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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
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 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
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For more information about the Institute of Medicine, visit the IOM home page at: www.
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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
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modified Danio rerio. Photo courtesy of www.glofish.com.
The serpent has been a symbol of long life, healing, and knowledge among almost all
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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
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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
OCR for page R22
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
