SYNTHETIC GENOMICS | Options for Governance

Home , Synthetic genomes, Synthetic genomics

Michele S. Garfinkel, The J. Craig Venter Institute, Rockville, Maryland, Drew Endy, Massachusetts Institute of Technology, Cambridge, Massachusetts, Gerald L. Epstein, Center for Strategic and International Studies, Washington, District of Columbia and Robert M. Friedman, The J. Craig Venter Institute, Rockville, Maryland

October 2007 The views and opinions expressed in this 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 report, 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. EXECUTIVE SUMMARY

Summary Table of Options

Gene Firms Oligo Manufacturers DNA Synthesizers Users and Organizations

Does the Option:

II-2. Ownersmust be of licensed DNAI1-3. synthesizers Licensingrequired ofto equipment,buyIII-1. reagents Educationpractices plus and inlicenseabout servicesuniversityIII-2. risks Compilein and curriculaSynthetic best a manualIII-3. Biology Establish bestfor Laboratories” “Biosafety practices a clearinghouseIII-4. Broadenresponsibilities for IBC reviewIII-5. Broadenoversight IBC by III-6.Nationalreview, Broadenenhanced plus Advisory IBC enforcement review, plus Enhance Biosecurity IA-1. ordersGene rms mustIA-2. screen Biosafetypeople who of cers IA-3.place mustHybrid: biosafetyorders certify Firms of cerIA-4. must must aboutFirms screen verify mustorders and people storeIB-1. informationOligonucleotidemust screen IB-2.orders manufacturers Biosafetypeople who of cer IB-3.place must Hybrid: biosafetyorders verify Firms of cer IB-4.must must Firmsaboutscreen verify must orders and people storeII-1. informationOwnersmust register of DNA their synthesizers machines

by preventing incidents?

by helping to respond?

Foster Laboratory Safety

by preventing incidents?

by helping to respond?

Protect the Environment

by preventing incidents?

by helping to respond?

Other Considerations:

Minimize costs and burdens to government and industry?

Perform to potential without additional research?

Not impede research?

Promote constructive applications?

Key to Scoring:

Most effective for this goal. Most effective performance on this consideration. Reading the evaluation diagrams Relatively effective. Moderately effective. These diagrams found throughout the report allow for easy compari- Somewhat effective. sons within and between options regarding their effectiveness in achiev- Minimally effective. ing the policy goals of biosecurity and biosafety, and their performance Not relevant. on other considerations.

Reading down the columns allows for an evaluation of the performance of a particular option on one goal relative to the other goals. Read- ing across the rows allows for comparison of the effectiveness of each option with respect to the others on any given goal or consideration. Those that perform better are indicated with circles that have more dark fill; those that perform worse have less fill.

These comparisons are qualitative: they only indicate that one option performs better or worse than another, but not by how much.

iii

Table of Contents

Executive Summary i Introduction 1 Benefits and Risks 10 The Study 16 Framing a Policy Response 17 Policy Options (including Summary Tables) 19 I. Options for Synthesis Firms 21 II. Options for Equipment and Reagents 31 III. Options for Users and Organizations 38 Choosing a Portfolio of Options 48 Appendices 53 Endnotes 54 Author Biographies 56 Institute Information 57

Figures

Figure 1: Commercial and In-House Gene and Genome Synthesis 3 Figure 2: Construction of Genes and Genomes from Oligonucleotides 4 Figure 3: Research Application of Synthetic Genomics 11

Tables

Table 1: Estimate of number of Gene Synthesis Companies Worldwide 2 Table 2: Obtaining Viruses 14 Table 3: Summary of Options Presented in this Report 20 Options Table IA: Summary of Options for Gene Synthesis Firms Options 28 Options Table IB: Summary of Options for Oligonucleotide Synthesis Firms 30 Options Table II: Summary of Options for Monitoring or Controlling Equipment or Reagents 35 Options Table III: Summary of Options for Users and Organizations 46 Options Table IV: Summary of All Options 49 Table 4: Summary of Portfolios 51

SYNTHETIC GENOMICS | Options for Governance

Introduction

Synthetic genomics combines methods for the chemical synthesis of DNA with computational techniques to design it. These methods allow scientists to construct genetic material that would be impossible or impractical to produce using more conventional biotechnological approaches.

For instance, synthetic genomics could be used to intro- technology—a technology with broad and varied beneficial duce a cumulative series of changes that dramatically alter applications, but one that could also be turned to nefari- an organism’s function, or to construct very long strands of ous, destructive use.1, 2 Such technologies have been around genetic material that could serve as the entire genome of a ever since the first humans picked up rocks or sharpened virus or, some time in the near future, even of more complex sticks. But biology brings some unique dimensions: given the organisms such as bacteria. self-propagating nature of biological organisms and the relative accessibility of powerful biotechnologies, the means to Scientists have been improving their ability to manipulate produce a “worst case” are more readily attainable than for DNA for decades. There is no clear and unambiguous many other technologies.3 threshold between synthetic genomics and more conventional approaches to biotechnology. Chemical synthesis can The four authors embarked on this study of synthetic ge- be used to make incremental changes in an organism’s genomics to assess the current state of the technology, identify nome, just as non-synthetic techniques can generate an en- potential risks and benefits to society, and formulate options tirely new genome. Nevertheless, the combination of design for governance of the technology. Assisted by a core group and construction capabilities gives synthetic genomics the of 14 additional people with a wide range of expertise, we potential for revolutionary advances unmatched by other held three expert workshops and a large invitational meet- approaches. ing with a diverse set of decision-makers, subject-matter Synthetic genomics allows scientists and engineers to focus experts, and other important stakeholders. We obtained ad- on their goals without getting bogged down in the underlying ditional information by commissioning papers from experts molecular manipulations. As a result, the breadth and diver- on various topics. An overview of the information elicited sity of the user community has increased, and the range of from these activities and a detailed description of the policy possible experiments, applications, and outcomes has been options for governance are contained in this report. substantially enlarged. The goal of the project was to identify and analyze policy, Such revolutionary advances have the potential to bring technical, and other measures to minimize safety and security significant benefits to individuals and society. At the same concerns about synthetic genomics without adversely affect- time, the power of these technologies raises questions about ing its potential to realize the benefits it appears capable the risks from their intentional or accidental misuse for of producing. We hope that this study will contribute to a harm. Synthetic genomics thus is a quintessential “dual-use” wider societal discussion about the uses of the technology. Introduction to Synthesis

Researchers have had the basic knowledge Alternatively, a scientist may wish to assemble and tools to carry out the de novo synthesis gene- or genome-length DNA on his or her of gene-length DNA from nucleotide pre- own starting from smaller pieces of DNA cursors for over 35 years.4 At first, however, called oligonucleotides or oligos. Oligos are these “from scratch” synthesis techniques were sub-gene length stretches, typically from about extremely difficult, and constructing a genei of 15 base-pairs to about 100 base-pairs long. just over 100 nucleotidesii in length could take The smaller oligos can be used in laboratories years. Today, using machines called DNA syn- in diagnostic assays and other standard labora- thesizers, the individual subunit bases adenine tory protocols. The longer oligos, though, from (A), cytosine (C), guanine (G), and thymine (T) about 40 base-pairs on, can actually be used can be assembled to form the genetic mate- to construct gene- and genome length DNA rial DNA in any specified sequence, in lengths (Figure 2). of tens of thousands of nucleotide base-pairsiii using readily accessible reagents.iv Number of Gene Synthesis Country Companies (minimum) Precisely how a scientist or engineer will obtain the pieces of DNA of interest will vary United States 24 depending on the resources and preferences Germany 5 of that individual (Figure 1). The most straightforward way to obtain a gene- or genome- Canada 4 length stretch of DNA is to order it from a China 2 commercial gene synthesis company. There are France 2 at least 24 firms in the United States and at least an additional 21 firms worldwide that Russia 2 provide this service (Table 1). Many of these Australia 1 Synthetic genomics firms use proprietary technologies to produce extremely long pieces of DNA; the longest Netherlands 1 is a quintessential strand reported to date is 52,000 base pairs, Norway 1 “dual-use” synthesized by Blue Heron Biotechnology of technology—a Bothell, Washington.5 Currently, many types South Africa 1 technology with of technologies used by firms are proprietary Switzerland 1 and are not available for purchase by individual broad and United Kingdom 1 varied beneficial users (Figure 1, Panel A). applications, but Table 1: Estimate of number of DNA synthesis companies worldwide capable of supplying one that could gene- and genome-length productsv. also be turned to nefarious, i Genes range in length from typically hundreds to a few thousand nucleotides long; they can, however, vary widely, destructive use. and the full definition of what constitutes a gene may include sequences as small as the tens and into the tens of thousands of nucleotides. ii A nucleotide is a basic unit of nucleic acids; it consists of several chemical groups including its defining base and may be ribonucleic or deoxyribonucleic acid (RNA and DNA respectively) iii A base-pair is the combination that occurs in a double helix of DNA: A pairs with T; G pairs with C. In describing length, “bases” and “base pairs” are frequently used interchangeably. iv “Reagents” is an inclusive term describing many of the chemicals and related substances used in laboratory processes. v These numbers represent minimums based on our ability to confirm that companies referencing gene- or genome synthesis are in fact capable of doing so. There almost certainly are additional companies involved in synthesizing genomes but we could not independently identify and confirm these.

2 Synthetic Genomics | Options for Governance INTRODUCTION

Panel A

Panel B

Figure 1: Mail order or make it yourself. The basis of gene- and genome synthesis is the machines that produce polynucleotides for subsequent manipulation.

Panel A: Commercial genes or oligos. Firms throughout the world use synthesis technologies (in many cases proprietary) to make completed, characterized gene- or genome-length DNA for customers. In this example, customers simply enter the desired sequence through a screen interface; about 6-8 weeks later the DNA is delivered. (Credit: Blue Heron Biotechnology)

Panel B: A laboratory-benchtop oligonucleotide synthesizer. Individual laboratories can buy oligonucleotide synthesizers to generate oligos that can then be manipulated to make a full-length gene or genome. These synthesizers are available commercially from manufacturers such as Applied Biosystems, or may be purchased secondhand on auction sites such as LabX and eBay. These are similar in function to machines used by commercial oligonucleotide synthesis companies.

Synthetic Genomics | Options for Governance 3 Pstl TOP 1-130 Pstl 1 2 129 130 5’ ...... 3’

3’ ..... 5’ Design oligos 131 132 258 259 8 hrs PCR ampliﬁcation of assembled 3 hrs BOT 131-259 full-length chromosomes ΦX

Synthesize oligos ~4 days

Gel-purify ampliﬁed chromosomes 8 hrs

Purify top strand and bottom strand oligos in seperate pools by gel electrophoresis 2 days

Circularize the synthetic linear chromosomal DNA so that it is infectious 4 hrs

5’-phosphorylate the oligos 4 hrs

Electroporate into E. coli and plate Taq ligate the pooled top and bottom for phage plaques 24 hrs oligos overnight at 55°C 18 hrs

Polymerase cycling assembly (PCA) of ligation products into full-length 12 to 24 hrs Sequence phage from chromosomes, 35 to 70 cycles individual plaques

Total time ~2 weeks

Figure 2: Gene- and genome-length DNA construction using oligonucleotides. Oligonucle- otides may be purchased or synthesized in a laboratory. They are then subjected to a series of biochemical manipulations that allows them to be assembled into the gene or genome of interest. This example illustrates the construction of the bacteriophage phiX174 (approximately 5500 nucleotides) in about 2 weeks. (Smith et al. 2003 PNAS 100: 15440. Copyright National Academy of Sciences.)

Oligos can either be ordered from a commer- Many universities are letting their synthesizers cial oligonucleotide manufacturer, or they can lay idle, or are even re-selling or trading them be made easily within a laboratory using a spe- in for other equipment.vii The research com- cialized machine for that purpose. It is unclear munity in the United States is therefore heavily exactly how many firms commercially produce dependent on commercial suppliers for oligo oligos.vi Oligos are so important to modern production. biology that many universities and firms had established central production facilities to However, even the most versatile firms may produce them for in-house use. At present, not completely meet the needs of specific us- however, economies of scale permit commer- ers; thus, some scientists prefer to make oligos cial firms to make them less expensively, and in their own laboratories. This can be done frequently more quickly, than these facilities. on a commercially available oligo synthesizer, a

vi Based on a variety of Web searches and discussions with participants at our workshops, it seems reasonable to estimate a minimum of 25 companies in the United States alone that have major efforts in oligonucleotide production; there are probably many more that are capable of making oligonucleotides but for which this is not a major part of their business, or that do not have a Web presence and thus were overlooked in our searches.

4 Synthetic Genomics | Options for Governance INTRODUCTION

relatively inexpensive, standard piece of equip- dard molecular biology laboratory tool, the ment that fits easily on a laboratory benchtop polymerase chain reaction. In a straightforward (Figure 1, Panel B). fashion, on the order of days, any gene could be mutated at any number of locations in the Regardless of the technique used to construct a sequence and tested for any given property. gene or genome, DNA synthesis technologies This technique had implications for everything offer a much more efficient way to do many from the study of evolution to the discovery of the same things that can be done with stan- and testing of new drugs.10 dard recombinant DNA or other biochemical or molecular biology techniques. However, the Other groups of researchers were explor- efficiency of modern synthetic DNA technolo- ing the problems involved in the synthesis of gies together with improved design capabilities gene-length pieces of DNA via their work offers the potential for revolutionary advances. with viruses, which can serve as model sys- Synthetic genomics may lead to qualitatively tems for a variety of biological inquiries and new capabilities, broadening the number of are important in their own right. In 1981, Vin- users of biotechnology, and enabling complex cent Racaniello and David Baltimore described applications to be developed by separating the construction of an infectious poliovirus by higher-level design concepts from the underly- the joining of cDNA clones.viii; 11, 12 In 1999 an Prior to the attacks ing molecular manipulations. influenza virus type A was generated entirely of September 11, from cloned DNA virus segments.13 (Earlier, 2001, biosecurity Early Milestones others had made infectious virus from cDNA clones, but those systems required helper vi- discussions occurred The first complete chemical synthesis of a ruses.14) more among gene was described in the early 1970s by Har professionals con- Gobind Khorana and his colleagues. It was an In all of these synthesis experiments, the goals cerned specifically arduous task, taking Khorana and 17 co-work- of the researchers were both scientific and ap- about bioterrorism plied: to understand the natural world more ers years to assemble a very small gene (207 than among base-pairs).6, 7 Scientists had been “reading” completely, and to apply that knowledge to- the genetic code for years. Khorana and col- ward beneficial applications. The potential for members of the leagues were the first to accomplish the next misusing these techniques for bioterrorism research community. step: “writing” the code of the building blocks was acknowledged, but prior to the attacks of life by making a small but functional gene. of September 11, 2001, these discussions occurred more among professionals concerned In the decades following Khorana’s achieve- specifically about biowarfare and bioterrorism ment, scientists searched for an efficient chem- than among members of the biological re- ical means to synthesize genes. Many groups search community or the public. published articles describing a wide variety of approaches to the synthesis of long stretches In 2002, a team of researchers at the State of DNA.8, 9 By the mid-1990s, Willem Stem- University of New York led by Eckard Wimmer mer and co-workers were able to synthesize a reported the assembly of an infectious polio- large gene and vector system (approximately virus constructed in the laboratory directly 2700 base-pairs) using a variation of a stan- from nucleic acids.15 Although this work was

vii Discussion at 26-27 September 2005 Workshop: Technologies for Synthetic Genomics. viii cDNA (“complementary” or “copy” DNA) clones are pieces of DNA isolated from a source such as cells; they are processed so that they can be used easily in the laboratory. For example, they are usually inserted into a piece of carrier DNA called a vector that allows for the easy amplification of the piece of DNA of interest.

