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University of Otago Law Theses and Dissertations |
Last Updated: 11 April 2024
Navigating the Risks of Artificial DNA: Do We Need an International Treaty?
Isaac Heron
A dissertation submitted in partial fulfilment of the degree of Bachelor of Laws (with Honours) at the University of Otago - Te Whare Wānanga o Otāgo.
7 October 2023
Table of Contents
D International Biosecurity and Biosafety Initiative for Science (and the Nuclear Threat Initiative)
.........................................................................................................................................................26
Chapter I: Introduction
It has long been possible to create DNA and RNA (“nucleic acids”) from scratch, with no need for a physical template from a biological organism,1 and now a range of commercial suppliers across the world provide this service for various forms of genetic research.2 This – known as nucleic acid synthesis (NAS) - is a vital enabler for the growing “synthetic biology” field, which aims to make biology “programmable” through engineering techniques.3 One common application of “synthetic biology” is creating artificial microbial life, which in some is possible with highly accessible and affordable technologies.4 Consequently, if someone wants to create a new pathogen or re-create an existing one, it is no longer necessary to isolate it from its natural environment. This technology both therefore presents a risk of facilitating bioterrorism and has a range of potential research benefits,5 so it can neither be completely prohibited nor left unregulated.6NAS risks contributing to bioterrorism because of the potential for bad actors to order dangerous sequences online, as illustrated by a Guardian reporter successfully ordering a piece of smallpox DNA for delivery to a residential address in 2006.7 Consequently, several large companies have formed the “International Gene Synthesis Consortium” (IGSC), whose members voluntarily screen orders for dangerous sequences and ensure their customers are legitimate.8 However, many NAS companies have not joined the IGSC, and their screening
1 SL Beaucage and Marvin H Caruthers “Deoxynucleoside phosphoramidites—a new class of key intermediates for deoxypolynucleotide synthesis” (1981) 22(20) Tetrahedron letters 1859 at 1859; and MH Caruthers and others “Deoxyoligonucleotide synthesis via the phosphoramidite method” (1983) 3 Gene amplification and analysis 1.
2 National Academies of Sciences, Engineering and Medicine Biodefense in the age of synthetic biology (2018) at 151.
3 At 9, 11, 34 and 101.
4 National Academies of Sciences, Engineering and Medicine, above n 2, at 41; Sarah M Richardson and others “Design of a synthetic yeast genome” (2017) 355(6329) Science 1040; and John Hopkins Medicine “First Fully Artificial Yeast Genome Has Been Designed” (9 March 2017) John Hopkins Medicine
<www.hopkinsmedicine.org>; and National Academies of Sciences, Engineering and Medicine, above n 2, at 3.
5 National Academies of Sciences, Engineering and Medicine, above n 2, at 44-53; and Secretariat on the Convention on Biological Diversity Synthetic Biology (United Nations Environment Programme and Convention on Biological Diversity, CBD Technical Series No 100, April 2022) at 42-46.
6 Amanda Kobokovich, Rachel West, Michael Montague, Tom Inglesby and Gigi Kwik Gronvall (2019) “Strengthening Security for Gene Synthesis: Recommendations for Governance” 17(6) Health Secur 419 at 419- 420; and National Academies of Sciences, Engineering and Medicine, above n 2, at 151.
7 James Randerson “Lax Laws, Virus DNA and Potential for Terror” (14 June 2006) Guardian
<https://www.theguardian.com/science/2006/jun/14/weaponstechnology.uk>.
8 International Gene Synthesis Consortium “Home” <https://genesynthesisconsortium.org/>; Kobokovich and others, above n 6, at 421.
practices are mostly unknown.9 The United States Department of Health and Human Services has also created voluntary guidance for NAS companies which makes similar recommendations to the IGSC’s approach.10
Currently, no country in the world directly mandates that NAS companies carry out screening.11 However, various countries have implemented regimes to control the transfer of listed biological materials between individuals in line with article IV of the Biological Weapons Convention 1975 (BWC), which requires them to take all “necessary measures” to prevent the acquisition and development of biological weapons.12 In some cases, nucleic acid sequences are included on these lists, which therefore indirectly obliges companies to screen their orders for these sequences.13 These regulations are ad hoc and have been widely criticised,14 and inexplicably often only cover the export of nucleic acids, not domestic sales.15 This means in some jurisdictions where NAS companies operate, they have no legal obligation to screen orders from domestic customers. As the costs of screening rise as a proportion of total NAS costs, any businesses carrying out voluntary screening will have an increasing incentive to abandon this practice, if they have not already.16
9 International Gene Synthesis Consortium Harmonized Screening Protocol© v2.0 (19 November 2017) at 1; and Michael Schulson “Experts Debate the Risks of Made-to-Order DNA” (21 December 2022) Undark Magazine
<https://undark.org/2022/12/21/experts-debate-the-risks-of-made-to-order-dna/>.
10 Department of Health and Human Services Screening Framework Guidance for Providers of Synthetic Double- Stranded DNA (2010).
11 Hoffman and others “Safety by design: Biosafety and Biosecurity in the age of synthetic genomics” (2023) 26(3) iScience 1 at 2.
12 Biological Weapons Convention, art IV [Biological Weapons Convention]; and Treasa Dunworth, Robert J Mathews and Tim McCormack “National Implementation of the biological weapons convention” (2006) 11 JCSL 93 at 110-115.
13 See for example 70 FR 13316 § 73.3(c)(1)-(2); and Anti-terrorism, Crime and Security Act 2001 (UK), Schedule 5, F50(c).
14 Arturo Casadevall and David A Relman “Microbial threat lists: obstacles in the quest for biosecurity?” (2010) Nat Rev Microbiol 8(2) 149 at 149-153.
15 See for example 感染症の予防及び感染症の患者に対する医療に関する法律 1998 (JP), arts 6, 56-18, 56- 19 and 56-20 (translation: Act on the Prevention of Infectious Diseases and Medical Care for Patients with Infectious Diseases); Infectious Disease Control and Prevention Act 2009 (KR), arts 2(19) and 21(1). National Health Security Act 2007 (Cth), ss 3, 31(1) and 35(1); and Security Sensitive Biological Agents Regulatory Scheme – Fact sheet 5 – List of Security Sensitive Biological Agents 2016 (Cth) at 2.
16 Diane DiEuliis, Sarah R Carter and Gigi Kwik Gronvall "Options for synthetic DNA order screening, revisited" (2017) 2(4) MSphere 10-1128 at 2; and Sarah R Carter and Robert M Friedman DNA Synthesis and Biosecurity: Lessons Learned and Options for the Future (J Craig Venter Institute, October 2015) at 15; Department of Health and Human Services, above n 10, at 151; James Diggans and Emily Leproust “Next steps for access to safe, secure DNA synthesis” (2019) 7 Front bioeng biotechnol 86 at 2.
This inadequate situation has raised significant concerns among both academics and in the media.17 However, there is disagreement about how best to respond. Some argue for a new international treaty that requires member states to regulate NAS.18 Others at the opposite extreme argue it is best to continue to support the industry to be the primary regulator in the international arena. This approach is known as “transnational private regulation” (TPR).19 Still others, such as Braden Leach, argue the BWC already requires states to regulate NAS since this is a “necessary measure” to prevent biological weapons production.20 This paper evaluates these competing arguments. It does this by firstly illustrating the existing international regime’s many deficiencies. Then, it aggregates the regulations states have enacted to comply with the BWC for all jurisdictions that house IGSC members and evaluates whether states are breaching the BWC by failing to adequately regulate NAS. Finally, it compares the options of negotiating a new treaty, TPR, or amending or clarifying the BWC, and concludes they all have merit. However, the sensible place to start would be to attempt TPR alongside a clarification that the BWC requires states to regulate NAS.
17 See for example Kevin M Esvelt Delay, Detect, Defend- Preparing for a Future in which Thousands Can Release New Pandemics (Geneva Centre for Security Policy, November 2022); Kelsey Piper “It’s time to close the gene synthesis loophole that could lead to a human-made pandemic” (27 July 2023) Vox <https://www.vox.com/future- perfect/2023/7/27/23808920/gene-dna-synthesis-biotechnology-pandemic-viruses-twist-bioscience-pathogens- ginkgo-bioworks>; Schulson, above n 9.
18 Grant Wilson “Minimizing Global Catastrophic and Existential Risks From Emerging Technologies Through International Law” (2013) 31(2) VELJ 307 at 355.
19 Justin Firestone “The Need for Soft Law to Regulate Synthetic Biology” (2020) 60(2) Jurimetrics 139 at 169; and Stephen M Maurer “Taking self-governance seriously: Synthetic biology’s last, best chance to improve security” (working paper, University of California, Berkeley, 2012) at 13.
20 Braden Leach “Necessary Measures: Synthetic Biology and the Biological Weapons Convention” (2021) 25
STLR 141 at 150.
Chapter II: Introduction to Nucleic Acid Synthesis
This chapter outlines the necessary background to understand nucleic acid synthesis (NAS) and the role it plays in the synthetic biology field. It then explains the risks NAS poses and why this creates a need for regulation.
I Nucleic Acid Synthesis
It has long been possible to create DNA from scratch, with no need for a physical template from a biological organism.21 This technology has since become fundamental to modern biotechnology, whether to advance research on the genetic code’s workings, develop vaccines, or for gene editing.22 Now virtually any DNA can be obtained by ordering the desired sequence from a variety of companies, or in some cases by using a benchtop DNA synthesiser.23 Moreover, several public DNA sequence databases contain the required information about which sequences to order.24
The ability to synthesise genetic material extends past DNA. Some companies also produce RNA, another type of “nucleic acid” which stores genetic information.25 Quite different processes are also involved in producing short DNA or RNA sequences called oligonucleotides (“oligos”) which do not reach the length of a “gene” (a sequence capable of encoding a protein),26 This is because quite different processes are required to synthesise shorter “oligos” and then connect them through “gene assembly”.27 This paper refers to synthetic nucleic acid (SNA) to cover all these variations, and to their production as nucleic acid synthesis (NAS).
The NAS industry is currently undergoing a significant transformation. While NAS costs have long been gradually falling, they have fallen much more slowly than for SNA sequencing.28
21 Beaucage and Caruthers, above n 1, at 1859; and Caruthers and others, above n 1, at 151.
22 Kobokovich and others, above n 6, at 419-420; and National Academies of Sciences, Engineering and Medicine, above n 2, at 151.
23 National Academies of Sciences, Engineering and Medicine, above n 2, at 151.
24 Akpoviri, Baharum and Zainol “Digital Sequence Information and the Access and Benefit-Sharing Obligation of the Convention on Biological Diversity” (2023) at 26.
25 Sarah R Carter, Jamie M Yassif and Chris Isaac Benchtop DNA Synthesis Devices: Capabilities, Biosecurity Implications, and Governance (Nuclear Threat Initiative, May 2023) at 12.
26 Maurer, above n 26, at 4.
27 National Academies of Sciences, Engineering and Medicine, above n 2, at 151-152; and Phillip Kuhn and others “Next generation gene synthesis: From microarrays to genomes” (2017) 17(1) Eng Life Sci 6 at 6.
28 Mary Ann Liebert “The Long and Winding Road: On Demand DNA Synthesis in High Demand” (27 July 2023)
GEN Genetic Engineering & Biotechnology News <www.genengnews.com>.
Now, however, a range of new NAS methods are coming onto the market which likely lower costs substantially, especially for gene-length SNAs.29 These technological changes have also enabled a new generation of benchtop synthesis devices which research labs could purchase to produce gene-length SNAs themselves.30 Benchtop devices already exist but their limitations have so far led to most research labs to rely instead on commercial SNA suppliers.31
II Synthetic Biology
NAS is a key enabling technology for synthetic biology,32 which “collectively refers to concepts, approaches, and tools that enable the modification or creation of biological organisms”.33 The field is sometimes difficult to distinguish from overall genetic engineering,34 but the key feature of synthetic biology is the use of approaches from engineering disciplines, for example the “standardization of components”, such as the creation of interchangeable biological parts known as Bio-Bricks™.35 Synthetic biology also involves “the use of software and computational modeling for designing biological systems from those components, and the construction of prototypes based on those designs”.36
29 See for example Kobokovich and others, above n 6 at 421-422; ANSA Biotechnologies “Early Access Program”
<https://ansabio.com/early-access>; Liebert, above n 28; SynBioBeta “$10M Series A Funding Fuels Camena Bioscience's DNA Synthesis Revolution” <https://www.synbiobeta.com/read/10m-series-a-funding-fuels- camena-biosciences-dna-synthesis-revolution>;
Camena Biosciences “Camena Bioscience uses gSynth™ to synthesise a 2.7kb plasmid”
<https://www.camenabio.com/gSynth-production-long-DNA-molecules>; Molecular Assemblies “Molecular Assemblies Ships to Sixth Customer Oligonucleotides Generated by Fully Enzymatic DNA Synthesis Technology” (16 May 2023) <https://molecularassemblies.com/press-releases/molecular-assemblies-ships-to- sixth-customer-oligonucleotides-generated-by-fully-enzymatic-dna-synthesis-technology/>; DNA Script “DNA Script Announces World’s First Enzymatic Synthesis of a High-Purity 200-Nucleotide Strand of DNA” (27 February 2019) <https://www.dnascript.com/press-releases/dna-script-announces-worlds-first-enzymatic- synthesis-of-a-high-purity-200-nucleotide-strand-of-dna/>; DNA Script “DNA Script Presents Data at AGBT Confirming Functional Performance of the Company’s Enzymatic Synthesis (EDS) Technology” (1 March 2021)
<https://www.dnascript.com/press-releases/dna-script-presents-data-at-agbt-confirming-functional-performance- of-the-companys-enzymatic-synthesis-eds-technology/>; TelesisBio “Sola Enzymatic DNA Synthesis Technology” <https://telesisbio.com/innovation/sola-technology/>; Evonetix “Technology”
<https://www.evonetix.com/technology/>; Elegen Bio “Partnering”
<https://www.elegenbio.com/company/partnering>; and Constructive Bio “CONEXER: a new era in genome writing” (28 June 2023) <https://www.constructive.bio/news/conexer-a-new-era-in-genome-writing>.
30 Carter, Yassif and Isaac, above n 25, at 13 and 17.
31 Jiahao Huang “DNA synthesizer: Why the innovation never took off” (31 July 2018) LinkedIn
<www.linkedin.com>; Liebert, above n 28; Carter, Yassif and Isaac, above n 25, at 11.
32 Secretariat on the Convention on Biological Diversity Synthetic Biology, above n 5, at 25.
33 National Academies of Sciences, Engineering and Medicine, above n 2, at 9.
34 Kavita M Berger and Rocco J Casagrande “Twentieth-century nonproliferation meets twenty-first-century biotechnology” (2020) 27(4-6) Nonproliferation Rev 541 at 548.
35 National Academies of Sciences, Engineering and Medicine, above n 2, at 101; and Firestone, above n 19, at 148.
36 National Academies of Sciences, Engineering and Medicine, above n 2, at 11.
The most obvious application of synthetic biology is creating artificial biological entities. So far this has been done for small entities like viruses or single-celled organisms such as bacteria and (partially) yeast.37 This involves two steps: firstly, synthesising and assembling the entity’s genome (its full set of nucleic acid sequences), and secondly, “booting” it into a living cell.38 Booting takes on many forms. For example, some viruses’ genetic material can simply be delivered into a host cell, while others rely on the host cell expressing additional biological components (“exogenous factors”).39
Synthetic biology’s potential applications have generated significant excitement. These include engineered bacteria designed to support maize growth,40 gene drives which spread sterility through populations of disease-causing insects,41 the RNA vaccines for COVID-19 and Ebola,42 and mammalian artificial chromosomes used to build anticancer drugs.43 Artificial organism creation specifically has been useful for basic research such as determining the minimum genome required to support life.44 Others, such as Hanson and Lorenzo, believe synthetic biology’s potential is overhyped. They argue synthetic biology proponents overstate the ability to directly apply engineering approaches to biology,45 and the extent to which speeding up any biological design process can speed up the overall product design process, which requires many other steps.46 Despite this scepticism, Hanson and Lorenzo acknowledge progress in synthetic biology has been substantial and will continue to be so, but at a slower rate than its enthusiasts assume.47
37 National Academies of Sciences, Engineering and Medicine, above n 2, at 152; Richardson and others, above n 4.
38 National Academies of Sciences, Engineering and Medicine, above n 2, at 153.
39 At 154.
40 Secretariat on the Convention on Biological Diversity Synthetic Biology, above n 5, at 42.
41 At 42-43.
42 At 46.
43 Venter “Synthetic chromosomes, genomes, viruses, and cells” at 2716.
44 Secretariat on the Convention on Biological Diversity Synthetic Biology, above n 5, at 49.
45 Andrew D Hanson and Víctor de Lorenzo “Synthetic Biology – High Time to Deliver” (2023) 12(6) ACS Synth Biol 1579 at 1580.
46 At 1580-1581.
47 At 1581.
III Reasons for Concern
While NAS has many benefits, it also risks facilitating biological weapons creation since it sidesteps the need to isolate pathogens from their environment.48 The most prominent examples used to make this point include the past use of commercially ordered DNA (by legitimate scientific institutions) to create poliovirus, the 1918 influenza virus, and horsepox.49 Moreover, significant concerns were raised in 2005 when a United States journalist found multiple DNA synthesis companies did not screen their orders for dangerous sequences,50 and in 2006 when reporters successfully purchased smallpox DNA segments from a United Kingdom company.51
This creates a “dual-use dilemma”, which is when the same information or materials can be used both for legitimate and harmful purposes.52 Harmful uses of SNA can be split into use by state actors, malicious non-state actors (bioterrorists) and unintended harm caused by the recreation of pathogens for scientific research. In theory, these all could contribute to the creation of dangerous pathogens designed to cause substantial harm, including taking millions of lives. Some circles even worry about the more extreme threat of pathogens designed to wipe out humanity or severely limit its potential, a risk known as an “existential risk” or “global catastrophic biological risk”.53
Those concerned about state actors creating bioweapons note the long history of bioweapons deployment in warfare,54 and multiple state-led programmes created in the 20th century.55 They note that bioweapons can be manufactured cheaply using widely accessible equipment, but can
48 National Academies of Sciences, Engineering and Medicine, above n 2, at 44-53.
49 Kai Kupferschmidt “How Canadian researchers reconstituted an extinct poxvirus for $100,000 using mail-order DNA” (6 July 2017) Science <https://www.science.org/content/article/how-canadian-researchers-reconstituted- extinct-poxvirus-100000-using-mail-order-dna>.
