The Goldilocks Dilemma and Polycentric Governance: Risks and Regulation in Synthetic Biology

 

The Goldilocks Dilemma and Polycentric Governance: Risks and Regulation in Synthetic Biology

 

Table of Contents

 

Introduction. 2

I.         What is Synthetic Biology?. 3

A.       Risk Categories: Biosafety and Biosecurity…………………………………………………….. 6

II.       Governance of Biosafety Risks: 7

A.       What is Biosafety?………………………………………………………………………………………. 7

B.       Biosafety: Historical Development and Limits. 8

C.       Government: Existing US Regulations for Containment and Risk Assessment 10

C.       Governance: Other Biosafety Considerations. 15

III.      Governance of Biosecurity Risks: 17

A.       Introduction: Biosecurity and the Sociology of Risk. 18

B.       Polycentric Biosecurity Governance. 19

C.       Street-level Governance and the Internet………………………………………………………….. 22

A.       Federal Efforts at the International Scale. 24

B.       NSABB: Oversight, Science Advising, Interdependence……………………………….. 25

VI.      Conclusion: Goldilocks and Governance. 26

V.       Endnotes…………………………………………………………………………………………………………….. 29………

 

 

INTRODUCTION

This essay is a survey of how basic risk categories associated with synthetic biology are defined, assessed and actively managed. The inquiry is motivated by “the Goldilocks Dilemma” and the idea of complex polycentric governance. The former conveys the uncertain but necessary quest for just the right amount of synthetic biology regulation: not too much, not too little; and if possible, just the right amount.[i] The latter suggests shifting roles for states in managing network interdependence. According to the governance framework, negotiating the provision of social benefits and managing synthetic biology risks cannot be accomplished solely through formal regulations and enforcement institutions. A global knowledge system of diverse social actors at sub-national, national, and supra-national scales must perform informal norm-setting, education and outreach, and technical knowledge production.[ii] Furthermore, governments must actively collaborate in the development and execution of these complex socio-political interactions.[iii]

In Section I define synthetic biology and select two risk categories: biosafety and biosecurity.[iv] I introduce the issue of framing effects and anticipate some conclusions. Sections II and III explore each risk category in greater depth, identifying key uncertainties and points of contestation in existing and suggested regulatory frameworks, such as disputes over whether synthetic biology risks represent something completely novel or just an extension of biotechnology risks.[v]

Section II on biosafety begins with a historical introduction to biosafety and surveys the existing US regulatory framework for synthetic biology governance. Potential gaps in these frameworks, their policy implications, and current attempts at closing these gaps are discussed.[vi] Section III discusses bioterrorism, DIY biology, the role of the internet, and the use of educational outreach and science advisory roles to encourage a culture of responsibility for managing biosecurity risks.

Section IV concludes by exploring the significance of two competing risk assessment frameworks: first, the innovation moratorium regime of a March 2012 ETC Group publication, The Principles for the Oversight of Synthetic Biology, that would require “precautionary risk assessments” to justify synthetic biology innovation; and second, the 2010 Presidential Commission for the Study of Bioethical Issues, which calls for “reasonable risk assessments.” The difference between these two frameworks encapsulates the main theme of the essay: that engaging the Goldilocks Dilemma is a difficult but necessary polycentric governance issue that proceeds in a regulatory environment subject to improvement and modification in light of new knowledge and circumstances.[vii]

Throughout the essay, I hope to demonstrate to some extent what complex polycentric governance looks like, and what solutions to the Goldilocks Dilemma might require.

I.             What Is synthetic biology?

“The field of synthetic biology encompasses the design and construction of new biological parts, devices, and systems, as well as the re‐design of existing, natural biological systems for useful purposes.”[viii] Today, synthetic biology research takes place on at least five main fronts, using basic enabling technologies that have emerged from biotechnology, bioinformatics, genomics, and other fields. The five main fronts are:

1. DNA synthesis: for ‘printing’ DNA sequences, genes, genomes, and custom DNA nanostructures at increasingly low cost and high speeds.
2. The standardization school: for developing “Lego-like”[ix] functional units of DNA that can be combined in unforeseen ways to yield simplified organisms with novel properties
3. 3.      Genetic code expansion: for producing an artificially increased basic genetic language of base pairs, amino acids, and proteins
4. 4.      Synthetic genetic circuits: for discrete control over regulation of gene expression in living organisms
5. Metabolic engineering: for precisely controlling and modifying complex, multi-level homeostatic functions of existing and novel organisms[x]

2011 BCC Research statistics suggest that the global synthetic biology market was approximately US$1.1 billion in 2010, with most investment coming from the chemical and energy sectors. These forecasts anticipate a 45% annual compound growth rate for the next five years, to $10.8 billion in 2016.[xi] A 2006 ten-year projection from Beachhead Consulting anticipates a US$3.5 billion synthetic biology health care market by 2016.[xii] Despite billions in R&D investments from public and private sources, however, revenues from synthetic biology products in 2010 were only a few million dollars.[xiii] In comparison, revenues from the global biotechnology industry in 2010 were over US$80 billion, with forecasts for revenues tipping US$100 billion by 2013 and growing to US$160 billion by 2016.[xiv]

Many biotechnology firms have invested heavily in synthetic biology research in hopes of developing inexpensive techniques for producing biologics. Investment was spurred in 2010 by the US Patient Protection and Affordable Care Act, which created an accelerated approval pathway for biologics that are functionally similar to existing FDA-approved substances, regardless of the techniques utilized to produce those substances.[xv]

Framing synthetic biology as a promising extension of existing biotechnology tools and technologies implies that the risks attending its development are similar to risks that attended biotechnology’s emergence: “Placing a new name on an old technology does not create a new hazard.”[xvi] Alternatively, framing synthetic biology as a field that is fundamentally new and different from what has come before suggests that unprecedented risks are introduced, which may require new regulatory frameworks, at least, or outright bans on innovation activity until more information can be gathered for anticipating risks, at the extreme.

The history of biotechnology’s emergence and applications from the 1970s to the 1990s, such as genetically modified crops, would seem to suggest that framing the risks associated with synthetic biology innovation will significantly impacting its development in the coming decades.[xvii] At present, synthetic biology is in its very formative years of development, with most commercial investment centered in biofuels and pharmaceuticals research. Public debates about the implications of this emerging technology have not reached fever pitch, in large part because products like foodstuffs that might attract wider public attention have not been developed. Previous experience with emerging technologies suggests that these formative years provide a crucial window in which social control over the technology can be exercised.

During these formative years of synthetic biology research, it is therefore imperative to determine with technical rigor what the real risks are. Identifying and understanding the risks involved in synthetic biology is a very complex process. Crafting policies to manage risks through regulations and research guidelines is also highly complex. The basic difficulty could be termed the Goldilocks Dilemma. Too little regulation might produce unacceptable risks. Too much regulation might prevent highly desirable benefits.

I will argue that synthetic biology as it exists today is neither entirely novel nor invariably conventional. Modification of existing regulatory institutions should therefore be neither radically precautionary nor unduly lax. How much regulatory modification is warranted depends entirely on what the real risks are. So, what are the real risks?

risk categories: biosafety and biosecurity

A group of policy scholars and synthetic biologists recently commented on the environmental and social implications of the aforementioned BCC Research forecasts for the March 2012 issue of Nature:

Such a prediction conjures images of a world of ‘living factories’ filled with synthetic microbes made up of modular genetic parts. It also raises the possibility that these synthetic microorganisms could escape into the environment, perhaps in large quantities.[xviii]

As synthetic biology research expands to include a multiplicity of laboratory settings in many countries, the probability of hazardous or deadly materials unintentionally harming laboratory personnel, the environment, or the public—termed a biosafety threat—increases.[xix] (See Figure 1)

Fig 1: US and European companies, government laboratories, private research institutions, and universities conducting synthetic biology research, and policy centers examining issues surrounding synthetic biology.[xx] Innovation not depicted also takes place in Asia, Australia, Singapore, the Middle East, and South America. Proliferation of institutional labs is one source of biosafety risks. Other sources include garage labs (not depicted) and DIY community labs.

