Directed Evolution for Development and
Production of Bioactive Agents

A Meeting Summary

Daniel Talmage and Dionna Ali
Rapporteurs

Committee on Science and Technology for Defense Warning

Division on Engineering and Physical Sciences

NATIONAL RESEARCH COUNCIL
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.

www.nap.edu



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Directed Evolution for Development and Production of Bioactive Agents A Meeting Summary Daniel Talmage and Dionna Ali Rapporteurs Committee on Science and Technology for Defense Warning Division on Engineering and Physical Sciences THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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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. This study was supported by Contract HHM402-10-D-0036 between the Defense Intelligence Agency and the National Academy of Sciences. Any views or observations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project. International Standard Book Number-13: 978-0-309-28626-8 International Standard Book Number-10: 0-309-28626-3 Limited copies of this report are available from the Division on Engineering and Physical Sciences, National Research Council, 500 Fifth Street, NW, Washington, DC 20001; (202) 334-2400. Copyright 2013 by the National Academy of Sciences. 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 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 www.national-academies.org

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COMMITTEE ON SCIENCE AND TECHNOLOGY FOR DEFENSE WARNING BRENDAN B. GODFREY, Chair, University of Maryland THOMAS E. ROMESSER, Vice Chair, Northrop Grumman Aerospace Systems (retired) ILHAN A. AKSAY, Princeton University ANN N. CAMPBELL, Sandia National Laboratories JOHN F. CASHEN, Aerospace and Defense Consultant EDWARD M. GREITZER, Massachusetts Institute of Technology ELLIOTT D. KIEFF, Harvard University FRANCIS R. LANDOLF, Core Consulting, LLC PATRICK LINCOLN, SRI International DARRELL D.E. LONG, University of California, Santa Cruz DAVID F. McQUEENEY, IBM Research RANDOLPH L. MOSES, Ohio State University MONICA OLVERA DE LA CRUZ, Northwestern University MIKHAIL SHAPIRO, University of California, Berkeley ELIAS TOWE, Carnegie Mellon University Staff TERRY JAGGERS, Lead DEPS Board Director DANIEL E.J. TALMAGE, JR., Study Director DIONNA ALI, Senior Program Assistant CHRIS JONES, Financial Associate v

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Acknowledgment of 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 (NRC’s) Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Brendan B. Godfrey, University of Maryland, Diane E. Griffin (NAS/IOM), Johns Hopkins Bloomberg School of Public Health, J. Jerome Holton, The Tauri Group, and Mikhail G. Shapiro, University of California at Berkeley. Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the views of individual participants, nor did they see the final draft of the report before its release. The review of this report was overseen by Gerald F. Joyce (NAS), The Scripps Research Institute. Appointed by the NRC, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authors and the institution. vi

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Contents 1 MEETING SUMMARY 1 Objectives and Scope, 1 Presentations, 1 Protein Switches and the Genetic Code, 2 Directed Evolution of New Viruses for Gene Therapy, 3 Expanding the Synthetic Capabilities of Yeast, 5 One Handful of Soil: 10,000,000,000 Microbes, 100,000 Different Species, 6 Digital Chemistry: The Fabrication and Application of Ordered Molecular Arrays, 7 Cell-Penetrating Mini-Proteins, 9 Discussion, 10 Final Comments, 11 APPENDIXES A Workshop Presentations and Participants 15 B Biographies 17 vii

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