5 built on the prior examples of synthesis noted the synthesis not just of viruses but of whole above, Wimmer’s work demonstrated for the bacteria, which have much larger genomes. first time in a post-September 11 world the Today, a number of groups are working to feasibility of synthesizing a complete microor- design and construct from scratch bacterial ganism—in this case, a human pathogen—us- genomes as well as simple chromosomes of ing only published DNA sequence information eukaryotic cells (those containing a cell nucle- and mail-ordered raw materials. us), such as yeast.19

The next year, a group from the Venter Insti- Implications of the Technology tute (formerly the Institute for Biological En- ergy Alternatives) published a description of a “Since the sequence is generated by chemical similar technique applied to the construction synthesis, there is full choice in the subsequent of phiX174 (a virus that infects bacteria, called manipulation of the sequence information. a bacteriophage).16 The advance here was not This ability is the essence of the chemical ap- so much in length of the DNA strand, as this proach to the study of biological specificity in virus is somewhat smaller than poliovirus, but DNA and RNA,” Khorana observed in 1979.20 in efficiency: compared to the one year or so Today, the rapidly-advancing technology of required to synthesize and validate infectious synthetic genomics embodies this powerful poliovirus, a precise copy of a fully-functional approach. Whereas other recombinant DNA phiX174 was synthesized in approximately 2 methods start with an organism’s genome and weeks. Although both poliovirus and phiX174 modify it in various ways, with results that are are relatively small viruses, approximately 7400 constrained by the original template, synthetic and 5400 nucleotides respectively, the lessons genomics permits the construction of any learned from these synthesis experiments are specified DNA sequence, enabling the synthe- directly applicable to learning how to construct sis of genes or entire genomes. larger and more complex genomes. This capability provides a new and powerful Designing ways More recently, DNA synthesis techniques have tool for biotechnology, whose most far-reach- to impede been applied to constructing viruses that could ing benefits may not yet even be envisioned. malicious uses of not otherwise be easily obtained in nature or But along with such power comes the po- the technology, from laboratory collections. The genome of tential for harm. Given this inherent dual-use the influenza virus strain responsible for the risk, designing ways to impede malicious uses while at the same 1918 influenza pandemic was constructed of the technology, while at the same time not time not impeding, from scratch, using only the sequence data impeding, or even promoting, beneficial ones beneficial ones available from analyses of DNA from frozen or poses a number of policy challenges for all poses a number paraffin-fixed cells recovered from epidemic who wish to use, improve, or benefit from 17 of policy challenges. victims. Late in 2006, a viral “fossil” of a hu- synthetic genomics. man endogenous retrovirus—a viral genome that had been incorporated directly into the Further, the ability to carry out DNA synthe- human genome at some earlier point in hu- sis is no longer confined to an elite group of man evolution, in this case, around 5 million scientists as was the case for the first several years ago—was resurrected using a variety of decades of research using recombinant DNA. synthetic techniques,18 further illustrating the Now, anyone with a laptop computer can ac- feasibility of reconstructing extinct viruses. cess public DNA sequence databases via the Internet, access free DNA design software, and Additional dramatic increases in the speed and place an order for synthesized DNA for delivery. accuracy of DNA synthesis would be necessary to permit realization of an important goal In addition, synthetic genomics raises new for many in the synthetic biology community: safety issues for those who would be most im-

6 Synthetic Genomics | Options for Governance INTRODUCTION

mediately affected by this research: laboratory far fewer labs than might utilize it otherwise. A policy framework staff as well as the community and the envi- A policy framework to address the devel- to address the ronment surrounding the laboratories. Many opment and use of synthetic genomes for use of synthetic of these safety issues were considered three contained use must precede any analysis of decades ago at the meeting on recombinant the intentional release of engineered micro- genomes for DNA at the Asilomar Conference Center in organisms into the environment; thus we have contained use must Pacific Grove, California, which established the focused on the former. As with several other precede any analysis foundation of biosafety as it is practiced in the general concerns about biotechnology and of the intentional United States today. genetic modification, the intentional release release of engineered of genetically modified microorganisms into microorganisms into Interestingly, at the beginning of the Asilomar the environment is still quite controversial. All meeting it was decided not to consider biolog- such uses are regulated by the Environmental the environment. ical warfare issues, even though the organizers Protection Agency under the Toxic Substances were apparently cognizant of these concerns Control Act.24 at the time and were even prodded a bit about them. According to a contemporaneous We follow several earlier studies that have report on the meeting, “[T]here seems enough looked at societal issues related to synthetic hazard already in pure and simple carelessness, genomics and synthetic biology and that have and at the outset of the conference it has made policy proposals or recommendations. been agreed that the issue of new horizons in Among the earliest was a study examining the biologic warfare will not even be raised; for the bioethics of synthesizing a bacterium25, follow- moment, it is first things first.”21 ing a proposal to use synthetic genomics to construct a minimal bacterial genome.26 Sev- The major biosafety issue discussed at Asilo- eral National Research Council committees mar—the safety of transmitting genes from one have reported on a number of biological se- organism to another organism via a third organ- curity issues.27, 28, 29 The best-known of these, ism (a vector such as a virus or bacterium)— commonly called the Fink Committee Report, has echoes in concerns expressed for synthetic was the basis for the establishment of the Na- genomics today: how to assess the safety of tional Science Advisory Board for Biosecurity chimeric organisms; i.e., those that have ge- (NSABB). 30 The NSABB has already released nomes derived from a very large number of a report on biosecurity concerns related to initial sources. Specifically, using standard re- the synthesis of select agents,31 and an NSABB combinant DNA cut-and-paste techniques, it working group has developed draft guidance is possible to readily assemble a chimera from and tools for the responsible communication tens of sources, but synthetic constructions of dual-use research, including institutional re- could be from hundreds of sources or more. view issues.32 How to evaluate such constructions for biological safety concerns remains murky.22 In 2004, immediately following the first international Synthetic Biology meeting (SB 1.0) While few data suggest that such higher-order George Church put forth a proposal for the chimeras will be dangerous just so, this concern oversight and regulation of DNA synthesizers, has nonetheless prompted some to suggest and for screening for select agent sequences that all synthetic genomics protocols should in DNA orders.33 Later that year, the Biological take place under levels of biological contain- and Environmental Research Advisory Com- ment used for the most dangerous human and mittee of the Department of Energy pub- agricultural pathogens (i.e. Biological Safety lished its own report on the need for action Level -3 or -4).23 Requiring such containment to ensure responsible and thoughtful pursuits would have the effect of making such work in synthetic biology.34 Voluntary community- quite expensive, and would thus restrict it to based approaches for security and safety are

7 discussed in detail in a white paper by Stephen the past eight years, and particularly since the Maurer and others at the University of Califor- events of September 11, other overlapping nia, Berkeley.35 ethical and safety concerns have arisen, and many groups and individuals have expressed Other groups and individuals have made spe- worries about the conduct of synthetic ge- cific proposals as well. The ETC Group pub- nomics research with respect to a broad array lished an introduction to synthetic biology of societal issues. The Rathenau Institute, for that discussed a number of concerns regarding example, has issued a report raising a wide ar- the technology and calling for a ban on the ray of societal and research community issues intentional environmental release of synthetic that warrant more rigorous analytical atten- organisms “lacking a clear pedigree”36. Partici- tion, including the ethics of constructing new pants at the international Synthetic Biology 2.0 synthetic organisms.40 conference issued a statement calling for the scientific community to take steps to mitigate Finally, state-sponsored creation of biological This study focuses security concerns related to synthetic biology, weapons is a concern for all biotechnologies, including synthetic genomics. The Biological on three key such as promoting technologies to ensure that orders for DNA sequences do not con- and Toxin Weapons Convention (BWC), a societal issues: tribute to the illicit production of dangerous treaty with 156 States Parties and another bioterrorism, pathogens.37 The International Consortium for 16 signatories that have not yet ratified 41it worker safety, and Polynucleotide Synthesis, an industry group establishes a crucial international norm pro- protection of com- of commercial DNA synthesis firms, has -de scribing the development, acquisition, or munities and the scribed a potential framework for the screen- production of biological agents as weapons, ing of orders.38 whether produced by synthetic genomics or environment in the any other means. However, the BWC includes vicinity of research The societal concerns about this type of no verification and enforcement mechanisms laboratories. emerging technology are broad in scope and for preventing states from applying synthetic include cultural and ethical concerns about genomics in this way, and many would argue manipulating life, economic implications for that effective measures for that purpose are developed and developing regions, issues re- not feasible. At any rate, multilateral verifica- lated to ownership and intellectual property, tion and enforcement are beyond the scope concerns about environmental degradation of this paper. Individual nations may also apply and potential military uses, and so on. Each of diplomatic or military pressure to other na- these issues deserves thorough consideration. tions they believe to be violating norms such As mentioned above, at the time of the first as the BWC. suggestion of building bacteria from scratch, an ethics study was commissioned and the results Societal issues addressed in this study were published along with the publication of preliminary data on defining a minimal bacte- This study focuses on three key societal issues: rial genome. The study group found that there bioterrorism (for reasons described above), was nothing inherent in synthetic genomics re- worker safety (a critical part of the scientific search that made it unethical: “The prospect of enterprise), and protection of communities constructing minimal and new genomes does and the environment in the vicinity of legiti- not violate any fundamental moral precepts or mate research laboratories (those most likely boundaries....”39 to be affected by an accident).

Nevertheless, the authors noted that: “…[con- We restricted our purview to synthetic ge- structing minimal and new genomes] does raise nomics and did not attempt to evaluate or questions that are essential to consider before assess broader issues associated with research the technology advances further.” Indeed, over involving pathogenic microorganisms in partic-

8 Synthetic Genomics | Options for Governance INTRODUCTION

ular or biotechnology in general. These latter ing responsibility is an outcome of the analysis issues, including the deliberate environmental and not an input to it. release of genetically modified organisms, have been controversial for decades and are be- We made no assumptions as to whether the yond the scope of this effort. options should be voluntary or legally binding (regulatory) in nature and if so, who the regula- Further, we do not deal with state-sponsored tors should be. By the same token, we do not research and development programs. No gov- presuppose that the scientific community will ernance measure imposed by a national gov- automatically address these issues on its own. ernment will be effective at constraining that government’s own activities if the responsible Many have pointed out that the ability to de- officials within that government choose to tect, contain, and treat illness that might result evade, ignore, or interpret their way around from the accidental or intentional release of a them. Moreover, no measure taken by re- harmful synthetic organism can be no better searchers, firms, or other non-state entities than the ability to respond to naturally occur- operating within a government’s jurisdiction ring outbreaks or to bioterrorism attacks with can necessarily be relied on to resist pressure existing pathogens, which many believe to be Some of the by that government. In the current interna- inadequate.42 To remedy this broader vulnera- tional system, the only way to deal with abuses bility, a robust public health infrastructure, rou- options can be of national governments is through the actions tine surveillance for unexpected threats, and a implemented of other governments, either collectively or flexible, responsive, and adaptive capability for only by government individually. Such mechanisms are beyond the developing, producing, and distributing medical regulation; others scope of this study. countermeasures (detection, diagnosis, vac- only by community cines, drugs, etc.) is critical. Biodefense funding agreement. But Our goal was to develop policy options to ad- through the National Institutes of Health is ad- assigning responsi- dress the incremental (novel) risks and benefits dressing some of these needs.43 The recently presented by synthetic genomics technologies. created Biomedical Advanced Research and bility is an outcome These policy options, presented in a later sec- Development Authority (BARDA)44 will ad- of the analysis, not tion, are organized by actions to be taken and dress these needs as well. Improvements in an input to it. policies to be adopted, rather than in terms of the general ability to detect and respond to who would implement them. Although some public health threats in general will of course of the options addressed here can be imple- apply to any threats from synthetic genomics mented only by government regulation, and specifically as well. others only by community agreement, assign-

9 Benefits and Risks

Benefits

Recombinant DNA technologies allow individu- these basic technology services will have far- als to construct novel DNA molecules by joining reaching economic impacts as enablers of in- and modifying fragments of pre-existing genetic novation in many industrial sectors.” material. Today, such work is typically carried out by experts in laboratory settings. The work itself Synthetic genomics is even today changing the is often ad hoc and laborious. It is not uncom- nature of basic molecular biological research. mon for skilled researchers to commit months As an enabling technology, DNA synthesis of effort to constructing the genetic material has already proved to be a significant time needed just to start a specific experiment. saver by shortening the time needed for time- consuming recombinant DNA techniques; in DNA synthesis By contrast, DNA synthesis allows “decoupling” the coming 5 to10 years DNA synthesis will allows “decoupling” the design of engineered genetic material from continue to become less expensive as well. the actual construction of the material. DNA Using synthetic genomics to rapidly change the the design of can be readily designed in one location and sequence of various genes or whole genomes engineered genetic constructed elsewhere. As a result, research- is becoming a powerful tool for basic research material from the ers can devote their time and energy to focus- in a number of disciplines. For example, vari- actual construction ing on the actual challenges of their research ous laboratories are using synthetic genomics of the material. (Figure 3). A secondary result of this techno- to understand the mechanisms of evolution logical advance is that experiments may be at the molecular level,47, 48 to define regula- designed to look at wide varieties of sequence tors of specific genes or gene pathways and variations in experimental settings. to establish, at the molecular level, the minimal requirements for life.49 Over the course of the study, we identified several major areas where synthetic genomics This capability to make subtle changes at the could make a unique or significant contribu- DNA sequence level may lead to more efficient tion: as an enabling technology that is changing research and production of vaccines for hu- the nature of basic biological research and as a man and animal health and related diagnostics. powerful tool of applied biotechnology with the Specifically, the ability to assemble and mutate potential for developing new pharmaceuticals, sequences rapidly could allow for the devel- biological sources of transportation fuels, and opment of broadly protective vaccines against, manufacturing of other bio-based products. and diagnostics for, viruses that themselves are diverse and variable, such as the viral causative A recent report46 from Bio Economic Re- agents of severe acute respiratory syndrome search Associates estimates that the current (SARS)50 and hepatitis C.51 global market for DNA synthesis reagents and services is nearly $1 billion, and that the DNA synthesis techniques have already been “productivity of DNA synthesis technologies applied in research on new or improved drugs. has increased approximately 7,000-fold over For example, the antimalarial drug artemisinin the past 15 years, doubling every 14 months. is naturally produced in the plant Artemisia Costs of gene synthesis per base pair have annua through a complex metabolic pathway fallen 50-fold, halving every 32 months. At that cannot feasibly be reconstructed in yeast the same time, the accuracy of gene synthesis using conventional biotechnological methods.52 technologies has improved significantly.” The Purification from the natural plant source is a article concludes that “the rapid expansion of process that is inefficient, expensive, and can

10 Synthetic Genomics | Options for Governance BENEFITS AND RISKS

Figure 3, Panel A: Research protocol without synthetic genomics.45

Figure 3, Panel B: Research protocol with synthetic genomics.

FIGURE 3. An immediate application of synthetic genomics. Much time in research and other laboratories is spent manipulating DNA to then conduct experiments. Synthesizing the desired sequence directly saves time and thus allows scientists and engineers to focus on the actual experiments. A second result of this advance is that experiments may be designed to look at wide varieties of sequence variations in experimental settings. Panel A describes a research protocol that took three years of effort. In contrast, ordering the equivalent DNA (Panel B) may take six weeks from order to delivery.

Synthetic Genomics | Options for Governance 11 Using synthetic contaminate the product with other plant mate- and microbes are being engineered to produce genomics to rial. Supply depends on the weather and even raw materials that can be used to manufacture rapidly change the the political situation in regions where the plant products that today are typically petroleum- is found. As a first step toward the eventual based. The expectation is that biologically based sequence of production of artemisinin in yeast, researchers manufacturing will lead to more environmentally various genes or inserted a synthetic gene for the precursor friendly products and methods of production. whole genomes is artemisinic acid into a strain of yeast that had For example, the environmental impacts of plastic becoming a power- been engineered to produce large amounts of manufacturing might be lessened through the ju- ful tool for basic product. The production of artemisinic acid in dicious use of bioengineering of metabolic pathways using synthetic genomics as one tool.58, 59 research in a number yeast is currently being optimized for industrial scale-up. of disciplines. Finally, millions of new genes are being discov- Another research group53 has described the ered through metagenomic surveys of micro- total synthesis of a 32,000 base-pair gene organisms living in natural environments, look- cluster that codes for polyketide synthase. This ing at thousands of species at the same time. DNA synthesis was notable for its length (it Some of these newly identified genes could remains one of the longest syntheses pub- be important for engineering specific pathways lished to date) and more important that it into microbes as described above. Because the yielded an active gene product. The enzyme it genes come from microorganisms that typi- encodes is in a class of enzymes that are in the cally cannot be cultured in the laboratory, the synthetic pathways of extremely important genes or genomes of interest are known only drugs (including antibiotics, transplant rejec- by their DNA sequence. Synthetic genomics tion suppressors, and potential anti-cancer could allow for the reconstruction of these drugs). Synthesizing many variants of these potentially important new genes. genes could provide pools of potential drugs, which could then be screened for the desired properties.54 Risks

Synthetic genomics could also contribute to We looked specifically at three potential risks the search for carbon-neutral energy sources. from the use of synthetic genomics: the risk of A major application of synthetic genomics its use in bioterrorism, risks to the health of could be in overcoming biological barriers to laboratory workers and to the public, and pos- cost-effective production of biofuels.55 Con- sible harm to the environment from accidental solidated bioprocessing (CBP) of cellulosic release of microbes with synthetic genomes. biomass to ethanol is a particularly promising target for this new technology. Scientists are To help us better understand the magnitude trying to engineer a single organism to include of current risks, we commissioned papers all the multiple steps needed to produce etha- from two well-known virologists. We asked nol from cellulose (or at least the fermentable them to assess the ease or difficulty of syn- sugars preceding ethanol production).56 While thesizing a long list of pathogenic viruses, and the use of synthetic genomics to produce all to compare that to the ease or difficulty of of the enzymes needed for CBP is not the obtaining that virus by other means. We were only technique available, it is among the most convinced by their analyses and further discus- promising. If successful, CBP might be able to sion at the workshops and the meeting that produce ethanol at a cost competitive with today, any synthesis of viruses, even very small gasoline.57 or relatively simple viruses, remains relatively difficult. In the near future, however, the risk of Sometimes called “white biotechnology,” bio- nefarious use will rise because of the increas- based manufacturing is becoming a reality. Plants ing speed and capability of the technology and

12 Synthetic Genomics | Options for Governance BENEFITS AND RISKS

its widening accessibility. How much the risk while the naked nucleic acids of some viruses will increase remains a matter of debate. are infectious on their own (mostly positive- stranded RNA viruses), other viruses require Over the next five years, the key concern is for additional molecular components to replicate synthesis of a small number of highly patho- and hence be infectious. genic viruses that are otherwise difficult to obtain. Ten years from now, it may be easier to Even more important, synthesis is by no means synthesize almost any pathogenic virus than to the only way a potential bioterrorist might obtain it through other means. Eventually, the obtain a “threat” virus (a virus that is easily synthesis of bacterial pathogens may become disseminated or transmitted, has a potential possible as well. public health impact or could cause public panic, or that could cause social or economic In discussions in the workshops and the invita- disruption). Most viruses can be obtained in tional meeting, we also considered risks from the nature, although several are hard to find and a Over the next five construction of microbes not currently seen as few are no longer extant. years constructing pathogens of any specific biosecurity concern, an infectious virus and from experiments involving the synthesis of Extinct viruses that are also potential threat will remain more completely novel DNA sequences. While these agents are of greatest concern with respect scenarios may be of concern in the future they to the application of synthetic genomics, as difficult than are not a major issue today. The policy options there is no other way to obtain them. Variola obtaining it from that we propose later in this paper are appli- (smallpox) virus remains of highest concern; nature or from cable both to today’s risks and to those that the 1918 influenza virus follows closely behind. laboratory stocks... might emerge over the next decade. (In both cases, samples of the viruses exist in a with a few impor- few laboratories, but access to these stocks is tant exceptions. The commissioned papers focus on the im- tightly controlled). pact of synthetic genomics on the production of viruses that could be used as agents Of the viruses that are still found in nature, of bioterrorism or biological warfare.60, 61 The some are easier to find than others. For ex- papers explore in detail the risks posed by the ample, many viruses have reservoirs that are construction of various classes of viruses.ix unknown, poorly understood, or only accessible during active outbreaks: the filoviruses The techniques used for synthesizing genomes such as Marburg and Ebola are among these. as discussed above are by no means the only Thus, acquiring such viruses would require way to construct a viral genome. For several some luck, good timing, the skill to recognize years, laboratories have been synthesizing viral and isolate the virus of interest, and the abil- genomes using other techniques. The differ- ity to transport the virus safely away from the ence now is that the new techniques provide site of an outbreak. Foot-and-mouth disease incremental improvements in cost, speed, and virus, while endemic in parts of the world, is accuracy. Viruses can be constructed using not found in the United States. While it would synthetic genomics with varying degrees of be possible for someone to introduce the vi- difficulty. Sequence data are available for many rus into the United States to precipitate an highly pathogenic viruses, but the quality (ac- outbreak, doing so would require a series of curacy) of these sequences varies. In addition, steps that might draw attention to a person

ix There are several different approaches to categorizing viruses. One is that described by David Baltimore; it classifies viruses according to the strategy they use to generate messenger RNA. Because at least a good part of the ease or difficulty of constructing a virus synthetically hinges on whether synthesized DNA could produce infectious mRNAs on its own, this was for us a particularly useful organizational scheme.

