DRAFT ONLY: DO NOT CITE OR CIRCULATE Synthetic Genomics Options for Governance Michele S. Garfinkel,* Drew Endy,‡ Gerald L. Epstein, # and Robert M. Friedman* *The J. Craig Venter Institute, Rockville, Maryland # Center for Strategic and International Studies, Washington, District of Columbia ‡ Massachusetts Institute of Technology, Cambridge, Massachusetts The views and opinions expressed in this draft report are those of the authors and not necessarily those of the other study Core Group members, the participants of the workshops discussed in this draft, or of the institutions at which the authors work. The authors assume full responsibility for the report and the accuracy of its contents. We gratefully acknowledge the Alfred P. Sloan Foundation for support of this study. DRAFT ONLY: DO NOT CITE OR CIRCULATE (page intentionally left blank) 27 Nov 2006 Synthetic Genomics: Options for Governance 2 DRAFT ONLY: DO NOT CITE OR CIRCULATE TABLE OF CONTENTS Introduction.......................................................................................................................5 Benefits...............................................................................................................................9 Risks..................................................................................................................................11 Framing a Policy Response.............................................................................................16 The Portfolio of Governance Options............................................................................18 Policy Options Presented (TABLE)...............................................................................19 Policies for commercial synthesis firms.........................................................................21 Policies for monitoring or controlling equipment or reagents.....................................................................................................31 Policies for controlling publications and data for which open communication poses more risks than benefits.....................................................................................................................38 Policies for the roles of users and organizations in promoting safety and security in the conduct of synthetic genomics protocols..........................................................................................46 Choosing a Portfolio of Options.....................................................................................55 Summary of Options (FIGURE)....................................................................................56 Summary of Portfolios (TABLE)...................................................................................58 27 Nov 2006 Synthetic Genomics: Options for Governance 3 DRAFT ONLY: DO NOT CITE OR CIRCULATE (page intentionally left blank) 27 Nov 2006 Synthetic Genomics: Options for Governance 4 DRAFT ONLY: DO NOT CITE OR CIRCULATE INTRODUCTION For decades, scientists have been searching for an efficient means to chemically synthesize genes, the building blocks of life. The first complete chemical synthesis of a gene was described in the early 1970s by Har Gobind Khorana and his colleagues. It was an arduous task, taking Khorana and 17 others years to assemble the very small (207 base-pairs) gene.1 Scientists had been “reading” the genetic code for years. Khorana and colleagues were the first to go the other way: from genetic code to a small, but functional, biological building block. By the mid-1990s, Willem Stemmer and co-workers were able to synthesize a much larger gene and vector system (approximately 2700 base-pairs) using a variation of a standard molecular biology laboratory tool, the polymerase chain reaction.2 Stemmer’s technique has proven to be very useful in pharmaceuticals research. In both Khorana’s and Stemmer’s experiments, as well as in those from other laboratories that were also interested in chemical synthesis of biological molecules, the goals of the researchers were both scientific and applied: to understand the natural world more completely, and to use that knowledge to make the world better. In 2002, a team of researchers at the State University of New York led by Eckard Wimmer reported the assembly of an infectious poliovirus constructed in the laboratory directly from nucleic acids.3 Although this work was built on the prior examples of “from scratch” DNA synthesis noted above, Wimmer’s work demonstrated for the first time in a post-September 11th world the feasibility of synthesizing a complete microorganism—in this case a human pathogen—using only published DNA sequence information and mail- ordered raw materials. The next year, a group from the Venter