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
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu
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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 Human 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.
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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.
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Suggested citation: IOM (Institute of Medicine). 2011. The Science and Applications of Synthetic and Systems Biology. Washington, DC: The National Academies Press.
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. 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 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. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council.
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 documents. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution.
2 Forum member since September 1, 2011.
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.
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)
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 Institute of 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.
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 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 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 comments 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.
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 government, academia, and industry to regularly meet and examine issues of shared concern regarding research, prevention, detection, and management of emerging, 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.
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. Frederick 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 approach 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 contributions 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 activity. 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 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. 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 Institute of 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.
Contents
A1 Commercial Applications of Synthetic Biology
David A. Berry
A2 Synthetic Biology: Applications Come of Age
Ahmad S. Khalil and James J. Collins
A3 The Genome as the Unit of Engineering
Andrew D. Ellington and Jared Ellefson
A4 Synthetic Biology—A New Generation of Biofilm Biosensors
James Chappell and Paul S. Freemont
A5 Synthetic Biology and the Art of Biosensor Design
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
Sai T. Reddy and George Georgiou
A7 The New Science of Sociomicrobiology and the Realm of Synthetic and Systems Ecology
E. Peter Greenberg
A8 Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome
Daniel G. Gibson, John I. Glass, Carole Lartigue, Vladimir N. Noskov, Ray-Yuan Chuang, Mikkel A. Algire, Gwynedd A. Benders, 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”
Gerald F. Joyce
A10 Manufacturing Molecules Through Metabolic Engineering
Jay D. Keasling
A11 Novel Approaches to Combat Biofilm Drug Tolerance
Kim Lewis
A12 Next-Generation Synthetic Gene Networks
Timothy K. Lu, Ahmad S. Khalil, and James J. Collins
A13 Engineering Scalable Biological Systems
Timothy K. Lu
Bernhard Palsson
Bali Pulendran, Shuzhao Li, and Helder I. Nakaya
A16 Solving Vaccine Mysteries: A Systems Biology Perspective
Lydie Trautmann and Rafick-Pierre Sekaly
A17 Systems Biology of Vaccination for Seasonal Influenza in Humans
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
Sean C. Sleight, Bryan A. Bartley, and Herbert M. Sauro
A19 Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli
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’
Kevin Clancy and Christopher A. Voigt
A21 Prokaryotic Gene Clusters: A Rich Toolbox for Synthetic Biology
Michael Fischbach and Christopher A. Voigt
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
Tables, Figures, and Boxes
TABLES
A4-1 The Most Common Causes of Nosocomial Infections
A5-1 Reporter Genes Commonly Used in Whole-Cell Biosensors
A8-1 Genomes that have been assembled from 11 pieces and successfully transplanted
A15-1 Methods to Measure Antibody Correlates of Protection
A18-1 Evolutionary Half-Life of T9002 and Reengineered T9002 Genetic Circuits
FIGURES
WO-2 Construction of bacteria that are capable of light-dark edge detection
WO-6 Cost per base of DNA synthesis and sequencing
WO-7 Schematic presentation of directed evolution studies
WO-8 Breeding by DNA shuffling
WO-12 Type III secretion system
WO-13 “Refactoring” gene clusters
WO-14 Phases and data used to generate a metabolic reconstruction
WO-15 XBP-1 target genes correlated to the maximum HAI response