13 Virus Type; length of Select Where Found Difficulty of Synthesis nucleic acid Agent

Variola dsDNA;180kb Yes Locked lab Difficult

1918 influenza ssRNA, negative Yes Locked lab Moderately difficult stranded; 8 segments ~10kb total

H2N2 ssRNA, negative No Laboratories Moderately difficult influenza stranded; 8 (extinct 1968) segments ~20kb total

Poliovirus ssRNA, positive No Laboratories; in Easy stranded; ~7.7kb widely in nature Africa and Asia

Filoviruses ssRNA, negative Yes During active Moderately difficult to (Ebola, Marburg) stranded; ~19kb outbreaks difficult

Foot-and-mouthss RNA, positive Yes Certain hoofed Easy disease virus stranded; ~9kb animals

SARS ssRNA, positive No 2003 strain in labs Moderately difficult stranded; ~30kb to difficult

Table 2: When is synthesis the preferred route for obtaining viruses? The column labeled “Dif- ficulty of Synthesis” is the consensus of various virologists and molecular biologists who partici- pated in our workshops and meetings. The judgment applies to someone with knowledge of and experience in virology and molecular biology and an equipped lab but not necessarily with advanced experience (“difficulty” includes obtaining the nucleic acid and making the nucleic acid infectious).

with malicious intent. A motivated bioterrorist at least in the United States, they are handled particularly might want to avoid any attention under BSL-3 conditions and their distribution that might come with moving in and out of is thus at least somewhat monitored. Inquiries the country. about obtaining these viruses from individuals not known to be legitimate researchers should For several years, Viruses are also stored in laboratories as raise suspicions. It is worth noting as well that laboratories have experimental stocks and clinical isolates, and approximately 8000 patient samples that may been synthesizing some can be obtained from repositories, harbor the virus likely are stores in hospital viral genomes such as the American Type Culture Collection freezers throughout the world. To date, there using other (ATCC).62 Every virus on the Select Agent has been no systematic effort track, recover, 63 techniques. The List is located in a laboratory somewhere. and centrally preserve and isolate these speci- difference now Select agent viruses are subject to oversight mens from the larger community. and regulation, but other viruses that are not is that the new on the list may also be of concern. For exam- A key hurdle for constructing a robustly infec- techniques provide ple, the coronavirus responsible for the 2003 tious virus is being able to replicate the correct incremental im- SARS outbreak is almost certainly extinct in genomic sequence. This task is not as straight- provements in cost, nature. While many labs may have epidemic forward as it would initially appear, as viruses speed, and accuracy. strains or clinical isolates in their possession, that have been maintained in a laboratory set-

14 Synthetic Genomics | Options for Governance BENEFITS AND RISKS

ting tend to accumulate mutations; these labo- virus supplying that particular sequence was Ten years from ratory strains are the source for many viral in nature or in the laboratory. Thus, poliovirus now, it may sequences currently in databases (the DNA is relatively easy to synthesize because it has a be easier to sequences in databases are continually being small genome made up of positive-stranded synthesize almost updated, however, especially for viruses of RNA and because a large amount of data is scientific and societal interest). Further, merely available on sequences of known virulence. any pathogenic synthesizing the genome is only one step in a Variola (smallpox) virus, in contrast, is harder virus than to process that requires many steps. to synthesize because it is a very large DNA obtain it through virus for which there are fewer data relating other means. For the purposes of this report, we take as a infectivity to sequence. given that now, or within a few years, any virus with a known sequence can or will be able to The key conclusion from the papers and dis- be constructed in a relatively straightforward cussion at the workshops was that over the manner. How functional any of these con- next five years constructing an infectious virus structed viruses would be is not clear. Several will remain more difficult than obtaining it from important factors must be kept in mind. For nature or from laboratory stocks, with a few example, the source of a virus is paramount. important exceptions. In ten years, however, Viruses found in nature (particularly during an the situation might be reversed. For someone active outbreak) will probably always be the hoping to inflict harm, constructing a patho- only “sure thing.” Constructed viruses (or even genic virus might actually be easier than going viruses somehow obtained from a laboratory) could be as virulent as wild type viruses, but to the trouble of isolating it from nature or could just as easily be attenuated. stealing it from a secure laboratory.

Table 2 contains our best “guesstimate” of Constructing a “designer virus” or “super- the overall difficulty of synthesizing specific pathogen” from scratch was seen as a more viruses. This evaluation is based on several distant concern, although several examples of factors: bigger viruses (longer nucleic acid unexpected increases in pathogen virulence sequences) are harder to synthesize than using recombinant DNA approaches have smaller ones; positive-stranded RNA viruses been published in the literature.64 Given the (in which the nucleic acid is infectious on its current limitations on the understanding of own) are easier to construct than negative- viral pathogenesis and the immune response, stranded RNA viruses, which in turn are easier using synthetic genomics to increase the patho- than DNA viruses. Finally, available sequence genicity of known viruses was considered to data does not always report how virulent the be a more probable risk.

15 The Study

The goal of this study was to formulate governance options malicious use of the technology. Based on commissioned that will minimize safety and security risks from the use of papers, the attendees examined the materials, equipment, synthetic genomics, without unduly impeding its development and know-how needed to go from raw materials to phos- as a technology with great potential for social benefit. We phoramidite precursors to finished oligonucleotides to full- focused on three concerns: bioterrorism, worker safety, and length genes. The workshop also explored the capabilities protection of communities and the environment in the vicin- of current computer software for screening oligonucleotide ity of legitimate research laboratories. We did not attempt and gene-length orders for defined DNA sequences found to evaluate or assess broader societal issues associated with in pathogens. Focusing mostly on viruses, participants also use of biological weapons in particular or biotechnology in considered explicitly how the availability of certain kinds of general, for example, we did not consider deliberate release equipment (e.g. DNA synthesizers) and know-how affect of engineered microorganisms in the open environment. how easy or difficult it is to construct a microorganism from These broader issues have been controversial for decades raw materials. and are beyond the scope of this analysis. The second workshop explored both the applications (ben- Our goal in this study was to construct policy options based efits) and potential dangers or misuses (risks) of the tech- on the incremental (novel) risks and benefits presented by nology. Risks and Benefits Specifically Attributable to Synthetic synthetic genomics technologies. Specifically, these are the Genomics, held in February 2006, explored the question, risks and benefits beyond those associated with today’s “How does a world with synthetic genomics differ from a widely-used biotechnologies. world without it?” With respect to security or safety risks, a key finding of this workshop was that today there are far The four authors of the report designed and held several easier ways to obtain a pathogen than by synthesis, with a workshops to gather and help analyze information. We as- few important exceptions. However, within a decade it may sembled a core group of 18 people (including ourselves) be possible to synthesize any virus. Moreover, in many cases described in Appendix I; most attended every workshop it could be easier to synthesize a virus than to find it in and were very important in assuring that we identified, re- nature or to obtain it from a laboratory. searched, and analyzed each policy challenge and option. In addition to the core group, each workshop involved other The workshop also explored various aspects of biosafety. A experts relevant to the workshop topic. key concern was the number of new researchers coming The core group described in Appendix I included a wide into the field from non-microbiology backgrounds, and thus variety of perspectives, including synthetic genomics re- lacking experience in handling dangerous pathogens, increas- searchers, commercial suppliers of synthesized DNA, policy ing the risk of laboratory accidents. Issues surrounding the analysts who focus on bioterrorism, and those who focus on risk assessment of novel genes and genomes (those made the legal, ethical, and societal implications of biotechnology. as chimeras from many different initial sources) were briefly The invitational meeting, described below, included an even discussed. wider range of participants and perspectives. At the final workshop in May of 2006,Governance , we began Each workshop also included government observers, mostly to evaluate the various policy options that were identified ex officio members of the National Science Advisory Board during the first two workshops. We explored the current on Biosecurity. Government officials also attended the invi- regulatory mechanisms governing synthetic genomics and tational meeting. evaluated new measures with potential for mitigating risk while preserving benefits. We held three workshops over 20 months. The first workshop in September 2005 examined Synthesis Technologies. An invitational meeting was held in December 2006, bring- This workshop focused on currently available DNA synthe- ing together, in addition to those who attended the earlier sis technologies and how those technologies might evolve workshops, many governmental agencies, scientists, and, most over the next 5 to 10 years. This workshop also identified important, additional stakeholders who were not present at opportunities for technical interventions to impede the our earlier workshops. FRAMING A POLICY RESPONSE

Framing a Policy Response

In the mid-1970s, influential scientists who mechanisms can help to effect an international had pioneered the emerging techniques of consensus on some of these issues, probably genetic engineering called for a moratorium much faster and more effectively than govern- on recombinant DNA research until the safety mental negotiations or treaties would. implications of that work could be more thor- oughly reviewed. The 1975 Asilomar Conference As discussed above, the scientific community marked the initiation of such a review, which has already begun to address what actions it has continued on an ongoing basis ever since. can take on its own to protect the ability of Although the initial concerns were clearly ap- science to advance without contributing to propriate at the time, subsequent experience state biological weapons programs or to the has shown not only that recombinant DNA actions of rogue bioterrorists. At the same research can be performed safely, but that time, the scientific community, law enforce- many of the restrictions put into place after ment, and national security officials and oth- the conference were unnecessarily restrictive. ers are exploring whether a legally binding On numerous occasions over the subsequent regulatory regime is needed to lessen the risk thirty years, restrictions on recombinant DNA that research materials, expertise, and facilities research have been relaxed, showing the wis- could be used to make weapons. dom of a governance regime that can be readily tailored on the basis of additional experience. A preferred policy solution would both minimize the risks from nefarious uses and mini- There have been suggestions that synthetic mize the impediments to beneficial uses of the genomics needs “another Asilomar.”65 But Asi- technology. Thus, our challenge has been to lomar was an exercise in self-governance: the formulate a series of governance options, rec- Our challenge community determined and imposed on itself ognizing and evaluating the trade-offs between has been to those procedures needed to ensure safety.66 their ability to reduce the safety and security Bioterrorists, by definition, are not willing to risks from the use of synthetic genomics and formulate a series accept the norms of the research community, the burdens that they would impose on scien- of governance and no community can control all subsequent tists, industry, and the government. options, recognizing uses of the research results or techniques it the trade-offs develops. We have also tried to catalyze discussion with- between their in the scientific community on the responsible ability to reduce The research community can, however take conduct of synthetic genomics research, while actions to lessen the risk that scientific and at the same time broadening that discussion risks, and the technical advances might be misapplied. Such to include other communities, including the burdens that they actions will help maintain confidence among funders, potential regulators, and customers of would impose. decisionmakers and the public that the con- synthetic biology research and applications. tinued advance of science and technology will be beneficial to society. Both questions came to the fore after the attacks of September 11, 2001, and the subsequent anthrax letter mailings, which threatened to change the re- lationship between the security community, the biological sciences, and the public. More- over, community action and other less formal

17 Policy goals

In the following sections, we present 17 op- Additional considerations tions for the governance of synthetic genomics. These options address three key policy goals: Finally, we discuss two additional key considerations: • Enhancing biosecurity, either by preventing incidents of bioterrorism • Thinking beyond the U.S border to or by helping law enforcement identify possible international implementation. those responsible if incidents should occur. • Keeping pace with evolving science and • Fostering laboratory safety, either by technology. preventing accidents or by helping to respond in the event an accident does A general concern for the implementation of occur. every option is whether lack of international implementation would render that option in- Protecting the environment, the • effective. Obviously, all of the options would people and natural ecosystems outside be more effective if adopted by all countries the laboratory. involved in synthetic genomics. However, this fact does not eliminate the value of unilateral For each of the 17 options, we have included implementation; it may just lead to a smaller our judgment about their relative effectiveness incremental improvement. Under each of the for achieving each of these three goals. options we briefly explore the importance of international implementation. Other evaluation criteria A final consideration is that the science and Of course, the overall desirability of an option technology of synthetic genomics is relatively depends on a host of other considerations, as new and is advancing and evolving rapidly. well. Thus, we have evaluated how well each There is no crystal ball with which to pre- option fares with respect to four other key dict the future, nor are there policies robust criteria: enough to accommodate all plausible futures. Policymakers To keep pace with such a dynamic situation, Does the option hold down costs and might choose to • policymakers might choose to adopt a frame- other burdens to both government work of “adaptive decision making.” Following adopt a framework and the affected industry? this approach, policymakers would put in place of adaptive decision • Can the option be implemented today, a suite of options that match today’s technolo- making to keep or is additional research required before gies, the magnitude of today’s risks and ben- pace with the it will be effective? efits, and societal priorities. The keys to success are to 1) closely monitor the progress of rapidly changing Does the option unduly impede • the science and technology, and 2) be prepared biological research or progress by the technology of and willing to modify the suite of options ac- biotechnology industry? synthetic genomics. cordingly. Not only might tomorrow’s choice • Does the option help to promote of options be different, but the array of options constructive applications of the from which to choose from might be drastically technology? altered as well.

18 Synthetic Genomics | Options for Governance POLICY OPTIONS

Policy Options

Identifying intervention points The portfolio of policy options

We identified several promising points for Below are three groups of policy options rel- policy intervention by considering the several evant to the governance of synthetic genom- We identified ways a gene or genome can be synthesized. ics. The evaluations are presented both in text four “factors of Specifically we identified four “factors of pro- and in a summary chart. The chart is helpful production” duction” needed to construct genes or ge- for comparing the effectiveness of the various needed to nomes: raw materials and reagents, sequence options in enhancing security and safety against information, equipment, and know-how. other considerations, such as implementation construct genes costs. Policy options were evaluated as de- or genomes: raw To thwart the intent of a potential bioterrorist, scribed above. materials and points for policy intervention include: reagents, sequence The options presented in Table 3, below, are information, • At the point of DNA synthesis itself derived from a variety of inputs. In our initial research, we identified a general set of- con equipment, and Gene synthesis companies (selling cerns and stakeholders that would be relevant know-how. whole genes and genomes) to any discussions of security and safety. Over Oligonucleotide manufacturers (selling the course of the three workshops and discus- short stretches of DNA) sions with the core group and other partici- Laboratory-benchtop DNA synthe- pants, we developed a deeper understanding sizers used in individual laboratories to of the needs of various actors and how these make short stretches of DNA groups interact with each other. Some of the options were suggested by individuals; others Raw materials (when linked with the were developed by discussions of the larger control of DNA synthesizers) group. In all cases, we evaluated each policy option on the criteria (policy goals and other con- The points for potential intervention to en- siderations) described in the previous section. hance laboratory safety and minimize risks to the environment include: Reading the evaluation diagrams The investigator, through such mechanisms • Five levels of effectiveness (plus “not relevant”) as were assigned, with circles having more dark fill Education indicating better performance on a given goal Training tools, such as manuals and or consideration. These levels are qualitative: clearinghouses they only indicate that one option performs • Oversight bodies, such as Institutional better or worse than another, but not by how Biosafety Committees much. Comparisons can be made within or between options. The options below address each of these intervention points.

19 Table 3: Table of Options

IA. Policies for commercial gene- and genome synthesis firms

1. Require commercial firms to use approved software for screening orders. 2. People who order synthetic DNA from commercial firms must be verified as legitimate users by an Institutional Biosafety Officer or similar “responsible official”. 3. Commercial firms are required to use approved screening softwareand to ensure that people who place orders are verified as legitimate users by a Biosafety Officer. 4. Require commercial firms to store information about customers and their orders.

IB. Policies for commercial oligonucleotide synthesis firms

II. Policies for monitoring or controlling equipment and reagents

1. Owners of DNA synthesizers must register their machines. 2. Owners of DNA synthesizers must be licensed. 3. A license is required to both own DNA synthesizers and to buy reagents and services.

III. Policies for users and organizations for promoting safety and security in the conduct of synthetic genomics research

1. Incorporate education about risks and best practices as part of university curricula. 2. Compile a manual for “biosafety in synthetic biology laboratories.” 3. Establish a clearinghouse for best practices. 4. Broaden Institutional Biosafety Committee (IBC) review responsibilities to consider risky experiments. 5. Broaden IBC review responsibilities and add oversight from a national advisory group to evaluate risky experiments. 6. Broaden IBC review responsibilities, plus enhance enforcement of compliance with National Institutes of Health biosafety guidelines.