 

            There are additional risks associated with the intentional use of synthetic biology as a weapon to inflict harm, termed biosecurity threats. Misuse of research equipment, genetic materials, and technical knowledge by disgruntled lab personnel or “biohackers” without institutional affiliation are significant concerns. Much synthetic biology research, termed “dual-use research,” could be utilized for either constructive or malevolent purposes, depending upon the user. Synthetic biology research used to assist either non-state or state-sponsored criminal actors pursuing political ends is termed bioterrorism, defined as:

The unlawful use, or threatened use, of microorganisms or toxins derived from living organisms to produce death or disease in humans, animals, or plants… creat[ing] fear and/or intimidat[ing] governments or societies in the pursuit of political, religious, or ideological goals.[xxi]

            While biosafety and biosecurity threats are present in many research fields, such as biotechnology and materials science, features of synthetic biology amplify these concerns. [xxii] The basic instruments, materials, and knowledge that produce biosafety and biosecurity threats are widely available and increasingly inexpensive. For under US$1000 using eBay, anyone with a valid credit card can buy most of the necessary equipment to start a Do-it-Yourself (DIY) synthetic biology lab, including a modest DNA synthesizer, centrifuge, nutrient solutions, glass pipettes, etc.[xxiii]

Governance of biosafety and biosecurity risks requires an agile mixture of formal regulations, voluntary guidelines, education and outreach activities, and informal norm-setting practices through government, academia, civil society groups, media, and a multiplicity of publics and stakeholders. Some groups—“DIY” biologists, biohackers, and “biopunks”[xxiv] using cheap equipment to satisfy basic curiosity—may be less likely to follow applicable laws or best practices in confining and containing hazardous materials than institutionally-affiliated researchers. Specific efforts to target these innovators are currently underway, such as FBI outreach programs and DIY codes of conduct.

 

 

II.           Governance of Biosafety Risks

WHAT IS BIOSAFETY?

Biosafety is defined in the US Department of Health and Human Services’ Biosafety in Microbiological and Biomedical Laboratories (BMBL) as “the discipline addressing the safe handling and containment of infectious microorganisms and hazardous biological materials.”[xxv] The two core principles of this discipline are containment and risk assessment.

Containment aims to protect ecological health and human life, both laboratory personnel and the public. All aspects of the laboratory are viewed with biosafety in mind, from safety equipment and research materials to the clothing and training of researchers in how to handle and dispose of infectious or hazardous materials.[xxvi]  

Risk assessment concerns decision-making procedures for determining in detail what sort of laboratory environment is required for handling specific materials in a given experimental setting. A brief historical tour will, I think, illuminate exactly how powerful and crucial a discipline risk assessment is for effective synthetic biology governance.

BIOSAFETY: HISTORICAL DEVELOPMENT AND LIMITATIONS

Biosafety as a technical discipline carries an 80-year legacy of increasingly sophisticated empirical observations and decision procedures applied to decision contexts of significant complexity and uncertainty. As described in BMBL’s introduction, hundreds of people died from Laboratory-Associated Infections (LAIs) from the 1930-1970s.[xxvii] The process of determining exactly 1) which biosafety practices performed in the presence of 2) which specific hazardous materials eliminated 3) which harmful effects required considerable vigilance. Biosafety in Microbiological and Biomedical Laboratories organizes 80 years-worth of hazardous microorganisms, their corresponding risk values (on a scale of 1 to 4), and the necessary laboratory biosafety profile (on a scale of 1 to 4) required to keep humans and the environment safe from the properties of each substance. Risk assessment is thus a rather noble knowledge enterprise. The tools of biosafety—four biosafety levels, four risk criteria, select agent summaries, and a comparatively improved laboratory culture of responsibility—actively disperse throughout the regulatory systems of most nations.[xxviii]

The history of biosafety guidelines demonstrates that contemporary regulatory frameworks are cumulative. Insofar as biosafety is an ongoing struggle against accidents, mental lapses, and human err, regulatory frameworks designed to deliver biosafety protections should be understood as ongoing projects in which, as synthetic biology thought-leader Drew Endy puts it, “accidents will happen.”[xxix] Because biosafety is cumulative, when risk assessors want to determine what level of biosafety is appropriate for a particular synthetic biology research program, the cumulative knowledge of known hazardous microorganisms will be consulted straightaway. However, what makes synthetic biology potentially unique is the prospect of eventually engineering microorganisms that bear little or no resemblance to the select agents in the biosafety databases of the NIH and other federal agencies. Alternatively, chimeric organisms with DNA from potentially hundreds of harmless species could combine in unexpected ways to produce novel hazardous interactions. Rodemeyer 2009 and Bar-Yam 2012 suggest such cases will emerge as synthetic biologists develop deeper understanding of cells as engineering platforms. Research programs to address these concerns and adapt risk assessment tools are thus quite important.

The December 2010 publication of 18 policy recommendations from the US Presidential Commission for the Study of Bioethical Issues, titled New Directions: The Ethics of Synthetic Biology and Emerging Technologies, requires 7 additional reports to be published no later than June 2012 on topics including analysis of potential threats from novel organisms or chimeric organisms (Recommendation 5: Risk Assessment Review and Field Release Gap Analysis). To conduct such analysis, first the existing US regulatory framework has to be understood and any gaps in agency risk assessment procedures identified. The relevant agencies include the NIH, EPA, FDA, USDA.[xxx] Specifically, the question is how to ensure adequate risk assessment tools for complex synthetic genetic materials in the absence of a precedent in the cumulative biosafety record of mankind. Rather than viewing this process as a radical departure in the history of the biosafety discipline, a historical perspective I think suggests that biosafety has always involved adapting to the use of substances with complex and unknown properties.

GOVERNMENT: EXISTING U.S. REGULATIONS FOR CONTAINMENT AND RISK ASSESSMENT

National Institutes of Health

In 1986 the US Office of Science and Technology Policy published the Coordinated Framework for Regulation of Biotechnology, which attempted to comprehensively regulate the release of recombinant DNA (rDNA) into the environment.[xxxi] Under the Coordinated Framework, rDNA was framed as presenting no additional risks compared to traditional genetic engineering techniques such as chemical mutagenesis or nuclear irradiation in plant breeding (both unregulated activities.) To some observers this was a policy contradiction: why regulate something that is no more risky than activities that are unregulated? In fact, the Coordinated Framework’s portrayal of rDNA as not qualitatively different from existing technologies masked an underlying uncertainty as the actual risks involved. Thus, what seemed like a policy contradiction to some was actually a sophisticated approach to actively engaging uncertainty and managing a multiplicity of risk perceptions and appraisals of potential benefit. The Coordinated Framework utilized existing agencies and regulations with minor modifications to manage whatever biosafety risks there might turn out to be.

The 2010 Presidential Commission for the Study of Bioethical Issues concluded that synthetic biology poses no additional risks at the present time compared to rDNA technologies. Just as in 1986, this framing demonstrates coexisting perceptions of significant potential benefits and the uncertain mix of perceived risks and actual risks that presently obtain or might arise

The 1986 Coordinated Framework functions as the basis for synthetic biology regulation in the US. The NIH Guidelines for Research Involving Recombinant DNA Molecules are the first line of defense for biosafety, covering laboratory tests that utilize rDNA technologies.[xxxii] These guidelines are rooted in the same containment and risk assessment practices as the BMBL. The NIH Guidelines add a risk assessment bureaucracy that includes the NIH Director (for approving high risk research), a Recombinant DNA Advisory Committee (RAC) and Institutional Biosafety Committees (IBCs). RAC is a federal advisory committee housed within NIH’s Office of Biotechnology Assessment whose task is to continually advise the NIH on technical matters and social, ethical, and legal implications of rDNA and synthetic biology technologies. IBCs are the ground-level authorities for implementing and managing the NIH Guidelines. IBCs include at least 5 qualified experts or risk assessors, at least two from outside academia; an IBC must be established in each institution receiving NIH funds.

Because the NIH is not a regulatory agency, IBCs have a significant responsibility to self-govern their research activities and self-report biosafety breaches. The NIH lacks a robust capacity (resources, personnel, and statutory authority) to monitor and enforce its Guidelines, although monitoring does take place. Some observers have suggested that laboratories may have incentives to cover-up laboratory breaches of the NIH Guidelines, as penalties can include loss of NIH funding, not to mention increased public scrutiny. NIH Guidelines have been voluntarily adopted by many industries and by other federal agencies, but laboratories not receiving NIH funds are not obligated to follow the Guidelines.[xxxiii]

There are good reasons to think the NIH Guidelines are presently capable of regulating synthetic biology and providing adequate biosafety protections with only slight modifications and perhaps increased resources for monitoring and enforcement. Researchers are currently producing what Rodemeyer 2009 terms “first-generation” synthetic biology products, from biofuels to vaccines. Up to 95% of synthetic biology research to date has involved recombining naturally-occurring genetic materials rather than synthesizing novel repertoires of DNA sequences, gene circuits, or metabolic pathways.[xxxiv]

However, Bar-Yam 2012 makes clear that anticipated developments in bioengineering capacities are likely to produce microorganisms that do not clearly fit within NIH Guidelines or the larger Coordinated Framework. [xxxv] IBCs tasked with conducting risk assessments have a cumulative set of risk characteristics, select agents, and inferences from comparable chemical properties to draw upon. In response to the possibility of chimera organisms composed of DNA strands from hundreds of different species, for example, an NIH RAC Biosafety Working Group recently altered NIH Guidelines to establish a modified risk assessment framework. Under this arrangement, IBCs will focus on two levels of analysis: source DNA sequences will be assigned to one of four risk groups, and functional attributes of the chimera will be categorized. The highest risk group of any source DNA sequence will determine what level of containment is required.[xxxvi]

The variety of expertise required to make these determinations places tremendous responsibility on each institution’s IBC. Synthetic biologists themselves are not sure whether new experiments will produce pathogenicity, for example, from combining non-pathogenic materials. Emergent properties can arise unexpectedly from combinations of materials that in themselves are unproblematic.

