cell controlled by a synthetic genome, 64 WO-27 Two-pronged attack strategy for biofilm removal with enzymatically active DspB-expressing T7DspB phage, 70 WO-28 Targeting bacterial defense networks, 71 WO-29A Antibody discovery strategies, 79 WO-29B Isolation of monoclonal antibodies from responding patients, 79 WO-30 A simple biofilm biosensor, 81 WO-31 Cartoon describing Newcastle University 2010 iGEM team’s BacillaFilla, 85 A1-1 Schematic of the Joule Unlimited Helioculture systems approach, 114 A1-2 A summation of the accumulated photon losses for algal and direct fuel processes, as well as a theoretical maximum photonic energy conversion, 115

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xix TABLES, FIGURES, AND BOXES A4-1 An electron micrograph of Staphylococcus aureus bacteria biofilms on the luminal surface of an indwelling catheter, 160 A4-2 The engineering cycle as an approach for synthetic biology, 168 A4-3 The principle and biological example of an AND gate, 174 A5-1 Demonstration of the Edinburgh pH-based arsenic biosensor, Escherichia coli JM109/pSB1A2-BBa_J33203 with bromothymol blue as pH indicator, following static overnight incubation, 184 A5-2 Detection of arsenic by B. subtilis 168/pTG262-arsR-xylE: absorbance at 377 nm vs. arsenic concentration (ppb arsenic as sodium arsenate), 191 A5-3 Altered response characteristics of a whole-cell arsenic biosensor through reassembly of the components, 192 A5-4 Escherichia coli cells producing a variety of pigments, 195 A7-1 Quorum sensing in Vibrio fischeri, 216 A7-2 Diagram of the acyl-HSL quorum-sensing regulatory circuit in P. aeruginosa, 217 A7-3 Some examples of acyl-HSL quorum-sensing signals, 219 A8-1 The assembly of a synthetic M. mycoides genome in yeast, 226 A8-2 Analysis of the assembly intermediates, 227 A8-3 Characterization of the synthetic genome isolated from yeast, 229 A8-4 Characterization of the transplants, 232 A8-5 Images of M. mycoides JCVI-syn1.0 and WT M. mycoides, 233 A10-1 Conversion of sugars to chemicals by means of microbial catalysts, 245 A10-2 Use of synthetic regulators to modulate metabolic pathways that have a toxic intermediate, 249 A10-3 The future of engineered biocatalysts, 252 A11-1 Persisters and biofilms, 255 A11-2 Resistance and tolerance, 256 A11-3 A model of a relapsing biofilm infection, 257 A11-4 The two faces of recalcitrance, 259 A11-5 Candidate persister genes, 261 A11-6 The HipA toxin causes dormancy in E. coli by phosphorylating elongation factor Tu, which inhibits protein synthesis, 262 A11-7 Persister induction by antibiotic, 264 A11-8 The high-tech platform, 266 A11-9 A diffusion chamber for growing bacteria in situ, 268 A11-10 Understanding the mechanism of uncultivability, 270 A11-11 A high-throughput screen for antimicrobials in an animal model, 272