50 Peter Aldhous “The bioweapon is in the post” (2005) at 1.
51 Randerson, above n 7.
52 World Health Organisation Global guidance framework for the responsible use of the life sciences (2022) at 36. 53 Wilson, above n 18, at 311; and Jaime M Yassif, Shayna Korol and Angela Kane “Guarding Against Catastrophic Biological Risks: Preventing State Biological Weapon Development and Use by Shaping Intentions” (2023) 21(4) Health Secur 258 at 258.
54 Firestone, above n 19, at 151.
55 Glenn Cross and Lynn Klotz “Twenty-First Century perspectives on the Biological Weapon Convention: Continued Relevance or Toothless Paper Tiger” (2020) 76(4) Bull At Sci 185 at 185 and 187-188.
still cause widespread harm because they are self-replicating.56 Sceptics point out that modern military bioweapons deployment is essentially non-existent because it is so difficult to prevent bioweapons from harming one’s own people.57 Regardless, while theoretically a state-led bioweapons programme might use ordered SNAs or benchtop synthesisers,58 they likely have sufficient resources to create the required material themselves if necessary. Regulating NAS therefore likely contributes little to avoiding risks of state use.
The greatest threat from NAS is therefore bioterrorism. There are many examples of non-state groups willing to risk harming themselves to harm others, the most famous perhaps being the Japanese Aum Shinrikyo cult which both attempted to deploy biological weapons (anthrax) and successfully deployed chemical weapons in the Tokyo subway.59 This is not a one-off risk, there was at least at one time 3,000 named apocalyptic groups around the world.60 That said, even if non-state actors manage to obtain SNAs many other steps are required to convert this into a bioweapon. These steps require a range of “tacit knowledge”, which is not easy to articulate and mostly comes from “learning by doing”.61 To some extent, the synthetic biology project aims to remove this “tacit knowledge” barrier by making biology “programmable”, although it is unclear to what degree they have succeeded in this or to what degree they will in the future.62 Separately, other technologies such as artificial intelligence may also reduce this barrier.63 Moreover, the tacit knowledge barrier will not stop those who choose to, or have already, taken the time to train in synthetic biology at legitimate institutions.64
On balance, the level of risk posed by bioterrorist access to SNA likely varies substantially with the application in question. A United States National Academies of Sciences, Engineering
56 Leach, above n 20, at 143-144.
57 Cross and Klotz, above n 55. at 185-188.
58 Leach, above n 20, at 144, n 16.
59 Firestone, above n 19, at 153.
60 Paul Cruickshank, Don Rassler and Kristina Hummel “A View from the CT Foxhole: Lawrence Kerr, Former Director, Office of Pandemics and Emerging Threats, Office of Global Affairs, U.S. Department of Health and Human Services” (April 2022) <https://ctc.westpoint.edu/a-view-from-the-ct-foxhole-lawrence-kerr-former- director-office-of-pandemics-and-emerging-threats-office-of-global-affairs-u-s-department-of-health-and- human-services/>.
61 James Revill and Catherine Jefferson “Tacit knowledge and the biological weapons regime” (2014) 41 Sci Public Policy 597 at 599; and Catherine Jefferson, Filipa Lentzos and Claire Marris “Synthetic Biology and Biosecurity: Challenging the Myths” (2014) 2(115) Front Public Health 1 at 4-5.
62 Revill and Jefferson, above n 61, at 603; National Academies of Sciences, Engineering and Medicine, above n 2, at 101; and Esvelt, above n 17, at 10.
63 Emily H Soice, Rafael Rocha, Kimberlee Cordova, Michael Specter and Kevin M Esvelt "Can large language models democratize access to dual-use biotechnology?” (2023) <https://arxiv.org/pdf/2306.03809.pdf> at 1.
64 Firestone, above n 19, at 165; and Schulson, above n 9.
and Medicine’s 2018 review concludes three risks from synthetic biology are particularly concerning:65
(1) Recreation of known pathogenic viruses.
(2) Editing known pathogenic bacteria to become more dangerous.
(3) Using cells to synthesise harmful biochemicals.
While NAS is relevant to all these risks to the extent that it is relevant to any synthetic biology application, it particularly assists with the first. This is because once the viral genome is synthesised the only remaining step is “booting”; there is no need for further optimisation experiments.66 Since viral genomes are small this would likely be an accessible approach for anyone with “relatively common cell culture and virus purification skills and access to basic laboratory equipment”.67
Finally, scientific recreation of dangerous pathogens creates unintended risks. Such experiments have been done to test whether it is possible to warn society,68 for vaccine research,69 or to predict how a pathogen could change to become more dangerous and therefore how to defend against this.70 Such research risks the pathogen escaping in a lab accident.71 Further, the experiment’s published results may give other malicious actors useful information,72 a risk known as an “information hazard”.73 There is substantial disagreement about how these risks and benefits balance for regulatory purposes.74 Depending on what
65 National Academies of Sciences, Engineering and Medicine, above n 2, at 3. 66 National Academies of Sciences, Engineering and Medicine, above n 2, at 39. 67 At 41.
68 Kupferschmidt, above n 49.
69 Kai Kupferschmidt “A paper showing how to make a smallpox cousin just got published. Critics wonder why” (19 January 2018) Science <https://www.science.org/content/article/paper-showing-how-make-smallpox-cousin- just-got-published-critics-wonder-why>
70 Michael Selgelid “Gain-of-Function Research: Ethical Analysis” (2016) 22 Sci Eng Ethics 923 at 923. See for example Sander Herfst and others "Airborne transmission of influenza A/H5N1 virus between ferrets" (2012) 336(6088) Science 1534.
71 Selgelid, above n 70, at 925.
72 Gregory Lewis, Piers Millett, Anders Sandberg, Andrew Snyder‐Beattie and Gigi Gronvall "Information hazards in biotechnology" (2019) 39(5) Risk Anal 975 at 980.
73 Nick Bostrom “Information hazards: A typology of potential harms from knowledge” (2011) 10 Rev Contemp 44 at 45.
74 W Paul Duprex, Ron AM Fouchier, Michael J Imperiale, Marc Lipsitch, and David A Relman "Gain-of-function experiments: time for a real debate." (2015) 13(1) Nat Rev Microbiol 58; Kupferschmidt, above n 69; Gregory D Koblentz “A biotech firm made a smallpox-like virus on purpose. Nobody seems to care” (21 February 2020) Bulletin of the Atomic Scientists <https://thebulletin.org/2020/02/a-biotech-firm-made-a-smallpox-like-virus-on- purpose-nobody-seems-to-care/>.
regulations (if any) are created, SNA providers should have a role in avoiding assisting regulation violators.
The degree of risk from NAS is uncertain, yet there seems to be agreement at least some regulation is needed.75 On its face, there is no benefit to providing access to dangerous sequences except to legitimate researchers. The only obvious counterargument is that the delay from screening slows synthetic biology research in general, or else important research involving pathogens (for example vaccine production in response to cases like COVID-19).76 However, the broad benefits of synthetic biology have a tendency to be as overexaggerated as the risks, and the limits of both come from similar sources such as the tacit knowledge required to make effective use of SNA. Further, the potential harm from a pandemic-causing pathogen is so severe that even a very small risk of it occurring should not be tolerated,77 especially since it is being weighed against relatively speculative benefits. The concern about delaying research used to respond to a pandemic is more relevant, but at least on its face a delay in responding to a pandemic is less important than taking steps to avoid one.
Consequently, some regulation is needed to restrict access to SNA, which chapters II and III show is lacking.
75 Schulson, above n 9.
76 Casadevall and Relman, above n 14, at 153.
77 Esvelt, above n 17, at 13.
Chapter III: International Regulations
I Introduction
Given SNA companies operate and service customers worldwide, regulating NAS requires international coordination. Apart from private sector self-regulation, this coordination is largely lacking, as this chapter’s analysis of the following regimes will show:
(1) the international bioweapons non-proliferation regime: the Biological Weapons Convention,78 United Nations Security Council Resolution 1540,79 and the voluntary Australia Group regime;80
(2) private sector self-regulation in the form of the International Gene Synthesis Consortium and two related organisations: the International Association on Synthetic Biology and the International Biosecurity and Biosafety Initiative for Science; and
(3) the United States Department of Health and Human Services’ Screening Framework Guidance for Providers of Synthetic Double-stranded DNA.81
II Non-proliferation regimes
A Biological Weapons Convention
The Biological Weapons Convention (BWC) 1975 prohibits the development, production and stockpiling of biological weapons.82 It currently has 185 state parties with eight non- members.83 As an international legal instrument it binds states,84 so it cannot regulate SNA companies directly. However, international instruments can mandate that states regulate their nationals.85 The BWC does this through article III by requiring states “not to transfer to any
78 Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction 1015 UNTS 163 (opened for signature 10 April 1972, entered into force 26 March 1975.
79 SC Res 1540 (2004).
80 The Australia Group “Home” Australian Government Department of Foreign Affairs and Trade
<https://www.dfat.gov.au/publications/minisite/theaustraliagroupnet/site/en/index.html>.
81 Department of Health and Human Services, above n 10.
82 Una Jakob “The Biological Weapons Convention” in Eric Myjer and Thilo Marauhn (eds) Research Handbook on International Arms Control Law (Edward Elgar, Cheltenham, 2022) 259 at 259; and Biological Weapons Convention, art I.
83 United Nations Office for Disarmament Affairs “Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction”
<https://treaties.unoda.org/t/bwc/participants>.
84 Responsibility of States for Internationally Wrongful Acts [2001] vol 2, pt 2 YILC 26 at [76], arts 2, 5 and 8.
85 Secretariat on the Convention on Biological Diversity Synthetic Biology, above n 5, at 126.
recipient whatsoever, directly or indirectly” any biological weapon.86 Article IV requires states to “take any necessary measures to prohibit and prevent the development, production, stockpiling, acquisition or retention” of biological weapons.87 Unfortunately, however, the BWC lacks any significant enforcement mechanisms.88 Further, states often view non- compliance with articles III and IV as “technical non-compliance” compared to article I violations related to state stockpiling of weapons.89
Article I defines biological weapons as “microbial or other biological agents, or toxins whatever their origin or method of production, of types ... that have no justification for prophylactic, protective or other peaceful purposes”.90 This definition is broad and purpose- based to avoid prohibiting peaceful uses of dual-use items and to adapt to new technology over time .91 Moreover, article X requires states to “facilitate ... the fullest possible exchange of equipment, materials and scientific and technological information for the use of bacteriological (biological) agents and toxins for peaceful purposes”.92 This creates a substantial tension, since the BWC creates opposing obligations depending on whether an item is intended for such “peaceful purposes” but does not define this term.93
Many states have chosen to implement articles III and IV in three key ways. Firstly, they implement article IV’s prohibition through legislation criminalising biological weapons use.94 Secondly, they implement articles III and IV together by creating lists of pathogens and toxins which must be carefully controlled within their own borders.95 For example, the United States
86 Biological Weapons Convention, art III.
87 Article IV.
88 Jonathan B Tucker “Strengthening the biological weapons convention” (1995) ACT 25(3) 9 at 9; United Nations Office for Disarmament Affairs “Implementation Support Unit”
<https://disarmament.unoda.org/biological-weapons/implementation-support-unit/>; and Jenifer Mackby “BWC Meeting Stumbles Over Money, Politics” (2019) Arms Control Association
<https://www.armscontrol.org/act/2019-01/news/bwc-meeting-stumbles-over-money-politics>.
89 Angela Woodward “The Biological Weapons Convention: implementing legislation and compliance” in Verification and Implementation (Verification Research, Training and Implementation Centre, 2015) 129 at 133- 134 and 139-140.
90 Biological Weapons Convention, art I (emphasis added).
91 Jakob, above n 82, at 264.
92 Biological Weapons Convention, art X.
93 Jack M Beard “The shortcomings of indeterminacy in arms control regimes: The case of the biological weapons convention” (2007) 101(2) AJIL 271 at 282.
94 Dunworth, Mathews and McCormack, above n 12, at 100-105.
95 Treasa Dunworth, Robert J Mathews and Tim McCormack “National Implementation of the biological weapons convention at 113-115.
Department of HHS must create a Select Agents and Toxins List (SATL).96 Unless an exemption is granted, it is prohibited to “possess, use or transfer any HHS select agent or toxin without a certificate of registration issued by the HHS Secretary”.97 It is also prohibited to transfer a select agent or toxin to individuals or entities who are not registered to possess, use or transfer that particular agent or toxin.98 As discussed in detail in chapter III, some jurisdictions include nucleic acids on their relevant control list, and the transfer of SNA between companies and their customers is therefore controlled by their jurisdiction’s equivalent biological agent transfer regime.
Thirdly, states often implement articles III and IV by creating lists of biological materials that cannot be exported from their country without a licence.99 Often these implement the Australia Group (AG) Common Control Lists (CCLs). The AG is an informal group of countries set up to harmonise world export control regimes, and to become a member a country must implement their CCLs.100 The AG was originally controversial because developing states saw it as a protectionist regime that breached article X, while those in favour argued it implemented articles III and IV.101 After the anthrax attacks of 2001, however, the focus of the BWC changed towards terrorism prevention, leading to a gradual acceptance of export controls.102 This was in turn facilitated by United Nations Security Council Resolution 1540, covered below.103
As is discussed in chapter III, the AG lists include some types of nucleic acid sequences,104 and therefore in many jurisdictions SNA companies must apply for an export licence to sell such sequences to overseas customers.
96 Public Health Security and Bioterrorism Preparedness and Response Act 2002 Pub L 107-188 § 201, 116 Stat 637, §§ 201-204, 221 and 231; and 42 USC § 262a.
97 70 FR 13316 § 73.7(a).
98 § 73.16(a)-(b).
99 Dunworth, Mathews and McCormack, above n 12, at 110-113.
100 The Australia Group “Guidelines for Transfers of Sensitive Chemical or Biological Items” Australian Government Department of Foreign Affairs and Trade
<https://www.dfat.gov.au/publications/minisite/theaustraliagroupnet/site/en/guidelines.html>, arts 1-3 and 7; and United States Government Australia Group Common Control List Handbook Volume II: Biological Weapons- Related Common Control Lists (Australia Group, Revision 6, January 2021) at ix-xi.
101 Jakob, above n 82, at 269.
102 Una Becker Light at the End of the Tunnel (Peace Research Institute Frankfurt, Report No 79, May 2017) at 2 and 15-17.
103 SC Res 1540, preamble.
104 The Australia Group “List of Human and Animal Pathogens and Toxins for Export Control” Australian Government Department of Foreign Affairs and Trade (30 November 2022)
<https://www.dfat.gov.au/publications/minisite/theaustraliagroupnet/site/en/human_animal_pathogens.html>.
B United Nations Security Council Resolution 1540
Unlike the BWC, United Nations Security Council Resolution (UNSCR) 1540 explicitly targets non-state actors.105 It is often described as “universalising” the three existing international non-proliferation regimes related to nuclear weapons,106 chemical weapons,107 and biological weapons.108 This is because, unlike international treaties, Security Council resolutions bind all United Nations members.109 It also explicitly mandates many of the actions discussed above, including export controls, alongside some additional requirements like regulating “related materials”. Article 3 says all states shall:110
... establish domestic controls to prevent the proliferation of ... biological weapons and their means of delivery, including by establishing appropriate controls over related materials and to this end shall:
(a) Develop and maintain appropriate effective measures to account for and secure such items in production, use, storage or transport;
...
(d) Establish, develop, review and maintain appropriate effective national export and trans-shipment controls over such items, including appropriate laws and regulations ...
This provision’s relationship with articles III and IV of the BWC is unclear. It appears to require states to enact the domestic transfer requirements (under part (a)) and export requirements (under part (d)) that many have implemented under the BWC. Indeed, states reporting to the UNSCR 1540 Committee often list these regulations as ways they have implemented this article.111 However, UNSCR 1540 article 4 states “none of the obligations set forth in this resolution shall be interpreted so as to conflict with or alter the rights and obligations” in the BWC.112 BWC parties also have not formally clarified the two instruments’ relationship,
105 SC Res 1540, preamble.
106 Treaty on the Non-Proliferation of Nuclear Weapons 729 UNTS 161 (opened for signature 1 July 1968, entered into force 5 March 1970).
107 Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction 1974 UNTS 45 (opened for signature 13 January 1993, entered into force 29 April 1997).
108 Biological Weapons Convention; and Ana Sánchez-Cobaleda “Defining “dual-use items”: legal approximations to an ever-relevant notion” (2023) Nonproliferation Rev 1 at 8-9.
109 Charter of the United Nations, art 25.
110 SC Res 1540, art 3 (emphasis added).
111 United Nations Security Council Resolution 1540 Committee “Approved 1540 Committee Matrix: United States” (9 December 2020) <https://www.un.org/en/sc/1540/documents/USA%20revised%20matrix.pdf> at 14 and 34.
112 SC Res 1540, art 4 (emphasis added).
instead stating in BWC review conferences that UNSCR 1540 “is consistent with the provisions of the Convention” and “information provided ... in accordance with Resolution 1540 may provide a useful resource for State Parties in fulfilling their obligations under [Article IV]”.113
Despite having a stronger verification mechanism in theory than the BWC, UNSCR 1540 is not enforced. The UNSCR 1540 Committee merely facilitates states in the implementation process.114 This is in response to criticisms of UNSCR 1540’s legitimacy since it was imposed on states rather than requiring their consent.115 Perhaps as a result, in 2022 only 25% of the article 3(a)-(b) measures had been undertaken regarding biological materials,116 and only 40% of UN members had developed national export control lists for biological materials.117
C Interpreting the Biological Weapons Regime
While many states have chosen to implement domestic transfer controls and export controls for certain listed biological materials, this does not necessarily mean it is required. This point becomes important in chapter III, so I clarify it here.
The Vienna Convention on the Law of Treaties 1969 governs treaty interpretation.118 Article 31(1) states any treaty must be interpreted “in accordance with the ordinary meaning to be given to the terms of the treaty in their context and in the light of its object and purpose”.119 Article 31(3) states three pieces of context must also be considered. Firstly, cases of “subsequent agreement between the parties regarding the interpretation of the treaty”.120 Secondly, “subsequent practice in the application of the treaty which establishes the agreement
113 See for example Final document of the 8th Review Conference: 8th Review Conference of the States Parties to the Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction UN Doc BWC/CONF.VIII/4 (11 January 2017) [8th Review Conference] at [17].
114 United Nations Security Council Resolution 1540 Committee “1540 Matrices”
<https://www.un.org/en/sc/1540/national-implementation/1540-matrices.shtml>.
115 Perrone Giulia “Response and Recovery in the Event of CBRN Terrorism” in Andrea de Guttry, Federico Casolari, Micaela Frulli and Ludovica Poli (eds) International Law and Chemical, Biological, Radio-Nuclear (CBRN) Events (Brill Nijhoff, Boston, 2022) 141 at 146-147.