20 Synthetic Genomics | Options for Governance OPTIONS FOR COMMERCIAL FIRMS

A small number of firms—on the order of Although it is I. Policies for commercial 50 worldwide, with about half in the United certainly possible to synthesis firms States—specialize in synthesizing gene- and synthesize a gene- genome-length pieces of double-stranded DNA which are sometimes incorporated into or genome-length living cells for shipment. Again, using the ex- piece of DNA using De s c r i p t i o n o f t h i s intervention p o i n t ample of the 1918 influenza virus, the genome a DNA synthesizer consists of eight segments ranging in size from in one’s own 67 Today, most researchers who need custom about 900 to 2300 base pairs. A bioterrorist laboratory, the could conceivably order the eight segments DNA sequences order them from commer- work can be cial suppliers. Although it is certainly possible and then, with minimal additional manipulation, accomplished more to synthesize a gene- or genome-length piece insert them into an animal cell to form the of DNA from its basic building blocks using a complete virus. efficiently and DNA synthesizer in one’s own laboratory, the accurately by firms work can be accomplished more efficiently For a potential bioterrorist, assembling a that specialize in and accurately by firms that specialize in this genome from these larger pieces would be this service. service. A researcher ordering a particular less difficult technically than starting with piece of DNA submits the desired sequence the shorter-length oligos, and far less time- electronically over the Internet. The DNA is consuming. Much of the highly skilled labor synthesized in a specialized facility and then needed to synthesize a genome is, in essence, shipped to the researcher. By using such firms, readily available for hire in the form of exper- researchers obtain more accurate DNA for tise within the synthesis firms. Thus, we believe their experiments, avoid the need for expen- that options that focus on firms that can syn- sive equipment, and minimize the amount of thesize gene and genome-length stretches of technical expertise needed. DNA and RNA are top priorities for preventing nefarious uses of synthetic genomics. Similarly, the easiest path for a bioterrorist to synthesize a pathogen would be to obtain The difficulty of constructing a genome from custom-ordered DNA from a commercial commercially synthesized oligos is compa- firm. For most pathogens at present, however, rable to the difficulty of starting with oligos synthesizing a genome would be more diffi- constructed in one’s own lab with a privately cult than either stealing it from a laboratory owned DNA synthesizer. However, ordering or isolating it in nature. However, as discussed oligos from commercial firms clearly saves above, for a few viral pathogens that are very time compared to synthesizing them in one’s difficult to obtain otherwise, synthesis isa own lab; thus, screening by oligo suppliers plausible alternative. may be the next best intervention point for preventing potential incidents of bioterrorism Today, two types of firms supply synthesized using synthesized DNA. DNA. The first type supplies shorter-length oligonucleotides (single-stranded DNA), typically up to 100 base pairs in length. The bulk De s c r i p t i o n o f o p t i o n s of the synthetic DNA (and RNA) market is for such shorter-length pieces, which are used Commercial DNA synthesis firms have no for a variety of purposes. As the first step in interest in supplying potentially harmful pieces synthesizing the 1918 influenza virus, for ex- of DNA to users who are not using them for ample, a researcher (or a bioterrorist) might legitimate research purposes or who may be order several hundred oligo-length pieces of unaware of danger to themselves or others. DNA that could be assembled to construct the entire 14,600 base pair genome.

21 Below we present options to: 1) detect and I-1. Require commercial firms to use thus prevent shipment of harmful genes or ge- approved software for screening orders nomes, 2) detect people who place orders but have no legitimate need for such sequences, As mentioned above, commercial firms can and 3) record these shipments for surveillance use computer software to compare the DNA or forensic purposes. sequence submitted by their customers to the sequences of known pathogens. Several Two general approaches are possible for screen- groups and individuals have proposed this op- ing DNA orders prior to synthesis. First, one tion: first, George Church in a white paper;69 can use computer software to compare the and later the Synthetic Genomics Working submitted DNA sequence to that of known Group of the National Science Advisory Board pathogens. First-generation software for this for Biosecurity;70 members of the International purpose is available and already in use at sev- Consortium for Polynucleotide Synthesis, an eral gene- and genome synthesis companies.68 industry group of commercial DNA firms;71 However, software improvements and a more and many researchers in a Declaration of the refined list of potentially harmful genes and ge- Second Meeting on Synthetic Biology.72 nomes would greatly enhance the effectiveness of computer-based screening. These research First-generation screening software currently needs are discussed later in this section. exists73 and is being used by several firms today.x Firms that supply synthesized DNA The entire responsibility and burden for screen- could be required to use “certified” software ing does not have to fall on the commercial that compares the sequence of submitted firms that synthesize DNA. The vast majority DNA orders to those of known pathogens. of their customers are employed by universities, research institutes, or private firms such as As mentioned previously, commercial DNA pharmaceutical companies. Most such institu- synthesis falls into two rather distinct products: tions employ a trained biosafety professional. 1) synthesis of short oligonucleotides, typically By requiring that biosafety professionals be up to about 100 bases long and 2) gene-length part of the ordering process, one can ensure synthesis, producing pieces of DNA hundreds that all orders are from legitimate researchers to thousands of base pairs long. Designing working at known institutions and not from a screening system that is effective—both rogue individuals. technically and administratively—for screening shorter, oligo-length pieces will be more Finally, there is merit to storing information of a challenge than designing one for gene- about previously placed orders for forensic length pieces of DNA. Many short stretches purposes in the event of a bioterrorist at- of DNA from common genes look virtually tack. The sequence of the pathogen can be the same in benign organisms and pathogens. compared to past synthesis orders to identify Moreover, since oligos are used in a wide vari- potential matches. ety of different applications, the sheer volume of production of oligos far exceeds that for In the following section, we first describe each synthesis of genes and genomes. In addition, of these options and then compare the advan- the turnaround times with which oligos are tages and disadvantages of each. typically delivered is much shorter, making it more difficult to incorporate anything other than completely automated screening into the production process.

x Discussions about this and related approaches at Workshop 1 of this project based on commissioned paper from R. Jones. http://dspace.mit.edu/handle/1721.1/39656

22 Synthetic Genomics | Options for Governance OPTIONS FOR COMMERCIAL FIRMS

Fortunately (at least with respect to bioterror- burdens the first time a researcher places an ism), synthesizing a pathogen is more difficult order with a firm, repeat orders from previ- and more time-consuming when starting with ously verified individuals would be processed oligos than with gene-length pieces of DNA. more rapidly. Thus, screening could be required only for gene synthesis companies that supply longer Note that for some DNA sequences, firms are sequences (for example, greater than 500 already required to limit shipments to those base pairs), or for all commercially synthesized researchers authorized to receive them. The DNA, regardless of length, including those Select Agent regulations cover transfers of syn- from oligo suppliers. The strengths and weak- thetic DNA or RNA within the United States nesses of this and other options are discussed if the genetic material can be expressed as a separately for gene synthesis companies and select virus or toxin.74 (This is, however, only a Firms that supply for oligo suppliers in a later section. small portion of the total genetic sequence of synthesized DNA all pathogens on the Select Agent list.) could be required For sequence screening to be effective, the FBI to use “certified” or similar agency must establish a procedure Facilities sending and receiving Select Agent software that com- for commercial firms to follow in the event materials must be registered with either the pares the sequence that a suspicious sequence is detected. Clearly, Centers for Disease Control and Prevention if the order is from a bioterrorist attempting (CDC) (for human pathogens) or the Animal of submitted DNA to synthesize a pathogen, the FBI should be and Plant Health Inspection Service (APHIS) orders to those of notified. However, the alarm might go off for of the U.S. Department of Agriculture (for ani- known pathogens. two other reasons. mal and plant pathogens), and each transaction must be reported. The NSABB has pointed First, the specified DNA sequence might be out that even for this small subset of the Select very similar to one found in a benign organ- Agent list, reporting requirements are not well ism as well. (Many genes, such as those that understood by either commercial firms or the take care of basic metabolic functions, have researchers themselves. close relatives in many organisms.) To avoid this situation, the screening software must be Finally, to ensure that legitimate laboratory combined with a carefully constructed list of workers fully understand the nature of the sequences that can detect pathogens of con- DNA that they have ordered, the results of cern while avoiding false alarms. screening should be sent to the researchers along with the synthesized DNA. While it is The second type of false alarm is of a differ- unlikely that potentially harmful sequence ent nature. The DNA order might have been would be ordered and thus used inadvertently, placed by a legitimate researcher from aca- it is certainly a possibility worth avoiding. demia or a pharmaceutical company working with a dangerous pathogen to better understand the nature of the disease or its cure. If I-2. People who order synthetic DNA from the software is working as designed, this type commercial firms must be verified as legitimate of alarm should far outnumber any other. users by an Institutional Biosafety Officer or similar “Responsible Official” Thus, some method must be used to determine whether the order is from a legitimate Rather than making the DNA synthesis firms researcher or not. Currently, firms that use responsible for verifying the identity of a re- screening software assume the responsibility searcher who places an order, this responsibil- of determining whether the order is being ity could be shifted to the research institutions placed from a legitimate researcher. A type of where the scientists work. In particular, under identity check will add costs and administrative this option, staff members that place orders

23 for synthetic DNA would have to be verified vironment, or consistency with a researcher’s as legitimate users by the institution’s biosafety lines of experimental inquiry. Clearly, however, officer. In order to accept an order, commer- examining each order individually would add cial firms would need to see that a registered to his or her workload and might slow down institutional biosafety officer or otherwise- the approval process considerably. authorized institutional official had approved the individual researcher to place such orders. I-3. Commercial firms must use approved software for screening orders; people who The institutional biosafety officer would not place orders must be verified by a registered have to screen each shipment for hazard. Institutional Biosafety Officer Rather, the biosafety officer would merely verify that the person ordering the DNA was Yet another option is to combine options I-1 a legitimate user of synthetic DNA. Such ap- and I-2. Under this hybrid approach, to place proval might need to be reviewed once per an order for synthesized DNA, a researcher year and might be linked to biosafety certifica- would have to be verified as a legitimate user tion or training requirements. A list of verified by a biosafety official, and commercial DNA researchers could be maintained and updated suppliers would also be required to screen the electronically so that individual orders could orders for hazardous sequences. be approved with minimal time delay. The biosafety official would be asked to cre- This approach is somewhat similar to that ate two lists of researchers: 1) legitimate users used by the American Type Culture Collection of synthetic DNA, and 2) the subset of those (ATCC), a nonprofit organization that stores researchers who are conducting experiments Rather than and distributes biological materials such as cell with pathogens or with DNA derived from a lines, bacteria, animal and plant viruses, and an- pathogen. In the event that an order submit- making the DNA tisera. ATCC will only ship potentially hazard- ted by a legitimate user of synthetic DNA was synthesis firms ous material with the approval of a registered identified by software screening as potentially responsible for biosafety professional. Likewise, shipments of hazardous, but that researcher had not been verifying the radioactive materials can only be received by approved by the biosafety official to use po- identity of a those who are licensed by the Nuclear Regula- tentially hazardous DNA, the biosafety official researcher who tory Commission (or equivalent state regula- would have to be consulted before the DNA tory body) to receive them. order could be filled. places and order, this responsibility Lists of verified users could be maintained ei- The biosafety official preparing these lists might could be shifted ther by each institution or by a centralized third be either the institutional biosafety officer or the to the research party. Under the latter approach, institutional chair of the Institutional Biosafety Committee institutions where officers would submit lists of legitimate users (IBC). IBCs were created under the National scientists work. to an Internet-based verification company Institutes of Health (NIH) Guidelines for Recom- such as VeriSign, which would issue “electronic binant DNA Research to assess the biosafety certificates” to those users. This would mini- and environmental risks of proposed recombi- mize the administrative burdens to both the nant DNA experiments conducted in academic institutions and synthesis firms, and because and commercial settings, and to decide on the the verification would occur electronically, al- appropriate level of biocontainment. low virtually instantaneous approval. In addition, shipments of certain types of A biosafety officer, at his or her discretion, might hazardous genes or portions thereof, instead choose to screen individual orders as well, of being shipped directly to the individual examining the research from the perspective researcher, might be sent to the institutional of laboratory safety, potential harm to the en- biosafety officer or to the chair of the IBC. For

24 Synthetic Genomics | Options for Governance OPTIONS FOR COMMERCIAL FIRMS

example, commercial firms could be required Co m p a r i n g t h e Op t i o n s to send synthesized DNA longer than 500 base pairs whose sequence matches that of a gene Options for Gene Synthesis on the hazardous list only to approved institu- Companies A far more tional biosafety officials, rather than directly to minimalist approach the researcher who placed the order. The primary purpose for implementing any would be simply to of the first three options above is to prevent I-4. Require commercial firms to store informa- require commercial a potential bioterrorist from obtaining DNA firms to store tion about customers and their orders from a commercial firm. The fourth option, rather than focusing on prevention, might help information about A far more minimalist approach would be law enforcement officials respond to an inci- customers and simply to require commercial firms to store dent, should it occur. their orders. information about customers and their orders. The Toxic Substances Control Act (TSCA) Options Table IA below summarizes our judg- already requires firms to retain records, in- ments about how well each of the options cluding the identity of the customer, for many would enhance biosecurity if implemented at types of chemicals and other substances (in- gene synthesis companies; that is, firms that cluding, in some cases, DNA sequences) for at produce gene- and genome-length stretches least 5 years, but it does not appear that this of DNA. The Table also includes our evaluation requirement has been applied to firms making of each option’s effectiveness for meeting two synthetic DNA. other important goals: improving laboratory safety and protecting the environment. Finally, Commercial DNA suppliers would be required the Table compares the options according to a to register with a designated agency such as series of other important considerations, such the FBI. Information about each order would as the costs and difficulties of implementation. be stored at the firm for a specified period In a later section, we discuss the effectiveness of time and would be made available to the of these options when implemented by firms FBI under certain specified conditions, such that produce shorter oligonucleotides. as the aftermath of a biological attack. In that event, once the pathogen used in the attack Relative effectiveness for achieving goals had been isolated and sequenced, its sequence could be compared to orders for synthesized For preventing bioterrorists from obtaining long DNA to try to find a match. stretches of a potentially pathogenic genome, we judge Option I-3, the hybrid approach, to To ensure that orders could be associated be the most effective; followed by Option I-1, with individuals, firms might not be allowed to screening by approved software; and finally Op- deliver synthesized DNA to anonymous Post tion I-2, requiring that customers be verified as Office boxes. (FedEx has a similar requirement.) legitimate users of synthetic DNA by their insti- Although the association between the shipping tution’s biosafety officer. Option I-3 melds the address of an order and a bioterrorist attack to strengths of the other two options. Screening which that order may have contributed does software will identify potentially harmful pieces not necessarily mean that the individuals re- of DNA, regardless of whether the intended sponsible for the order had anything to do with use is nefarious or legitimate. Verification from an attack, such an association could neverthe- an institutional biosafety officer is a simple way less provide a powerful investigative tool. of determining whether the customer appears to be a legitimate user of that potentially harmful piece of DNA.

25 Option I-3 is likely to be the most effective op- burdensome, and while we believe that Option tion for avoiding harmful laboratory accidents I-3 would be the most effective for preventing a and releases to the environment. Under this potential attack, it is likely to be the most costly option, a biosafety officer would be notified if and burdensome to implement. a user who has not been verified to use pathogenic sequences in his or her research ordered Options I-1 and I-3, both of which rely on com- one or more such sequences, either inadver- puterized screening of orders, will require sev- tently or deliberately. Option I-1 (screening eral additional components to work effectively. alone) might avoid some accidental orders of First, a list of dangerous pathogens (e.g., Select harmful sequences, but it would likely be less Agents) and potentially harmful genes (e.g., for effective. antibiotic resistance) must be prepared. Such lists might be compiled by a U.S. government By requiring firms to store information about agency such as CDC, which administers cur- orders for several years and to supply that rent regulatory controls on dangerous human information to the FBI in the event of a bioter- pathogens; the Department of Homeland Se- rorist attack (Option 4), it might be possible curity; or perhaps by an advisory body that is to identify the individual or group responsible sanctioned by either of those agencies. for an attack with a synthetic organism. This option might also be used in the event of an Second, the same agency would also be re- accidental release of a synthetic organism into sponsible for testing and certifying the screen- the environment. Such records would provide ing software, although this task might also be one of very few possible leads for identifying delegated to an advisory group. the perpetrating individuals or groups “after the fact.” Moreover, the knowledge that such Third, commercial gene synthesis companies would be required to register with the imple- orders would be revealed after an attack could menting agency and certify that approved deter any would-be terrorist from placing such software is being used. That agency might also orders for hazardous DNA with commercial perform periodic random tests to determine firms, forcing him or her to utilize more dif- whether the software was, in fact, in use. ficult means for obtaining the pathogen. Finally, the FBI or a similar agency must estab- Relative effectiveness on other criteria lish a “hotline” for commercial DNA synthesis firms to call when they detect a suspicious While effectiveness in achieving goals is ex- sequence. That agency would need to estab- tremely important, policy choices must be lish thresholds of concern to determine when made with other criteria in mind. An option firms should call the hotline and reject a suspi- whose costs exceed its benefits, or that ham- cious order. pers legitimate researchers more than bioterrorists, is not likely to be chosen. The need for additional research is a second important consideration listed in Options Table IA. The bottom half of Table IA displays our judg- For Options I-1 and I-3 to be effective, two tech- ments of the effectiveness of each of the four nical improvements are crucial: better screening options in meeting a series of other important software and a tailored list of risky sequences criteria. For example, the first row examines against which orders will be screened. the costs and burdens of each option to government and to DNA synthesis firms. Note that the The software itself must be improved to costs and burdens of the first three options identify risky orders more effectively and ef- are inversely proportional to their effective- ficiently. Both the error rate and the amount ness for preventing a bioterrorist attack. We of additional human screening required must judge Options I-2 and I-3 to be somewhat be reduced.