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xx TABLES, FIGURES, AND BOXES A12-1 Tunable genetic filter, 287 A12-2 Genetic signal converters, 290 A12-3 Adaptive learning networks, 294 A12-4 Amyloid-based memory, 296 A12-5 Cell-cycle counter for biological containment, 299 A12-6 Autonomous chemotaxis, 302 A13-1 A basic design cycle for synthetic biology includes creating well- characterized parts (e.g., regulatory elements, genes, proteins, RNAs), constructing synthetic devices and modules and designing and assembling higher-order networks, 312 A13-2 DNA sequencing and synthesis technologies are advancing at exponential rates, outpacing the ability of synthetic biologists to construct useful and scalable biological circuits, 313 A13-3 Combinatorial high-throughput methods will be useful in the assembly of well-characterized libraries of synthetic parts and devices, 315 A13-4 Control theory techniques for modelling synthetic biological circuits, 317 A14-1 Growth of genome sequences and genome-scale metabolic reconstructions, 326 A14-2 The four-step paradigm for metabolic systems biology, 328 A15-1 Using systems biology to predict the immunogenicity of the YF-17D vaccine, 343 A15-2 Systems biology approaches allow the identification of predictive gene signatures of immunogenicity for many vaccines, 346 A15-3 Integrating systems biology approaches into clinical trials, 351 A15-4 A framework for systems vaccinology, 359 A16-1 Systems biology approaches in the vaccine development, 366 A17-1 Analysis of humoral immunity to influenza vaccination, 374 A17-2 Molecular signature induced by vaccination with LAIV, 376 A17-3 Molecular signatures induced by vaccination with TIV, 378 A17-4 Molecular signatures that correlate with titers of antibody to TIV, 382 A17-5 Signatures that can be used to predict the antibody response induced by TIV, 384 A17-6 CaMKIV regulates the antibody response to vaccines against influenza, 387

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xxi TABLES, FIGURES, AND BOXES A18-1 The T9002 genetic circuit, 398 A18-2 Evolutionary stability dynamics of T9002 evolved under low-input (−AHL) and high-input (+AHL) conditions, 399 A18-3 T9002 loss-of-function mutation, 400 A18-4 T9002 reengineering, 401 A18-5 Evolutionary stability dynamics of T9002 and reengineered T9002 circuits, 403 A18-6 Loss of mutations in nine independently evolved populations, 404 A18-7 Most common loss-of-function mutations in reengineered T9002 circuits, 406 A18-8 Evolutionary half-life versus initial expression level in T9002 and T9002-E circuits evolved with different inducer concentrations, 410 A19-1 Multivariate-modular approach for isoprenoid pathway optimization, 420 A19-2 Optimization of taxadiene production through regulating the expression of the upstream and downstream modular pathways, 421 A19-3 Fed-batch cultivation of engineered strains in a 1-liter bioreactor, 424 A19-4 Engineering Taxol P450 oxidation chemistry in E. coli, 426 A20-1 The compiler is focused on assembling the circuitry that links the inputs and outputs of a larger project, 432 A20-2 A genetic compiler, 433 A20-3 Semantics of genetic programs, 436 A20-4 Automated program design using logic minimization algorithms, 438 A20-5 Connecting genetic circuits, 441 A21-1 Gene clusters encode organelles and molecular machines, 453 A21-2 Gene clusters described in this review are compared, 454 A21-3 Utilization and breakdown pathways encoded in gene clusters are shown, 459 A21-4 Chemical production pathways are often encoded within gene clusters, 462 A21-5 Complex regulatory pathways can be encoded by gene clusters, 470 A22-1 The glycolytic pathway in Trypanosoma brucei, 484 A22-2 The positive feedback from the ATP produced by glycolysis to the initial kinase reactions can lead to toxic accumulation of hexose phosphates, 486 A22-3 The glycolytic and trypanothione pathways are linked through the oxidative pentose phosphate pathway, 488

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xxii TABLES, FIGURES, AND BOXES BOXES WO-1 Early Synthetic Biology Designs: Switches and Oscillators, 12 WO-2 The International Genetically Engineered Machine Competition, 89 A2-1 Early Synthetic Biology Designs: Switches and Oscillators, 120 A2-2 Synthetic Biosensors: Transcriptional and Translational Architectures and Examples, 122 A2-3 Synthetic Biosensors: Post-translational and Hybrid Architectures and Examples, 128 A2-4 The Impact of Synthetic Biology on the Therapeutic Spectrum, 132 A2-5 Controlling Metabolic Flux: Evolutionary Strategies and Rational Design, 140 A2-6 Controlling Metabolic Flux: Hybrid Approaches, 142 A2-7 Recommendations for Improving the Synthetic Biology Design Cycle, 144 A4-1 The Mechanisms of Biofilm-Associated Virulence, 162 A4-2 Strategies and Examples of Biosensor Design, 172 A15-1 Prediction and Classification Based on Gene Expression Signatures, 340