The same uncertainties that attend laboratory oversight attend each stage of the development of synthetic biology products, especially field tests. The EPA, USDA, and FDA regulate “the use and commercial production of genetically modified microbes, plants, and food and drugs.”[xxxvii] Each agency has its own risk assessment styles to secure biosafety and promote innovation.

FDA

The FDA regulates food additives, human and animal drugs, biologics, medicines, and medical devices, requiring extensive field testing, epidemiological studies, and other pre-market risk assessments. The FDA’s 1938 Federal Food and Drug and Cosmetic Act (FDCA) must approve any new manufacturing processes for pharmaceuticals, and no drug, biologic, or medical device may be sold without prior FDA approval. As mentioned previously, some market forecasters anticipate a US$3.5 billion synthetic biology impact in the health care sector by 2016. Companies like Life Technologies have reportedly placed US$100 million annually in synthetic biology research partnerships for pharmaceutical development.[xxxviii] The 2010 US Patient Protection and Affordable Care Act created an accelerated approval pathway for biologics that are functionally similar to existing FDA-approved substances, suggesting that some applications of synthetic biology may not face new regulatory barriers.[xxxix]

USDA

The USDA regulates plant and animal pests, with synthetic biology research covered by the Animal and Plant Health Inspection Service (APHIS). APHIS functions in biotechnology research to cover potential plant pests; in regards to the increased capacity of synthetic biologists to engineer microorganisms with entirely novel genetic materials, APHIS also regulates “unclassified organisms and/or organisms whose classification is unknown”[xl] In order to approve field testing of synthetic microorganisms, APHIS will require researchers to submit information on physical structure, environmental impact, potential invasiveness, and physiological impacts on other organisms. APHIS does not require information on potential human health risks. [xli] In some cases APHIS can require a full Environmental Impact Assessment (EIS) under the authority of the 1965 National Environmental Protection Act (NEPA). Furthermore, if the developer cannot provide adequate information, APHIS typically denies requests by default.

Meeting APHIS requirements may be difficult for synthetic biology researchers as each of the five main research fronts advance and begin to converge.[xlii] Dana et al 2012 suggests four key uncertainties that need to be researched in order to generate adequate risk assessments in the regulatory system.[xliii] First, natural and synthetic organisms will have structural differences, and it is not clear how these structures will interact in a non-contained environment. Second, bioengineered microbes have uncertain survivability in natural ecosystems. Some scientists suggest that engineered genetic components cannot outcompete four billion years of evolution, suggesting minimal risk. Other scientists note that engineered microbes could be designed to lay dormant for many years in a host environment. Controlled, long-term experiments are required to assess the impacts of such microbes on microbiomes, plants and animals. Third, synthetic microorganisms could adapt opportunistically to new ecological niches. This could happen in a short span of time. Fourth, low-level gene transfer from synthetic microorganisms to natural systems is quite likely. “Microorganisms are known for their ability to exchange genetic material with other organisms or to take up free DNA from the environment.”[xliv]

Paradoxically, the sort of long-term research called for by Dana et al. 2012 would seem to require contained field tests—precisely the activity that might be unacceptably risky! This is a situation where governance, trust, and flexibility are more important than strict interpretation of regulations. Dana et al. 2012 recommends a US$20-40 million research program over 10 years designed to conduct these long-term experiments, allowing government to develop new risk assessment tools for APHIS and other regulatory agencies based upon data from actual trials rather than computer simulations or guesswork.

The 10 year timeline is tolerable precisely because the general consensus of synthetic biologists is that completely novel synthetic microorganisms cannot currently be constructed. As one practitioner has stated, “We don’t even understand e. coli yet.” Rodemeyer separates “first generation” synthetic biology products best characterized as semi-synthetic biotechnology from the kinds of completely synthetic microorganisms that might be produced in coming decades (to say nothing of higher-order synthetic organisms like plants or animals). First generation synthetic biology products, on this view, will continue to fit comfortably within existing regulatory frameworks, perhaps with slight modifications. However, risk assessment tools will be forced to co-evolve over time with more sophisticated research, and procrastination on the regulatory front may jeopardize biosafety.[xlv] This regulatory adjustment process is another manifestation of the Goldilocks Dilemma: seeking just the right amount of regulation at just the right time to ensure biosafety, while allowing synthetic biology research to continue responsibly without undue constraints.

EPA

The EPA covers pesticides and “new chemical substances.”  The Toxic Substances Control Act (TSCA) functions in the Coordinated Framework as a catch-all for any chemical substances that are not covered by other regulations. Recombinant DNA and synthetic microorganisms are/will be regulated as “new chemical substances.” Under EPA regulations, synthetic biology field tests require researchers to submit either a Microbial Commercial Activity Notice (MCAN) or, for non-contained field tests, a TSCA Environmental Release Application (TERA) within 60 days of a proposed field trial. MCANs require information on ecological characteristics of experimental substances, by-products, and data on potential health and environmental impacts. However, it is TSCA and not the developer who is responsible for proving potential biosafety hazards. As a result, developers are not required to conduct years of detailed preliminary experiments to provide this information, as in the risk assessments of agencies like the FDA. Developers only need to provide information that is “easily accessible.” As of 2007, only one-third of MCANs included test data on the chemical properties of experimental substances, and only 15% of these provided data on potential human health impacts.[xlvi] Between 1997 and 2009, the EPA received only 16 MCANs. In the absence of easily accessible data, EPA relies upon computer models to assess the likely environmental and human health impacts of substances.

If the EPA cannot determine significant risks are present, the developer may proceed to market with the product, unless another agency has jurisdiction over the product. This poses some potential problems for synthetic biology related to biosafety. As discussed previously, synthetic microorganisms in the future may not have predictable dynamics, and may exhibit emergent properties in the environment. Computer models alone may not provide sufficient predictive power. In addition, some synthetic materials may not have clear ecological characteristics, health or environmental impacts. As the field progresses further beyond the ken of the cumulative scientific knowledge of mankind, gaps in the risk assessment process for field testing may widen. The US Presidential Commission for the Study of Bioethical Issues has called for a white paper on this topic, which is due for publishing by the end of June 2012.[xlvii] Potential policy recommendations include a requirement for contained field tests only until such time as better data are available for determining whether non-contained field tests, which entail low-level gene transfer to the environment, cross a threshold of acceptable risk. In such case, TERAs, which are required for non-contained field tests, would not be accepted for synthetic biology research.

If non-contained field tests are prohibited for sufficiently advanced synthetic microorganisms—and this is a line that has yet to be established—the US government will face several problems. First, internal to the bureaucracy, gaps do in fact exist in the risk assessments of the various agencies. For example, non-commercial field tests designed for basic research purposes are currently exempt from EPA and NIH oversight. APHIS is the likely agency to cover field trials and environmental release of synthetic organisms under the “non-classified organisms” category, but this has not been made explicit in the regulations themselves.

GOVERNANCE: OTHER BIOSAFETY CONSIDERATIONS

Beyond the bureaucracy, biosafety threats could arise from other nations, from citizen scientists, or from activists within the research community itself. Synthetic biology is unquestionably an international phenomenon; given the potential variety of risk assessment strategies that attend different place-based and culturally distinct knowledge production systems, a US policy of containment for field testing may not persuade other nations to adopt similar regulations. This is a case when polycentric governance is required over and above the formal activities of international relations. If good evidence emerges within the global research community that synthetic microorganisms can both survive and alter environments and human health, global norm-setting would require both formal and informal dynamics. By the same token, attempts at formal regulation in the absence of clear evidence justifying a policy of strict containment would likely produce backlash from various social actors.