26 Synthetic Genomics | Options for Governance OPTIONS FOR COMMERCIAL FIRMS

Improvement is also needed in the list of be verified as legitimate users perhaps once a harmful genes and genomes to which the year, or until the relevant biosafety officer in- submitted sequence is compared. The current dicated that certain users should no longer be software relies on the Select Agent list, which authorized to order synthetic DNA (perhaps was designed for an entirely different purpose: because they had left the institution). Within to restrict physical access to a list of pathogens universities or other large research institutions that could be used as bioweapons. with biosafety officers, this extra step would add to the administrative burden but should The combined DNA sequence of all pathogens be readily accommodated. on the Select Agent list may not provide the most effective basis for screening software. For The greatest impact would be felt by research- that purpose, additional pathogens might be included. The DNA sequence of individual genes ers working for small start-up firms that do of concern could also be added, such as virulence not have a biosafety officer. In such cases a genes or genes that confer certain types of anti- mechanism would have to be established to biotic resistance (perhaps limited, for example, to allow such scientists to be verified by indepen- third-line or other critical antibiotics). dent consultants. (Independent consultants are already being used by smaller institutions Moreover, some DNA sequences found in to help accomplish NIH-required and other select agents are not very useful for screening. reviews of human subjects research and re- The sequences of some metabolic genes are search with animals.) Nevertheless, if such a largely conserved throughout a wide variety of review mechanism were too burdensome, organisms, making them poor candidates for small start-up firms might shift to in-house distinguishing pathogens from benign organ- DNA synthesis instead. isms. To help avoid false alarms, the screening list may have to be divided into two sublists: None of the options are effective for promoting DNA sequences that are found only in patho- constructive applications, though there might be gens, and DNA sequences that are found some modest benefit to the added interaction both in pathogens and in benign organisms. between researchers and biosafety officers. Regulatory sublists may also be required. As The current mentioned above, some pieces of DNA are screening software already subject to the requirements of the Se- Options for Firms that Synthesize lect Agent regulations. Commercial firms need Oligonucleotides relies on the Select to know those sequences for which additional Agent list, which regulations apply. Options Table IB displays our judgments was designed for about the effectiveness of requiring firms that an entirely different Yet another important consideration is the ex- synthesize oligonucleotides to adopt one or purpose: to restrict tent to which each option impedes or burdens more of these options. Again, oligonucleotide physical access to legitimate research while seeking to prevent il- suppliers synthesize and sell pieces of DNA legitimate uses or accidents. All of the options typically shorter than 100 bases long. In gen- a list of pathogens fare reasonably well on this criterion. Software eral, while implementing these options at oligo that could be used screening will increase the cost of gene synthe- supply firms will certainly add another layer of as bioweapons. sis somewhat, but not by very much. Several protection, the risk reduction per unit of effort firms already screen today for select agents would be lower for these firms than for sup- and remain competitive. pliers of longer gene and genome stretches of DNA. Verification of legitimate users by an -institu tional biosafety officer would add a new approval step. Each order would not have to be verified; instead, individual researchers would

27 Options Table IA: Summary of Options for Gene Synthesis Firms

Does the Option: Enhance Biosecurity IA-1. Geneorders rms mustIA-2. screen Biosafetypeople who of cer placeIA-3. must Hybrid:ordersbiosafety verify Firms of cerIA-4. must must Firmsabout screen verify mustorders and people store information

by preventing incidents?

by helping to respond?

Foster Laboratory Safety

by preventing incidents?

by helping to respond?

Protect the Environment

by preventing incidents?

by helping to respond?

Other Considerations:

Minimize costs and burdens to government and industry?

Perform to potential without additional research?

Not impede research?

Promote constructive applications?

Key to Scoring:

Most effective for this goal. Most effective performance on this consideration. Relatively effective.

Moderately effective.

Somewhat effective.

Minimally effective.

Not relevant.

28 Synthetic Genomics | Options for Governance OPTIONS FOR COMMERCIAL FIRMS

Relative Effectiveness for Achieving described above for the options implemented The costs Goals at gene synthesis companies. In many cases, and burdens of however, implementing these options at oligo screening for As can be seen by comparing Options Tables houses would be less effective or desirable. IA and IB, implementing Options 1 and 3 at industry will oligo supply firms would be significantly less -ef The costs and burdens of screening for indus- be higher at fective for preventing incidents of bioterrorism try will be higher at oligo supply firms than oligonucleotide than the same option implemented at gene at gene synthesis companies on a per-unit supply firms than synthesis companies. This conclusion is based or per-dollar of business basis because the at gene synthesis on two factors. First, the shorter the piece of “false positives” that must be resolved will be desired DNA, the lower the confidence that more frequent with shorter sequences. Simi- companies because the particular sequence is found exclusively in larly, software-based screening options require the “false positives” a pathogenic organism and is not present in more research and development to be effec- that must be a benign organism as well. Options 1 and 3 tive for screening shorter-length oligos. The far resolved will be rely on computer software to distinguish po- wider variety of uses for oligos than for genes more frequent with tentially harmful from benign pieces of DNA. and genomes means that many more scientists shorter sequences. When the results are ambiguous, the only so- will be inconvenienced by regulations applied lution is to request a review of the data by a to oligo supply houses. Finally, none of these knowledgeable staff member. Next-generation options is effective at promoting constructive software might be able to clarify these cases applications by researchers. to some extent, but a degree of ambiguity is inevitable for very short pieces of DNA. Additional Concerns

Moreover, because oligo-length stretches of Two additional considerations merit discussion, DNA have many applications other than syn- although they are difficult to rate qualitatively thetic genomics, the amount of risk reduction as we do in the sections above. These issues per unit of screening effort will be low. For are the ability of each of the options to func- oligo synthesis, not only is the needle in the tion successfully in an international context and haystack that one is searching for shorter, but their ability to keep pace with rapidly changing the haystack is larger as well. science and technology. The comments below apply to options for both gene synthesis com- Thus, for preventing potential bioterrorists panies and oligonucleotide suppliers. from synthesizing a harmful organism from commercial oligos, we are hard-pressed to determine whether software-based screening Thinking past the U.S. border (Option I-1) is superior to having biosafety offi- All of the options will lose effectiveness if cers verify legitimate users (Option 2). Option implemented in the United States alone; hence, I-3, combining the strengths of both Options international harmonization would be desirable. I-1 and I-2, is again clearly the most effective Today, the majority of gene synthesis firms are approach. Option I-1 and Option I-3—those located within the United States and Europe. that rely on screening—are the most effective Customers can be located anywhere in the for fostering laboratory safety and protecting world. Import rules might be able to limit the the environment. amount of DNA synthesized in other countries that is shipped to the United States. But Relative Effectiveness on Other Criteria none of the options could address the potential problem of a synthesized pathogen that is The pattern of relative effectiveness of these smuggled across a U.S. border. options in meeting the other important criteria listed in Options Table IB generally follows that

29 Options Table IB: Summary of Options for Oligonucleotide Synthesis Firms

Does the Option: Enhance Biosecurity IB-1. Oligonucleotidemust screen ordersIB-2. manufacturers Biosafetypeople who Of cer placeIB-3. must Hybrid:ordersBiosafety verify Firms Of cerIB-4. must mustFirmsabout screen verify mustorders and peoplestore information

by preventing incidents?

by helping to respond?

Foster Laboratory Safety

by preventing incidents?

by helping to respond?

Protect the Environment

by preventing incidents?

by helping to respond?

Other Considerations:

Minimize costs and burdens to government and industry?

Perform to potential without additional research?

Not impede research?

Promote constructive applications?

Key to Scoring:

Most effective for this goal. Most effective performance on this consideration. Relatively effective.

Moderately effective.

Somewhat effective.

Minimally effective.

Not relevant.

30 Synthetic Genomics | Options for Governance OPTIONS FOR EQUIPMENT AND REAGENTS

Options Table IB: Summary of Options for Oligonucleotide Synthesis Firms Option I-1, computer screening of orders, is virulence, rather than simply matching DNA among the easiest of these options to har- sequences. monize internationally. Lists of pathogens of concern vary somewhat by country as do Perhaps an even greater challenge will occur if reporting rules and requirements, but the laboratory benchtop synthesizers improve in software modifications to handle such differ- ease of use and quality of product to the point ences would be modest. Option I-4 would where they are as simple to use as ordering also be quite straightforward to implement from a commercial firm. The next section dis- internationally if archived sequence informa- cusses options that apply to laboratory DNA tion were shared not only with national law synthesizers. enforcement agencies under some specified set of conditions, but also with international partners. Such sharing might well be possible, II. Policies for monitoring or given the already considerable amount of information sharing that occurs among intel- controlling equipment and ligence agencies around the world. However, reagents the intensely proprietary nature of some gene orders, together with concerns about linkages between foreign intelligence agencies and their countries’ firms, might make such international De s c r i p t i o n o f t h i s intervention p o i n t information sharing among countries politically unacceptable. If a bioterrorist could not simply mail order the desired genes or oligonucleotides to construct International harmonization under Option I-2 a pathogen, the next approach he or she might would rely on the framework of biosafety rules try would be to construct the genome from in place in each of many different countries. scratch. This would involve producing oligos Though it would not be impossible to identify using a DNA synthesizer, followed by assembly and certify responsible officials at research of the oligos into the genome of interest. At a institutions around the world, the differences minimum, the synthesis step would require the among national biosafety frameworks would acquisition of an oligonucleotide synthesizer make harmonization a challenge. Option I-3, (purchased or built) and a relatively small set a combination of Options I-1 and I-2, would of chemicals. thus be as difficult to harmonize internationally as Option I-2 alone. In attempting to monitor or control the equipment or materials needed to synthesize DNA, Keeping pace with evolving science and the most readily accessible intervention point technology would be at the level of the DNA synthesizer itself. (See Figure 1, Panel B for a photograph Options I-1 and I-3, which rely on software of a laboratory benchtop synthesizer.) DNA screening, will have the greatest difficulty keep- synthesizers produce short segments of DNA ing pace with rapidly changing science and with specified sequences of the four bases (A, technology. Today, synthesizing a small viral T, G, and C). The device automates the series genome as it exists in nature is still a challenge, of chemical reactions needed to add a specific so that screening tools can focus on known base to an existing strand of DNA, repeating DNA sequences. In the not-too-distant future, the process as many times as necessary with however, scientists may be able to modify the appropriate reagents until the desired base pathogens so that they are not as easily de- sequence is complete. tected. Software screening tools will then have to recognize the genetic mechanisms behind

31 DNA synthesizers range in size from that of a These options would enhance security by im- microwave oven to that of a refrigerator, cost peding illegitimate activity and by helping to anywhere from a few thousand dollars or even expose it. Forcing individuals with illicit intent to less (used) to over a hundred thousand dollars obtain DNA synthesizers surreptitiously, to lie to (high-end, new), and can typically produce tens governmental authorities, or to build their own to hundreds of different DNA sequences at synthesizers would complicate their planning, a time. At least 15 firms in the United States open up additional possibilities for detection, and at least an additional seven worldwide sell and provide unambiguous grounds for pros- new or refurbished DNA synthesizers. Tens of ecution if they are caught. Use of an ostensibly thousands of these machines have been manu- legitimate synthesizer for illegitimate purposes factured, and they are available not only from might be detected or deterred more easily if all scientific supply vendors but also used in the synthesizers were declared and accountable to aftermarket, including on the auction site eBay. specific owners of record. However, registration or licensing of synthesizers would also impose Similar to ordering short pieces of DNA from some costs and regulatory burdens for legiti- a commercial supplier, short oligonucleotides mate users and for government. must be “cleaned up” and assembled in the proper order to form gene- or genome-length In effect, these measures would serve as what strands of double-stranded DNA. the arms-control community calls a “confidence- building measure”—a measure that is meant to give an indication of good intent but that can- De s c r i p t i o n o f Op t i o n s not provide reliable proof of compliance. One Methods to monitor or control DNA synthe- major difference between legitimate and ille- sizers include registration (a requirement to gitimate users of biology and biotechnology is notify the government when selling, buying, or that legitimate users should be willing to reveal otherwise possessing a DNA synthesizer) and their activities, within limits, whereas illegitimate licensing (government permission is needed users would seek to conceal theirs. before a DNA synthesizer can be acquired or retained). Registration or licensing of a synthe- II-1. Registration of DNA synthesizers Forcing individuals sizer could also be made a requirement for with illicit intent procuring specialized raw materials (especially Newly manufactured or imported synthesiz- to obtain DNA the phosphoramidite precursors) necessary ers would be given unique identifiers, and synthesizers sur- for synthesis, key spare parts of synthesizers manufacturers, importers, and distributors would collect and report to the government reptitiously, or to (such as the capillary tube assembly), and service contracts for synthesizers, which would information about the purchasers of these build their own make it more difficult to operate synthesizers machines. Criteria would also have to be synthesizers would that were not incorporated into this regime. developed to specify how and when custom- complicate their built synthesizers would have to be registered. planning, opening Any of these options would assign to each If such a regime were implemented compre- up additional synthesizer an official owner of record who would have responsibility for that machine. hensively, it would have to include all existing possibilities for This list of owners of record would identify DNA synthesizers and not just newly pur- detection. to the government the people or institutions chased ones. On the other hand, the regime authorized to synthesize DNA. Discovery of might be designed to capture only new and a synthesizer that had not been registered or presumably more capable synthesizers, leav- licensed would constitute prima facie grounds ing the older machines unregulated. Such a for suspicion. system would be easier to administer, albeit less complete. In either case, there would

32 Synthetic Genomics | Options for Governance OPTIONS FOR EQUIPMENT AND REAGENTS

need to be provisions for formally decom- II-3. Licensing of synthesizer owners, missioning machines as they were retired, plus license required to procure reagents and for re-registering them when they were or services sold or transferred. Failure to register might incur administrative or even criminal penalties, Any controls on DNA synthesizers would be without the need to prove illegitimate intent. strengthened by additional controls that would Registrations could, but need not, be made a prevent those with unregistered or unlicensed matter of public record. Providing public access machines from being able to procure key re- to registration information would increase the agents, such as the phosphoramidites that DNA transparency of DNA synthesis activities and synthesizers convert into oligonucleotides. give private citizens and interest groups some However, such controls would be complicated ability to monitor them. This ability to monitor by the fact that although DNA synthesis is ab- would be particularly attractive to outsiders solutely dependent on phosphoramidites, syn- who are interested in what firms and research thesis forms a negligible share of the market for them. Pharmaceutical companies use these institutions are doing with DNA synthesizers, materials to produce drugs such as AZT (a and who may suspect that these institutions treatment for HIV infection) in amounts that would prefer to keep their activities out of are orders of magnitude greater than those public view. By the same token, such monitor- required for gene synthesis. On a yearly basis, ing may not be welcomed by the firms and individual laboratories or gene synthesis firms research institutions conducting DNA synthe- might consume grams or a few kilograms of sis, who may not consider their use of such phosphoramidites respectively whereas phar- devices to constitute a waiver of the right to maceutical manufacturers use thousands of protect proprietary information. kilograms of phosphoramidites per year.75 For a material control system on these materials II-2. Licensing of DNA synthesizer to be consistent, these vastly larger customers owners would have to be brought into the regime and required to register before getting permission In the case of licensing, the procedures would to purchase phosphoramidites, and penalties be similar to those for registration, with the would have to be applied to those who re- additional element that the government could transferred the controlled commodities to specify the criteria required of registrants unregistered users. However, it would be ex- and could deny licenses to applicants who tremely difficult to enforce such a regime with did not meet the criteria. Such a system a precision needed to detect the diversion of would be similar in concept, if not detail, to the grams of material involved in DNA syn- the current system under which individuals thesis out of the many thousands of kilograms must be granted permission by the U.S. gov- of material consumed for pharmaceutical pur- ernment to have access to select agents. poses.

Note that a regime that did not “grandfather” It would be easier to implement a system in all existing DNA synthesizers raises the pos- which unregistered or unlicensed synthesizers sibility that an individual or institution could be would be ineligible to be serviced, although it denied a license for equipment that it already would similarly be difficult to ensure that all in- possessed, making its continued possession il- dividuals or firms capable of servicing synthe- legal and forcing its divestiture. sizers would comply with such a requirement.

33 Co m p a r i n g t h e Op t i o n s such illegitimate activity as it was taking place. Moreover, any attempt to do so would likely Relative effectiveness for achieving goals mitigate much of the motivation for preferring in-house synthesis over contracting out for The options discussed above are intended only gene synthesis in the first place (i.e., ease of to enhance biosecurity. However, the security use, rapid turnaround time, and absolute con- benefits would be modest because no such fidentiality). regime could have high confidence in preventing illegitimate synthesis. Options Table II below Option II-1, a registration requirement, might summarizes the potential contributions of the succeed in deterring synthesis by individuals or various options to enhancing biosecurity. organizations so intent on maintaining secrecy that they would not be willing to register for Option II-1, registration, and Option II-2, li- use with their real names. (Obviously, the iden- censing of equipment, are only minimally to tities of registrants or licensees would have to somewhat effective for enhancing biosecurity. be validated to prevent them from using false Synthesizers are relatively small and, at pres- names.) Option II-2, licensing, would potentially ent, easy to acquire and hide. It would be very have greater biosecurity value than registration difficult to ensure that all existing synthesizers in that it would not only ban synthesis by unli- were identified and brought into a registra- censed users but would give the government tion/licensing regime. Likewise, it would not be the authority to limit who can be licensed. physically difficult to possess, maintain, and op- This ability could be important if the govern- erate an unregistered machine unless airtight ment had intelligence identifying individuals controls could be placed on the necessary raw who sought to abuse DNA synthesis. As with materials (Option II-3). the Select Agent Rule, it would be possible to subject all individuals seeking routine access to It is worth noting that synthesizers can be built a DNA synthesizer to a security vetting proce- A more serious from scratch, although with significant reduc- dure, such as fingerprinting and checks against security liability tions in throughput and efficiency compared criminal and terrorist databases. than unregistered with a purchased product.76 There are few synthesizers, however, externally observable indicators (other than It is difficult to say how effective the existing is the possibility that supply of reagents) that would denote the Select Agent restrictions have been at imped- existence or operation of an unregistered syn- ing anyone from obtaining pathogens for illicit registered synthe- thesizer. Therefore, Option II-3, requiring that purposes. Of 14,724 individuals for whom the sizers could be used materials or maintenance be provided only for CDC was asked to grant access to Select for illicit purposes. synthesizers that are licensed would increase Agents, 107 were identified as “restricted per- still further the difficulty of operating unregis- sons” and denied approval. Of those 107, one tered machines. was denied on the basis of being “reasonably suspected by any Federal law enforcement or A more serious security liability than unreg- intelligence agency of having knowing involve- istered synthesizers, however, is the possibil- ment with an organization that engages in do- ity that registered synthesizers could be used mestic or international terrorism.”77 There is for illicit purposes, either by the registrants no way of knowing whether anyone has been themselves (i.e., an apparently legitimate firm deterred from seeking access to select agents set up as a cover for illicit activity) or by indi- for fear of being turned down. Nevertheless, viduals who have access to legitimately regis- there would be little reason to prefer licenses tered machines (e.g., employees of a firm or to registration unless the authorities had the students at a university). It would be difficult legal authority to deny them on the basis of for an owner of record or any governmental information suggesting that an applicant was authority to monitor the usage of registered seeking to use DNA synthesizers for illegiti- DNA synthesizers closely enough to detect mate purposes.