116 2022 comprehensive review of the status of implementation of Security Council resolution 1540 (2004) UN Doc S/2022/899 (1 December 2022) [UNSCR 1540 Comprehensive Review] at [56].
117 At [64].
118 Vienna Convention on the Law of Treaties 1155 UNTS 331 (opened for signature 23 may 1969, entered into force 27 January 1980) [Vienna Convention].
119 Vienna Convention, art 31(1).
120 Art 31(3)(a) (emphasis added).
of the parties regarding its interpretation”.121 Thirdly, “any relevant rules of international law
applicable in the relations between the parties” under article 31(3)(c).122
In terms of “ordinary meaning”, Braden Leach argues article IV’s strong phrase, “necessary measures”, “compels energetic state action to prevent the development of bioweapons within its jurisdiction”.123 However, article X strongly says that states must facilitate the “fullest possible” exchange of biological materials for peaceful purposes. As to purpose, Leach cites the preamble to say the BWC’s purpose is “to exclude completely the possibility of bacteriological (biological) agents being used as weapons”.124 This supports actions like regulating lists of pathogens but can only go so far, otherwise article X would have no effect.
Ultimately, what determines the balance between the two provisions is whether dangerous biological materials, whose intended purpose is unknown at the time of transfer, are “biological agents” with “no justification” for “peaceful purposes”.125 If they are, then they come under article IV, if not, then they come under article X. The “ordinary meaning” of the phrase “no justification” would seem to say any dual-use material, which always can have some peaceful justification, must be exchanged under article X.126 However, the subsequent practice by many states of implementing domestic transfer and export controls shows that states have taken the pragmatic approach of using the characteristics of a given product to predict whether it is likely to be used for harmful purposes and controlled it accordingly.127 In fact, statements at BWC review conferences constitute a “subsequent agreement” that the BWC requires domestic transfer controls.128
Export controls are more complex because BWC review conference documents both implore states to implement export controls and remind them not to breach article X.129 Export controls
121 Art 31(3)(b) (emphasis added).
122 Art 31(3)(c) (emphasis added).
123 Leach, above n 20, at 152; Biological Weapons Convention, art IV.
124 Leach, above n 20, at 152; Biological Weapons Convention, preamble.
125 Biological Weapons Convention, art I.
126 For full discussion see Lena Raxter “A Dangerous Loophole: the Biological Weapons Convention’s New Interpretation that Better Addresses Potentially Deadly Biological Research” (2021) 49.2 IJLI 102.
127 Sánchez-Cobaleda, above n 108, at 15-17.
128 Seventh Review Conference of the States Parties to the Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction UN Doc BWC/CONF.VII/7,sect.II (22 December 2011), cls 9 and 11(c); and Draft conclusions on subsequent agreements and subsequent practice in relation to the interpretation of treaties [2018] vol 2, pt 2 YILC 23 at 11(3).
129 8th Review Conference, above n 113, at [9]-[10].
are therefore permitted but this suggests some restrictions are not permissible, which might call into question the AG’s legality given it was originally contested.130 However, now many states have implemented the AG lists, and states that previously objected stopped long ago.131 To be relevant, this “state practice” must “establish the agreement of the parties” regarding the BWC’s interpretation.132 Actions by some states, with passive acquiescence by other states, in circumstances where these other states could be reasonably expected to state any objections, is often sufficient to constitute “agreement”.133 Implementing AG lists therefore does not breach article X.
Finally, UNSCR 1540 requires the creation of both domestic transfer and export controls.134 Despite its formally uncertain relationship with the BWC,135 it would be absurd if UNSCR 1540 obliged parties to violate the BWC, so Vienna Convention article 31(3)(c) (considering “other rules of international law”) likely applies. It is also probably untenable to interpret these instruments’ requirements separately. Firstly, article I is the only plausible source of the meaning of “biological weapon” within UNSCR 1540. Moreover, UNSCR 1540 defines the “related materials” article 3 controls as “materials ... covered by relevant multilateral treaties and arrangements, or ... national control lists, which could be used for the design, development production or use of ... biological weapons ...”.136 The few scholars discussing the point believe this means article 3 adopts the same dichotomy between peaceful and non- peaceful purposes as the BWC,137 as clearly the BWC is the only “relevant multilateral treat[y]” that it could be referencing. The only other way a biological agent not regulated by the BWC could become regulated by UNSCR 1540 is through other “arrangements” such as the Australia Group, or “national control lists”, which would cover domestic transfer controls. Both sets of lists, however, were intended to implement the BWC,138 so under this approach UNSCR 1540’s requirements are still limited to the BWC’s requirements.
130 Jakob, above n 82, at 269.
131 Becker, above n 102, at 13-15.
132 Vienna Convention, art 31(3)(b).
133 Irina Buga “Subsequent Practice as a Means of Treaty Interpretation” in Modification of Treaties by Subsequent Practice (Oxford Scholarship Online, April 2008) 16 at 64-68; and Draft conclusions on subsequent agreements and subsequent practice in relation to the interpretation of treaties, above n 128, at 10(2).
134 SC Res 1540, arts 3(a) and (d).
135 SC Res 1540, art 4; and 8th Review Conference, above n 113, at [17].
136 SC Res 1540, preamble (emphasis added).
137 Sánchez-Cobaleda, above n 108, at 8-9; and Johannes Rath, Monique Ischi, and Dana Perkins "Evolution of different dual-use concepts in international and national law and its implications on research ethics and governance" (2014) 20 Sci Eng Ethics 769 at 776-777.
Overall, the BWC and UNSCR 1540 both likely require states to implement some kind of regulations over domestic transfers and exports of potentially harmful biological materials, and these may take the form of the AG lists without breaching article X of the BWC.
IV Private Sector Self-regulation
A International Gene Synthesis Consortium
Perhaps surprisingly, the most stringent rules governing gene synthesis come from industry self-regulation through the International Gene Synthesis Consortium (IGSC). The IGSC was formed in 2009 by five large gene synthesis companies,139 and has since grown to 31 members.140 It is often claimed that IGSC members constitute approximately 80% of the global gene synthesis market,141 but the true figure is unknown.142 The 80% claim is from the IGSC’s launch document in 2009,143 and it is highly implausible that it has remained constant throughout the substantial fluctuations in both IGSC members and the size of the gene synthesis market.144 This is also separate from the proportion the IGSC takes up of the overall SNA industry, which is much larger.145
139 Stephen M Maurer “End of the Beginning or Beginning of the End? Synthetic Biology's Stalled Security Agenda and the Prospects for Restarting it” (2011) 45(4) Valp ULR 1387 at 1432-1433; and
International Gene Synthesis Consortium “World’s Top Gene Synthesis Providers Establish Tough Biosecurity Screening Protocol” (19 November 2009) <https://genesynthesisconsortium.org/wp-content/uploads/IGSC- Launch-Announcement.pdf>.
140 International Gene Synthesis Consortium “Application for Membership” <International Gene Synthesis Consortium “Home”>.
141 DiEuliis, Carter and Gronvall, above n 16, at 1; Carter and Friedman, above n 16, at 15; Leach, above n 20, at 155.
142 Schulson, above n 9.
143 International Gene Synthesis Consortium, above n 140, and see also International Gene Synthesis Consortium, above n 9, at 1.
144 Nuclear Threat Initiative “Financial Incentives for Biotechnology Investors to Improve Biosecurity” (22 March 2019) <https://www.nti.org/analysis/articles/financial-incentives-biotechnology-investors-improve- biosecurity/>; BCC Research “Synthetic Biology: Global Markets” (March 2022)
<https://www.bccresearch.com/market-research/biotechnology/synthetic-biology-global-markets.html>; James Diggans “Synthetic gene-length DNA: Evolving export control concerns” (July 2019) Bureau of Industry and Security <https://tac.bis.doc.gov/index.php/documents/public-presentations/398-twist-mtac-briefing/file> at 6; Diggans and Leproust, above n 16, at 2; and PR Newswire “International Gene Synthesis Consortium Adds New Global Members to Advance Biosecurity Objectives” (18 April 2017) <https://www.prnewswire.com/news- releases/international-gene-synthesis-consortium-adds-new-global-members-to-advance-biosecurity-objectives- 300440386.html>; and Internet Archive “Wayback Machine” (19 February 2023)
<https://web.archive.org/web/20230219224207/https://genesynthesisconsortium.org/>.
145 Maurer, above n 26, at 4.
IGSC members voluntarily agree to its “Harmonised Screening Protocol” (HSP). Under the current version, IGSC members use automated screening systems that compare the similarity between any order’s sequence and, firstly, entries in a “Regulated Pathogen Database” (RPD), to which only IGSC members have access, and secondly in one or more public sequence database.146 The RPD is a curated set of sequences from the genomes of the pathogens listed on various national control lists, including the Australia Group lists and the United States Select Agent List.147 If the automated screen identifies a match in either dataset, a human expert reviews the sequence to determine whether it is dangerous “using common IGSC screening criteria”.148 IGSC members also screen customers against several lists of persons with which they are legally obligated not to do business.149 When the sequence is potentially dangerous, IGSC members ensure the customer comes from a legitimate research institution,150 and do not fill the order if they are not.151
B Limitations of the International Gene Synthesis Consortium
The main critique of the IGSC is that it is voluntary.152 Non-members make up an unknown portion of the SNA market, with unknown screening practices.153 It is easy to find non-member SNA companies online whose websites do not mention biosecurity,154 and a 2015 analysis found two non-members mostly relied on trusted customer relationships and rarely screened sequences.155 As of 2015, general compliance with some form of screening was common in the United States and European Union.156 However, many new companies now exist in Asia,157 which is expected to be the market’s main future growth region.158 It is also not clear if all
146 International Gene Synthesis Consortium, above n 9, at 2.2.
147 At 2.2.
148 At 2.4.
149 At 3.1-3.2.
150 At 3.3.
151 At 5.1.
152 DiEuliis, Carter and Gronvall, above n 16, at 1.
153 Schulson, above n 9.
154 Schulson, above n 9.
155 Carter and Friedman, above n 16, at 17.
156 At 17.
157 International Gene Synthesis Consortium, above n 8; Bioneer “Healthier Future for Humanity with Genomic Technology” <https://bioneer.com/>; BGI “Gene Synthesis Service” <https://www.bgi.com/us/gene-synthesis- service-synthesis-of-all-sizes>; and Synplogen “Synplogen” <https://www.synplogen.com/en/>.
158 Mordor Intelligence “Gene Synthesis Market Size & Share Analysis - Growth Trends and Forecasts (2023 - 2028)” (2022) <https://www.mordorintelligence.com/industry-reports/gene-synthesis-market>; Precedence Research “DNA Synthesis Market (By Service: Oligonucleotide Synthesis, Gene Synthesis; By Application: Research and Development, Therapeutics, Diagnostic; By End-User: Biopharmaceutical Companies, Academic and Research Institutes, Contract Research Organizations) - Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2023-2032” (April 2023) <https://www.precedenceresearch.com/dna-
United States companies screen now: in 2022 Undark Magazine found at least three non-IGSC United States companies were not willing to provide information about their screening practices.159 Further, while NAS costs continue to fall overall, screening costs have stayed constant because they still require review by a human expert. Screening is therefore becoming an increasing proportion of total NAS costs and increasingly constitutes a competitive disadvantage.160 Consequently, we might expect that over time most non-IGSC members, and perhaps even IGSC members, may screen only according to their legal obligations, if at all.
Further, the IGSC only grants voting membership to large gene synthesis companies, and non- voting associate membership to smaller companies, not-for-profits and academic institutions.161 When the IGSC was formed small companies raised concerns about taking on obligations under the HSP if they could not control its content.162 This has since likely contributed to the IGSC’s failure to cover the whole market.
Despite constituting the best available DNA screening rules, the HSP itself also has several limitations. Firstly, it only appears to cover “genes” above 200bp.163 This would partially be justified because as sequences get smaller screening algorithms produce more false positives.164 However, the industry consensus appears to be that current algorithms can screen accurately down to 50bp (“oligo” length).165 Even if IGSC members choose to screen down to 50bp, malicious actors could break their order into even smaller pieces and assemble them later.166 There are a range of solutions for this, including using digital methods to predict the likely sequence a customer is trying to produce if they order many oligos from the same
synthesis- market#:~:text=The%20global%20DNA%20synthesis%20market,19.6%25%20from%202023%20to%202032.
>; Grand View Research “DNA Synthesis Market Size, Share & Trends Analysis Report By Service Type (Gene Synthesis, Oligonucleotide Synthesis), By Application (Research And Development, Therapeutics), By End-use, By Region, And Segment Forecasts, 2023 – 2030” <https://www.grandviewresearch.com/industry-analysis/dna- synthesis-market-report>.
159 Schulson, above n 9.
160 DiEuliis, Carter and Gronvall, above n 16, at 2; Carter and Friedman, above n 16, at 15; Department of Health and Human Services, above n 10, at 151; Diggans and Leproust, above n 16, at 2.
161 International Gene Synthesis Consortium, above n 8.
162 Tucker (2010) “Double-Edged DNA: Preventing the Misuse of Gene Synthesis” <https://issues.org/tucker-2>
163 International Gene Synthesis Consortium, above n 9, at 9.1 and 9.3.
164 Carter and Friedman, above n 16, at 19.
165 Department of Health and Human Services, above n 10, at 42, 43, 62-64, 73-74, 77, 78, 182
166 Carter and Friedman, above n 16, at 19.
supplier,167 tracking the purchase of oligos by the same customer across time,168 and pooling purchase information into a centralised IGSC database.169
Secondly, the HSP does not include RNA and benchtop synthesisers. This is even though the industry is aware technology exists to convert RNA to DNA, and some viruses have pure RNA genomes.170 The new generation of benchtop synthesisers also clearly must be regulated to mitigate misuse risk.171 To be fair, the IGSC has members who produce a range of SNAs, and others who specialise in benchtop device manufacture,172 but this still means the HSP is incomplete.
Thirdly, many unknown and potentially dangerous organisms exist, and the ability to manipulate organisms in new ways to make them dangerous is increasing. Such unknown dangers will not be included on pre-defined threat lists that make up the Regulated Pathogen Database.173 The HSP sensibly covers a wider range of sequences by requiring additional screening against larger public databases,174 but this will not detect artificially designed sequences or those not included in the databases. However, solutions to this largely cannot come from rules. Instead, one commonly-suggested solution is to create and continually update a government-funded database of the full range of sequences that companies should screen against,175 although this will require careful control of access to the database to avoid creating information hazards.176 This approach also would not deal with completely novel sequences, which would require use of machine-learning-based functional prediction algorithms.177 Some
167 Department of Health and Human Services, above n 10, at 43.
168 Administration for Strategic Preparedness and Response Comments Received in Response to Federal Register Notice 2020-18444, Review and Revision of the Screening Framework Guidance for Providers of Synthetic Double-Stranded DNA (2020) at 98.
169 Maurer, above n 139, at 1431, n 204.
170 Administration for Strategic Preparedness and Response, above n 169, at 42-43, 45, 48- 50, 181-183 and 185-
188.
171 Carter, Yassif and Isaac, above n 25, at 6.
172 International Gene Synthesis Consortium, above n 8; Switchback Systems “Democratizing DNA Synthesis”
<https://switchbacksys.com/>; Evonetix “There’s more potential diversity within DNA than there are planets in the universe” <https://www.evonetix.com/gene-synthesis>; ANSA Biotechnologies “Next-Gen DNA Synthesis Using Enzymes” <https://ansabio.com/>; and Elegen Bio “Innovation Is Our DNA”
<https://www.elegenbio.com/>.
173 Maurer, above n 139, at 1424.
174 At 1423 and 1435.
175 Administration for Strategic Preparedness and Response, above n 169, at 15; Piper, above n 17.
176 Carsten Baum, Hongrui Cui, Ivan Damg˚ard, Kevin Esvelt, Mingyu Gao ,Dana Gretton, Omer Paneth, Ron Rivest, Vinod Vaikuntanathan, Daniel Wichs, Andrew Yao, Yu Yu Cryptographic Aspects of DNA Screening (SecureDNA, DNA Screening Technical Note, January 2020) at i.
177 Maurer, above n 139, at 1421. This possibility was also raised during the HHS Guidance submissions process,
see Administration for Strategic Preparedness and Response, above n 169, at 85-94.
progress has been made on such algorithms, but industry members are sceptical of their utility.178
Finally, it is not clear what criteria IGSC members use to determine whether a flagged DNA sequence is dangerous, but this will certainly be complicated. This is because many sequences, called “housekeeping” genes, code for functions which are shared between pathogens and non- pathogens because they are necessary for normal cellular function.179 Once a gene from a pathogen is flagged, experts will therefore have to analyse detailed information about that specific gene to judge whether it is likely to be dangerous.180
Several groups are attempting to solve many of these problems with automated solutions. These include SecureDNA,181 the Nuclear Threat Initiative Common Mechanism to Prevent Illicit DNA Synthesis,182 SeqScreen,183 ThreatSEQTM (by Battelle),184 FAST-NA (by Raytheon BBN),185 BLiSS (the Black List Sequencing Pipeline),186 and ACLID.187 The most sophisticated of these, SecureDNA, has many features which would go a long way towards solving many of the problems outlined above.188
C International Association for Synthetic Biology
The first private body to regulate NAS was not the IGSC, but a German trade association called the International Association of Synthetic Biology (IASB), which created a gene synthesis
178 Administration for Strategic Preparedness and Response, above n 169, at 85-94.
179 Department of Health and Human Services, above n 10, at 10.
180 Maurer, above n 139, at 1422.
181 See SecureDNA “Safeguarding DNA synthesis” <https://securedna.org/>; and also SecureDNA Random adversarial threshold search enables specific, secure, and automated DNA synthesis screening.
182Nuclear Threat Initiative “Common Mechanism to Prevent Illicit Gene Synthesis” (22 March 2019)
<https://www.nti.org/analysis/articles/common-mechanism-prevent-illicit-gene-synthesis/>.
183 See generally Advait Balaji, Bryce Kille, Anthony D Kappell, Gene D Godbold, Madeline Diep, R A Leo Elworth, Zhiqin Qian, Dreycey Albin, Daniel J Nasko, Nidhi Shah, Mihai Pop, Santiago Segarra, Krista L Ternus and Todd J Treangen “SeqScreen: accurate and sensitive functional screening of pathogenic sequences via ensemble learning” (2022) 23 Genome Biol 133.