When the 1986 Coordinated Framework was first implemented, establishing the risk assessment bureaucracies discussed previously, contestation over applying the legal framework immediately arose. Advanced Genetic Sciences, Inc. tested an experimental microbe on a strawberry patch it placed “on the roof of its corporate headquarters,” leading to a definitive lawsuit hinging on the question, How much risk is acceptable, and whose assessments are sufficient to determine the nature and extent of risks?[xlviii] Next, in 1987 a plant pathologist injected elm trees in Montana with genetically engineered bacteria, claiming that his violation of the Coordinated Framework’s regulation of environmental release was an act of “civil disobedience” against an “absurd” regulatory framework.[xlix] Today in the field of synthetic biology, “biopunks” have vowed to actively resist any laws that unfairly restrict intellectual freedom.[l] There is thus a possibility, backed by historical precedent, that strict regulation of non-contained field tests could provoke non-contained field tests, or outright environmental release of synthetic organisms.[li]

As Robert Carlson and others testifying before the Presidential Commission for the Study of Bioethical Issues remarked, “the cat is already out of the bag” and synthetic biology research cannot feasibly be prohibited. Governance of biosafety risks will require polycentric governance among a variety of social actors across academic disciplines and national boundaries. US regulatory frameworks are one key aspect of governance, but not the only.[lii]

In conclusion, I have provided a definition of biosafety, a historical exploration of its significance as a cumulative social process, a survey of the US regulatory framework for biosafety and a discussion of potential gaps in these regulatory frameworks. Polycentric governance seeking to solve the Goldilocks dilemma of just the right amount of regulation is, I think, the correct approach to governance of biosafety risks. Governance is an on-going process subject to contestation involving a variety of social actors and regulatory systems. If formal state authority is not thorough and flexible, backlash is likely to result. I have identified several positive signs that governance efforts are robust and committed to flexibility. As with most recommendations, I anticipate the need for continual reappraisal of the synthetic biology innovation and regulatory system at national and international scales, as well as a variety of informal norm-setting activities within and across local, national, and international innovation systems.

III. governance of Biosecurity risks

The thing about biosecurity that is really important to consider is that there is really no one magic bullet. It’s really a suite of solutions. You need technical solutions, meaning you have to actually be able to detect biological agents, respond to them, and deliver the therapeutic that is needed. You also need social solutions, to minimize the number of people who choose to misapply biological technology….We need to redouble our investments in cultural engineering, if you will.[liii] – Drew Endy

 

INTRODUCTION: BIOSECURITY AND THE SOCIOLOGY OF RISK

 

In November 1969, President Richard Nixon announced that the United States was unilaterally dismantling its offensive biological weapons program. At the time of this announcement, the US was spending US$300 million annually on R&D and manufacture of offensive biological weapons (roughly US$1.5 billion in 2012.)[liv] Nixon’s National Security Decisions 35 (November 1969, microorganisms) and 44 (February 1970, toxins) formally declared his policy intentions. In 1972 Nixon signed an Executive Order that formally terminated the program.[lv] Endy 2007 identifies several cogent arguments that grounded this policy decision: first, biological weapons could not be considered ‘strategic’ weapons because their spread could not be controlled; second, the US already had enough weapons of other kinds (i.e. nuclear) to deter an offensive attack from rival states; and third, because the US had no defense against offensive biological weapons attacks, the best defense against attack was to remove biological weapons from the realm of permissible weapons by convention. In 1975 the Biological Weapons Convention was ratified internationally. [lvi]

There are many countries that have made no such promise to dismantle offensive bioweapons programs. For example, when Secretary of Defense Leon Panetta testified before Congress on the present domestic conflict in Syria, Panetta stated that intervening in the Syrian government’s brutal repression was imprudent due to significant stockpiles of offensive biological weapons possessed by the Syrian regime. If international military forces targeted the regime, said Panetta, those biological weapons could wind up in the hands of a militarized regime far more dangerous than Bashar al-Assad. At least he can be trusted not to kill millions of people with pathogenic microbes.[lvii]

Unlike nuclear weapons, nation states are not the only entities with access to the tools required to construct offensive biological weapons. In the past 40 years, the nature of military conflict has shifted decisively toward asymmetrical, guerilla warfare. In asymmetrical war, states are vulnerable to destabilization from non-state actors through inexpensive, high-impact military actions often designed to manipulate public attitudes.

Because inexpensive equipment and materials can be misused to inflict enormous harms on large populations, the US military is compelled to take biosecurity threats from biotechnology and synthetic biology quite seriously. For as little as a few thousand dollars, anyone with sufficient drive could piece together a deadly pathogen in a garage lab and produce it in large quantities. Even more troubling, a disgruntled but bright university student with no real political agenda could sneak a pathogen out of a lab and release it on campus or a crowded plaza in large quantities. Bizarre cults such as the Japanese group Aum Shinrikyo (known today as Aleph) have in the past released bioweapons in crowded subway stations.[lviii]

The 2001 US anthrax attacks proved that even credentialed laboratory personnel can utilize defensive bioweapons research for criminal purposes. Suggestions are frequently made that terrorist groups like Al-Qaeda actively seek biological weapons (along with nuclear and chemical weapons) to wage asymmetrical war. Most recently, journalists and scholars have suggested that bioweapons could be manufactured within the DIY community, using the inexpensive tools of DNA synthesis. This is the new risk landscape.[lix]

The basic reality of biodefense is just this: “You have to be able to actually detect biological agents, respond to them, and deliver the therapeutic that is needed.” This is the technical side of biosecurity. A parallel process of “cultural engineering” is also a basic reality. A less troubling and more accurate word for “cultural engineering” would be polycentric governance.    

In what follows I will consider three interlocking patterns of biosecurity governance: education and outreach activities, oversight models, and science advisory institutions. In keeping with the primary motivation to portray polycentric governance as a necessary structure for managing the Goldilocks Dilemma, the inquiry expands to include a wide set of institutional actors whose role in forming biosecurity shared goals across disciplinary, national, and social borders is significant.

POLYCENTRIC BIOSECURITY GOVERNANCE

At the iGEM competition, the FBI has established a booth as part of its bottom-up approach to biosecurity regulation, the Biological Sciences Outreach Program.[lx] Students are informed that their ambitious pursuit of legitimate solutions to environmental and health problems through synthetic biology is really dual-use research. The man typically informing iGEM students is Edward H. You, Supervisory Special Agent in Countermeasures Unit 1 of the FBI Weapons of Mass Destruction Directorate. You has become something of an icon in the DIY community, known for interfacing with community laboratories and actually participating in DIY biology experiments (at once a sign of good faith and an act of reconnaissance.) You speaks frankly with students and practitioners about the limited capacity of government institutions to protect ecosystems and human populations from the deliberate misuse of rapid advances in synthetic biology enabling technologies. Only an international culture of responsibility developed, maintained, and improved upon by practitioners can save the world from determined terrorists, or so the narrative goes.

The FBI’s Biological Sciences Outreach Program is targeted at academics, students, citizen scientists, and other publics. A series of FBI Biosecurity Workshops have been held through this program at various universities nationwide. These bottom-up approaches complement other FBI strategies that target industries wielding the immense power of DNA synthesis.

The FBI Tripwire Initiative was developed in 2007 to influence a culture of responsibility in the DNA synthesis industry. The Tripwire Initiative has functioned as a reporting mechanism for synthesis companies who receive orders from customers requesting DNA strands that could be used for nefarious purposes.  The previously mentioned FBI Weapons of Mass Destruction Directorate places a WMD Coordinator at each of the FBI’s 56 field offices. Synthesis companies who receive suspect orders can alert a WMD Coordinator and trigger an investigation. These Coordinators also perform a two-way communication function between industry and US regulatory agencies. The Department of Health and Human Services (NIH & CDC), USDA, FEMA, DoD, EPA, Department of Commerce, and other agencies utilize the FBI’s communication network to provide DNA synthesis companies with access to up-to-date information on all aspects of hazardous DNA sequences. [lxi]

The Tripwire Initiative functions alongside federal initiatives for promoting DNA synthesis best practices through the November 2009 DHHS Screening Framework Guidance for Synthetic Double-Stranded DNA Providers, a voluntary agreement designed to establish a three-tier oversight structure for DNA synthesis firms. The Screening Framework includes customer screening recommendations, sequence screening recommendations, and government notification recommendations.

Government agencies are not the only social actors demonstrating concern with regulating DNA synthesis through promotion of best practices. Collaborative industry-academia partnerships and industry-industry self-regulation dynamics have actively pursued best practices and responsible innovation to manage biosecurity risks.

In 2006, before the FBI Tripwire Initiative commenced and prior to the DHHS Guidelines, the international Synthetic Biology 2.0 conference sought to draft codes of conduct for governing DNA synthesis companies. Researchers considered boycotting companies that refused to adopt best practices, circulating lists of DNA sequences posing biosecurity risks, and self-policing the research community by reporting scientists suspected of nefarious intent. Efforts to formalize these codes in 2007 failed for several reasons: some scientists viewed self-regulation as restricting intellectual freedom, and some external observers viewed self-regulation as insufficient to ensure biosecurity.[lxii]

The FBI Tripwire Initiative can be viewed in this context as a response to a widely discussed governance challenge developed over time by concerned practitioners across academic, industry, and government borders.