34 Synthetic Genomics | Options for Governance OPTIONS FOR EQUIPMENT AND REAGENTS

Options Table II: Summary of Options for Monitoring or Controlling Equipment or Reagents

Does the Option: Enhance Biosecurity I1-1. Ownersmust register of DNAI1-2. their synthesizers Owners mustmachines be of licensed DNAI1-3. synthesizers Licensingrequired ofto equipment, buy reagents plus and license services

by preventing incidents?

by helping to respond?

Foster Laboratory Safety

by preventing incidents?

by helping to respond?

Protect the Environment

by preventing incidents?

by helping to respond?

Other Considerations:

Minimize costs and burdens to government and industry?

Perform to potential without additional research?

Not impede research?

Promote constructive applications?

Key to Scoring:

Most effective for this goal. Most effective performance on this consideration. Relatively effective.

Moderately effective.

Somewhat effective.

Minimally effective.

Not relevant.

Synthetic Genomics | Options for Governance 35 By establishing an owner of record for each use phosphoramidites exclusively for applica- synthesizer, all three options would serve to tions unrelated to DNA synthesis. make the operators of these machines more accountable for what is done with them. Other aspects of implementing these options Therefore these policies may serve in part may also impose minor burdens, but would to promote responsible use of the machines, require no additional research. Neither the helping to foster a climate in which laborato- registration nor the licensing of synthesizers ries operate more safely and accidental releas- would require research per se; the identities es are minimized. However, any such biosafety of companies that manufacture and supply benefits would be quite indirect. synthesizers are known. Although it might be helpful to have a list of the serial numbers of Registering or licensing synthesizers would be every synthesizer ever made commercially, at of very limited utility in responding to the ac- least initially such information would not be cidental or deliberate release of an organism required. With respect to requiring registra- constructed with synthesized DNA. Unlike tion for the purchase of reagents, additional bullets, which can be associated uniquely with information might be required. For example, the gun that fired them, pieces of synthesized it would be useful to pinpoint the sources of DNA cannot be attributed to a particular syn- phosphoramidites and other reagents used in thesizer. Authorities investigating the release DNA synthesis. Because many of these raw of a biological agent possibly incorporating materials are manufactured outside the United synthesized DNA might find a list of registered States, it might be difficult to compile a com- DNA synthesizers helpful in identifying the plete list of suppliers. locations known to have the capability of synthesizing DNA. Nevertheless, such a list would Modest paperwork and record-keeping would be far less useful than the sequence-specific be involved in transferring registration during information available about commercially syn- the purchase, sale, or resale of synthesizers, and thesized DNA under Option I-4. in verifying that purchasers of materials or services were legitimate users. Licensing could be Relative effectiveness on other criteria considerably more complicated, depending on the information and processing time required The bottom half of Options Table II is our by licensing authorities and the likelihood of evaluation of the effectiveness of each op- misleading data (such as a false entry on a ter- tion with respect to other considerations. The rorism watch list) that incorrectly indicated an costs and burdens to government and industry increased risk of illegitimate use. In either case, would be minimal in a regime requiring only a registration or licensing requirement could the registration of synthesizers; the same ap- impede research to some degree as these pa- plies to licensing though somewhat less so. In perwork issues were dealt with. both cases, however, the paperwork and tracking issues would be relatively straightforward Additional concerns compared to Option 3, requiring registration to purchase reagents. Because of the large volume Thinking past the US border of reagents used in DNA synthesis that are also consumed for other purposes (e.g., in pharma- A registration or licensing scheme could be im- ceutical production), a registration requirement plemented solely with respect to synthesizers to purchase reagents would confer a significant produced within or imported into the United burden to a larger number of users, as well as States. Because the markets for synthesizers the agency tracking such registrations. To reduce and reagents are inherently international, how- this burden, however, it might be possible to is- ever, such a regulatory regime would become sue waivers to pharmaceutical companies that more useful (in terms of capturing synthesizer

36 Synthetic Genomics | Options for Governance OPTIONS FOR EQUIPMENT AND REAGENTS

capability) the more widely it was deployed incentive to register U.S.-based synthesizers. around the world, which would require that If imposed unilaterally, however, such controls other countries enact equivalent policies. In would not be effective in impeding those that case, harmonized requirements among with unregistered synthesizers from acquiring different national systems would be desirable, the necessary reagents directly from foreign both in terms of imposing equivalent burdens sources unless effective import controls on on researchers and manufacturers worldwide those reagents were also imposed. and in minimizing the burden that vendors and distributors face in tailoring export policies to Keeping pace with evolving science and specific destinations. It is not likely that the cost technology or burden of implementing a registration regime would be severe enough to drive research out One area in which policies governing synthe- of a country that imposed such a regime. Still, it sizers could evolve in the future would be to is conceivable that an onerous and inappropri- implement a requirement for DNA synthesiz- ate licensing process—particularly one that ex- ers to keep tamper-proof archives of every cluded significant numbers of applicants—could sequence that had been synthesized for pos- induce researchers to seek work in countries sible access by government investigators after that do not impose such regulations. a bioterrorism incident. Such an option would be analogous to option I-4, proposed above, A licensing regime may be more difficult to that would require commercial synthesis firms harmonize internationally than a registration to archive the DNA sequences of all their ship- regime, since different countries may adopt dif- ments. However, the utility of such a scheme ferent criteria for who should or should not be and the difficulty of implementation differ in licensed. For example, the United States bans these two cases. A DNA synthesis firm would access to select agents, without exception, to have no incentive to frustrate or evade an nationals of countries on the State Depart- archiving requirement, whereas a terrorist op- Because the ment’s list of “state sponsors of terrorism.” This erating a DNA synthesizer would have every markets for particular list is unlikely to be adopted even by reason to do so, and (since the machine would synthesizers and other nations that agree to impose nationality be in his or her possession) the means to try. reagents are tests for access to synthesizers, since countries As a result, it would be much more technically inherently inter- will find it very hard to agree on whose na- challenging and disruptive to the industry to national, a tionals pose unacceptable risks. Also still to be build a reliable, tamper-proof archival capability determined is how internationally harmonized into all DNA synthesizers than it would be for regulatory regime security standards for granting access to DNA commercial firms to keep track of their orders. would become synthesizers would be negotiated. more useful the Moreover, in the near-term, we do not believe more widely it was International harmonization would be more that the use of DNA synthesis is as attractive deployed around important to a regime that regulated access to to would-be bioterrorists as other means of the world. key reagents than it would be to a regime that acquiring or developing potential bioterrorist regulated only the synthesizers themselves. agents. Therefore, we judge that for the next Given that the producers of the key reagents few years, the security benefit of requiring syn- used in DNA synthesis are located for the thesizers to securely archive their sequences most part outside the United States, there would be too low, compared to the difficulty would be little hope of effectively controlling and disruption that such a requirement would access to these materials without the coopera- impose. tion of the countries in which the suppliers are located. Of course, controls on reagents could However, we also acknowledge that in the fu- be imposed on a strictly domestic basis in the ture, synthesis of many dangerous pathogens United States for the purpose of providing an will become considerably easier than other

37 means of acquiring such agents for malicious to develop safer laboratories and reduce the use, at which point the relative security value risk that synthetic pathogens are released acci- of implementing an archiving requirement for dentally. Further, prior review of experiments synthesizers may grow to the point that poli- could help steer researchers away from lines cymakers may wish to consider it. of research that are potentially dangerous with respect to biosecurity. Although these options are proposed for synthetic genomics research, they include elements that could apply to all III. Policies for the roles of microbiology laboratories. users and organizations in The current biosafety framework is in large promoting safety and security part due to the foresight of the scientists in the conduct of synthetic who invented recombinant DNA- and related genomics protocols technologies thirty years ago. Any new framework for managing security risks arising from advances in DNA synthesis technologies must build on these existing practices, which have De s c r i p t i o n o f t h i s intervention p o i n t enabled the demonstrably safe development and application of recombinant DNA technol- The focus of this intervention point is the user ogy over the past three decades. of DNA synthesis technology and the institutions, organizations, and extra-institutional In considering how best to build on the exist- communities that support and oversee such ing biosafety regime, it is useful to recognize work. Unlike the options identified for other two characteristics of the communities that are intervention points, these options apply only using DNA synthesis technologies today. First, to legitimate users of DNA synthesis technol- many of the individuals involved in develop- ogy and do not, therefore, directly support ing and applying DNA synthesis technologies biosecurity measures aimed at frustrating il- are not life scientists. Many come from various legitimate use. Indirectly, these options may branches of engineering and some are from have positive implications for biosecurity. Col- the physical sciences and the social sciences lectively, the options address how users are and humanities. Second, the conversations trained, how the safety of their work is judged, that led to development of today’s biosafety and how standards of practice can be enforced framework took place a generation ago, and either informally or formally. are largely unknown to many practitioners and almost all students in engineering and science. Legitimate researchers carry out their work Taken together, these points indicate both with the assumption that they are pursuing the need and the opportunity for developing constructive lines of inquiry and that their re- a constructive culture, in which developers, search will seek to benefit society. In order to practitioners, and consumers of gene and ge- carry out their work, scientists and engineers nome synthesis technology work together to (especially, although not exclusively, at universi- address the social issues associated with the ties) have at their disposal a number of support technology itself. mechanisms that provide guidance or enforce rules. With appropriate training and practice, investigators know the resources available to them and the rules they need to follow. By encouraging and using the potentially close relationships between researchers and the bodies that guide them, it should be possible

38 Synthetic Genomics | Options for Governance OPTIONS FOR USERS AND ORGANIZATIONS

De s c r i p t i o n o f Op t i o n s duct research in synthetic genomics. Further training in research ethics, the societal impli- We have identified six options to enhance the cations of science, and related aspects of law The current would also be helpful. Although the precise safety and security of legitimate uses of synthetic biosafety framework genomics. Some rely on self-governance from mechanisms could vary, the general approach within the scientific community, for example, would be to educate students about biosafety is in large part due education of trainees by senior researchers. and biosecurity issues at the same time that to the foresight of Others rely on outside involvement in gover- they are being introduced to experimental the scientists who nance. Some of the options include penalties concepts in synthetic genomics. invented recombinant for non-compliance, but many of them estab- DNA and related lish a norm that legitimate researchers would Students must be made explicitly aware of be expected to follow during their professional the need for biosecurity measures such as the technologies thirty research activities and that, if violated, would screening of DNA sequence orders or about years ago. identify the transgressor as irresponsible. what might constitute suspicious activities in the laboratory. Another issue that would have The first three options (education, a safety to be included in a synthetic genomics curricu- manual for synthetic biology, and a clearing- lum is that of “dual-use research of concern” house mechanism for best practices) involve discussed by both the Fink Committee and the institutions and/or individual experts outside National Science Advisory Board for Biosecu- the immediate community of synthetic biolo- rity.78 NSABB defines this as “research in the gists e.g., university administrators, CDC, and life sciences that is directly and immediately NIH. Another approach to implementing the applicable for hostile purposes,” clearly a topic first three options would be through apro- that all researchers should understand. fessional society. Although there are at least four professional societies for bioengineer- Continued improvements in DNA synthesis ing or biomedical engineering in the United technology will lead to dramatic increases in States alone, none of these societies has yet the amount of DNA being synthesized and developed standards of practice for engineers a rapid increase in the diversity of the edu- whose work involves the intentional manipula- cational backgrounds, professional disciplines, tion of genetic material. More than thirty years and types of technical expertise held by the after Asilomar, there is no “American Society users of the technology. Today many users of Genetic Engineers” or similar body. Given of DNA synthesis technology are research the growing interest in developing biology as a professionals who work at well-funded com- technology, and the expanding capabilities for mercial organizations (e.g., biotechnology and doing so, including synthetic genomics, this new pharmaceutical companies). Many of these research community might consider establish- professionals lack access to continuing-educa- ing a new organization that explicitly supports tion programs that could inform them about activities such as professional education or the the social implications of synthetic genomics licensing of practicing biological engineers. and its governance. Thus, early exposure at the college or university level to these concerns is III-1. Education about risks and best critical for at least priming these workers to practices as part of college and univer- consider broader societal issues. sity curricula The annual student synthetic biology competi- Education about the risks of synthetic genom- tion called iGEM (International Genetically En- ics and training in laboratory best practices gineered Machine)79 has been expanding par- could be provided for undergraduates, gradu- ticipation rapidly. The 2006 event, the third one ate students, and even faculty who have been held, drew about 380 students from around the working in other fields and now wish to con- world. 700-800 have registered for the 2007

39 event. When surveyed in 2006, only about (WHO) published a guidance document on 1% of the participating students said that they laboratory biosecurity to complement its exist- were aware of the 1975 Asilomar Conference ing manual on laboratory biosafety.82 Any laptop on recombinant DNA research, the reasons computer for the conference, and, most important, the All of these documents are clearly useful for can be used to research oversight framework that resulted. work in synthetic genomics. However, there access public are a few defining aspects of this new research Finally, it is worth re-emphasizing that the level that the existing documents do not address DNA sequence of technical expertise required to use DNA now but will need to in the future. One major databases, place synthesis technology is quite modest and get- concern is with multi-source chimeras that are an order for DNA ting lower. For example, any laptop computer assembled from the DNA of hundreds of dif- synthesis, and can be used to access public DNA sequence ferent organisms (in contrast to the up to tens arrange for rapid databases on the Internet, download and use of sources used by existing genetic engineer- delivery by free software for editing DNA (including so- ing methods) as well as entirely novel synthetic phisticated protein design software), place an constructs. In neither case is it known if, or to overnight mail. order for DNA synthesis on a website, and ar- what degree, chimeras containing DNA from range for rapid delivery by overnight mail. Thus, many different non-pathogenic sources could it is naïve to expect that all well-intentioned become pathogenic. The data on this topic are users of DNA synthesis will have completed mostly anecdotal: experiments using recombi- a degree program in biology, biological engi- nant DNA have been conducted for upwards neering, or a related field whose curriculum of 30 years and to date there is no evidence of mandates some form of biosafety and biose- pathogens having been created from bona fide curity training. Moreover, for individuals whose non-pathogenic precursors. At the same time, education does provide such training, there is there has been little study of the emergence of little opportunity to update this knowledge as pathogencity as a result of the recombination technology and best practices evolve. Thus, as of pieces of nucleic acid. With respect to the noted above, a professional society for syn- design and construction of totally novel viral thetic biologists could play a key role in imple- genomes, virtually no data exist indicating how menting these ongoing activities, as it would be one could make or avoid making a pathogen. the one institution that most workers in the field could have in common. Thus, it would be helpful to develop a new compilation of biosafety guidelines for research- III-2. Compilation and use of a manual ers working with a large number of aggregated for “Biosafety in Synthetic Biology Labo- synthetic genes, or with synthetic genomes. ratories” Certainly, the existing biosafety guidance could be modified to cover synthetic genomics and Though several laboratory manuals and guides synthetic biology. However, given that synthetic already exist for use by researchers and by the genomics differs in several respects from cur- Institutional Biosafety Committees (IBCs) re- rent genetic engineering techniques, it would sponsible for the safe conduct of research at seem worthwhile to prepare a new biosafety their institutions, none are specifically designed manual, even if it incorporates large verbatim for synthetic genomics. The National Institutes sections of the BMBL or any other existing set of Health (NIH) issues guidelines for the safe of guidelines. handling of recombinant DNA,80 and the CDC and NIH together publish a handbook, Biosafe- A new biosafety manual for synthetic biology ty in Microbiological and Biomedical Laboratories might be drafted at the CDC and NIH, which (BMBL)81 that covers general laboratory safety. are already responsible for the current BMBL. Several clinical laboratory guides are avail- Other agencies might also want to be involved able. Recently, the World Health Organization in drafting and updating such a document. Cer-

40 Synthetic Genomics | Options for Governance OPTIONS FOR USERS AND ORGANIZATIONS

tainly, a non-governmental organization such gency, such a clearinghouse could provide in- A professional as the American Biological Safety Association formation helpful to responders (see below) society for could make an important contribution to such but it would not serve as a reporting hotline synthetic biologists a document, either independently or in collabo- or as part of an emergency response. ration with or under contract to the CDC. A could play a key role professional society, particularly one dedicated Several clearinghouses for best practices ex- in implementing specifically to synthetic biology, could also par- ist in other fields and might serve as models ongoing educational ticipate in or coordinate these efforts. for this option. For example, the National activities, as it Fire Protection Association maintains a web would be the one Irrespective of which agency leads such an ef- site containing a comprehensive library of institution that fort, a critical component would be the need information and has a toll-free number for for active participation by current researchers advice on technical questions.83 The University most workers in and practitioners, and ongoing review and up- of Chicago has a clearinghouse for scientists the field would dating. As outlined in earlier sections of this trying to find the answers to questions about have in common. report, the science of synthetic genomics is regulatory compliance.84 With respect to re- changing rapidly, and the social context of the porting and analysis, American Whitewater’s research is changing rapidly as well. The current safety program maintains an outstanding data- 5th edition of the BMBL follows the 4th edition base on paddling accidents, including fatalities, that had been in use for over seven years, from and includes a vehicle for anyone to enter ad- 1999-2007. For a new manual titled “Biosafety ditional data.85 in Synthetic Biology Laboratories” (BSBL) to be effective, it would have to be revised in re- Regardless of how such a clearinghouse would sponse to new data in a timely manner. be run, a key aspect is to allow people to share data on mistakes and accidents. Anonymous A BSBL could also be a critical component for reporting should be possible, which would the institutional expert review of experimen- encourage submissions even from those who tal protocols. A well-written biosafety manual might fear criminal or civil sanctions if they (and the training that would accompany it) were identified and who would otherwise could address in one place safety problems not report. However, submissions would not that are generic to molecular biology and have to be anonymous, and some researchers those specific to synthetic genomics and syn- might even prefer to be identified so that they thetic biology. Particularly if IBCs take on new can explain to others the nuances of avoiding or expanded responsibilities, supplying them future mistakes or accidents. with a manual that has everything in one place would seem to be a minimum contribution to A clearinghouse could be established by either ensuring best practices. a government agency or a professional society of synthetic biologists, should such a society be A laboratory biosafety manual for synthetic established. genomics would focus exclusively on minimizing the physical hazards associated with such III-4. Broaden IBC review responsibilities experiments and would not address the issue to consider risky experiments of dangerous knowledge. The Fink Committee86 recommended that III-3. Clearinghouse for best practices Institutional Biosafety Committees become more attentive not just to the biosafety im- An on-line or telephone clearinghouse could plications of certain areas of research involv- be established as a centralized source for in- ing DNA (“dangerous research”) but to the formation on laboratory best practices for biosecurity risks associated with such research synthetic genomics. In addition, during an emer- (“dangerous knowledge”).