184 Battelle ThreatSEQ™ Web Service: Advanced DNA Screening Platform (Brochure, November 2018; and see Loren Blinde “Battelle tapped for IARPA Fun GCAT program” (11 January 2018) Intelligence Community News
<https://intelligencecommunitynews.com/battelle-tapped-for-iarpa-fun-gcat-program/>.
185 Raytheon BBN “FAST-NA Scanner” <https://fastna.myshopify.com/>.
186 L Simirenko “Bliss: The Black List Sequence Screening Pipeline” (paper presented to Synthetic Biology: Engineering, Evolution and Design (SEED), Chicago, July 2016).
187 ACLID “On a mission to secure the bioeconomy” <https://www.aclid.bio/about>.
188 SecureDNA “Features” <https://securedna.org/features/>.
Code of Conduct in 2009.189 The IGSC arose because companies DNA 2.0 and GeneArt responded by proposing an alternative fully automated, “fast” and “cheap”, proposal which would skip the public database alignment and only screen against listed pathogens.190 DNA 2.0 and GeneArt quickly abandoned this alternative approach but did not join the IASB, instead grouping with three additional companies to create the IGSC.191 Unlike the IASB, the IGSC was only open to large companies and did not hold public meetings.192 Shortly after the IASB announced its final Code, the Consortium announced its competing “Harmonized Screening Protocol” which in substance was almost identical to the IASB Code.193 Since then, no public IGSC communications have acknowledged the IASB’s existence.194
Now, in 2023, the IGSC has clearly become dominant and the IASB essentially forgotten. Possibly the most recent mention of IASB’s activity was Carter and Friedman’s 2015 review which found several companies still adhered to the IASB Code.195 However, the IASB Code has not been updated as originally planned,196 it no longer has a functioning website, and it seems it never instituted any of its original policy plans.197
D International Biosecurity and Biosafety Initiative for Science (and the Nuclear Threat Initiative)
Non-government organisations (NGOs) have also started to play a key role in this space since the Nuclear Threat Initiative (NTI), a global nonprofit aiming to reduce nuclear and biological threats,198 launched its Biosecurity Innovation and Risk Initiative.199 This initiative aims to develop and promote a range of concrete measures to “reduce global catastrophic biological risks associated with advances in technology”.200 NTI then partnered with the World Economic
189 Maurer, above n 139, at 1432; and compare International Association of Synthetic Biology The IASB Code of Conduct for Best Practices in Gene Synthesis (3 November 2009) with International Gene Synthesis Consortium, above n 9.
190 Maurer, above n 139, at 1432.
191 Maurer, above n 139, at 1432-1433; and International Gene Synthesis Consortium, above n 140.
192 Maurer, above n 139, at 1431-1434.
193 At 1433
194 At 1434, n 224.
195 Carter and Friedman, above n 16, at 13.
196 International Association of Synthetic Biology, above n 190, cl 6.
197 Clause 9.
198 Nuclear Threat Initiative “Building a safer world through innovation, cooperation, and action”
<https://www.nti.org/about/>.
199 Nuclear Threat Initiative “Biosecurity Innovation and Risk Reduction Initiative Launch” (29 October 2018)
<https://www.nti.org/events/biosecurity-innovation-and-risk-reduction-initiative-launch/>.
200 Nuclear Threat Initiative, above n 201.
Forum to create the DNA Synthesis Screening Technical Consortium,201 which will create a “Common Mechanism to Prevent Illicit DNA Synthesis”. This will be automated, low cost, accessible to all DNA synthesis companies and benchtop device producers and will screen against “authoritative lists” of pathogen and toxin sequences.202 However, if these “authoritative lists” are national select agents, this is little more than DNA 2.0 and GeneArt’s original “fast and cheap”, but less effective, solution.203
However, more interestingly, NTI has also created a new institution: the International Biosecurity and Biosafety Initiative for Science (IBBIS). IBBIS will initially house the Common Mechanism,204 but in the long-term aims to fix the current lack of international institutions dedicated both to “strengthening biosecurity and bioscience governance and to reducing emerging biological risks associated with technology advances”.205 Long-term visions for IBBIS involve working with private international institutions like SynBioBeta, public international platforms like the BWC,206 with national governments to help them improve their biosecurity oversight practices,207 and with the biotechnology industry to help them regulate themselves.208
201 Nuclear Threat Initiative “NTI and WEF Convene Third Annual Meeting of DNA Synthesis Screening Technical Consortium” (23 May 2022) <https://www.nti.org/news/nti-and-wef-convene-third-annual-meeting-of- dna-synthesis-screening-technical-consortium/>.
202 World Economic Forum Biosecurity Innovation and Risk Reduction: A Global Framework for Accessible, Safe and Secure DNA Synthesis (Insight Report, January 2020) at 7 and 15-16.
203 For a general criticism of the Nuclear Threat Initiative’s initial proposal see Rocco Casagrande and Audrey A Cerles “NTI/WEF white paper on DNA synthesis advances the discussion but misses the mark” (2020) 18(1) Health Secur 67.
204Nuclear Threat Initiative, above n 201.
205 Margaret A Hamburg, Jaime Yassif, R Alta Charo, Hayley Severance “Taking Action to Safeguard Bioscience and Protect Against Future Global Biological Risks” (2 September 2022) American Association for the Advancement of Science (AAAS): Science and Diplomacy
<https://www.sciencediplomacy.org/perspective/2022/taking-action-safeguard-bioscience-and-protect-against- future-global-biological>; International Biosecurity and Biosafety Initiative for Science “IBBIS: International Biosecurity and Biosafety Initiative for Science” <https://ibbis.bio/wp-content/uploads/2023/05/IBBIS-One- Pager-March-2023_QR-Code.pdf >.
206 International Biosecurity and Biosafety Initiative for Science “IBBIS at Biosecurity Innovation and Risk Reduction Initiative Annual Meeting” (2023) <https://ibbis.bio/ibbis-at-biosecurity-innovation-and-risk- reduction-initiative-annual-meeting/>.
207 International Biosecurity and Biosafety Initiative for Science “Our Work” <https://ibbis.bio/our-work/>; Nuclear Threat Initiative, above n 201; International Biosecurity and Biosafety Initiative for Science, above n 206.
208 International Biosecurity and Biosafety Initiative for Science, above n 208.
V The United States “HHS Guidance”
The United States Department of Health and Human Services’ Screening Framework Guidance for Providers of Synthetic Double-stranded DNA (“HHS Guidance) is the only government- produced SNA screening recommendations in the world. It was produced after the IASB and IGSC standards and surprised commentators by being less stringent than either.209 The current HHS Guidance is therefore subject to the same criticisms as the IGSC Harmonised Screening Protocol, including for being voluntary. Two additional points are worth making.
Firstly, the HHS Guidance is less stringent than either private standard specifically because it recommends a “best match” algorithm. This involves comparing every 200bp sequence within the order with a public database to identify the highest similarity entry.210 If any sequence has a “best match” with a United States Select Agent or Australia Group agent, companies should flag it and perform follow up customer screening.211 The HHS Guidance therefore relies entirely on pre-defined pathogen lists, making their approach entirely automatable.212
Secondly, the HHS Guidance is currently under review. In response to industry submissions, the draft revised guidance overcomes many of the deficiencies of both the current HHS Guidance and IGSC Harmonised Screening Protocol. For example, it covers sequences down to 50bp, covers all types of SNA, and makes recommendations regarding benchtop devices.213 It retains “best match” but now says providers may choose “other screening approaches that they assess to be equivalent or superior”.214 Hopefully these changes will encourage these updates in the HSP.
209 Maurer, above n 139, at 1434-1435.
210 Department of Health and Human Services, above n 10, at 11.
211 At 11.
212 Maurer, above n 139, at 1387-1391 and 1421-1435.
213 Department of Health and Human Services Screening Framework Guidance for Providers and Users of Synthetic Oligonucleotides (Federal Register Vol 87 No 3, 29 April 2022) at 25496-25497.
214 At 25498.
Chapter IV: Are States Violating the Biological Weapons Convention?
I Introduction
This chapter examines whether current state SNA regulations comply with the BWC articles III and IV, and UNSCR 1540. Clarifying states’ existing obligations is important for answering this paper’s overall question of which international regulatory regime is preferable. If the BWC already requires states to regulate NAS then the status quo may be sufficient. This chapter concludes there is a highly plausible argument that the BWC requires states to include SNAs in their existing domestic transfer and export control lists, and possibly even to regulate the SNA screening process directly.
II Domestic Implementation of the Biological Weapons Convention
Currently, no country directly mandates that SNA companies screen orders.215 However, in some cases their domestic transfer or export control laws include certain types of nucleic acids. On the other hand, a substantial portion of states do not have either form of regulation, as discussed in chapter II.216 Despite this stark fact, all SNA providers I could find operate within countries that do have some kind of regulation for both domestic biological agent transfers and biological agent exports.217
215 Hoffman and others “Safety by design: Biosafety and Biosecurity in the age of synthetic genomics” (2023) 26(3) iScience 1 at 2.
216 UNSCR 1540 Comprehensive Review, above n 116,at [56] and [64].
217 See the list of IGSC member companies on its website: International Gene Synthesis Consortium, above n 8. I will take Pálya and Delaney’s lead in not providing information about non-members to avoid contributing to information hazards: Oscar Delaney and Hanna Pálya “Safe DNA Synthesis” (September 2022) Centre for the Study of Existential Risk
<https://www.cser.ac.uk/media/uploads/files/DNA_Synthesis_UK_Policy_Brief_Science.pdf> at 3, n 5.
I otherwise studied all countries with IGSC or IASB member nationals: the United States,218 the United Kingdom,219 Canada,220 Germany,221 the European Union,222 China,223 South Korea,224 Singapore,225 Japan,226 and Australia.227 The United States is covered in section C as a special case because it does have some regulatory instruments related specifically to SNA screening, and some screening legislation is currently in front of Congress. Otherwise, there are two key problems with domestic regulations in all cases studied. Firstly, there is usually a large discrepancy between their export control regimes, which are uniformly based on Australia Group (AG) Common Control lists and therefore cover SNAs, and their domestic transfer regulations, which often do not cover SNAs. Secondly, these regulations always define their lists at the species level, not the sequence level, which creates significant interpretive difficulties.
218 Integrated DNA Technologies “Contact Us” <https://sg.idtdna.com/pages/about/contact-us>.
219 Edinburgh Genome Foundry “Home” <https://www.ed.ac.uk/biology/research/facilities/edinburgh-genome- foundry>.
220 Bioneer “Customer Focused Support from Bioneer” <https://us.bioneer.com/page/w/contact/contact>.
221 ATG: Biosynthetics “We Provide Molecular Research and Synthetic Biology Tools for Professionals”
<https://atg-biologics.com/>.
222 Integrated DNA Technologies, above n 219.
223 BGI, above n 158.
224 Bioneer “Home” <https://eng.bioneer.com/>.
225 GenScript “Contact Us” <https://www.genscript.com/contact.html?src=pullmenu>.
226 Integrated DNA Technologies, above n 219.
227 Integrated DNA Technologies, above n 219; and LabMate “IDT completes acquisition of Geneworks” (10 March 2017) <https://www.labmate-online.com/news/news-and-views/5/integrated-dna-technologies-europe/idt- completes-acquisition-of-geneworks/41859>.
A Export Controls
The export control regulations in all the countries studied implement the AG Common Control Lists.228 This includes China and Singapore even though they are not AG members.229 These Common Control Lists all cover nucleic acid synthesis devices,230 as well as nucleic acids that meet the following definition:231
Any ... genetic element that codes for, any of the following:
(a) any gene or genes ... specific to any listed virus; or(b) any gene or genes specific to any listed bacterium or fungus, and which
- in itself or through its transcribed or translated products represents a significant hazard to human, animal or plant health, or
(c) any listed toxins or their sub-units.
The only apparent analysis of this comes from the industry itself. Twist Biosciences has interpreted “gene or genes” to mean the biological definition of being “capable of encoding a protein”, and extends this to include any edited sequence that produces a protein with an equivalent function.232 Twist also appears to have interpreted “specific” as “unique”.233 These
228 15 CFR chapter VII, subchapter C § 744.1 (Supp 1) at at 1C351and 1353-1C354; Retained Dual-Use Regulation (EC) No 428/2009 (UK), art 3 and Annex 1 at [1C351]-[1C354]; Export and Imports Permits Act RSC 1985 c E-19, s 3(1); A Guide to Canada’s Export Controls 2023 at 5505, 7-12(10) and 7-13; Strategic Goods (Control) Order 2023 (SG), Part 2, Division 1, Subdivision 5, cl 8 and Schedule at 1C351-1C354 and 2B352(i); Regulations of the People's Republic of China on Export Control of Dual-Use Biological Agents and Related Equipment and Technologies 2002 (CN), Annex, Part I(1)-(3) and (5), and Part II(1)-(5) and (7);
輸出貿易管理令別表第一及び外国為替令別表の規定に基づき貨物又は技術を定める省令 1991 (JP), art 2-2 (translation: Ordinance of the Ministry Specifying Goods and Technologies Pursuant to Provisions of the Appended Table 1 of the Export Control Order and Appended Table of the Foreign Exchange Order); Defence and Strategic Goods List 2019 (Cth), div 3.10 and Part 1, Category 1, 1C351-1C354, 2B32 and 2D351; Regulation 2021/821 of the European Parliament and of the Council [2021] OJ L206/1, art 4 and Annex I, 1C351, 1C353- 1C354 and 2B351(i). I could not find South Korea’s primary legislation, but it is an AG member according to The Australia Group “Australia Group Participants” Australian Government Department of Foreign Affairs and Trade
<https://www.dfat.gov.au/publications/minisite/theaustraliagroupnet/site/en/participants.html>. According to Seung Hwan Choi “South Korea's System of Export Control on Strategic Items and Its Effective Enforcement Policy to Facilitate Economic Cooperation between South and North Korea” (2005) 5(1) J Korean L 95 at 109, at least as of 2005 South Korea’s relevant regulation covering biological materials exports was the Public Notice of Export/Import, Annex 5 (the source does not give the year).
229 The Australia Group, above n 229.
230 The Australia Group “Control List of Dual-use Biological Equipment and Related Technology and Software” Australian Government Department of Foreign Affairs and Trade (20 November 2022)
<https://www.dfat.gov.au/publications/minisite/theaustraliagroupnet/site/en/dual_biological.html> at I(10).
231 The Australia Group, above n 104. See also The Australia Group “List of Plant Pathogens for Export Control” Australian Government Department of Foreign Affairs and Trade (30 November 2022)
<https://www.dfat.gov.au/publications/minisite/theaustraliagroupnet/site/en/plants.html>.
232 Diggans, above n 145, at 17-18.
233 At 9.
are logical interpretations of the wording but are not self-evident, making it likely different SNA providers would come to different conclusions. Defining a sequence at the gene level also leaves the AG lists vulnerable to the same critique as the IGSC Harmonised Screening Protocol and HHS Guidance that customers could get around the export requirements by ordering many smaller sequences to assemble later.234
Illustrating the problem with using lists that control at the species rather than sequence level, industry members have noted it is difficult to establish when sequences meet the requirement of “endowing or enhancing pathogenicity” (because of “housekeeping genes”), and therefore when an export licence is required.235 According to Twist, the lengthy delay required to establish whether a licence is needed and then apply for it often causes customers to cancel orders and switch to a domestic provider, who may or may not screen.236
The final problem with the AG lists is the fact that they are lists. As with the HHS Guidance (but not the IGSC’s HSP), which in turn relies on such lists,237 this means that they impose no obligations on companies to screen for unfamiliar but possibly dangerous sequences.
B Domestic Transfer Controls
Across these countries, the regulations for domestic biological material transfers fall into three categories: those that cover SNAs, those that (probably unsuccessfully) attempt to cover SNAs, and those that clearly do not cover SNAs.
(i) Countries That Regulate Nucleic Acids – the United States and the United Kingdom
The details of the United States Select Agents and Toxins Lists (SATLs) were covered in chapter II. Their key implication is that if United States SNA companies receive an order for a SATL sequence, they must be registered to possess and transfer it, and the customer to possess it.238 The SATL directly references “nucleic acids that can produce infectious forms of any of
234 Diggans, above n 145, at 16.
235 Administration for Strategic Preparedness and Response, above n 169, at 10, 88, 108 and 170.
236 Administration for Strategic Preparedness and Response, above n 169, at 158; and Diggans, above n 145, at 19.
237 Department of Health and Human Services, above n 10, at 3.
238 70 FR 13316 §§ 73.7(a) and 73.16(a)-(b).
the select agent viruses”239 and “synthetic nucleic acids that encode for the toxic form(s) of any of the toxins listed”.240 Department guidance clarifies that virus sequences are covered if they are “inherently infectious and are immediate precursors to virus production” because they can immediately generate infectious forms of the virus within a host without assistance from “exogenous factors”.241
The United Kingdom’s equivalent list of “dangerous substances” references “any nucleic acid deriving from a micro-organism listed ... that can encode infectious or replication competent forms of any of the listed micro-organisms”.242 They also include “any nucleic acid sequence derived from the micro-organism which when inserted into any other living organism alters or enhances that organism’s ability to cause serious harm to human health”.243
These are the two best examples of legislation regulating domestic SNA transfers, but both are deeply flawed. For example, while the United States approach is reasonably clear, the United Kingdom does not define any of its vague terms, although they seem to refer to similar concepts to the United States approach. The main difference is that the United Kingdom regulation’s wording is not limited to viruses, although it is difficult to establish what it means to “encode” a “replication competent” bacterial cell.
The United States approach conflicts with and is less comprehensive than its own HHS Guidance which recommends screening against the “best match” of any select agent,244 not just “inherently infectious” viral sequences. The United States and United Kingdom also both apply different definitions to the Australia Group lists, creating additional complexity for industry compliance. More importantly, they do not justify why they limit the sequences covered to those inherently capable of causing harm. If a dangerous sequence requires “exogenous factors” to begin proper biological functioning, that does not stop it from being harmful if someone capable of manipulating it in the right way gets access to it. This is presumably why the AG does not make this distinction.
239 § 73.3(c)(1).
240 70 FR 13316 § 73.3(c)(2).
241 Centers for Disease Control and Prevention Guidance on the Regulation of Select Agents and Toxin Nucleic Acids (Revision, February 2020) at 6. Also see discussion in chapter II.
242 Anti-terrorism, Crime and Security Act, Schedule 5, F50(c) (emphasis added); see also Anti-terrorism, Crime and Security Act 2001 (United Kingdom), s 59(1).