Several industry-industry collaborations also contributed to a culture of responsibility for managing the biosecurity risks of DNA synthesis technologies. In 2006, gene synthesis companies self-organized the International Consortium for Polynucleotide Synthesis, Inc, a non-profit organization for establishing best practices and managing biosecurity risks.[lxiii] In April 2008, 30 international biotechnology firms active in synthetic biology formed the International Association for Synthetic Biology (IASB) to produce and circulate best practices throughout the gene synthesis industry. In November 2009, IASB published The IASB Code of Conduct for Best Practices in Gene Synthesis in collaboration with the University of California’s Goldman School of Public Policy.

Companies that endorse the Code agree to keep records of suspicious inquiries and immediately alert national governments of suspected illegal activities. All DNA synthesis orders are screened against GENBANK, NIH’s online database of all publically available DNA sequences. GENBANK is updated every two months.[lxiv] Orders are further reviewed against Australia Group “biological dual-use organisms,” the US National Select Agent Registry, and national lists in the host countries of each firm.  Companies pledge to follow the recommendations of a Technical Experts Group on Biosecurity which further compiles and update lists of problematic DNA sequences.[lxv] 

These government, industry, and academic efforts to manage biosecurity risks demonstrate clearly what polycentric governance through socio-political actions looks like in practice. International, national, and sub-national efforts are required to produce complex, self-organizing biosecurity governance regimes. Furthermore, these networks must be linked through communication networks that allow the best available knowledge to circulate for timely consumption.

STREET-LEVEL GOVERNANCE AND THE INTERNET

At the sub-national level where the FBI’s Biological Sciences Outreach Program functions, DIY practitioners who suspect nefarious activity in the amateur synthetic biology community are encouraged to alert an FBI WMD Coordinator, anonymously if necessary. Edward You’s collaborative engagement with the DIY community thus serves a vital street-level governance function. By maintaining a presence in the community, the FBI influences the production, validation, and circulation of knowledge. Practitioners who might not otherwise be attentive to biosecurity risks are made aware of the FBI’s national security concerns. The FBI’s friendly and collaborative approach decreases the likelihood that a revolutionary ethos will develop in the DIY community reminiscent of violent student movements from the 1960s, which could drastically increase biosecurity threats.

Additional street-level governance patterns with biosecurity implications take place through the internet, which is a massively important feature of the synthetic biology innovation system.

            The internet is one of the most important tools for developing and maintaining cultures of responsibility. Examples of online governance tools in the synthetic biology community include: blogs, newsletters, document databases, news forums, multimedia caches of radio interviews and academic conferences, open courseware from MIT, UC Berkeley, etc., online DNA sequence databases (openwetware.org), the Registry of Standardized Biological Parts online ordering form, and social networking sites for organizing “bio-hackerspaces,” community labs, and meet-ups. Each of these tools can be utilized for developing shared goals and coordinated actions in the research community. Likewise, the frequent presence of biosecurity professionals and FBI agents interacting with these governance tools indicates that even the internet is a “dual-use” technology.[lxvi]  

Through the internet tens of thousands of synthetic biology practitioners and onlookers—academics, students, amateurs, artists, journalists, intellectuals, humanists, trans-humanists, atheists, Republicans, etc.— develop opinions on the key synthetic biology risk issues: intellectual property regimes, regulatory frameworks, socioeconomic impacts, biosafety, and biosecurity. Through websites such as Columbia University’s Synthetic Biology Project, citizens can literally keep track of government promises and plans of action. The internet provides an unprecedented tool for citizen oversight of government.

As synthetic biology progresses, efforts to utilize the internet for polycentric governance and socio-political interactions will almost certainly increase in sophistication and scope. Just as the development of synthetic biology applications cannot be foreseen but only dimly anticipated, so to with applications of the internet for synthetic biology governance.

At international biosecurity conferences and board meetings, policy recommendations typically include reforms of Science, Technology, Engineering and Mathematics (STEM) curricula for K-12 and university education. Risks from emerging technologies suggest that ethical training and humanistic values should be incorporated into the socialization process for tomorrow’s synthetic biology innovators. Increasingly, these conferences and board meetings are demonstrating awareness of the internet as a means for supplementing these policy recommendations at reduced cost.

For professional bioengineers and biosecurity professionals, there are international online biosecurity resources and tool kits translated into many languages. For policy scholars and social scientists there are online regional biosecurity surveys. As an education and outreach tool, the internet is unparalleled in its cost effectiveness and potential impacts looking forward.

It is possible that synthetic biology students in China or other countries with significant internet censorship might not have access to some of these internet tools, despite commitments to the free flow of scientific knowledge. I have not seen research conducted in this area. Zhang 2011 discusses Chinese media portrayals of synthetic biology—typically very positive—but does not discuss whether a range of opinions are available to interested parties through the internet.

If the Chinese government were planning to construct a series of biodefense labs in regions prone to disastrous earthquakes, for example, the internet could act as a resource for citizens to both become aware of this policy and elicit a rationale from government officials. This hypothetical situation indicates more broadly how the internet could increase government accountability, improve science and society interactions, and increase long-term biosecurity. These last comments connect street-level or bottom-up biosecurity governance patterns to international contexts via the internet.

FEDERAL EFFORTS AT THE INTERNATIONAL SCALE

There are many education and outreach programs that place at this international scale. For example, the US Department of State’s Biosecurity Engagement Program (BEP) was designed to coordinate international pathogen security and biosafety projects, training for lab personnel and policymakers, infectious disease surveillance programs, and global biosecurity risk management programs.[lxvii] BEP interfaces with biosafety and biosecurity programs through the World Health Organization (WHO), Food and Agriculture Organization, and World Organization for Animal Health.

BEP sponsors a variety of international biosecurity workshops designed to facilitate international governance. In 2011, BEP convened experts from 32 countries in Istanbul to anticipate biosecurity challenges that might result from increasing numbers of high-containment biological laboratories (US: BSL3 and BSL4). Laboratories were considered complex systems with architectural, environmental, and social components. Lab directors from Brazil, Pakistan, Russia, Turkey, Sweden, and other countries discusses specific technical and social tensions involved in the design, construction, and operation of high-containment labs that encourage a culture of responsibility.[lxviii]

Such international efforts are of vital importance if synthetic biology is considered a global knowledge and innovation enterprise. Without professional standards for the construction and operation of research facilities using hazardous substances, and without international communication networks for sharing hazardous chemical agent lists and other relevant information, mankind’s legacy of cumulative biosafety knowledge would be wasted and biosecurity risks would proliferate. Education and outreach programs take place worldwide in dozens of languages, from street-level internet discourse to supra-national meta-analysis of high-containment laboratory construction.

NSABB: OVERSIGHT, SCIENCE ADVISING, INTERDEPENDENCE

While there are many instances of science advisory institutions contributing to a culture of responsibility and a furtherance of technical knowledge of biosecurity risk governance[lxix], the US National Science Advisory Board for Biosecurity (NSABB) provides a good example of how science advisory institutions function in the formation of incremental advances toward solutions of the Goldilocks Dilemma. NSABB has over a six year period developed recommendations for oversight models designed to govern individual laboratories and research programs, with cumulative effects that cover much of the US synthetic biology innovation system.

            NSABB was established by the Department of Health and Human Services and is administered by the Office of Biotechnology Assessment. NSABB has 25 voting members and 18 ex officio members from various government agencies. Each of these members has expertise in some area of the life sciences relevant to assessing “dual-use research of concern.” All members are appointed by the Secretary of DHHS for the purpose of advising the United States Government on matters of life science, dual use research, and biosecurity. In keeping with the NIH mandate to regulate laboratory research rather than field tests and environmental release, NSABB’s focus is to advise the Executive branch on national policies related to assessing biosecurity risks and dual-use research of concern prior to, during, and after laboratory research program activities.[lxx]

            In 2006, 2008, and 2010 NSABB released white papers formulating federal oversight policies for assessing and managing risks arising from dual-use research. The April 2010 Addressing Biosecurity Concerns Related to Synthetic Biology publication claims that existing NIH Guidelines, USDA Select Agents regulations, and other agency regulations are “more than adequate” to address biosafety and biosecurity concerns arising from synthetic biology research within institutional venues. However, NSABB sees oversight gaps for research conducted by non-biologists without adequate biosafety training and amateur biologists operating in non-institutional research settings.