41 The Committee listed seven experiments of There are at least three different biosafety con- concern for biosecurity reasons: (1) demon- cerns with respect to the process and prod- strating how to render a vaccine ineffective; ucts of synthetic genomics in the laboratory. (2) conferring resistance to therapeutically First, similar to the situation with traditional useful drugs; (3) enhancing the virulence of a microbiology, there are concerns about work- pathogen or rendering a nonpathogen viru- ing with specific, identifiable pathogens. Next lent; (4) increasing transmissibility; (5) altering are concerns about working with chimeras host range; (6) enabling the evasion of a di- that combine genes from different organisms agnostic or other detection; and (7) enabling (specifically when large portions of the engi- weaponization.87 While such experiments may neered product are derived from a pathogen). strike investigators as extreme, they do hap- Finally, concern has been expressed about the pen under various guises. For example, many possible emergence of pathogenicity from Anonymous gene therapy experiments seek to develop vi- assembling pieces of DNA from dozens or reporting to a ral vectors that can evade the human immune even hundreds of different source organisms. clearinghouse system. This characteristic is clearly related to If many pieces of non-pathogenic DNA are should be possible, the concern of enhancing the virulence of a combined in ways that have never occurred in but some researchers pathogen, yet many investigators (and IBCs) nature, could this process possibly give rise to may not think of it that way. something dangerous? might prefer to be identified so that There is likely to be disagreement as to As the new field of synthetic genomics begins they can explain the whether IBCs could or should handle the new to expand rapidly, it would be desirable to nuances of avoiding task of assessing the security implications of have some type of formal process to identify future mistakes dual-use research. The original purpose of the and review experiments for both safety and security concerns. IBCs are a logical choice for or accidents. IBCs (specifically, to deal with recombinant DNA protocols) has been greatly expanded such a task. Minimally, such a review would and problems have already been documented be for the seven specific types of experi- with IBCs failing to fully carry out their exist- ments identified in the Fink Report, but local ing biosafety missions.88 Assuming, however, committees could decide to expand on this that some oversight of security issues is a le- list. Indeed, the NSABB has released a draft gitimate role for IBCs, it would then become guidance document for generically identifying the responsibility of the institutions (and by dual-use research of concern that expands on extension, the funders of research) to ensure the Fink criteria.89 that the committees are sufficiently staffed and educated (see III-5). III-5. Broaden IBC review, plus oversight from a National Advisory Group to Although the initial product of synthetic ge- evaluate risky experiments nomics projects is a strand of DNA that is chemically indistinguishable from any other Historically, review of recombinant DNA ex- natural or recombinant DNA, synthetic ge- periments and enforcement of biosafety rules nomics has raised new concerns with respect have taken place at the local or institutional to laboratory and environmental safety. These level. This approach has proven quite success- concerns relate both to the process (Is there ful over time. Occasionally, however, a pro- anything about working with synthetic DNA posed experiment is so novel that the exper- that is inherently different than working with tise available on the local IBC is not adequate natural DNA?) and the product (Are products to assess its risk, or the experiment may be made from synthetic DNA likely to be more controversial or difficult to assess for other dangerous than products made with genetic reasons. In such cases, the NIH’s Recombinant engineering?). DNA Advisory Committee (RAC) provides oversight of experiments that cannot be ad-

42 Synthetic Genomics | Options for Governance OPTIONS FOR USERS AND ORGANIZATIONS

dressed by local IBCs. The best-known group level of review above any new national-level of experiments subjected to such review is oversight body. In the case of the RAC, for ex- various gene therapy protocols. ample, the NIH director has final say on the approval of recombinant DNA research proto- A similar national oversight body might be cols. Given that any review process for synthetic established to review the biosafety of selected genomics would have an important security synthetic genomics experiments, for example, component, the official to which the national those involving the construction of chimeric body reports should have security as well as microorganisms using DNA from many dif- scientific responsibilities. This individual could ferent organisms, an area where there is little still be the NIH director, or it could be a senior precedent and hence a lack of local expertise. official with science and security responsibilities It would be This review and oversight body might also be in another Executive Branch Agency. desirable to have asked for biosecurity advice in cases where an some type of experimental protocol has a clear potential for III-6. Broader IBC review, plus enhanced formal process to misuse for hostile purposes. Such a national enforcement of compliance with bio- identify and review review body could be housed in a number safety guidelines of agencies. It could be the RAC itself or the experiments for National Science Advisory Board for Biosecu- In addition to any penalties that institutions both safety and rity (NSABB) which, like the RAC, is operated might levy against principal investigators who security concerns. by the NIH Office of Biotechnology Activities. fail to comply with IBC rules, penalties can be Given the confluence of science and security levied against their institutions (usually univer- responsibilities that such a review body would sities). These institutional penalties range in need to have, the NSABB, which is comprised severity, up to the revocation of NIH grants. of nongovernmental experts skilled in the Criminal penalties are a possibility as well, but science, safety, and security disciplines, could they would typically not be invoked unless be a logical choice. However, that body was an individual was harmed. These most severe established in a purely advisory capacity with penalties are rare. Recently, the CDC issued no operational responsibilities; assigning it the a cease-and-desist order for work on Select mission of reviewing and overseeing certain Agents at Texas A&M University following synthetic genomics experiments, or other is- multiple infractions that resulted in a worker sues that local IBCs could not resolve, would becoming ill from a Brucella infection.90 significantly change the Board’s role. Beyond the more or less voluntary nature of Alternatively, a national oversight committee compliance with the NIH Guidelines, investiga- could be placed in a different agency within tors and institutions are subject to legally bind- the Department of Health and Human Ser- ing regulations, including the Toxic Substances vices (DHHS) such as the CDC, or it could be Control Act, the rules of the Nuclear Regula- taken out of HHS entirely. In addition, such a tory Commission, and the rules of the Occu- body could be located outside of government. pational Safety and Health Administration, as For example, it might be administered by a well as tort liability. Our focus here is specifi- consortium of universities, with the voluntary cally on researchers following guidelines. participation of commercial biotechnology and pharmaceutical firms. This option proposes that biosafety rules and guidance relevant to synthetic genomics, both To make a national biosecurity oversight sys- those that already exist and new ones that may tem more or less equivalent to the current be developed, should to be strictly enforced. RAC system, in which decision-making author- Moreover, the punitive measures provided for ity is vested in government officials to whom in the relevant Guidelines would be invoked the RAC reports, there should be an additional whenever warranted, with the expectation

43 that others will take compliance more seri- research might be misused and how to antici- ously if they see cases in which noncompliance pate and reduce that risk. Moreover, improved is punished. laboratory security as a result of such training could help to prevent would-be bioterrorists This approach would represent a change in from obtaining dangerous biological materials philosophy with respect to the oversight of by stealing them or using facilities to which science, which has typically relied on a pre- they should not have access. sumption of good faith on the part of the research community, reserving punitive mea- Option III-2, the development and use of a new biosafety manual for synthetic genomics, A national sures for particularly egregious cases. A more adversarial approach might require new types scores very high both for preventing biosafety oversight body of oversight for these committees, or it may incidents and helping to respond to an envi- might be established simply be the case that more committees are ronmental release. In the latter case, the man- to review the bio- needed as responsibilities expand. ual would contain step-by-step instructions for safety of selected dealing with an accident. Equally effective in the event of an environmental release would synthetic genomics Co m p a r i n g t h e Op t i o n s be a telephone hotline to a good information experiments such clearinghouse that would provide explicit in- All of the options discussed above are aimed at as those involving structions (Option III-3). legitimate researchers. Specifically, they address the construction of biosafety (the safety of laboratory workers and Option III-4, broadening IBC review respon- microorganisms using the surrounding communities, and protection sibilities to include the “experiments of con- DNA from many of the environment) and mechanisms for cern” as defined by the Fink committee and different organisms. achieving it. A few of the options also confer the NSABB would have a modest impact benefits for biosecurity. A summary table is on biosecurity. Combining the broadening found below in Options Table III. of IBC review responsibilities with oversight by a National Advisory Group (Option III-5) Relative effectiveness for achieving goals would achieve a somewhat higher score for preventing a biosecurity incident. In both For fostering laboratory safety (specifically, the cases, however, the impact would be indirect. safety of workers) and protecting the surround- A review and oversight mechanism would not ing communities and the environment, Option prevent specific incidents of bioterrorism but III-1, educating laboratory workers, is of great might result in the modification of dual-use ex- importance. This option involves teaching periments in a way that reduces their utility for workers how to avoid laboratory accidents and potential bioterrorists. None of these options what to do in case one occurs. The curriculum would help in responding to actual incidents. would involve both formal classroom teaching and practical training in the laboratory with an Broadening IBC review is judged as moder- experienced researcher. The latter approach ately effective in preventing incidents that could be particularly effective because most could harm either laboratory workers or training in laboratory best practices occurs on nearby populations. We judge this option to a one-on-one basis and is highly valued by stu- be somewhat less effective in responding to dents. In the event of an accidental release of incidents than education or the use of a man- a pathogen into the environment, prior educa- ual. However, when combined with oversight tion is likely to be less effective, as it will most by a national advisory group or with enhanced likely only cover generalities. enforcement, the combinations are relatively effective at preventing biosafety incidents. Education could also have a positive impact None of the options III-4, III-5, or III-6, alone or on biosecurity particularly if the training pro- in any combination, is particularly effective for gram includes consideration of how biological responding to incidents.

44 Synthetic Genomics | Options for Governance OPTIONS FOR USERS AND ORGANIZATIONS

Relative effectiveness on other criteria about risks and best practices, and Option III-3, a clearinghouse for best practices. Although none of the options discussed above would require additional research per se, for From the standpoint of the researcher or prac- many of the options, at least some additional titioner, virtually all of the review and oversight information would be necessary. For example, options would impede research to some ex- for educating new entrants to the field, -al tent. However, the availability of tools such as though there are no standard curricula, there a BSBL or an information clearinghouse would are some examples of training programs for not impede the advance of synthetic genom- both the scientific and professional ethics as- ics and might even accelerate progress by pects of research. For the use of a new manual, suggesting better ways to carry out research a BSBL does not yet exist, but other biosafety protocols; a National Advisory Group might manuals with significant relevant information also facilitate research by offering “gold stan- already do. The one area that would appear dard” advice that could be difficult to come by to require genuinely new research would be at the local level. to address concerns over the construction of novel chimeras. Although, as discussed above, Additional Concerns the possibility exists that a pathogen could emerge from the combination of otherwise Thinking past the U.S. border benign pieces of DNA, there is little primary research on this topic. Laboratory best practices, while to some degree culture-specific, tend to spread interna- Once these issues have been clarified, it is pos- tionally through spontaneous adoption as well sible that the options discussed above could as efforts of the community. The American make a significant contribution to enhancing Biological Safety Association, for example, has the biosafety in synthetic genomics research, endeavored to include the laws and practices but with varying impacts in other areas. These of other countries in its training materials,xi and impacts could also depend on how the pro- biosafety meetings, regardless of the country grams are implemented. For example, depend- they are held in, draw international attendees.xii ing on who is chosen to run the clearinghouse, Formal curricula in schools and universities can it could either minimize costs to government and be exported to other countries and informal industry (and universities) or increase costs. education occurs at international meetings, Establishing education programs and prepar- through collaborators, etc. Thus, the options Improved lab- ing a BSBL would require some initial financial concerning education and biosafety (Options oratory security investment on the part of government, aca- III-1, 2, and 3) could not only be implemented demia, and perhaps industry. If implemented internationally but potentially could have posi- as a result of good effectively, however, these biosafety measures tive impacts on the conduct of research by training could help should minimize overall operating costs in the influencing the behavior of scientists and engi- to prevent would-be long run. Moreover, if a professional society of neers throughout the world. bioterrorists from synthetic biologists were established and as- obtaining dangerous sumed primary responsibility for developing Options III-4, III-5, and III-6, however, are more biological materials these programs, they would entail essentially difficult to harmonize internationally. Institu- no costs to government or industry. tional biosafety committees and national-level by stealing them. advisory groups tend to focus on local or do- Two of the options are most effective for pro- mestic concerns. Certainly, other countries be- moting the constructive applications of synthetic side the United States could propose parallel genomics. These are Option III-1, education oversight mechanisms, and they could work

xi See, e.g., http://www.absa.org/resguides.html xii See, e.g., http://www.absa50.org/program.html 45 Options Table III: Summary of Options for Users and Organizations

Does the Option: Enhance Biosecurity III-1. Educationpractices inabout universityIII-2. risks CompileSynthetic andcurricula best a BiologymanualIII-3. Establish practicesforLaboratories” “Biosafety a clearinghouseIII-4. in BroadenCommittee for bestInstitutional reviewIII-5. Broaderoversight responsibilities Biosafety IBC by Review,NationalIII-6. Broadenenhanced plus Advisory IBC enforcement Group review, plus

by preventing incidents?

by helping to respond?

Foster Laboratory Safety

by preventing incidents?

by helping to respond?

Protect the Environment

by preventing incidents?

by helping to respond?

Other Considerations:

Minimize costs and burdens to government and industry?

Perform to potential without additional research?

Not impede research?

Promote constructive applications?

Key to Scoring:

Most effective for this goal. Most effective performance on this consideration. Relatively effective.

Moderately effective.

Somewhat effective.

Minimally effective.

Not relevant.