WO-16 Schematic for theoretical construction of a generic vaccine chip
WO-17 CAMK4 expression on postvaccination day 3
WO-18 A framework for systems vaccinology
WO-19 Adoptive T-cell immunotherapy
WO-20 Clinical trial timeline on patient 5
WO-21 The effectiveness of T-cells based upon their functionality is reflected in this analogy
WO-23 Gyrase inhibitors induce an oxidative damage cellular death pathway
WO-24 A common mechanism induced by bactericidal antibiotics
WO-26 Overview of steps in making a cell controlled by a synthetic genome
WO-28 Targeting bacterial defense networks
WO-29A Antibody discovery strategies
WO-29B Isolation of monoclonal antibodies from responding patients
WO-30 A simple biofilm biosensor
WO-31 Cartoon describing Newcastle University 2010 iGEM team’s BacillaFilla
A1-1 Schematic of the Joule Unlimited Helioculture systems approach
A4-2 The engineering cycle as an approach for synthetic biology
A4-3 The principle and biological example of an AND gate
A5-4 Escherichia coli cells producing a variety of pigments
A7-1 Quorum sensing in Vibrio fischeri
A7-2 Diagram of the acyl-HSL quorum-sensing regulatory circuit in P. aeruginosa
A7-3 Some examples of acyl-HSL quorum-sensing signals
A8-1 The assembly of a synthetic M. mycoides genome in yeast
A8-2 Analysis of the assembly intermediates
A8-3 Characterization of the synthetic genome isolated from yeast
A8-4 Characterization of the transplants
A8-5 Images of M. mycoides JCVI-syn1.0 and WT M. mycoides
A10-1 Conversion of sugars to chemicals by means of microbial catalysts
A10-2 Use of synthetic regulators to modulate metabolic pathways that have a toxic intermediate
A10-3 The future of engineered biocatalysts
A11-2 Resistance and tolerance
A11-3 A model of a relapsing biofilm infection
A11-4 The two faces of recalcitrance
A11-5 Candidate persister genes
A11-7 Persister induction by antibiotic
A11-9 A diffusion chamber for growing bacteria in situ
A11-10 Understanding the mechanism of uncultivability
A11-11 A high-throughput screen for antimicrobials in an animal model
A12-2 Genetic signal converters
A12-3 Adaptive learning networks
A12-5 Cell-cycle counter for biological containment
A13-4 Control theory techniques for modelling synthetic biological circuits
A14-1 Growth of genome sequences and genome-scale metabolic reconstructions
A14-2 The four-step paradigm for metabolic systems biology
A15-1 Using systems biology to predict the immunogenicity of the YF-17D vaccine
A15-3 Integrating systems biology approaches into clinical trials
A15-4 A framework for systems vaccinology
A16-1 Systems biology approaches in the vaccine development
A17-1 Analysis of humoral immunity to influenza vaccination
A17-2 Molecular signature induced by vaccination with LAIV
A17-3 Molecular signatures induced by vaccination with TIV
A17-4 Molecular signatures that correlate with titers of antibody to TIV
A17-5 Signatures that can be used to predict the antibody response induced by TIV
A17-6 CaMKIV regulates the antibody response to vaccines against influenza
A18-1 The T9002 genetic circuit
A18-3 T9002 loss-of-function mutation
A18-5 Evolutionary stability dynamics of T9002 and reengineered T9002 circuits
A18-6 Loss of mutations in nine independently evolved populations
A18-7 Most common loss-of-function mutations in reengineered T9002 circuits
A19-1 Multivariate-modular approach for isoprenoid pathway optimization
A19-3 Fed-batch cultivation of engineered strains in a 1-liter bioreactor
A19-4 Engineering Taxol P450 oxidation chemistry in E. coli
A20-3 Semantics of genetic programs
A20-4 Automated program design using logic minimization algorithms
A20-5 Connecting genetic circuits
A21-1 Gene clusters encode organelles and molecular machines
A21-2 Gene clusters described in this review are compared
A21-3 Utilization and breakdown pathways encoded in gene clusters are shown
A21-4 Chemical production pathways are often encoded within gene clusters
A21-5 Complex regulatory pathways can be encoded by gene clusters
BOXES
WO-1 Early Synthetic Biology Designs: Switches and Oscillators
WO-2 The International Genetically Engineered Machine Competition
A2-1 Early Synthetic Biology Designs: Switches and Oscillators
A2-2 Synthetic Biosensors: Transcriptional and Translational Architectures and Examples
A2-3 Synthetic Biosensors: Post-translational and Hybrid Architectures and Examples
A2-4 The Impact of Synthetic Biology on the Therapeutic Spectrum
A2-5 Controlling Metabolic Flux: Evolutionary Strategies and Rational Design
A2-6 Controlling Metabolic Flux: Hybrid Approaches
A2-7 Recommendations for Improving the Synthetic Biology Design Cycle
A4-1 The Mechanisms of Biofilm-Associated Virulence
A4-2 Strategies and Examples of Biosensor Design
A15-1 Prediction and Classification Based on Gene Expression Signatures