“Accountability for high-consequence biological agents and toxins, and critical relevant biological materials and information” is a key feature of the National Science Advisory Board for Biosecurity (NSABB)’s definition of biosecurity. NSABB’s basic policy dilemma is actually a governance dilemma: governments and government-funded labs are not the only entities responsible for protecting, controlling, and providing accountability for dual-use synthetic biology research; and yet, NSABB is not confident that industry and non-institutional DIY biologists are capable of providing biosecurity.

The NSABB’s proposed oversight framework acknowledges this shared responsibility by recommending education and outreach activities in addition to improved risk assessment tools for government-funded research.

NSABB’s reports corroborate Drew Endy’s view that there is “no one silver bullet” solution that will increase biosecurity. Both technical and socio-political approaches are required. In this section I have explored socio-political interactions that demonstrate the irreducible complexity of biosecurity risk management at multiple scales. These governance dynamics co-evolve with the regulatory frameworks and biosafety practices considered in Section I. The synthetic biology innovation system encompasses all of these interactions and more.

Policy recommendations from government agencies and civil society groups must be designed to function within this complex governance environment.    

IV.        Conclusion: GOLDILOCKS, GOVERNANCE

A much-cited March 2012 ETC Group report endorsed by a global coalition of over one hundred civil society groups recommends an immediate global moratorium on all synthetic biology innovation until long-term “precautionary risk assessments” can be conducted prior to field testing of synthetic microorganism. The report argues that extreme environmental, economic, biological, and societal harms might result from field testing, environmental release, and commercial synthetic biology innovations. The ETC Group’s position is “precautionary” risk assessments cannot currently be produced due to fundamental uncertainties and technical ignorance about exactly how synthetic microorganisms will function if released into the environment, inhaled by humans, or ingested by animals.[lxxi]

In contrast to the ETC Group’s “precautionary risk assessments,” the Presidential Commission for the Study of Bioethical Issues frequently situates its 18 policy recommendations in a conceptual framework that seeks to develop “reasonable risk assessments” that can be conducted prior to field testing or environmental release.

What is the relationship between ‘precautionary’ and ‘reasonable’ risk assessment? Both the ETC Group and the PCSBI acknowledge some degree of technical ignorance about biosafety and biosecurity risks. The ETC Group, however, places an extraordinary burden of proof on governments and researchers to comprehensively establish whether synthetic biology poses environmental, human health, or socioeconomic risks. If ignorance and uncertainty as to the possible risks cannot be absolved by comprehensive risk assessments, a precautionary risk assessment would require governments to prohibit any and all field testing and commercialization of synthetic biology products.

The basis of this precautionary risk assessment is the Precautionary Principle (PP), which could be summed up by the phrase “better safe than sorry.”[lxxii] On this approach to risk management, only “fully established” scientific analyses demonstrating biosafety can justify allowing emerging technologies to proceed from R&D to commercial products. If risk assessors cannot fully establish the safety of emerging technologies, PP requires governments to prohibit innovation.

It is not clear from the version of PP utilized by the ETC Group what criteria “full and inclusive” risk assessments should meet to demonstrate safety. Due to the uncertain properties of the fully-synthetic microorganisms anticipated in the future, it is likely that any risk assessments conducted today would be unable to fully and inclusively demonstrate the safety of these materials. A precautionary risk assessment would thus force policymakers, by default, to prohibit even contained field tests, due to the possibility of low-level gene transfer or airborne drift.

In terms of the Goldilocks Dilemma, precautionary risk assessments will lead to too much regulation. A full and complete scientific analysis of the automobile, for example, would include a proliferation of possible safety hazards, from chemical emissions and pollution to increased risk of personal injury. Would a precautionary risk assessment then require an immediate global moratorium on vehicle manufacture?

By contrast, the PCSBI’s stated goal is to develop “reasonable risk assessment” tools for regulating synthetic biology field tests and environmental release. The PCSBI acknowledges that uncertainties are pervasive and that experts are still quite ignorant of the actual risks that might attend non-contained field tests and environmental release of synthetic microorganisms. Confronting these uncertainties requires a concerted effort to develop both technical expertise and effective communication with professional communities, amateur practitioners, and the public. PCSBI mandates that white papers identifying significant obstacles to producing reasonable risk assessments be published by June 2012.

Many scholars have noted that in order to understand how field tests or environmental release of synthetic microorganisms might affect the natural microbiome, plants, and animals, long-term and isolated field tests need to be conducted. From a precautionary perspective this is self-contradictory and duplicitous. However, it is true. There is simply no way of getting around the need to experiment with isolated field tests in order to understand the risks that attend field tests. The task, then, is to develop these exploratory risk assessments in a responsible way. As any biosafety expert would say, containment is very important. But not too much containment, as this produces laboratory conditions that do not allow a realistic portrayal of how synthetic microorganisms will interact with the environment. Not too much, not too little; and if possible, just right. That is the policy prescription for reasonable risk assessment. It is the same Goldilocks Dilemma that presents itself in all aspects of synthetic biology risk and regulation.

What remains realistic is the expectation that over

time research in synthetic biology may lead to new products for clean energy, pollution control, and more affordable agricultural products, vaccines, and other medicines. The Commission therefore focused on the measures needed to assure the public that these efforts proceed with appropriate attention to social, environmental, and ethical risks.[lxxiii]

Reasonable risk assessment is a more adequate approach to synthetic biology regulation than precautionary risk assessment. However, reasonable risk assessment also acknowledges irreducible uncertainty. For this reason, polycentric governance is crucial for producing both technical knowledge and cultural communications across academic disciplines, industries, civil society groups, government agencies, media outlets, and various publics at sub-national, national, and supra-national scales. Socio-political interactions in a policy environment of the principled exchanged of relevant knowledge is the best method for responsible synthetic biology governance.

Risk management on this view is constituted by an irreducibly complex multiplicity of informal and formal behaviors in an enormous variety of venues. In this essay I have explored this complexity, problematized the risk assessment process with historical and sociological analyses, and portrayed existing regulatory frameworks and institutional dynamics as co-evolving examples of polycentric governance. The Goldilocks Dilemma frames these dynamics in terms of an incremental, iterative, and reflexive reappraisal of the risk landscape as new knowledge and circumstances arise.

 

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[i] M. Rodemeyer. 2009. “New life, old bottles: regulating first-generation products of synthetic biology, SB2.0, March 2009”. Washington: Woodrow Wilson International Centre for Scholars. Hereafter Rodemeyer 2009. I acknowledge the Goldilocks dilemma implies commitments to reject policy recommendations that are too cautious or too lax. This seems to me a reasonable commitment. The question then becomes: how to determine the boundary between just enough and too much.

[ii] J. Kooiman. 2003. Governing as Governance. Sage Publications. See also R.A.W. Rhodes. 1996. “The New Governance: Governing without Government”. Political Studies XLIV, 652-667. “Knowledge systems” refer to the production, validation, circulation, and consumption of knowledge in specific venues, from academe to policy circles, civil society groups and various publics. See Miller, Munoz-Erickson, and Monfreda. 2010. “Knowledge Systems Analysis: A report for the Advancing Conservation in a Social Context Project”. This essay explores knowledge production as shaped by and actively shaping forms of political organization. Framing technologies as either new or familiar, with specific risks and short/long term benefits, functions to organize and manage social systems.

[iii] James C. Scott. 1998. Seeing Like a State: How Certain Schemes to Improve the Human Condition Have Failed. Yale University Press. Scott describes how mono-centric government programs such as Soviet food distribution in the age of Stalin failed to anticipate the social implications of their efforts at social control. In the latter case, massive informal economies and complex, improvised social dynamics were required in order to provide even minimal provision of social benefits. Street-level bureaucrats and functionaries interpreted central commands loosely, mitigating negative social impacts of regulations. 

[iv] Unfortunately, space constraints do not permit me to discuss patents/monopolies, socioeconomic impacts, and contested ethical commitments in the synthetic biology risk landscape. Previous versions of this essay included a case study of the BioBrick Public Agreement, a contract-based IP regime with a patent-left component designed to counterbalance the proprietary market ethos with sharing practices widely thought to foster innovation.

[v] Rodemeyer 2009 focuses on this question as an organizing principle of his essay. “New life, old bottles” hinges on a separation of synthetic biology into first generation and next generation applications. First generation applications are on the near horizon and do not require significant modifications of the 1986 Office of Science and Technology Policy (OSTP) Coordinated Framework for Regulation of Biotechnology, which coordinates NIH, FDA, USDA, EPA and other agency oversight of recombinant DNA innovation. As time passes, synthetic biology applications will be increasingly complex and unprecedented, making risk assessments increasingly difficult if not impossible. Regulatory agencies rely on risk assessments to make safety determinations. Thus, regulatory structures may have to be modified in the future, perhaps by developing better risk assessment tools, requiring strict containment on all experimental field testing.