243 Anti-terrorism, Crime and Security Act, Schedule 5, F50(d).
244 Department of Health and Human Services, above n 10, at 11.
(ii) Countries That Attempt to Regulate Nucleic Acids – Canada, Germany and Singapore
The following three countries all have legislation that theoretically could cover SNAs:
(1) Canada regulates the domestic transfer of any “human pathogen”,245 which is defined as “a micro-organism, nucleic acid or protein that ... (a) is listed [in one of the relevant schedules]; or (b) ... falls into [one of the relevant Risk Groups].”246 Risk Group Two, for example, “means a category of human pathogens that pose a moderate risk to the health of individuals ... and includes the human pathogens listed in Schedule 2”.247
(2) Germany regulates the domestic transfer of any “pathogen”,248 which is defined as “a replicable agent ... or any other biological transmissible agent that can cause an infection or communicable disease in a human”.249
(3) Singapore regulates the domestic transfer of any “biological agent”,250 defined as “any micro-organism ... or ... any component of a micro-organism or an infectious substance ... that is capable of causing death, disease or other biological malfunction in a human”.251 Both the First and Second Schedule include “any biological agent that is a constructed or reconstructed replication-competent form of any [pathogen] set out in this Part”.252
Under the Canadian legislation there are two ways that any given SNA sequence might be covered.253 The first is that the Canadian regulator could simply list a given nucleic acid sequence in the schedules, but as usual it only mentions the pathogen species’ names.254 Hagen therefore argues these provisions do not directly cover nucleic acids, since the legislature could have explicitly included them like in the United States and United Kingdom.255 A possible alternative view is that when the regulations constituting schedules 1-5 were created it was assumed that any reference to a given pathogen by name was enough to automatically include
245 Human Pathogens and Toxins Act SC 2009, c 24, s 7
246 Section 3(1) (emphasis added).
247 Section 3(1).
248 Infektionsschutzgesetz (IfSG) 2000 (Germany), s 44 (translation: Protection Against Infection Act).
249 Section 2(1) (emphasis added).
250 Biological Agents and Toxins Act 2005 (SG), ss 6(1), 11(1), 15(1) and 20(3).
251 Section 2.
252 First Schedule and Second Schedule.
253 Gregory Hagen “The Regulation of Synthetic Nucleic Acids under the Human Pathogens and Toxins Act” (2016) 49 UBCL Rev 377 at 387.
254 Human Pathogens and Toxins Act SC 2009, Schedules 1-4.
255 Hagen, above n 254, at 385.
its proteins and nucleic acid sequences as well. However, given the usual problem of “housekeeping” genes it would be impractical to convert from the pathogen name to any given sequence without further guidance. This approach therefore likely fails.
The second way the Canadian legislation might cover nucleic acids is that because “Risk Groups” are not defined exhaustively, they could apply to other biological material that poses a risk of the type described.256 Similarly, biological agents capable of causing harm are also covered by the German and Singaporean legislation. In all three cases the issue is whether a nucleic acid is “capable of causing harm” (or equivalent) since they must be “booted” into a cell to function. Hagen believes they cannot be interpreted this way.257 On the other hand, one might draw on the United States guidance which treats as “inherently infectious” an RNA sequence of a virus which could become viable upon entering a host cell without “additional exogenous factors”.258 This argument does not seem particularly plausible, however, since it is only the guidance that uses the phrase “inherently infectious”, the actual regulations being interpreted use the phrase “nucleic acids that can produce infectious forms” of a listed pathogen. The argument is even less compelling in the German and Singaporean cases since their legislation never explicitly references nucleic acids.
Consequently, in practice these regulations likely do not capture SNAs.
(iii) Countries That Do Not Regulate Nucleic Acids
The relevant legislative provisions in China,259 Japan,260 South Korea261 and Australia262 all do not appear to reference nucleic acids, nor are they drafted as broadly as in the German or Singaporean cases. It is therefore highly unlikely any of them cover nucleic acids.
256 Hagen, above n 254, at 387.
257 At 387.
258 Centers for Disease Control and Prevention, above n 242, at 6.
259 Ministry of Health (China) “Directory of Pathogenic Microorganisms Transmissible Between Humans” (11 January 2006), as cited in Hu Longfei, Xiang Dapen, Shi Yongxia, Huang Jicheng, Zheng Kui, Hong Ye, Li Xiaobo and Xing Luqin “Chinese Biosafety Laws and Regulations, Including Matters of Biosecurity and Oversight of Genetic Engineering Activities” in Amy E Smithson (ed) Beijing on Biohazards: Chinese experts on bioweapons nonproliferation issues (James Martin Centre for Nonproliferation Studies, Moneterey, 2007) 47 at 57-58.
260 感染症の予防及び感染症の患者に対する医療に関する法律 1998 (JP), arts 6, 56-18, 56-19 and 56-20 (translation: Act on the Prevention of Infectious Diseases and Medical Care for Patients with Infectious Diseases). 261 Infectious Disease Control and Prevention Act 2009 (KR), arts 2(19) and 21(1).
262 National Health Security Act 2007 (Cth), ss 3, 31(1) and 35(1); and Security Sensitive Biological Agents Regulatory Scheme – Fact sheet 5 – List of Security Sensitive Biological Agents 2016 (Cth) at 2.
In these countries, as in Canada, Germany, and Singapore, SNA companies therefore likely have no obligation to screen sequences for domestic customers.
C Prospective Screening Laws in the United States
As already discussed, the United States has produced the non-binding HHS Guidance. Additionally, California recently passed legislation requiring California State University to provide guidance to its researchers about purchasing from SNA companies that carry out screening. The legislation also requests the University of California to do the same.263 Finally, two directly relevant pieces of legislation are currently in front of the US Congress. Firstly, there is the Securing Gene Synthesis Bill 2023, which would require the HHS Secretary to, among other things,264 write a regulation requiring SNA and benchtop device companies to “implement screening protocols to detect misuse of de novo gene synthesis products”.265 It would also require government entities to purchase only from gene synthesis providers that screen.266 Secondly, new provisions related to DNA screening have been introduced to a bill re-authorising the Pandemic and All-Hazards Preparedness Act (PAHPA).267 This is much less targeted then the first bill, merely requiring an update to the HHS Guidance (which is already happening) within a year from the Act’s enactment, based on a “landscape review” of the gene synthesis market.268 However, industry has supported one PAHPA provision which requires the HHS Secretary to create a list of sequences of concern which SNA providers could consult for screening.269 Industry expert Emily Leproust has argued it would be best to combine this last with the Securing Gene Synthesis Bill provisions.270
D Conclusion
Overall, the many different regimes studied are ad hoc and poorly coordinated. More concerningly, in many jurisdictions in which SNA providers currently operate there are no legally binding obligations to screen sequence orders from domestic customers, even if they
263 EDC, title 3, div 2, part 40, ch 5.7 § 66360-66361.
264 Securing Gene Synthesis Bill 2023, 118th Cong, 1st Sess, § 2.
265 § 2(1)(C).
266 § 2(1)(F).
267 S.2333 - Pandemic and All-Hazards Preparedness and Response Act 2023, 118th Cong, 1st Sess, § 405.
268 §§ 405(a) and (c).
269 S.2333 - Pandemic and All-Hazards Preparedness and Response Act 405(b); and Piper, above n 17.
270 Piper, above n 17.
have to carry out this screening for international customers. There is no obvious rationale for this discrepancy between domestic transfer and export control laws. It also means there may be companies which, when sending SNAs to domestic customers, do not carry out any screening at all, since they have no legal screening obligations and screening is costly.
III Does the Biological Weapons Convention Require Regulation of Nucleic Acids?
I established in chapter II that states are obliged to implement some form of domestic transfer controls and export controls under both the BWC and UNSCR 1540, and that it is permissible under article X of the BWC to implement export restrictions as stringent as the BWC. I have also established that some states regulate both SNA exports and domestic transfers, but in a very inadequate and ad hoc way, while some regulate only SNA exports, and some regulate neither. The question now is whether any of these groups are breaching the BWC.
I will first ask whether SNA export controls are required, because this is the most straightforward question. Such controls are clearly permitted, since the AG lists are permitted, and they include nucleic acids. A simplistic view might assume this also means they are required, because surely the plain language of article X that requires states to participate in the fullest possible exchange of some material can only be overridden by another obligation in the treaty. On this view, the fact that it is permissible to enact export restrictions on any material despite article X necessarily must be because it is required under articles III and IV. However, it seems highly unlikely the BWC’s intention was to mandate a very specific policy when none is explicitly stated in its text, because it would be virtually impossible to comply. A more realistic interpretation is that there are some minimum measures that are required by article III and articles IV, and some measures which are considered so restrictive that they violate article X, and then there is a spectrum of acceptable options in between.
Are the AG lists, or at least their references to nucleic acids, included in the minimum requirements of articles III and IV? The Australia Group explicitly regards itself as a non- binding arrangement,271 so the “subsequent practice” of states enacting its lists cannot be enough to meet the Vienna Convention article 31(3)(b) requirement of establishing an
271 United States Government Australia Group Common Control List Handbook Volume II: Biological Weapons- Related Common Control Lists (Australia Group, Revision 6, January 2021) at ix.
“agreement” across all BWC that these types of restrictions are required by the BWC.272 However, they certainly suggest that at least a substantial proportion of state parties believe these actions are required by the BWC. Such examples of “subsequent practice” which do not reach the level of agreement can still be considered under article 32 of the Vienna Convention as a “supplementary means of interpretation”.273 It is currently unclear how much difference it makes when subsequent practice is taken into account under article 32 rather than 31.274 Ultimately, this uncertainty is probably resolved best by returning to the plain meaning of “necessary measures” in article IV and the purpose of the BWC “to exclude completely the possibility of bacteriological (biological) agents being used as weapons”.275 As Leach notes, and as I have shown in chapters I and II, there are good safety reasons for restricting access to SNAs and the IGSC is insufficient to regulate the market by itself, so if states do not regulate domestic SNA transfers then they are taking a substantial and unnecessary risk of SNAs being used to create bioweapons.276
Domestic SNA transfers are more complicated because most states (of those studied) do not regulate them. A straightforward “subsequent practice” analysis would say that states have determined that SNAs only need to be controlled at the export level. The problem is that there is no obvious rationale for this. States may believe the risk a biological agent could pose differs between domestic transfers and transfers to certain countries. However, this difference can be managed by applying regulatory decisions as to whether to grant export licences or licences in each case, it should not determine whether to have a regulation at all. The real explanation for the discrepancy between export and domestic transfer regulations is likely that many states have chosen to implement the AG list in full, including its innovation of covering nucleic acids, and did not turn their minds to the inconsistency with their domestic transfer rules. If this is true, then the practice of implementing this aspect of the AG lists should be given greater weight than the practice of failing to update domestic transfer controls to follow suit.277 Once
272 Vienna Convention article 32; and Draft conclusions on subsequent agreements and subsequent practice in relation to the interpretation of treaties, above n 128at 2(4), 4(3) and 7(2).
273 Vienna Convention article 32; and Draft conclusions on subsequent agreements and subsequent practice in relation to the interpretation of treaties, above n 128at 2(4), 4(3) and 7(2).
274 Buga, above n 133, at 75-78. Draft conclusions on subsequent agreements and subsequent practice in relation to the interpretation of treaties, above n 128, at 9(3).
275 Biological Weapons Convention, arts IV and I.
276 Leach, above n 20, at 155.
277 Draft conclusions on subsequent agreements and subsequent practice in relation to the interpretation of treaties, above n 128, at 9.
again, this approach would better reflect the BWC’s purpose, which would favour more stringent restrictions of biological agent transfers.
The analysis so far therefore implies states which have not implemented either SNA domestic transfers, or exports, or both, are violating their international obligations. Braden Leach wants to take this argument further, however, and argue that even states like the UK and US have breached their obligations for failing to directly regulate the SNA screening process itself.278 Leach bases his view on a simple analysis of weaknesses in the United States regime, the plain meaning of “necessary measures”, and the BWC’s purpose.279 I have shown so far that these weaknesses generalise to all jurisdictions with IGSC and IASB members. All their export regimes, based on the AG lists, have the usual weaknesses of not covering sequences that do not come from non-listed pathogens and it only covering an arbitrary minimal sequence length which bioterrorists could get around by ordering and later assembling many smaller sequences. Further, the most stringent domestic transfer controls in the UK and US have these problems and also are arbitrarily limited to sequences that create “inherent danger”. These factors, alongside the weaknesses of relying on the IGSC itself, makes it is difficult to regard these measures as enough to meet the BWC’s burden.
However, Leach does not address the problem of balancing article III and IV obligations and those of article X. Arguably, the analysis so far goes much of the way there: if “subsequent practice” shows that regulation of nucleic acids in general is required at least to the degree that they are regulated by the AG lists, there is no obvious reason why SNAs which are otherwise dangerous but not on these lists should not be regulated. This does not impose a new qualitative type of restriction on the exchange of biological materials, it simply involves enacting a law that is more effective at achieving its aim of keeping dangerous sequences away from malicious actors. While this does mean that no state is complying with the BWC, we must remember the BWC was intended to adapt to new technologies over time.280 It was therefore surely intended that at least for some period after a new danger arose that its regulation would be required by the BWC, even though no state had yet acted. On the other hand, this delay in responding to SNA has been particularly long, and at some point it must be possible at least in some cases to
278 Leach, above n 20, at 150.
279 At 152-157.
280 Jakob, above n 82, at 264.
say states have decided some particular action is not required. Leach’s argument therefore is therefore plausible, but not self-evidently correct.
IV Conclusion
States which regulate no forms of SNA transfers (domestic or exports) are likely breaching the BWC. Those which regulate only exports of SNAs are also likely in breach, although this argument is less certain than the first. Even less certain, it may be that all states are breaching the BWC, because the regulations of states which cover both types of transfer are inadequate and they instead need to regulate SNA screening practices directly. Because these results are clearly not self-evident, we cannot rely on the BWC in its current form to ensure sufficient action is taken to sufficiently safeguard against the potential dangers of NAS. The BWC’s requirements either need to be clarified or we need a new approach, or both. This is what chapter V discusses.
Chapter VI - Comparing Solutions for International Regulation
I Introduction
Scholars have suggested a range of approaches to internationally regulating synthetic biology, which are now adapted to NAS specifically and compared.
Wilson advocates for an international treaty for existential risks created by emerging technologies, including artificial intelligence, nanotechnology and synthetic biology.281 A body of experts would create regulations as required to prevent an “extremely bad worst case scenario”.282 In the SNA context this might involve identifying the screening protocol SNA companies should follow.283 He also suggests following the Montreal Protocol model of allowing treaty amendments by agreement over time to maintain flexibility.284 Wilson’s argument is from 2011, and given IBBIS now exists with a mandate to specifically regulate biotechnology risks, 285 a better approach in 2023 may be to create a specific “biotechnology risks” treaty otherwise based on his model.
Firestone and Maurer argue instead for a form of “transnational private regulation” (TPR), in which private actors create standards for companies around the world to follow.286 This extends IGSC-style governance to all aspects of synthetic biology.287 Confusingly, Firestone refers to TPR as “soft law”, and Maurer refers to it as “self-regulation”. This paper will use “soft law” to mean non-binding rules and norms, or “binding” rules which are so broad they leave significant flexibility in their application, as opposed to binding “hard law”.288 The HHS Guidance and IGSC’s Harmonised Screening Protocol are both “soft law”. This paper also
281 Wilson, above n 18, at 311.
282 At 355-356.
283 At 355.
284 At 357.
285 International Biosecurity and Biosafety Initiative for Science, above n 205
286 Fabrizio Cafaggi, ‘Transnational Private Regulation: Regulating Global Private Regulators’ in Sabino Cassese (ed.), Research Handbook on Global Administrative Law (Edward Elgar 2016) 212 at 212-213; and see generally Maurer, above n 19.
287 Firestone, above n 19, at 169.
288 Eduard Fosch Villaronga and Angelo Jr Golia "Robots, standards and the law: Rivalries between private standards and public policymaking for robot governance" (2019) 35(2) CLSR 129 at 131.
defines “self-regulation” to mean “any system of regulation in which the regulatory target [companies] ... through an industry association that represents targets – imposes commands and consequences upon itself”.289 The IGSC is an example of self-regulation. Later I show TPR is closely related to but distinct from both self-regulation and “soft law”.290
Xue and others propose a four-stage intermediate approach of “experimentalist governance” which combines “top-down” public regulation and “bottom-up” industry self-regulation.291 Firstly, create an international platform under the Biological Weapons Convention (BWC) where all parties agree on broad legally binding principles about how to regulate synthetic biology.292 Then, governments apply these principles to local conditions, finding a “dynamic balance between ‘hard law’ and ‘soft law’”, constantly taking into account feedback.293 Thirdly, an international scientific advisory body monitors individual nations’ progress, and assists international governmental organisations (IGOs) and international self-regulatory bodies in a similar process.294 Notably, their endorsement of “broad principles” means this theory in practice imposes “soft law” on states.295
One might also wonder, given chapter III’s analysis, whether the BWC could also be used to create a “hard law” solution in which states agree articles III and IV require enactment of specific legislation. This approach could be modelled off the Australia Group, except now through model legislation for SNA screening rather than select agents lists. In practice, this approach would be similar to a new treaty.
This chapter proceeds as follows. Part II considers the case for creating a new international treaty, as Wilson suggests (“model one”). It then compares this briefly to a “hard law” interpretation of the BWC (“model two”). Part III covers TPR (“model three”), and finds it might work for NAS, but will require substantial reform of the IGSC’s governance system. Part IV briefly explains how the “experimentalist governance” approach (“model four”) is not very
289 Cary Coglianese and Even Mendelson “Meta-Regulation and Self-Regulation” in Martin Cave, Robert Baldwin, Martin Lodge (eds) The Oxford Handbook on Regulation (Oxford University Press, Oxford, 2010) at 6. 290 Martijn Scheltema “Assessing Effectiveness of International Private Regulation in The CSR Arena” (2014) 13 Rich J Global L & Bus 263 at 265-266.
291 Yang Xue, Hanzhai Yu and Geng Qin “Towards Good Governance on Dual-Use Biotechnology for Global Sustainable Development” (2021) 13 Sustainability 14056 at 1 and 7-8.
292 At 8-9.
293 At 9-10.
294 At 11.
295 Villaronga and Golia, above n 288, at 131.
different from TPR when it is properly applied. Part V concludes that all four models suggested may be effective in different contexts, and that it is ill-advised to rule out any one too quickly.
II “Hard Law” Through an International Treaty
A Model One: A New International Treaty
The case for an international treaty involves two distinct steps: firstly, domestic “hard law” regulation, and then international “hard law” (a treaty) which mandates that states implement such regulations.