46 Synthetic Genomics | Options for Governance OPTIONS FOR USERS AND ORGANIZATIONS

to harmonize their respective procedures for of biotechnology. Our study does not pres- biosafety and biosecurity reviews of proposed ent policy options for controlling information experiments. However, it would be difficult to that go beyond what is being discussed among tie these national procedures together into a the scientific and security communities more single international system. broadly. We believe that ongoing discussions and policy options proposed by others, which Keeping pace with evolving science and are described below, adequately address the technology risks, benefits, and practical difficulties of synthetic genomics. Option III-3, an information clearinghouse, and to a lesser extent, Option III-2, a laboratory In February 2003, the editors of several pres- manual for synthetic biology, are two good tigious scientific journals issued a statement ways to help the community stay abreast of reiterating the importance of open scientific the biosafety implications of this rapidly chang- communication in research and technology ing technology. Given appropriate support, development, but acknowledging that “there both of these measures can be updated and is information that, although we cannot now used in real-time to deal with emerging safety capture it with lists or definitions, presents issues (and to some degree, security concerns). enough risk of use by terrorists that it should Option III-1, education, will of course deal with not be published.”91 The group went on to these sorts of changes as well, though some- conclude that “on occasion, an editor may what more slowly as curricula are adjusted conclude that the potential harm of publica- over time. tion outweighs the potential societal benefits. Under such circumstances, the paper should IBCs and other groups concerned with the be modified, or not be published.”92 Drafters oversight of research do their best to take into of this statement did not give government a account the latest scientific findings in making role in making this determination, but rather their decisions. Such changes may at times occur assigned this responsibility to editors, publish- slowly. On balance, however, oversight bodies ers, and the researchers themselves. are probably more effective at responding to a fluid research environment than are individual This idea was carried forward in the Fink scientists. To keep pace with changing science Committee, which in its October 2003 report and technology, Option III-5, which includes a recommended “relying on self-governance national oversight body, would likely be more by scientists and scientific journals to review effective than Option III-4, which places such publications for their potential national secu- burdens on local IBCs alone. rity risks.”93 The committee’s recommendation endorsed the statement from the editors and Mitigating risk by review prior to publishers group but did not provide guidance publication for what to do with information that may be excluded from publication. The Fink Commit- One issue that those involved in prior review tee did, however, reject the creation of a new of experiments will likely have to wrestle with category of “sensitive but unclassified” infor- is concern about the publication of experimen- mation in the life sciences, stating that the risks tal results and genetic sequences that could “of a chilling effect on biodefense research vital be exploited for malicious purposes. For sev- to U.S. national security as the result of inevita- eral years, the scientific community has been bly general and vague categories is at present considering whether and how restrictions on significantly greater than the risks posed by in- communication of sensitive research findings advertent publication of potentially dangerous might be an appropriate response to the po- results.” tential misuse of the biological sciences and

47 The NSABB formed a subgroup on commu- “Wikipedia” type mechanism in which results nications to pursue the issue. This subgroup are circulated worldwide immediately and are recognized that the communication of scien- then reviewed and vetted after the fact. Such a tific research involves several stages other than trend would place sole responsibility for what formal publication of final results. Reiterating to communicate on the individual scientist.. the importance of open and unfettered sharing of information and technologies for validating Ch o o s i n g a p o r t f o l i o o f o p t i o n s and advancing scientific research, the subgroup went on to consider how to assess the risks Options Table IV includes our evaluations of all and benefits of communicating research infor- 17 options proposed in the previous sections. mation. The subgroup formulated options for The challenge that faces decisionmakers is to the content, timing, distribution, and/or context choose a portfolio of options that will achieve of research information that poses security the multiple goals desired. concerns.94 Given the diversity of communication mechanisms, the subgroup recognized The top half of the table includes our judg- that to the extent a line of research can be ment of how relatively effective each option anticipated to raise questions about future dis- is for achieving the three key goals of enhanc- semination of results, it would be preferable to address those questions at the proposal ing biosecurity, fostering laboratory safety, and stage. Questions involving proposal review protecting the environment. Increasing the and research oversight are being addressed in number of options adopted will likely enhance a separate NSABB subgroup the Nation’s ability to achieve these goals, but no option is without drawbacks. Of particular relevance to synthetic genomics, a workshop was held at the National Academies The bottom half of the Table includes rankings in October 2003 to address concerns about of how well these options perform on four ad- the potential for misuse of genome sequence ditional important considerations: What costs data and to examine policies governing access and other burdens do they impose on gov- to databases containing those data. Its report ernment and industry? Can they perform to argued against any kind of monitoring of or potential today or do they require additional restrictions to access, concluding that “rapid, research? Will they unduly impede progress in unrestricted public access to primary genome synthetic biology and other related research? sequence data, annotations of genome data, Finally, do the options help to promote con- genome databases, and Internet-based tools structive applications, rather than just prevent for genome analysis should be encouraged.”95 undesirable ones? Since naturally-occurring pathogens represent ongoing public health threats, any restrictions Although we have provided our best judgments on the ability to understand and counter them about the broad benefits and costs of each of would have serious consequences. However, these options, our ability to do so is extremely this finding was motivated as much by the limited in some cases. For example, while we practical difficulties in limiting access to ge- have pointed out that synthetic genomics nome data as by the judgment that such limita- would rarely be the preferred method for tions would be undesirable. a bioterrorist to acquire a pathogen, we have no way of judging the overall likelihood In the longer run, however, scientific communi- of such an event. Thus, we can only judge the cation may rely less and less on “gatekeepers” relative effectiveness of the options for enhanc- such as peer reviewers, editors, and publishers. ing biosecurity; that is, how each option com- In the future, it is possible that scientific compares to the others. Quantitative estimates of munication will evolve from a formal system the added security provided by each option based on pre-publication review to an informal, are simply not possible.

48 Synthetic Genomics | Options for Governance CHOOSING A PORTFOLIO OF OPTIONS

Options Table IV: Summary of All Options

Gene Firms Oligo Manufacturers DNA Synthesizers Users and Organizations

Does the Option:

by preventing incidents?

by helping to respond?

Foster Laboratory Safety

by preventing incidents?

by helping to respond?

Protect the Environment

by preventing incidents?

by helping to respond?

Other Considerations:

Minimize costs and burdens to government and industry?

Perform to potential without additional research?

Not impede research?

Promote constructive applications?

Key to Scoring:

Most effective for this goal. Most effective performance on this consideration. Relatively effective. Moderately effective. Somewhat effective. Minimally effective. Not relevant.

49 Similarly, we can estimate the relative effect concern for the potential harm that might arise each option may have on the progress of the from synthetic genomics versus the desire to field of synthetic genomics, but we are not preserve its benefits and to avoid imposing able to take this analysis much further. While other costs on society. we believe that the potential of the technology is high, we have no crystal ball that can tell Decisionmakers will differ in their preferred us the future of the field with and without any balances. In addition, perceptions of the op- of the policy options. timal balance will change over time as more is learned about the risks and benefits of When making decisions about the governance synthetic genomics. Thus, the flexibility of the of synthetic genomics, policymakers will bring overall portfolio is another important consid- their own values, priorities, prior beliefs, and eration. Decisionmakers should expect that extent of risk aversion regarding safety and the program they adopt today will need to be security threats to their analyses and decisions. reconsidered in several years’ time. They will also emphasize different goals and other considerations, leading to varying assess- Again, the first portfolio includes those options ments of the desirability of each of the policy that provide the greatest benefit at the lowest options. To help each decisionmaker choose a cost and burden. For example, the first option preferred set of options, we have constructed listed in Table 2, Gene synthesis companies must several portfolios ranging from a modest set screen orders, is already being done voluntarily of controls on the new technology to one that by the majority of gene synthesis companies. is quite aggressive. This option is aimed simply at the relatively small fraction (perhaps 25%) of U.S. firms that Table 4 presents the mix of options within each do not. The next two options, requiring both of three illustrative scenarios. The options are Gene synthesis companies and oligo manufactures again arranged by “intervention point;” that is, to store information, is also being done today by whether they apply to gene- or genome syn- many U.S. firms for business and regulatory thesis companies, manufacturers of oligonucle- reasons. The goal of these options is to ensure otides, laboratory-benchtop DNA synthesiz- that all firms store their orders and that the FBI ers, or the users of the technology and the would be able to access such records in the organizations in which they work. Note that event that a bioterrorism incident involving a we can construct many groupings that would synthesized genome should occur. use slightly different options, with slightly different outcomes. These three portfolios are Education about the risks and best practices, presented as examples only. is already occurring in some university curricula, but not many. Accordingly, this option is The first portfolio is aimed at plugging the big- directed at the majority of students and re- gest holes in the current system of governance searchers new to the field who have not had for synthetic genomics. The options included rigorous biosafety training or have not had the are those that we judge to provide the greatest opportunity to think through the potential so- benefits at the lowest costs and burdens. The cietal impacts out of their research. Finally, the second and subsequent portfolios add options development and use of a Biosafety manual to enhance biosecurity and biosafety, but the developed explicitly for synthetic biology labora- relative “bang for the buck”—the added ben- tories (a “BSBL”) would make such information efit compared to the undesired impacts—of easily accessible to this expanding community these added options will be lower than those of scientists and engineers. in the preceding portfolios. Each successive portfolio strikes a different balance between

50 Synthetic Genomics | Options for Governance CHOOSING A PORTFOLIO OF OPTIONS

Table 4: Summary of Portfolios

Intervention Point Option Portfolio 1 2 3

Gene Foundries IA-1. Require commercial rms to use approved software for screening orders 

IA-2. People who order synthetic DNA from commercial rms must be veri ed as legitimate users by an Institutional Biosafety Of cer or similar “responsible of cial”

IA-3. Commercial rms are required to use approved screening software and to ensure that people who place orders are veri ed as legitimate users by a   Biosafety Of cer

IA-4. Require commercial rms to store information about customers and their    orders

Oligo Manufacturers IB-1. Require commercial rms to use approved software for screening orders

IB-2. People who order synthetic DNA from commercial rms must be veri ed as legitimate users by an Institutional Biosafety Of cer or similar “responsible of cial” 

IB-3. Commercial rms are required to use approved screening software and to ensure that people who place orders are veri ed as legitimate users by a  Biosafety Of cer

IB-4. Require commercial rms to store information about customers and their    orders

DNA Synthesizers II-1. Owners of DNA synthesizers must register their machines

II-2. Owners of DNA synthesizers must be licensed 

II-3. A license is required to both own DNA synthesizers and to buy reagents  and services

III-1. Incorporate education about risks and best practices as part of university Users and    Organizations curricula

III-2. Compile a manual for “biosafety in synthetic biology laboratories.”   

III-3. Establish a clearinghouse for best practices 

III-4. Broaden Institutional Biosafety Committee (IBC) review responsibilities to consider risky experiments  

III-5. Broaden IBC review responsibilities and add oversight from a national advisory   group to evaluate risky experiments

III-6. Broaden IBC review responsibilities, plus enhance enforcement of compliance with National Institutes of Health biosafety guidelines 

Synthetic Genomics | Options for Governance 51 The second portfolio adds several more op- Organizations would be required to shoulder tions to the mix. Again, the added benefits a new burden by Broadening local institutional of these options compared to the undesired review of proposed research involving DNA syn- impacts, are lower than in the first portfolio. thesis to include implications for bioterrorism. Some decisionmakers will judge these op- National level reviews for bioterrorism and bio- tions to be useful additions while others may safety could be introduced here to deal with choose to forgo them. issues that are not covered in a BSBL.

For example, the second portfolio adds an ad- The options in the third portfolio begin to ditional option for both gene synthesis compa- address concerns about biosecurity and bio- nies and oligo manufacturers: Orders can only safety that might never be encountered by be placed by legitimate researchers, as verified most legitimate users, or that may be consid- by a registered biosafety professional. As in the ered to be unduly burdensome. This portfolio first portfolio, gene synthesis companies must requires the Licensing of synthesizers plus li- still screen their orders, but because of the censing to buy reagents and services rather than lower effectiveness and increased burden of licensing of synthesizers alone. A Requirement screening short pieces of DNA as compared for oligo houses to screen their orders (under to genes, oligo manufacturers are not required the hybrid option) is introduced here, as its to do so. Oligo manufacturers are, however, technical feasibility remains unclear. A Clearing- required to ensure that orders come from house would be added to augment many of legitimate researchers. the topics included in a BSBL. Finally, Enhanced enforcement of biosafety guidelines is included The second portfolio also includes Licensing to increase the effectiveness of either current of DNA synthesizers. Though synthesizing a or expanded IBC reviews. pathogen with only a laboratory synthesizer and the necessary reagents requires additional time and skills, it is nonetheless possible.

52 Synthetic Genomics | Options for Governance APPENDICES

Appendices

I. Core Group Members II. Commissioned Papers

The Core Group for this study consisted of 18 The complete set of commissioned individuals with a wide range of expertise, and papers is available at http://dspace.mit.edu/ included scientific and engineering research- handle/1721.1/39658. ers; social scientists; and legal, regulatory, and Baric R. 2006. Synthetic Viral Genomics. policy analysts. http://dspace.mit.edu handle/1721.1/39652 Ralph Baric, University of North Carolina Collett M. 2006. Impact of Synthetic Genomics George M. Church, Harvard Medical School on the Threat of Bioterrorism with Viral Agents. http://dspace.mit.edu/handle/1721.1/39653 Drew Endy, Massachusetts Institute of Technology (project co-director) Fleming D. 2006. Risk Assessment of Synthetic Genomics: A Biosafety and Biosecurity Perspective. Gerald L. Epstein, Center for Strategic & http://dspace.mit.edu/handle/1721.1/39654 International Studies (project co-director) Furger F. 2006. From Genetically Modified Robert M. Friedman, J. Craig Venter Institute Organisms to Synthetic Biology: Legislation in the (project co-director) European Union, in Six Member Countries and Franco Furger, Independent Consultant Switzerland. http://dspace.mit.edu/handle/1721.1/39655 Michele S. Garfinkel, J. Craig Venter Institute (project co-director) Jones R. 2005. Sequence Screening. http://dspace.mit.edu/handle/1721.1/39656 Tom Knight, Massachusetts Institute of Technology Sanghvi Y. 2005. A Roadmap to the Assembly Lori Knowles, University of Alberta of Synthetic DNA from Raw Materials. http://dspace.mit.edu/handle/1721.1/39657 John Mulligan, Blue Heron Biotechnology Paula Olsiewski, Alfred P. Sloan Foundation (project program officer) III. Meetings Held Tara O’Toole, University of Pittsburgh Medical Workshops Center, Center for Biosecurity George Poste, Arizona State University, 26-27 September 2005. Cambridge, Massachu- Biodesign Institute setts. Technologies for Synthetic Genomics. Michael Rodemeyer, Pew Initiative on Food 27-28 February 2006. Rockville, Maryland. Risks and Biotechnology and Benefits from Synthetic Genomics. Susanna Hornig Priest, University of Nevada, 31 May-1 June 2006. Washington, District of Las Vegas (formerly at University of South Columbia. Governance Options. Carolina) Hamilton Smith, J. Craig Venter Institute Invitational Meeting

Jonathan B. Tucker, Monterey Institute of 4 December 2006. Washington, District of International Studies Columbia. Synthetic Genomics: Risks and J. Craig Venter, J. Craig Venter Institute Benefits for Science and Society.

53 Endnotes

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55 Author Biographies

Michele S. Garfinkel is a policy analyst at the J. Craig Venter In- Woodrow Wilson School of Public and International Affairs. stitute. Prior to joining the Institute she was a research fellow He serves on the editorial board for the journal Biosecurity at Columbia University’s Center for Science, Policy & Out- and Bioterrorism and on the Biological Threats Panel of the comes, where her work focused on health research policy. National Academies’ Committee on International Security Earlier, she held a staff position at the American Association and Arms Control. He received SB degrees in physics and for the Advancement of Science, where she co-authored electrical engineering from MIT and a PhD in physics from an early study on policy issues in stem cell research. She the University of California at Berkeley. He is a Fellow of the was a post-doctoral research fellow at the Fred Hutchinson American Physical Society. Cancer Research Center in Seattle. She received her AB in Genetics from the University of California, Berkeley and her Robert M. Friedman is Vice President for Public Policy at PhD in Microbiology from the University of Washington. She the J. Craig Venter Institute. Friedman directs JCVI’s Policy also holds an MA in Science, Technology, and Public Policy Center and is also active in several projects ongoing in its from the George Washington University where she was a Environmental Genomics Group. Prior to joining the Venter Shapiro Fellow in International Affairs. Institute, he was Vice President for Research at The Heinz Center, a nonprofit policy research organization that brings Drew Endy has been a faculty member at MIT since 2004. together collaborators from government, industry, environ- His research focuses on the design of integrated biological mental organizations, and academia. Earlier, he was a Senior systems and error detection and correction in reproducing Associate at the Office of Technology Assessment of the US machines. He organized the First International Conference Congress. For 16 years, he advised Congressional commit- on Synthetic Biology, co-founded the Registry of Standard tees on issues involving environmental and natural resources Biological Parts, the BioBricks Foundation, the International policy, including a 1986 study on Environmental Applications Genetically Engineered Machines competition, and Codon of Genetically Altered Organisms. He received his PhD from Devices, Inc. He earned BS and MS degrees in civil and en- the University of Wisconsin, Madison, in Ecological Systems vironmental engineering at Lehigh University, and a PhD in Analysis. He is a Fellow of the American Association for the biochemical engineering Dartmouth College. He also stud- Advancement of Science. ied genetics, molecular biology, and chemical engineering at UT Austin and UW Madison, and has worked as a fellow at the Molecular Sciences Institute in Berkeley and in the Departments of Biology and Biological Engineering at MIT.

Gerald L. Epstein is Senior Fellow for Science and Security in the CSIS Homeland Security Program, where he works on issues including biological weapons threats and potential tensions between the scientific research and national security communities. He also teaches in the Security Studies Pro- gram in Georgetown University’s School of Foreign Service. He came to CSIS from the Institute for Defense Analyses, where he was assigned to the Defense Threat Reduction Agency. From 1996 to 2001, he worked at the White House Office of Science and Technology Policy, serving for the last year in a joint appointment as Assistant Director of OSTP for National Security and Senior Director for Science and Technology on the National Security Council staff. Prior to his White House service, he held positions at the Congres- sional Office of Technology Assessment, Harvard University’s Kennedy School of Government, and Princeton University’s

56 Synthetic Genomics | Options for Governance Institute Information

The J. Craig Venter Institute (JCVI) is a not-for-profit re- The Massachusetts Institute of Technology’s Department search institute dedicated to the advancement of the sci- of Biological Engineering was founded in 1998 as a new MIT ence of genomics; the understanding of its implications for academic unit, with the mission of defining and establishing a society; and communication of those results to the scien- new discipline fusing molecular life sciences with engineering. tific community, the public, and policymakers. Founded by J. The goal of this biological engineering discipline is to advance Craig Venter, Ph.D., the JCVI is home to approximately 400 fundamental understanding of how biological systems oper- scientists and staff with expertise in human and evolution- ate and to develop effective biology-based technologies for ary biology, genetics, bioinformatics/informatics, information applications across a wide spectrum of societal needs includ- technology, high-throughput DNA sequencing, genomic and ing breakthroughs in diagnosis, treatment, and prevention of environmental policy research, and public education in sci- disease, in design of novel materials, devices, and processes, ence and science policy. JCVI was formed in 2006 through and in enhancing environmental health. The mission of MIT the merger of several affiliated and legacy organizations— is to advance knowledge and educate students in science, The Institute for Genomic Research (TIGR) and The Center technology, and other areas of scholarship that will best for the Advancement of Genomics (TCAG), The J. Craig serve the nation and the world in the 21st century. Venter Science Foundation, The Joint Technology Center, and The Institute for Biological Energy Alternatives (IBEA). The JCVI is a 501 (c)(3) organization.

The Center for Strategic and International Studies (CSIS) seeks to advance global security and prosperity in an era of economic and political transformation by providing strategic insights and practical policy solutions to decisionmakers. CSIS serves as a strategic planning partner for the government by conducting research and analysis and developing policy initiatives that look into the future and anticipate change. Founded in 1962 by David M. Abshire and Admiral Arleigh Burke, CSIS is a bipartisan, nonprofit organization headquar- tered in Washington, D.C. with more than 220 full-time staff and a large network of affiliated experts. Former U.S. senator Sam Nunn became chairman of the CSIS Board of Trustees in 1999, and John J. Hamre has led CSIS as its president and chief executive officer since April 2000.

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