[vi]  I will not include surveys of EU frameworks, international conventions related to biosafety, or other national contexts, due purely to spatial constraints. Bar-Yam 2012 is the best available concise survey of US, EU, and international regulations covering synthetic biology. What follows is a summary of Bar-Yam 2012.

EU law has primary and secondary sources. Primary law establishes power structures between the EU and Member States. Secondary law is where Directives and Regulations related to biotechnology and synthetic biology are drafted and passed through the EU hierarchy (European Commission, Council of Europe, European Parliament). Each of the 27 Member States is charged with applying these Directives and Regulations through their own legal systems. Member States have some discretion over how to apply these policies, with some states like Spain choosing occasionally to selectively ignore specific Directives and Regulations related to biotechnologies. Directives 90/219/EEC (contained use of GM microorganisms), 2001/18/EC (deliberate release into the environment of GMMs), and 2004/35/EC (environmental liability and remedying of damage), along with Regulations 1829/2003 (genetically modified food and feed) and 1830/2003 (traceability and labelling of GMOs and food/feed products from GMOs) are the foundation of the EU framework. There are additional Agreements and frameworks for biosecurity and transport of dangerous goods.

                                International conventions that are important to consider: the Convention on Biological Diversity, The Cartagena Protocol on Biosafety, the Nagoya-Kuala Lumpar Supplementary Protocol on Liability, The Biological Weapons Convention, and The Australia Group Guidelines are each convention capable of impacting synthetic biology governance in the future.

EU policies have more stringent labelling requirements, while US regulations are more strict with transport of materials. EU regulations focus on the process (rDNA, synthetic nucleic acids) while US regulations typically focus on products, allowing for functional equivalence and biosimilarity as a basis for reducing regulatory restrictions.

Other texts provide overviews of Chinese, Japanese, and other contexts. See also Zhang, Marris, and Rose. 2011.  “The Transnational Governance of Synthetic Biology: Scientific uncertainty, cross-borderness and the ‘art’ of governance”. BIOS Working Paper, BIOS, London School of Economics and Political Science, London, (hereinafter Zhang 2011), The authors discuss of China, ED, and US joint synthetic biology projects.

Simply put, if I wish to survey a range of risks, I have to balance breadth and depth. Let this suffice.

[vii] See Sheila Jasanoff. 2011. “Constitutional Moments in Governing Science and Technology”, Sci Eng Ethics 17: 621-638. Jasanoff examines how legal and judicial behaviors structure interactions between science and society, and how these practices modify research and innovation takes practices in laboratories and firms.

[viii] Shlomiya Bar-Yam, et al. 2012, The Regulation of Synthetic Biology: A Guide to United States and European Union Regulations, Rules and Guidelines. SynBERC and iGEM Version 9.1, January 10, 2012. http://synberc.org/sites/default/files/Concise%20Guide%20to%20Synbio%20Regulation%20OYE%20Jan%202012_0.pdf Hereafter, Bar-Yam 2012.

[ix] “Lego-like” is a cartoon image masking a complex reality. According to Robert Carlson, every time two standardized parts come together, they change shape and typically behave unexpectedly. Robert Carlson. 2010. Biology is Technology. Harvard University Press. Chapter 4. http://www.biologyistechnology.com/chapter-4.html. Accessed April 30, 2012.

[x] M.A. Loera Sanchez. March 18, 2012. “The Mainstream Fronts of Synthetic Biology”. Scientific American Blogs, http://blogs.scientificamerican.com/lab-rat/2012/03/18/the-mainstream-fronts-of-synthetic-biology-guest-post/ Accessed April 20, 2012.

[xi] BCC Research. 2011. Synthetic Biology: Emerging Global Markets. http://www.bccresearch.com/report/global-synthetic-biology-markets-bio066b.html# Accessed April 18, 2012.

[xii]  Zhang 2011, p. 7.

[xiii] Robert Carlson. 2010. Testimony for the Presidential Commission for the Study of Bioethical Issues. Meeting 1, Session 1. “Revenues from synthetic biology are maybe a couple of million dollars a year at this point, that’s all: reagents and instruments and what not.”

[xiv] Bourne Capital Partners, L.L.C. June 2011. “Biotechnology Market Overview”. Powerpoint presentation. http://www.bourne-partners.com/FileLib/Biotechnology%20Market%20Overview%20June%202011.pdf. Accessed May 1, 2012. See also Evaluate Pharma. 2009. “Biotech set to dominate drug industry growth”. http://www.evaluatepharma.com/Universal/View.aspx?type=Story&id=188700&sectionID=&isEPVantage=yes. Accessed May 1, 2012. Evaluate Pharma predicted a US$169 billion biotech pharmaceutical market in 2014. The global pharmaceutical market in 2011 as a whole was over US$850 billion. By contrast, early synthetic biology products like the artemesinin malaria vaccine derivative have been pledged to developing countries on a not-for-profit basis.

[xv] US Department of Health and Human Services. 2010. “Approval Pathway for Biosimilar and Interchangeable Biological Products; Public Hearing”. http://thehill.com/images/stories/blogs/biosimilars.pdf. Accessed May 1, 2012.

[xvi] S. Benner & M. Sismour. 2005. “Synthetic biology”. Nature Reviews Genetics, 6, 533-543: 541.

[xvii] Genetically modified crops were rejected in much of the European Union (excluding Spain and a few other locations) partly in response to popular media campaigns framing GM foods as monstrous Franken-foods, suggesting the hubris of inserting genetic material into biological systems.

[xviii] Genya V. Dana, Todd Kuiken, David Rajeski & Allison A. Snow. 01 March 2012. “Synthetic biology: four steps to avoid a synthetic biology disaster”. Nature 483. http://www.nature.com/nature/journal/v483/n7387/full/483029a.html Accessed April 28, 2012. Hereafter Dana et al 2012

[xix] Lynn Klotz & Ed Sylvester. 15 January 2012. “Preventing Pandemics: The Fight Over Flu” Nature Online. http://www.nature.com/nature/journal/vaop/ncurrent/full/481257a.html#/lynn-klotz-amp-ed-sylvester-worry-about-lab-infections . Klotz and Sylvester use historical data from SARS and avian flu research to suggest that there is a 34% chance of unintentional release of a modified SARS virus within 1 year if 42 labs are experimenting with the pathogen. The principle here is that exposure to risk increases significantly as more laboratories work with pathogenic materials.

[xx]  http://www.synbioproject.org/library/inventories/map/

[xxi] Gary Marchant. March 2012. ASU LAW 691 Powerpoint presentation. Class 17.

[xxii] Ibid.

[xxiii] Dan Garry. 2010. “Baking the Cake of Life with Do-It-Yourself Biology”. The Triple Helix at Arizona State University. http://asutriplehelix.org/baking_the_cake_of_life . Accessed April 25, 2012. Garry gets his information from David Ng 2009, “Using eBay to set up a molecular biology lab: costs less than $1000!”, http://scienceblogs.com/worldsfair/2009/04/using_ebay_to_set_up_a_molecul.php

[xxiv]  Meredith L. Patterson. 2010. “A Biopunk Manifesto”. UCLA Center for Society and Genetics Symposium. http://maradydd.livejournal.com/496085.html. Patterson is a trained molecular biologist and bioinformatics professional. Her manifesto places contemporary “citizen scientists” in a tradition that includes Michael Faraday, Benjamin Franklin, Steve Wozniak, and others whose inventions started in garages and other non-institutional settings. Patterson’s biopunk is willing to actively oppose laws that restrict freedom of access to the tools of innovation. Biopunks will utilize their engineering skill and ingenuity to invent cheap equipment if necessary, as evidenced by Patterson’s affiliation with OpenPCR.org, a start-up that has produced a $599 DNA synthesizer with a computer interface, allowing users to copy and paste DNA strings from websites like openwetware.org directly into the synthesis machine for easy ‘printing’.

[xxv] US Department of Health and Human Services. Biosafety in Microbiological and Biomedical Laboratories: 5^th Edition. http://www.cdc.gov/biosafety/publications/bmbl5/BMBL5_introduction.pdf Accessed April 21, 2012. Section 1—Introduction.

[xxvi] Ibid. Paraphrase Section 1—Introduction.

[xxvii]  LAIs continue to occur, though infrequently. Human err occurs in 2012 just as in the 1930s.

[xxviii]  To ensure that biosafety guidelines are established in every country that plans to fund synthetic biology research, international relations, professional organizations, joint academic research programs, and global civil society group interactions are all important.