The rationale for both arguments comes from the neoclassical economic theory of public goods, although it is more complex to apply at the international level. Beginning at the domestic level, avoiding a pandemic outbreak by screening SNA is a public good because it is “non- excludable” (you cannot limit the benefit of avoiding an outbreak to one subset of people) and “non-rival” (when one person benefits from avoiding an outbreak, this does not stop others from doing the same).296 Standard theory states this results in a “prisoner’s dilemma”: SNA companies would be better off if they all screened for harmful sequences because this would avoid causing an outbreak and they would be able to pass much of the cost of screening onto consumers, but any individual company has the incentive to avoid screening (“free-ride”) to charge a lower price and capture the rest of the market. Regulation must therefore impose penalties against free-riding to make everyone better off.297 Tucker once argued the “prisoner’s dilemma” was negligible for SNA because screening costs constituted a small proportion of total synthesis costs.298 The rising cost of screening as a proportion of synthesis costs means this argument no longer applies.299
However, avoiding disease outbreaks is more specifically a “weakest link” good, where
everyone must take action to achieve any benefit.300 If even one company across the world does
296 Scott Barrett “Introduction – the incentives to supply global public goods” in Why cooperate?: the incentive to supply global public goods (Oxford University Press, USA, 2007) 1 at 1-2.
297 Thomas Nechyba Microeconomics: an intuitive approach with calculus (2nd ed, Cengage Learning, 2017) at 900-901, 906, 1042 and 1047.
298 Jonathan Tucker “Double-Edged DNA: Preventing the Misuse of Gene Synthesis” (2010) Issues in Science and Technology <https://issues.org/tucker- 2/#:~:text=Fostering%20industry%20self%2Dregulation%2C%20backed,the%20risks%20of%20synthetic%20g enomics.>.
299 DiEuliis, Carter and Gronvall, above n 16, at 2; and Carter and Friedman, above n 16, at 15
not screen, a bioterrorist could simply order a pathogen from them. In theory, provided everyone else has already committed to taking action, any individual by themselves can prevent a pandemic outbreak, easily outweighing their personal costs.301 “Weakest link” public goods still may not be provided by some individuals, however, if they place a lower value on it or have a lower capacity to contribute.302 Some SNA companies may not perceive any risk from not screening or may not be able to afford it. Consequently, even under this structure not everyone complies, thereby justifying regulation.
Moving to international regulation, we have the problem of lacking a world government enforcer. Instead, all nations experience a different prisoner’s dilemma with respect to another “weakest link” good.303 The problem here is known as “trade leakage”,304 where in theory if even a single country fails to regulate SNA screening, then companies can simply move there. Companies are more likely to do this the higher the cost of screening as a proportion of total nucleic acid synthesis costs.
The usual solution suggested in such cases is an international treaty.305 However, without a world government these are much harder to enforce. Treaties therefore often include an agreed enforcement mechanism the collective imposes against treaty violators. A good example is the Montreal Protocol (created to protect the ozone layer), which stated all parties would impose trade restrictions on ozone-depleting goods from any non-compliant country.306 However, treaty parties cannot be forced to apply the penalty. Often it is not in their interest to do so since by refusing to trade they lose access to the market of non-participating countries. Enforcement is therefore itself a “prisoner’s dilemma”.307 According to Barrett, the Montreal Protocol was successful because any new amendment to what it required came into effect only after two- thirds majority ratification. By this point, a “tipping point” had been reached where the harm to any sanctioning country was small and the harm to the non-participating country was large,
301 See generally Scott Barrett “Weakest links - global public goods that depend on the states that contribute the least” in Why cooperate?: the incentive to supply global public goods (Oxford University Press, USA, 2007) 47 and compare Scott Barrett “Aggregate efforts: global public goods that depend on the combined efforts of all states in Why cooperate?: the incentive to supply global public goods (Oxford University Press, USA, 2007).
302 Jack Hirshleifer “From Weakest-Link to Best-Shot: The Voluntary Provision of Public Goods” (1983) Public Choice 371 at 380; and Barret “Weakest links”, above n 301, at 47-48.
303 Barrett “Weakest Links”, above n 301, at 57-59.
304 Barrett “Aggregate efforts”, above n 301, at 80.
305 Barrett, above n 296, at 19-20.
306 Barrett “Aggregate efforts”, above n 301, at 82-83; Montreal Protocol on Substances that Deplete the Ozone Layer 1522 UNTS 3 (opened for signature 16 September 1987, entered into force 1 January 1989), art 4.
so that the incentives reversed to be in the sanctioning country’s interest. The effectiveness of treaty enforcement mechanisms therefore depends on the design of the treaty, which in turn depends on what can be negotiated in the first place.308 Sometimes it is not politically feasible to include an enforcement mechanism,309 as with the BWC.310
Treaties therefore do not always work, creating some scepticism of their utility given their negotiation costs.311 However, some treaties are widely regarded as highly successful, including the Montreal Protocol and the Nuclear Nonproliferation Treaty.312 There are many theories for why states comply with international law despite the lack of external enforcement, some of which have been mentioned above such as reciprocal compliance or credible threats of retaliation, and others being to maintain a state’s reputation to enjoy future cooperation opportunities, or social persuasion mechanisms that act on state representatives.313
Instead of evaluating these theories I will simply highlight that state compliance with a treaty does not necessarily imply the treaty caused that state’s behaviour. Establishing this requires comparison to an unknown counterfactual.314 This is very difficult and requires careful statistics, qualitative analysis,315 or theoretical modelling.316 Such approaches have produced mixed results for the Montreal Protocol, although some evidence is quite positive.317 There is more robust support for the Nuclear Weapons Nonproliferation Treaty’s effectiveness.318 A
308 Barrett “Aggregate efforts”, above n 301, at 82-83.
309 At 94-98.
310 Tucker, above n 88, at 9.
311 Steven J Hoffman and others “International treaties have mostly failed to produce their intended effects” (2022) 119(32) PNAS e2122854119 at 1.
312 Emma Lee “How to Improve Multilateral Environmental Agreements: A Case Study in Balanced Institutional Design Mechanisms in the Climate Change and Ozone Regime” (BA (Hons) Thesis, Union College, 2021) at 2; ER Desombre “The Experience of the Montreal Protocol: Particularly Remarkable, and Remarkably Particular” (2000) 19 UCLA J Envtl L & Pol’y 49, at 77; and Scott Barrett “Conclusions: institutions for the supply of global public goods” in Why cooperate?: the incentive to supply global public goods (Oxford University Press, USA, 2007) at 192;
Matthew Fuhrmann and Yonatan Lupu “Do Arms Control Treaties Work? Assessing the Effectiveness of the Nuclear Nonproliferation Treaty” (2016) 60(3) ISQ 530 at 530.
313 GL Burci and others Implementation and Compliance in International Law: Implications For Pandemic Rulemaking (Global Health Centre, 2023) at 8.
314 Lisa Martin “Against compliance” (Apsa Annual Meeting Paper, 2011) at 1-2, 24 and 27.
315 At 27.
316 See for example James Murdoch and Todd Sandler “The voluntary provision of a pure public good: The case of reduced CFC emissions and the Montreal Protocol” (1997) 63(3) J Public Econ 331; and M Finus and S Tjøtta “The Oslo Protocol on sulfur reduction: the great leap forward?” (2003) 87(9-10) J Public Econ 2031.
317 Compare the methods and results generally of Murdoch (1997) “The voluntary provision of a pure public good: The case of reduced CFC emissions and the Montreal Protocol” and Finus M, Tjøtta S. The Oslo Protocol on sulfur reduction: the great leap forward? J Public Econ. 2003;87(9–10):2031–2048.
318 Fuhrmann, above n 312, at 530.
recent meta-analysis finds most international treaties fail to produce their intended effects, apart from those related to international trade and finance or which have enforcement mechanisms.319 Of all the treaty categories studied, the closest analogy to SNA regulation from this meta-analysis is the environmental treaties, especially the Montreal Protocol which the meta-analysis suggests was more successful because of its enforcement mechanism.320 The close analogy arises because both require a very specific set of costs (shifting away from using ozone-depleting substances such as CFCs, or SNA screening), to be imposed on a specific set of individuals (manufacturers of products containing these substances, or SNA companies), and the most significant challenge to both is the “trade leakage” problem.321
An international treaty’s effectiveness is therefore highly context-dependent. If we assume the Montreal Protocol was effective, then Wilson is correct to suggest a similar design which involves both flexibility and a strong enforcement mechanism. However, many unusual historical features may have contributed to the Protocol’s success.322 The value to states of avoiding ozone depletion was unusually high and the costs unusually low, and research over time found the harms of ozone depletion were larger than expected and the costs of feasible substitutes lower than expected, making states able to agree on an enforcement mechanism and make more demanding amendments over time.323 Other historical accounts note the role of civil society pressure and the fact that the particular substitutes to CFCs identified happened to most benefit large industry players actively involved in the treaty’s negotiation.324
It certainly seems feasible that any of these factors could apply to SNA screening. Civil society (through IBBIS) and industry (through the IGSC) could be mobilised to create enough pressure to successfully implement a flexible, effective enforcement mechanism. The costs to states are also relatively low since only SNA companies are affected. Incoming regulation may encourage further innovations in automated screening solutions to further reduce the adjustment costs. It is also possible that none of these factors materialise and treaty negotiation efforts fail. A new treaty should not be ruled out nor relied on alone.
319 Hoffman, above n 311, at 1.
320 Hoffman also included security treaties, but inspection of the specific treaties cover finds they were quite different from the BWC apart from the Nuclear Weapons Nonproliferation Treaty, which was actually successful: Hoffman, above n 311, appendix.
321 Barrett “Aggregate efforts”, above n 301, at 80; and Desombre, above n 312, at 77.
322 Desombre, above n 312, at 77; and Brian J Gareau “A critical review of the successful CFC phase-out versus the delayed methyl bromide phase-out in the Montreal Protocol” (2010) 10 Int Environ Agreem-P 209.at 210.
323 Barrett “Aggregate efforts”, above n 301, at 79.
324 Gareau, above n 322, at 210.
B Model Two: Treating the Biological Weapons Convention as “Hard Law”
As discussed in the introduction, a similar result might be reached by having BWC parties declare that articles III and IV require states to mandate SNA screening. Alternatively, any State Party can propose an amendment to the BWC under article XI, which becomes binding on all states who accept the amendment, provided a majority of the BWC State Parties accept.325 Either approach would avoid the costs of creating a new treaty. Further, Barrett argues that treaties are an inadequate response to “weakest link” public goods because it is quite likely at least one country will choose not to participate.326 An advantage of using the BWC in comparison is therefore that it would bind all current 185 parties to the BWC, with only eight non-parties across the world and four non-ratified signatories.327 Moreover, the UNSCR 1540 and the BWC probably impose the same requirements, and UNSCR 1540 essentially binds all states.328
On the other hand, the BWC was not created to respond to risks from emerging technologies.329 This might create difficulties such as having to resolve the tension between articles III and IV on one hand and X for every dual-use synthetic biology application. Secondly, the BWC lacks that crucial enforcement mechanism.330 Negotiating a new treaty with an enforcement mechanism, even with fewer parties, may be better. Moreover, this solution must overcome the current culture of seeing articles III and IV as “technical non-compliance”.331 A new treaty which focuses on regulating severe but low-probability risks, without referencing other harms like stockpiling weapons, may be better at mobilising compliance. Implementation under the UNSCR 1540 would also need to overcome its perceived illegitimacy.332
Finally, this may not be a pure “weakest link” case as would warrant attempting to achieve universal implementation. If most countries implement screening requirements, this would
325 Biological Weapons Convention, art XI.
326 Barrett “Weakest Links”, above n 301, at 61.
327 United Nations Office of Disarmament Affairs “Biological Weapons - Membership and Regional Groups”
<https://disarmament.unoda.org/biological-weapons/about/membership-and-regional-groups/>.
328 Charter of the United Nations, art 25.
329 Wilson, above n 18, at 351.
330 See for example Nicholas Cropper, Shrestha Rath and Ryan Teo Creating a Verification Protocol for the Biological Weapons Convention: A Modular-Incremental Approach (Nuclear Threat Initiative, June 2022).
331 Angela Woodward, above n 89, at 133-134 and 139-140.
332 Barrett “Weakest links”, above n 301, at 61.
surely disadvantage bioterrorists at least to some extent by removing many of their preferred purchasing options. Moreover, there may be other incentives that stop companies from moving to whichever country does not mandate screening. Currently all easily identifiable companies online operate in relatively rich countries, with the centres of growth in Asia still being in richer countries.333 Unless the proportional cost of screening becomes so stark as to overcome whatever advantages come from operating in such countries (presumably direct access to customers, stable political institutions, and similar factors), a universally binding approach is not needed.
C Conclusion
Either proposal would require much effort, achieve mostly similar outcomes, and may not succeed. Negotiating a new treaty involves an extensive time commitment, while clarifying the BWC would require getting past several key political barriers. It is not obvious which is likely to be more successful. However, it seems much more practical to firstly try clarifying the BWC, and if the BWC’s political barriers prove insurmountable then consider a new treaty.
III Model Three: Transnational Private Regulation
A Articulating and Extending Firestone’s Argument
Firestone is another international treaty sceptic, arguing their negotiation can take “years to decades to achieve”.334 He advocates instead for a “voluntary, nonprofit, international consortium [comprised] of all stakeholders to share information and concerns”. Alongside this, voluntary programmes, codes of conduct and certification programmes could be created with respect to various synthetic biology processes, presumably including NAS.335 Maurer also supports using “self-governance” and “private standards”.336 Firestone notes a similar model has been successful for other dual-use technologies. For example, medical radiation technology is regulated by the International Commission on Radiological Protection (ICRP), a voluntary organisation that encourages nations to adopt its radiation dose recommendations in formal
333 See the list of IGSC member companies on its website: International Gene Synthesis Consortium, above n 8. I will take Pálya and Delaney’s lead in not providing information about non-members to avoid contributing to information hazards: Delaney and Pálya, above n 218, at 3, n 5.
334 Firestone, above n 19, at 169.
335 Firestone, above n 19, at 169.
336 Maurer, above n 19, at 13.
regulations.337 Another is the Internet, with cybersecurity being largely governed by voluntary guidelines set by the National Institute of Standards and Technology (NIST) Cybersecurity Framework.338
Firestone calls his proposal “soft law”, but it is really “transnational private regulation” (TPR), a recently popularised alternative to international treaties. Its core feature is its primary reliance on private bodies (companies or NGOs) instead of states for central regulatory decision- making.339 This has been applied fairly successfully in many cases: “dolphin-safe” tuna fishing, food safety, sustainable forestry, sustainable fishing, sustainable coffee,340 many different forms of standardisation across the Internet, sustainable finance, advertising standards and anti- money laundering. While “soft” voluntary standards are often involved, there is still a role for “hard law”.341 Governments can implement the private standards in binding regulations (as with the ICPR),342 or impose obligations on companies that take on private standards.343 Finally, the industry association can impose “hard law” requirements either by contract or by making compliance with the industry standards a membership requirement,344 although domestic competition law will place limits on this approach.345
Similarly, while Maurer refers to “self-regulation”, TPR can involve a range of institutional forms. It is closely related to a shift in the understanding of domestic regulation sometimes called “new governance”.346 “New governance” moves past the neoclassical economics model that treats situations either as being best to leave to the market or as requiring external
337 Firestone, above n 19, at 145.
338 At 147.
339 Cafaggi, above n 286, at 212-213; and Kenneth W Abbott and Duncan Snidal “Strengthening International Regulation Through Transnational New Governance: Overcoming the Orchestration Deficit” (2021) 42(2) Vand J Transnat’l L 501 at 505-507.
340 Stephen M Maurer “The New Self‐Governance: A Theoretical Framework” (working paper, University of
California, Berkeley, 2015) at 4-9.
341 Abbott and Snidal, above n 339, at 505-507.
342 Clarke and Valentin (2008) (2008) “The History of ICRP and the Evolution of its Policies” at 101.
343 Fabrizio Cafaggi “A comparative analysis of transnational private regulation: legitimacy, quality, effectiveness and enforcement” (2014) Quality, Effectiveness and Enforcement at 27, 54, 62 and 66-70; and for detailed discussion see Verbruggen “Regulatory governance by contract: the rise of regulatory standards in commercial contracts”.
344 Cafaggi, above n 343, at 27, 54, 62 and 66-70; and for detailed discussion see Verbruggen “Regulatory governance by contract: the rise of regulatory standards in commercial contracts”.
345 Thomas A Hemphill “Self-Regulating Industry Behavior: Antitrust Limitations and Trade Association Codes of Conduct” (1992) 11 J Bus Ethics 915 at 916.
346 Abbott and Snidal “Strengthening International Regulation Through Transnational New Governance:
Overcoming the Orchestration Deficit” at 520-533.
“command-and-control” regulation.347 It instead considers a range of intermediate approaches, including self-regulation, “sanctioned” self-regulation, where governments approve private rules, “mandated” self-regulation where governments require self-regulation but do not mandate the rules’ content, and “co-regulation”, in which governments and private actors cooperate in the rules’ creation and enforcement.348 Some of these models are also examples of meta-regulation, which is when an external body regulates the process that the industry association uses when regulating its members. This for example might involve government approving the rules, mandating the creation of rules, or imposing transparency or other procedural requirements.349
According to Abbott and Snidal, TPR translates “new governance” ideas to the international arena.350 They argue that this approach shares many of the features of domestic “new governance”, but with the crucial difference that for international self-regulatory bodies states cannot impose intermediate formats such as meta-regulation or binding sanctions as required. Instead, individual states or international government organisations (IGOs) can only carry out “state orchestration”. This can involve “directive orchestration”, where states impose mandatory domestic rules. For example, the EU imposes conditions on firms that participate in certain private standard schemes.351 Secondly, it may be through “facilitative orchestration”, where states or IGOs take supportive actions, for example by convening and financially supporting the process of developing a private scheme.352 An alternative approach to filling this “orchestration deficit”,353 however, is to create private meta-regulators, other private organisations which enforce meta-regulation through contracts and membership requirements.354 A good example of this is the Global Food Safety Initiative (GFSI), which assesses the range of private food safety certification regimes used across the world against a
347 Abbott and Snidal, above n 339, at 520-521; and Ian Ayres and John Braithwaite “The Politics of an Idea” in
Responsive regulation: Transcending the deregulation debate. (Oxford University Press, USA, 1992) at 3.
348 Daniel E Walters and Hannah Jacobs Wiseman “Self-Regulation and Innovation” (Law & Economics Center at George Mason University Scalia Law School Research Paper Series 22-033, 2023) at 13-14.