Institute (formerly the Institute for Biological Energy Alternatives) published a description of a similar technique applied to the construction of phiX174 (a virus that infects bacteria, called a bacteriophage).4 The advance here was not so much in length, as the viruses are of similar sizes, but in efficiency: compared to the one year or so required to synthesize and validate infectious poliovirus, fully-functional phiX174 was synthesized in approximately 2 weeks. Both 1 Agarwal KL, Buchi H, Caruthers MH, Gupta N, Khorana HG, Kleppe K, Kumar A, Ohtsuka E, Rajbhandary UL, Van de Sande JH, Sgaramella V, Weber H, Yamada T. 1970. Total synthesis of the gene for an alanine transfer ribonucleic acid from yeast. Nature 227:27-34. Khorana HG, Agarwal KL, Buchi H, Caruthers MH, Gupta NK, Kleppe K, Kumar A, Otskua E, RajBhandary UL, Van de Sande JH, Sqaramella V, Terao T, Weber H, Yamada T. 1972. Total Synthesis of the Structural Gene for an Alanine Transfer Ribonucleic Acid from Yeast. Journal of Molecular Biology 72: 209-217. 2 Stemmer WP, Crameri A, Ha KD, Brennan TM, Heyneker HL. 1995. Single-Step Assembly of a Gene and Entire Plasmid from Large Numbers of Oliogodeoxyribonucleotides. Gene 164: 49-53. 3 Cello J, Paul AV, Wimmer E. 2002. Chemical Synthesis of Poliovirus cDNA: Generation of Infectious Virus in the Absence of Natural Template. Science 297: 1016-1018. 4 Smith HO, Hutchison III CA, Pfannkoch C, Venter JC. 2003. Generating a Synthetic Genome by Whole Genome Assembly: φX174 Bacteriophage from Synthetic Oligonucleotides. Proceedings of the National Academy of Sciences USA 100: 15440-15445. 27 Nov 2006 Synthetic Genomics: Options for Governance 5 DRAFT ONLY: DO NOT CITE OR CIRCULATE poliovirus and phiX174 are relatively small viruses, approximately 7400 and 5400 nucleotides (DNA subunits, where each subunit carries one letter of the genetic code: A, C, T, or G) respectively, but the lessons learned from these synthesis experiments are directly applicable to learning how to construct larger and more complex genomes. Further dramatic increases in the speed and accuracy of DNA synthesis would be necessary to lead eventually to the ultimate goal of the Venter Institute group: the synthesis not just of viruses but of whole bacteria. Today, a number of groups are working to design and construct from scratch novel bacterial genomes and simple eukaryotic chromosomes (e.g., yeast). “Since the sequence is generated by chemical synthesis, there is full choice in the subsequent manipulation of the sequence information. This ability is the essence of the chemical approach to the study of biological specificity in DNA and RNA”, Khorana noted in 1979.5 Today, the rapidly-advancing technology of whole genome assembly reflects this potent observation. Synthetic genomics is a suite of techniques that permit the construction of any specified DNA sequence, enabling the chemical synthesis of genes or entire genomes. These DNA synthesis technologies applied to beneficial applications should have very positive impacts for individuals and for society. However, the ability to reproduce very long sequences (in the tens or even hundreds of thousands of nucleotides) very rapidly and relatively inexpensively has led to concerns that bioterrorists could use these techniques to construct truly fearsome viruses such as smallpox from scratch. Synthetic genomics thus is a quintessential “dual-use” technology—a technology with broad and varied beneficial applications, but one that could also be turned to nefarious, destructive use.6 Such technologies have been around ever since the first humans picked up rocks or sharpened sticks. Nevertheless, dual-use bioscience and biotechnology, as exemplified by synthesis technology, pose special challenges, which are the subject of this report. Synthesis technologies Researchers have had the basic knowledge and tools to carry out de novo synthesis of gene-length DNA from nucleotide precursors for over 35 years. However, the techniques used on the first constructions were extremely difficult and constructing a gene of just over 100 nucleotides in length could take years. Today, using machines called DNA synthesizers, the individual subunit bases adenine (A), cytosine (C), guanine (G), and thymine (T) can be assembled de novo, in any specified sequence using readily accessible reagents. Individual researchers and 5 Khorana HG. 1979. Total Synthesis of a Gene. Science 203: 614-625. 6 Atlas RM, Dando M. 2006. The Dual-Use Dilemma for Life Sciences: Perspectives, Conundrums, and Global Solutions. Biosecurity and Bioterrorism 4: 276-286. Committee on Research Standards and Practices to Prevent the Destructive Application of Biotechnology, National Research Council of the National Academies. 2004. Biotechnology