349 Coglianese and Mendelson, above n 289, at 7; and Cafaggi, above n 286, at 233.
350 Abbott and Snidal, above n 339, at 533.
351 At 544.
352 At 545.
353 Abbott and Snidal, above n 339, at 512.
354 Verbruggen and Havinga “The Rise of Transnational Private Meta-Regulators” at 117-122; and Fabrizio Cafaggi and Andrea Renda “Measuring the Effectiveness of Transnational Private Regulation” (2014) SSRN
<https://papers.ssrn.com/sol3/papers.cfm?abstract_id=2508684> at 8 and 58-59.
set of common benchmarks and monitors each industry association’s governance and practice.355
Given this context, Firestone’s argument is simply that we should apply the modern orthodox approach to international regulation outlined above. One might respond that at least some forms of “new governance” have produced mixed results,356 or that it is inappropriate to default to self-regulation for severe but unpredictable risks.357 This second point is certainly one which distinguishes NAS from most of the examples of successful TPR implementation above, including Firestone’s examples. However, it is better to analyse exactly how the “new governance” and TPR justifications apply to the SNA context. I do this in the next section.
B Evaluating the Case for Transnational Private Regulation
This section analyses how the underlying theories that compare self-regulation and state regulation apply to NAS. For reasons given in chapter II, this paper has always only focused on how best to respond to the risks created by NAS. This section therefore focuses on answering only the following – is it possible for private companies to self-regulate just as effectively to reduce the risk of bioweapon creation as binding government regulation? The answer to this question determines where the best regulatory solution sits between these two extremes.
This analysis involves three steps: part (i) applies the theory for comparing self-regulation and government regulation to the NAS context, and ultimately concludes which is preferable depends on the circumstances. Sections (ii) and (iii) analyses these circumstances in detail, considering the external factors related to the IGSC’s initial development in section (ii) and internal factors related to the IGSC’s institutional design in section (iii). Finally, I conclude self-regulation could work in this context, but the IGSC in its current form is inadequate.
355 Cafaggi and Renda, above n 354, at 58-59 and 84; and Cafaggi, above n 286, at 231-235.
356 Jeroen van der Heijden “Why meta-research matters to regulation and governance scholarship: An illustrative evidence synthesis of responsive regulation research” (2021) 15 Regul Gov S123 at S134-S139.
357 Eric L Windholz (2018) Governing through regulation: Public Policy, Regulation and the Law (Taylor & Francis) at 235; and Jeremy Kidd “No Perfect Solutions for Market Imperfections” (2022) SSRN
<https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4254370> at 11-12.
(i) Comparing self-regulation and government regulation
The case for self-regulation centres on two critiques of “command and control” regulation: the “knowledge problem” and the “public interest problem”.358
The “knowledge problem” refers to the impossibility of knowing how best to intervene in any complex situation involving both complex science and human interactions.359 Regulation can therefore fail to improve the situation or make it worse. Industry members have a significantly more detailed understanding of the market that they can use to create superior regulations.360 Chapters II and III illustrated the private sector’s informational advantage many times. While the IGSC Harmonised Screening Protocol is certainly not perfect, it is substantially better than the government-produced HHS Guidance and certainly superior to chapter III’s “hard law” examples, especially because it does not rely on lists.
One might respond that many of these deficiencies can be corrected with proper expert consultation. However, the HHS Guidance had substantial inadequacies despite extensive industry consultation.361 Moreover, self-regulation can also better adjust to new information over time. This is sometimes separated into a “flexibility” benefit.362 Industry members will quickly receive feedback about what is and is not working well about a regulation and can then respond.363 For example, the IGSC over time has continually updated its Regulated Pathogen Database,364 its onboarding process,365 and in 2017 the HSP,366 while in comparison the HHS Guidance is still being updated.367 Industry still has to aggregate this knowledge, but international public regulation requires both aggregating information back to governments and to international treaty organisations. A flexible approach is especially important as automation initiatives like SecureDNA and the Common Mechanism are likely to continue to change the optimal screening approach over time.
358 Kidd, above n 357, at 2-3.
359 At 13-26.
360 At 24-25.
361 Maurer, above n 139, at 1434-1437.
362 Firestone at 167.
363 Kidd, above n 357, at 52-54.
364 Carter and Friedman, above n 16, at 10.
365 Diggans and Leproust, above n 16, at 2.
366 International Gene Synthesis Consortium, above n 9.
367 Department of Health and Human Services, above n 213, at 25496-25497.
The second “public interest” critique illustrates how public regulators often do not represent society’s interests, since they ultimately involve people who respond to incentives.368 However, the general consensus is that in most cases self-regulation worsens the “public interest” problem because government is still more accountable to the public whereas industry in the end acts in its own interests.369 Here this problem might look like SNA companies producing more lax rules that increase misuse risk, or failing to perform proper enforcement.
Therefore, the usual trade-off between the informational (and flexibility) advantage and the public interest disadvantage of self-regulation remains. This underpins the “new governance” view that the best way to mix public and private regulation is highly context dependent. In fact, the literature provides a range of insights about how exactly a self-regulatory regime’s context affects its compliance rate, which is essentially an analysis of how the “public interest” problem varies with context. This point is covered next.
(ii) Under which circumstances do effective self-regulatory bodies arise?
There are many possible motivations for companies to self-regulate, and which motivation applies affects the resulting regime’s effectiveness. These include a desire to protect the industry’s reputation,370 pressure from downstream customers,371 a desire to pre-empt government regulation, or the personal values of organisational leaders.372 This section focuses on the first two.
The IGSC was created shortly after media coverage of NAS risks.373 In industries where third parties cannot easily distinguish the practices of each business, which applies here due to private screening practices,374 such events tend to harm the reputations of all industry members.375 Businesses are incentivised to maintain their reputation because it gives them
368 Kidd, above n 357, at 27-36.
369 Peter Grajzl and Peter Murrell “Allocating Lawmaking Powers: Self-Regulation vs Government Regulation” (2007) 35 Science Direct 520 at 523-527; Chang Ma “Self-regulation versus government regulation: an externality view” (2020) 58(2-3) J Regul Econ 166 at 169-170; Kidd, above n 357, at 54-55.
370 Sebastian V Engelhardt and Stephen M Maurer “Industry Self-Governance and National Security: On the Private Control of Dual Use Technologies” (working paper, University of California, Berkeley, 2012) at 4.
371 At 1-2.
372 At 4.
373 Randerson, above n 7.
374 Carter and Friedman, above n 16, at 8.
375 Andrew A King, Michael Lenox and Michael L Barnett “Strategic Responses to the Reputation Commons Problem” in Michael L Barnett Limits to Stakeholder Influence (Stanford University Press, Redwood City, 2002) at 393.
access to profit-making mechanisms such as preferred access to products, regulators’ trust, a lower chance of being targeted by NGOs,376 and a lower chance of excessive regulatory responses when things go wrong.377 This creates a “reputation commons problem”,378 where individual firms can benefit from the reputation-enhancing actions of others (“free-ride”) while themselves carrying out reputation-harming behaviour.379 This creates the usual need for an external enforcer, here a self-regulatory body.380
However, often merely managing third party perceptions (“window-dressing) is easier than actually changing firm behaviour.381 This is a fairly common result of self-regulation,382 especially when external pressure is not maintained after the private standard’s creation.383 However, this “reputation commons” is another “weakest link” good because if any one business is found not to screen all other screening efforts have minimal effect,384 in which case commitments by others to comply may be sufficient to incentivise high compliance overall.385 IGSC members have also distinguished their reputation from non-members, which ensures non-compliance by non-members does not affect these incentives.386 However, “weakest link” theory also suggests some members with a lower incentive or capacity to comply may still not do so.387 If IGSC members believe any other members are not complying, this would break down the incentive system, leading to low compliance.
In terms of evidence of compliance, the latest review of IGSC member practices was in 2015,388 but most members have joined since then.389 Most members’ websites do not mention biosecurity or the IGSC,390 and when they have publicised terms and conditions they often do
376 Neil Gunningham, Robert Kagan and Dorothy Thornton “Social License and Environmental Protection: Why Businesses Go Beyond Compliance” (2004) 29(2) LSI 307 at 321.
377 Maurer (2012) “Industry self-governance and national security” at 4.
378 King, Lenox and Barnett, above n 375, at 394-395.
379 At 393.
380 At 400.
381 At 400.
382 Jodi J Short and Michael W. Toffel “Making Self-Regulation More Than Merely Symbolic: The Critical Role of the Legal Environment” (2010) 55(3) Adm Sci Q 361 at 362.
383 At 366 and 368.
384 Scott Barrett “Weakest links”, above n 301, at 47-48.
385 Hirshleifer, above n 302, at 380.
386 King, Lenox and Barnett, above n 375, at 401-402.
387 Barret “Weakest links”, above n 301, at 47-48.
388 See generally Carter and Friedman, above n 16.
389 Internet Archive “Wayback Machine” (26 October 2015)
<https://web.archive.org/web/20151026135045/https://genesynthesisconsortium.org/>.
390 Examples of websites that do not mention biosecurity or the IGSC include: Bioneer, above n 225; BGI, above n 158; Elegen Bio, above n 173; and GenScript “Home” <https://www.genscript.com/>; The Illinois Biological
not mention that they screen orders more stringently than legally required and that they have a right to refuse orders that fail screening.391 They presumably do not get enough reputational benefit from membership for it to be worth advertising on their website, and since customers likely would want to know of the possibility of orders being refused one might expect screening SNA companies to warn them about this, especially since some IGSC members do one or both of these.392 There is also some (weak) evidence of a “window dressing” incentive in one case. In December 2022 science journal Undark asked AZENTA (formerly Genewiz) about their biosecurity practices. They responded that they did screen but did not provide details or explain why they were not an IGSC member.393 By February 2023 they had become an IGSC member,394 so they must have hurriedly joined afterwards.
Maurer provides a different theory for the IGSC’s original creation based on downstream customer pressure from pharmaceutical companies at the time,395 who may also face a “reputation commons problem”, as Nike did when it received backlash for purchasing from suppliers that used sweatshops.396 If the market involves a small number of large downstream customers, with a competitive market of upstream suppliers, the downstream firms can each impose a “single-homing clause” in their purchase contracts, requiring their suppliers to adopt
Foundry for Advanced Biomanufacturing (iBioFAB) “The Illinois Biological Foundry for Advanced Biomanufacturing (iBioFAB)” <https://www.igb.illinois.edu/iBIOFAB>; Synbio Technologies “Changing the World, One Sequence at a Time” <https://synbio-tech.com/>; BGI, above n 158; Touchlight “The making of DNA” <https://www.touchlight.com/>; ANSA Biotechnologies, above n 173; and Aldevron “Home”
<https://www.aldevron.com/>.
391 Aldevron “Service Terms and Conditions” <https://www.aldevron.com/hubfs/files/aldevron-terms- conditions.pdf>; ATUM “Terms and Conditions” <https://www.atum.bio/resources/company/terms-and- conditions>; AZENTA “Terms and Conditions – Processing Services”
<https://www.genewiz.com/Public/Company/Policies/Terms-Conditions/?sc_device=Mobile>; and Bioneer “Terms and Conditions – Bioneer”
<https://us.bioneer.com/support/terms.aspx?AspxAutoDetectCookieSupport=1>.
392 Examples of webpages that mention biosecurity or the IGSC include: Molecular Assemblies “Supply Terms and Conditions” (20 September 2022) <https://molecularassemblies.com/terms-and-conditions/>, cl 1.5; Blue Heron Biotech “Terms and Conditions” <https://blueheronbio.com/wp- content/uploads/2018/05/BHB_Terms_and_Conditions.pdf>, cl 2; Telesis Bio “Telesis Bio Inc General Terms and Conditions of Sale”
<https://files.telesisbio.com/docs/46167_TELESIS_BIO_INC._GENERAL_TERMS_AND_CONDITIONS_OF
_SALE.pdf>, cl 4.5; Thermo Fisher “Gene Synthesis Conditions of Sale” (29 December 2020) <geneart-gene- synthesis-conditions-of-sale.pdf (thermofisher.com)>, cl 4; and Twist Biosciences “Supply Terms and Conditions” <https://www.twistbioscience.com/legal/supply-terms-conditions>, cl 2.
Examples of terms and conditions that mention the right to refuse orders that fail screening include:
393 Schulson, above n 9.
394 Internet Archive, above n 145.
395 Engelhardt and Maurer, above n 370, at 3; Stephen M Maurer and Sebastian V Engelhardt “Industry self- governance: A new way to manage dangerous technologies” (2013) 69(3) Bull At Sci 53 at 55; and Maurer, above n 26, at 9.
396 Engelhardt and Maurer, above n 370, at 3.
industry-wide standards for all their sales. This allows the downstream firms to use their market power to force upstream firms to comply.397
The are several problems with Maurer’s theory. He frequently asserts the “pharmaceutical industry” as a whole demanded DNA screening standards, but only ever gives AstraZeneca as an example.398 Further, for downstream customers to change the screening behaviour of upstream SNA companies, they must be able to verify compliance, yet screening practices are private.399 This is an example of the “information asymmetry” that makes Xue and others sceptical of using self-regulation to govern synthetic biology.400 Moreover, large pharmaceutical companies may not be under the reputational pressure described. A common point made about self-regulation is that society’s expectations regarding any issue are often “latent” since they are not aware of it, and therefore must be “activated” to affect firm behaviour.401 The IGSC member websites’ lack of biosecurity coverage or mention of screening in their terms and conditions, discussed above, also suggests they are not under this kind of customer pressure.
Consequently, theory provides mixed signals as to whether we should expect high IGSC compliance, and the (limited) evidence is not promising. However, this does not necessarily mean self-regulation is doomed. Governments and NGOs (especially IBBIS) could use “facilitative orchestration”402 methods such as taking steps to “activate” the concerns of wider society by publicizing the risks raised by NAS and scrutinising the current regime.403 Secondly, they could use “directive orchestration” to generate customer pressure by mandating that government-funded researchers only use SNA from companies that screen, following the Securing Gene Synthesis Bill model.404
397 At 2 and 14-15.
398 Engelhardt and Maurer, above n 370, at 3; and Maurer and Engelhardt, above n 395, at 55; and Stephen M Maurer and others “Making Commercial Biology Safer: What the Gene Synthesis Industry Has Learned About Screening Customers and Orders” (working paper, University of California, Berkeley, 2009); and Maurer, above n 26, at 9.
399 Carter and Friedman, above n 16, at 8.
400 Xue, Hanzhai and Qin, above n 291, at 6-7.
401 Abbott and Snidal, above n 339, at 561-562; and Villaronga and Golia, above n 288, at 141.
402 Abbott and Snidal, above n 339, at 545.
403 Maurer, above n 19, at 11 and 13.
404 Securing Gene Synthesis Bill 2023, 118th Cong, 1st Sess, § 2.
(iii) Institutional features of the IGSC
Another literature has recently developed that examines which institutional structures support an effective transnational private regulatory body.405 This is particularly important since the effectiveness of private regulation in general can be quite unpredictable in the abstract.406 The IGSC falls well below standard on four key criteria that are linked to effectiveness: (1) inclusiveness, (2) transparency, (3) enforcement, and (4) coverage of a set of companies with similar interests.
To be effective, TPR bodies should include all relevant stakeholders in decision-making.407 Accountability to a range of stakeholders such as NGOs, public interest groups, and other businesses in the supply chain increases the quality of the standards by drawing on the insights of multiple actors.408 Leach notes that the IGSC only represents members with an economic disincentive to screen properly, who also likely have an ideological bias against proper regulation because their roles primarily involve advancing the field.409 If the IGSC had a range of stakeholders involved in its decision-making, perhaps more effort would have been put into implementing a once-proposed “red teaming” system where experts attempt to directly get around the screening system and order dangerous sequences.410
Secondly, transparency refers to the provision of full information about processes underlying organisational decisions such as meetings, expert inputs and monitoring reports.411 Maurer in fact primarily supported the IASB model because it involved public meetings to which the media were invited. The IGSC instead has secret meetings and no accountability mechanisms,412 which means it is often difficult to establish why it makes any of its decisions. For example, 19 out of the 31 current members all joined after the beginning of 2020 with no explanation.413 Part of the explanation is likely that since 2015 IGSC has been deliberately
405 See for example Cafaggi and Renda, above n 354; Scheltema, above n 290; and Cafaggi, above n 343.
406 Short and Toffel, above n 382, at 362.
407 Cafaggi and Renda, above n 354, at 66.
408 Abbott and Snidal at 526.
409 Leach, above n 20, at 155.
410 Diggans and Leproust, above n 16, at 2.
411 Cafaggi and Renda, above n 354, at 67.
412 Maurer, above n 139, at 1432-1433.
413 Compare the IGSC website on 18 February 2020 to its present state: Internet Archive “Wayback Machine” (18 February 2020) <https://web.archive.org/web/20200218153924/https://genesynthesisconsortium.org/>; and International Gene Synthesis Consortium, above n 8.
pushing to expand its membership,414 but that does not explain why they have now included such a wide range of new members, many of whom are not traditional SNA companies.415 One might instead wonder if there has been a significant shift in the IGSC’s overall aims to become something broader than ensuring compliance with its HSP. The lack of transparency makes it impossible to say.
Thirdly, there is the question of enforcement, which is perhaps the most common and important deficiency of TPR.416 Simply setting rules without checking for or responding to violations is “obviously a very imperfect guarantee that the regulatory objectives will be achieved”,417 and earlier analysis shows there is reason to be sceptical IGSC that all members are complying. Competition law may limit the IGSC’s enforcement ability, but self-regulatory bodies often still have at least some enforcement mechanisms.418
Finally, there is some evidence that attempts to privately regulate a set of firms with heterogeneous interests is less likely to be successful than when all the members have a “common interest”, as this gives industry leaders power to “rein in potential outlier firms”.419 Currently, the IGSC membership list includes not only typical gene synthesis providers,420 but also biofoundries,421 various companies pioneering new benchtop synthesiser technology,422 and DNA screening software providers.423 Certainly, these groups should collaborate and communicate with each other at the deliberation level, but expecting the same type of behaviour from each (which membership seems to imply) seems inappropriate.
414 Carter and Friedman, above n 16, at 14.
415 International Gene Synthesis Consortium, above n 8; DAMP Lab “Home” <https://www.damplab.org/>; Edinburgh Genome Foundry, above n 220; The Illinois Biological Foundry for Advanced Biomanufacturing, above n 390; GP-write “Home” <https://engineeringbiologycenter.org/>; Nuclera “Access Your Target Proteins On Demand” <https://www.nuclera.com/>; Switchback Systems, above n 173; Evonetix, above n 173; ANSA Biotechnologies, above n 173; and Elegen Bio, above n 173.
416 Cafaggi and Renda, above n 354, at 114.
417 At 75.
418 Hemphill, above n 345, at 916; Cafaggi, above n 286, at 231-235.
419 Walters and Wiseman, above n 348, at 13.
420 International Gene Synthesis Consortium, above n 8.
421 International Gene Synthesis Consortium, above n 8; DAMP Lab, above n 415; Edinburgh Genome Foundry, above n 220; The Illinois Biological Foundry for Advanced Biomanufacturing, above n 390.
422 International Gene Synthesis Consortium, above n 8; Switchback Systems, above n 173; Evonetix, above n 173; ANSA Biotechnologies, above n 173; and Elegen Bio, above n 173.
423 ACLID, above n 188. Battelle, above n 185; and see Blinde, above n 184.
A failure of self-regulation for institutional reasons is often a prime opportunity for states to generate reform through meta-regulation.424 As already discussed, this gap cannot so easily be filled at the international level, and instead requires some combination of “state orchestration” and private meta-regulation. Perhaps IBBIS could take up the role of a private meta-regulator of a range of separate self-regulatory bodies, one for SNA companies, one for benchtop device companies and so on, using a similar model to the GFSI. This would solve the heterogeneity problem, and create an opportunity for IBBIS to introduce a range of other institutional reforms, such as including an enforcement mechanism, governance procedure requirements, a third-party certification mechanism that could assess whether any company’s screening practices or any screening software system meet a set of benchmarks, and the creation of a functionally separate part of the organisation in which many stakeholders are involved in developing these benchmarks.425 At the same time, states and IGOs such as the WHO could publicly comment on the current governance deficiencies in the IGSC and financially or logistically facilitate the creation of this new solution.
C Conclusion
The IGSC is currently inadequate, but various reforms through “state orchestration” and “private meta-regulation” may allow it to be effective. This would include states creating more incentives for self-regulation by requiring customers to demand screening, increasing public attention on the risks of NAS, introducing IBBIS as a new private meta-regulator of a set of different self-regulatory bodies related to NAS, and state support for IBBIS taking on this role.
IV Model Four: Experimentalist Governance – A “Soft Law” Approach to the Biological Weapons Convention
Xue and others’ experimentalist governance approach is very similar to TPR if we apply it carefully with the necessary use of private meta-regulation and state orchestration. This is because they suggest using a range of private regulatory regimes and flexible state governance approaches, which would include the suggestions above alongside other TPR features (such as states using some domestic “hard law’).426 The key difference is Xue and others suggest
424 Walters and Wiseman, above n 348, at 13.
425 Cafaggi and Renda, above n 354 at 65.
426 Xue, Hanzhai and Qin, above n 291, at 9-10.
initially agreeing on what broad principles the BWC requires, presumably under articles III and IV.
Where Xue and others’ approach ends up sitting on the continuum between “model two” (a “hard law” interpretation of the BWC) and “model three” (pure TPR), depends on the degree to which BWC parties view their commitments as binding. If they continue to view articles III and IV as only “technically” binding, then it is not much different to TPR. The more they come to view their commitments as binding, and the more prescriptive the requirements they agree to under the BWC, the closer it comes to a “hard law” approach.
V Conclusion
Ultimately, I would propose keeping all four models illustrated above on the table. While treaties have costs and may not be effective, and the TPR approach may have more merits than it first appears, it is still not compelling enough to exclude the value of using “hard law” at the international level. TPR still risks some states or some individual companies failing to come on board without strong external pressure. Different entities are likely to respond to different types of incentives, as are the same entities in different contexts and at different times, so the full range of incentives should be used.427 The two approaches are also complementary – for example an international treaty might allow states to directly implement private screening standards as binding regulations, provided they meet certain criteria. This would combine the flexibility and informational advantage of private actors with the coercive power of “hard law”. Some states, IGOs and IBBIS could push for the required reforms to the IGSC now under “model three”, and then these or other states could start trying to negotiate for a “hard law” clarification to the BWC (“model two”). If this fails, they may still be able to achieve a “soft law” BWC solution (“model four”), which could act as a stop gap while they attempt to negotiate a new treaty.
427 Catherine Jefferson, Filipa Lentzos and Claire Marris “Synthetic Biology and Biosecurity: Challenging the Myths” (2014) 2(115) Front Public Health 1 at 63-64.
Chapter VI: Conclusion
As this paper has illustrated throughout, there have long been concerns about the dangers of nucleic acid synthesis. These have mostly not translated into significant government action across the world, leading to a fragmented, ad hoc and highly inadequate international regime. I have shown that it may be that states’ responses have been so inadequate that they are in breach of the BWC, although whether BWC obligations extend to directly regulating the SNA screening process itself remains unclear.
In terms of how to proceed from here, I suggest a model which combines transnational private regulation with an international “hard law” approach in which states declare that the BWC does mandate SNA screening. Relying on transnational private regulation does not, however, mean that the IGSC should simply be left alone. I have shown that it has significant deficiencies and needs some external governance, likely in the form of a private meta-regulator, alongside continuous pressure from states and international government organisations to improve its practices. This should also be combined with amendment or clarification to the BWC, and if any of these approaches fail the option of negotiating a new treaty should be considered.
Despite the long period of neglect of this area, in the last few years interest in reform across the world has grown substantially, with the creation of IBBIS and the renewed action by legislatures in the United States. This creates the perfect opportunity to implement my suggested changes, and hopefully close this regulatory gap that currently risks inflicting substantial harm across the world.
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GL Burci and others Implementation and Compliance in International Law: Implications For Pandemic Rulemaking (Global Health Centre, 2023).
Sarah R Carter, Jamie M Yassif and Chris Isaac Benchtop DNA Synthesis Devices: Capabilities, Biosecurity Implications, and Governance (Nuclear Threat Initiative, May 2023).
Sara R Carter and Robert M Friedman DNA Synthesis and Biosecurity: Lessons Learned and Options for the Future (J Craig Venter Institute, October 2015).
Centers for Disease Control and Prevention Guidance on the Regulation of Select Agents and Toxin Nucleic Acids (Revision, February 2020).
Nicholas Cropper, Shrestha Rath and Ryan Teo Creating a Verification Protocol for the Biological Weapons Convention: A Modular-Incremental Approach (Nuclear Threat Initiative, June 2022).
Department of Health and Human Services Screening Framework Guidance for Providers of Synthetic Double-Stranded DNA (2010).
Agenda and the Prospects for Restarting it” (2011) 45(4) Valp ULR 1387 at 1387-1391 and 1421-1435.
Department of Health and Human Services Screening Framework Guidance for Providers and Users of Synthetic Oligonucleotides (Federal Register Vol 87 No 3, 29 April 2022)
Kevin M Esvelt Delay, Detect, Defend- Preparing for a Future in which Thousands Can Release New Pandemics (Geneva Centre for Security Policy, November 2022).
Marco Fey 3D printing and international security: Risks and Challenges of an Emerging Technology (Peace Research Institute Frankfurt, Report No 144, May 2017).
Lisa Martin “Against compliance” (Apsa Annual Meeting Paper, 2011).
International Association of Synthetic Biology The IASB Code of Conduct for Best Practices in Gene Synthesis (3 November 2009).
International Gene Synthesis Consortium Harmonized Screening Protocol© v2.0 (19 November 2017).
National Academies of Sciences, Engineering and Medicine Biodefense in the age of synthetic biology (2018).
Secretariat on the Convention on Biological Diversity Synthetic Biology (United Nations Environment Programme and Convention on Biological Diversity, CBD Technical Series No 100, April 2022).
SecureDNA Random adversarial threshold search enables specific, secure, and automated DNA synthesis screening.
United States Government Australia Group Common Control List Handbook Volume II: Biological Weapons-Related Common Control Lists (Australia Group, Revision 6, January 2021).
World Economic Forum Biosecurity Innovation and Risk Reduction: A Global Framework for Accessible, Safe and Secure DNA Synthesis (Insight Report, January 2020).
World Health Organisation Global guidance framework for the responsible use of the life sciences (2022).
G Conferences, Unpublished Papers and Theses
Carsten Baum, Hongrui Cui, Ivan Damg˚ard, Kevin Esvelt, Mingyu Gao ,Dana Gretton, Omer Paneth, Ron Rivest, Vinod Vaikuntanathan, Daniel Wichs, Andrew Yao, Yu Yu “Cryptographic Aspects of DNA Screening” (SecureDNA, DNA Screening Technical Note, January 2020).
Sebastian V Engelhardt and Stephen M Maurer “Industry Self-Governance and National Security: On the Private Control of Dual Use Technologies” (working paper, University of California, Berkeley, 2012).
Stephen M Maurer “Taking self-governance seriously: Synthetic biology’s last, best chance to improve security” (working paper, University of California, Berkeley, 2012).
Emma Lee “How to Improve Multilateral Environmental Agreements: A Case Study in Balanced Institutional Design Mechanisms in the Climate Change and Ozone Regime” (BA (Hons) Thesis, Union College, 2021).
Stephen M Maurer and others “Making Commercial Biology Safer: What the Gene Synthesis Industry Has Learned About Screening Customers and Orders” (working paper, University of California, Berkeley, 2009).
Stephen M Maurer “Beyond Treaties and Regulation: Using Market Forces to Control Dual Use Technologies” (working paper, University of California, Berkeley, 2010).
Stephen M Maurer “Five Easy Pieces: Case Studies of Entrepreneurs Who Organized Private Communities for a Public Purpose” (working paper, University of California, Berkeley, 2010).
Stephen M Maurer “Public Problems, Private Answers: Reforming Industry Self‐Governance Law for the 21st Century” (working paper, University of California, Berkeley, 2014).
Stephen M Maurer “The New Self‐Governance: A Theoretical Framework” (working paper, University of California, Berkeley, 2015).
L Simirenko “Bliss: The Black List Sequence Screening Pipeline” (paper presented to Synthetic Biology: Engineering, Evolution and Design (SEED), Chicago, July 2016).
PWJ Verbruggen “Regulatory governance by contract: the rise of regulatory standards in commercial contracts” (Radboud University Nijmegen, 2014).
Daniel E Walters and Hannah Jacobs Wiseman “Self-Regulation and Innovation” (Law & Economics Center at George Mason University Scalia Law School Research Paper Series 22- 033, 2023).
H Internet Materials
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Peter Aldhous “The Bioweapon is in the Post” (9 November 2005) NewScientist
ANSA Biotechnologies “Early Access Program” <https://ansabio.com/early-access>.
ANSA Biotechnologies “Next-Gen DNA Synthesis Using Enzymes” <https://ansabio.com/>.
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The Australia Group “Australia Group Participants” Australian Government Department of Foreign Affairs and Trade
<https://www.dfat.gov.au/publications/minisite/theaustraliagroupnet/site/en/participants.html
>.
The Australia Group “Control List of Dual-use Biological Equipment and Related Technology and Software” Australian Government Department of Foreign Affairs and Trade (20 November 2022)
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<https://www.dfat.gov.au/publications/minisite/theaustraliagroupnet/site/en/guidelines.html>.
The Australia Group “Home” Australian Government Department of Foreign Affairs and Trade
<https://www.dfat.gov.au/publications/minisite/theaustraliagroupnet/site/en/index.html>.
The Australia Group “List of Human and Animal Pathogens and Toxins for Export Control” Australian Government Department of Foreign Affairs and Trade (30 November 2022)
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The Australia Group “List of Plant Pathogens for Export Control” Australian Government Department of Foreign Affairs and Trade (30 November 2022)
<https://www.dfat.gov.au/publications/minisite/theaustraliagroupnet/site/en/plants.html>.
AZENTA “Terms and Conditions – Processing Services”
<https://www.genewiz.com/Public/Company/Policies/Terms- Conditions/?sc_device=Mobile>.
BCC Research “Synthetic Biology: Global Markets” (March 2022)
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Bioneer “Customer Focused Support from Bioneer”
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Bioneer “Healthier Future for Humanity with Genomic Technology” <https://bioneer.com/>.
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Loren Blinde “Battelle tapped for IARPA Fun GCAT program” (11 January 2018) Intelligence Community News <https://intelligencecommunitynews.com/battelle-tapped-for-iarpa-fun- gcat-program/>.
Blue Heron Biotech “Terms and Conditions” <https://blueheronbio.com/wp- content/uploads/2018/05/BHB_Terms_and_Conditions.pdf>, cl 2.
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Camena Biosciences “Camena Bioscience uses gSynth™ to synthesise a 2.7kb plasmid”
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Paul Cruickshank, Don Rassler and Kristina Hummel “A View from the CT Foxhole: Lawrence Kerr, Former Director, Office of Pandemics and Emerging Threats, Office of Global Affairs,
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<https://ctc.westpoint.edu/a-view-from-the-ct-foxhole-lawrence-kerr-former-director-office- of-pandemics-and-emerging-threats-office-of-global-affairs-u-s-department-of-health-and- human-services/>.
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James Diggans “Synthetic gene-length DNA: Evolving export control concerns” (July 2019) Bureau of Industry and Security <https://tac.bis.doc.gov/index.php/documents/public- presentations/398-twist-mtac-briefing/file>.
DNA Script “DNA Script Announces World’s First Enzymatic Synthesis of a High-Purity 200- Nucleotide Strand of DNA” (27 February 2019) <https://www.dnascript.com/press- releases/dna-script-announces-worlds-first-enzymatic-synthesis-of-a-high-purity-200- nucleotide-strand-of-dna/>.
DNA Script “DNA Script Presents Data at AGBT Confirming Functional Performance of the Company’s Enzymatic Synthesis (EDS) Technology” (1 March 2021)
<https://www.dnascript.com/press-releases/dna-script-presents-data-at-agbt-confirming- functional-performance-of-the-companys-enzymatic-synthesis-eds-technology/>.
Edinburgh Genome Foundry “Home”
<https://www.ed.ac.uk/biology/research/facilities/edinburgh-genome-foundry>.
Edinburgh Genome Foundry “Who We Are”
<https://www.ed.ac.uk/biology/research/facilities/edinburgh-genome-foundry/who-we-are>. Elegen Bio “Partnering” <https://www.elegenbio.com/company/partnering>.
Evonetix “Technology” <https://www.evonetix.com/technology/>.
Evonetix “There’s more potential diversity within DNA than there are planets in the universe”
<https://www.evonetix.com/gene-synthesis>. GenScript “Home” <https://www.genscript.com/>.
GP-write “Home” <https://engineeringbiologycenter.org/>.
Grand View Research “DNA Synthesis Market Size, Share & Trends Analysis Report By Service Type (Gene Synthesis, Oligonucleotide Synthesis), By Application (Research And Development, Therapeutics), By End-use, By Region, And Segment Forecasts, 2023 – 2030”
<https://www.grandviewresearch.com/industry-analysis/dna-synthesis-market-report>.
Margaret A Hamburg, Jaime Yassif, R Alta Charo, Hayley Severance “Taking Action to Safeguard Bioscience and Protect Against Future Global Biological Risks” (2 September 2022) American Association for the Advancement of Science (AAAS): Science and Diplomacy
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Jiahao Huang “DNA synthesizer: Why the innovation never took off” (31 July 2018) LinkedIn
The Illinois Biological Foundry for Advanced Biomanufacturing (iBioFAB) “The Illinois Biological Foundry for Advanced Biomanufacturing (iBioFAB)”
<https://www.igb.illinois.edu/iBIOFAB>.
Integrated DNA Technologies “Contact Us” <https://sg.idtdna.com/pages/about/contact-us>. Integrated DNA Technologies “Gene Synthesis - Biosecurity”
<https://sg.idtdna.com/pages/products/genes-and-gene-fragments/custom-gene-synthesis>.
International Biosecurity and Biosafety Initiative for Science “IBBIS: International Biosecurity and Biosafety Initiative for Science” <https://ibbis.bio/wp-content/uploads/2023/05/IBBIS- One-Pager-March-2023_QR-Code.pdf >.
International Biosecurity and Biosafety Initiative for Science “Our Work”
<https://ibbis.bio/our-work/>.
International Biosecurity and Biosafety Initiative for Science “IBBIS at Biosecurity Innovation and Risk Reduction Initiative Annual Meeting” (2023) <https://ibbis.bio/ibbis-at-biosecurity- innovation-and-risk-reduction-initiative-annual-meeting/>.
International Gene Synthesis Consortium “Home” <https://genesynthesisconsortium.org/>. International Gene Synthesis Consortium “Application for Membership”
<https://genesynthesisconsortium.org/wp-content/uploads/IGSCMembershipApplication11- 21-17.pdf>.
International Gene Synthesis Consortium “World’s Top Gene Synthesis Providers Establish Tough Biosecurity Screening Protocol” (19 November 2009)
<https://genesynthesisconsortium.org/wp-content/uploads/IGSC-Launch- Announcement.pdf>.
Internet Archive “Wayback Machine”
<https://web.archive.org/web/20230000000000*/https://genesynthesisconsortium.org/>.
Internet Archive “Wayback Machine” (18 February 2020)
<https://web.archive.org/web/20200218153924/https://genesynthesisconsortium.org/>.
Internet Archive “Wayback Machine” (19 February 2023)
<https://web.archive.org/web/20230219224207/https://genesynthesisconsortium.org/>.
Internet Archive “Wayback Machine” (26 October 2015)
<https://web.archive.org/web/20151026135045/https://genesynthesisconsortium.org/>.
John Hopkins Medicine “First Fully Artificial Yeast Genome Has Been Designed” (9 March 2017) John Hopkins Medicine <www.hopkinsmedicine.org>.
Gregory D Koblentz “A biotech firm made a smallpox-like virus on purpose. Nobody seems to care” (21 February 2020) Bulletin of the Atomic Scientists
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Kai Kupferschmidt “How Canadian researchers reconstituted an extinct poxvirus for $100,000 using mail-order DNA” (6 July 2017) Science <https://www.science.org/content/article/how- canadian-researchers-reconstituted-extinct-poxvirus-100000-using-mail-order-dna>.
Kai Kupferschmidt “A paper showing how to make a smallpox cousin just got published. Critics wonder why” (19 January 2018) Science
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Mary Ann Liebert “The Long and Winding Road: On Demand DNA Synthesis in High Demand” (27 July 2023) GEN Genetic Engineering & Biotechnology News
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<https://www.japaneselawtranslation.go.jp/en/laws/view/1993/en >.
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<https://ibbis.bio/our-work/>.
Jeremy Kidd “No Perfect Solutions for Market Imperfections” (2022) SSRN
<https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4254370>.
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Molecular Assemblies “Molecular Assemblies Ships to Sixth Customer Oligonucleotides Generated by Fully Enzymatic DNA Synthesis Technology” (16 May 2023)
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Molecular Assemblies “Supply Terms and Conditions” (20 September 2022)
<https://molecularassemblies.com/terms-and-conditions/>, cl 1.5.
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<https://www.un.org/en/sc/1540/national-implementation/1540-matrices.shtml>.
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