                                                Many other countries would need to be surveyed for an account of biosafety or biosecurity risks to be exhaustive. This point is significant because implementing regulations is highly site-specific, depending upon funding patterns, personnel, cultures of risk assessment, and other factors. Jasanoff 2010 notes that while English is hegemonic in the sciences, it is not in law and ethics; concepts like risk may function quite differently across national settings. [See Sheila Jasanoff July 9, 2010. NAS Committee on Science, Technology, and Law. Session 1 Lecture.] Changing the knowledge systems of another nation to coincide with risk assessment criteria and discourse that are not ‘native’ to those knowledge systems is a problem that applies equally across academic disciplines (physics, computer science, engineering) and across nationality.

For example, Animesh Roul’s research at Indian universities and research institutes suggests that “most Indian biologists are…convinced that the bioterrorism/biodefense issue is basically a Western (US-generated) concept and phobia.” [See National Research Council. 2008. The 2^nd Annual Forum on Biosecurity: Summary of an International Meeting, Budapest, Hungary, March 30 to April 2, 2008. Committee on International Outreach Activities on Biosecurity. National Academies Press. p. 36]

In another example, basic terms of risk discourse used in a technical sense by Western scholars, such as biosecurity, are found to be highly contested in Kenya and Uganda.[xxviii] These differences cannot help but impact knowledge production, validation, circulation, and consumption, leading to potentially unsafe policy formations and implementations in these research settings. If synthetic biology is set to be a US$10.6 billion industry in 2016, a better understanding of and communication within these unique innovation settings will be necessary. This is precisely the notion of polycentric governance I introduced in the introduction, where governance is thought of as a quest for shared or mutually understood ways of conceptualizing particular issues.

[xxix]  Drew Endy. July 8, 2010. Testimony. Overview and Context of the Science and Technology of Synthetic Biology. Presidential Commission for the Study of Bioethical Issues. Meeting 1, Session 1. http://bioethics.gov/cms/node/164. (Very end of presentation). Accessed April 24, 2012.

“Lastly, preparedness and reconciliation. Biosafety. Accidents will happen. We have the gene therapy experiences from Penn. More misuses will occur. We have the anthrax attacks from 2001. Nature is not the same as a representative liberal democracy and that creates a tension between our expectations and duties to protect the rights of the individual in a world that oftentimes can be cruel.”

[xxx] Other agencies are also important to consider, including OSHA and the NSF, but for purposes of this essay I will focus on NIH, FDA, EPA, and USDA.

[xxxi] Many groups were unhappy with the Coordinated Framework from its inception. In keeping with the Goldilocks theme: some thought the regulations were too much (industry reps) and some thought they were not enough. See Gary Marchant. 1988. “Modified Rules for Modified Bugs: Balancing Safety and Efficiency in the Regulation of Deliberate Release of Genetically Engineered Microorganisms”. Harvard Journal of Law and Technology Vol 1, Spring Issue. (Hereinafter Marchant 1988)

[xxxii] Updates to the NIH Guidelines have since added synthetic nucleic acids to the materials covered.

[xxxiii]  Industries can be held accountable for contaminating the environment or human populations through liability, negligence, statutory law and common law. Thus, biosafety is still required, even beyond NIH Guidelines.

[xxxiv]    Drew Endy, 2010, Testimony for Presidential Commission for the Study of Bioethical Issues, Meeting 4, Session 1.

[xxxv]   For example, “exact copies of dangerous genes are not covered if not made by recombinant methods.” Bar-Yam 2012, p. 5. Drastic possibilities for product development are currently anticipated for synthetic biology’s future, from self-assembling houses, neon trees, post-humans, new species of animals, and radical space exploration for the seeding of life on other planets. More mundane, but no less profound, contemporary examples of research that are not covered by the Coordinated Framework include attempts at revivifying extinct bird species through synthetic biology.

[xxxvi]    Rodemeyer 2009, Bar-Yam 2012.

[xxxvii]    Bar-Yam 2012. p. 5

[xxxviii]   John Carroll. 2010. “Life Technologies budgets $100 million for synthetic biology deals”. Fierce Biotech. http://www.fiercebiotech.com/story/life-technologies-budgets-100m-synthetic-biology-deals/2010-06-03. Accessed May 1, 2012.

[xxxix] US Department of Health and Human Services. 2010. “Approval Pathway for Biosimilar and Interchangeable Biological Products; Public Hearing”. http://thehill.com/images/stories/blogs/biosimilars.pdf. Accessed May 1, 2012.

[xl]   Rodemeyer 2009, Bar-Yam 2012.

[xli]      Rodemeyer 2009

[xlii]     The timeline of such convergence is uncertain. Perhaps 10 years, perhaps 20, maybe 50?

[xliii]     Dana et al. 2012

[xliv]   Synthetic Biology Engineering Research Center (SynBERC). 2012. “Nature Commentary: Four steps to avoid a synthetic-biology disaster”. http://synberc.org/content/articles/risk-research-commentary. Accessed April 30, 2012.

[xlv]    Rodemeyer 2009.

[xlvi] Linda-Jo Schierow. 2007. The toxic substances control act: implementation and new challenges. Washington, DC: Congressional Research Service, Library of Congress

[xlvii]  Presidential Commission for the Study of Bioethical Issues. December 2010. New Directions: The Ethics of Synthetic Biology and Emerging Technologies. http://www.bioethics.gov/documents/synthetic-biology/PCSBI-Synthetic-Biology-Report-12.16.10.pdf. Accessed April 1, 2012. Recommendation 5: Risk Assessment Review and Field Release Gap Analysis.

[xlviii]   Marchant 1988, p. 164.

[xlix]   Ibid.

[l]   Meredith L. Patterson. 2010. “A Biopunk Manifesto”. UCLA Center for Society and Genetics Symposium, Outlaw Biology? Public Participation in the Age of Big Bio. http://maradydd.livejournal.com/496085.html . Accessed April 27, 2012. Hereinafter, Patterson 2010.

[li] This essay format does not permit adequate space to cover international efforts at biosafety governance while still covering other synthetic biology risks. Important contributions, for example, have been made internationally by the World Health Organization’s Global Laboratory Initiative, which works to set norms using Tuberculosis as an organizing principle. 

[lii]  Examples of biosafety governance dynamics:

The annual iGEM competition at MIT brings together thousands of high school and undergraduate research teams from dozens of countries for a synthetic biology “jamboree.” To submit projects to judges, teams must answer questions about the potential biosafety risks and societal implications of their research.

The Registry of Standardized Biological Parts utilized by iGEM competition participants was opened up for public use in 2010 through the adoption of the BioBrick™ Public Agreement (BPA). DIY biologists and other researchers can utilize the tools of synthetic biology innovation, but only if they sign a contract that obligates them to follow biosafety guidelines. This is essentially a norm-setting practice designed at once to restrict the BioBricks Foundation’s liability for misuse of materials while also promoting best practices.

[liii]  Drew Endy. 2007. Interview with Quinn Norton. “Biosecurity Concerns”. Hereinafter Endy 2007. http://archive.org/details/InterviewWithDrewEndyOnSyntheticBiology. Accessed April 20, 2012.

[liv]  Jeanne Guillemin. 2006. Biological Weapons: From the Invention of State-Sponsored Programs to Contemporary Bioterrorism. 2006. Columbia University Press. p. 122-126.

[lv]   Gary Marchant. 2012. “Bioterrorism”. PowerPoint lecture. LAW 691.

[lvi]  Endy 2007 (paraphrase)

[lvii]  CSPAN. March 2012. Panetta testimony. (Paraphrase)

[lviii]  Marchant 2012. “Bioterrorism”.

[lix]  Risk analysis is a difficult procedure. Defining a problem and key variables that describe the problem, collecting data, and appraising evidence are each situated within institutional settings and place-based knowledge productions systems. Because each phase of the process can be contested, and because producing analyses that will be perceived as credible is a prime motivation of the process itself, most national-level analyses will include public engagement, independent advisors, and similar structural features.

Defining the biosecurity problem is difficult because multiple problem definitions may be presented by different groups, each with cogent arguments as to the severity or lack of severity of risks. A 2008 National Academies of Science report that included surveys of biologists in India, Kenya, and Uganda, for example, suggested that most biologists in these countries view biosecurity and biodefense risks as US-generated phobias with little grounding in reality.[lix] On this view, biosecurity is not a credible problem, but rather a pretext for pushing a global political or economic agenda.

Once problems are defined, there are additional difficulties with modeling key variables and collecting data. Quantifying biosecurity risks, like calculating risks of major earthquakes, could lead experts to conclude there is a 95% probability of a major event within the next ten years. Producing that knowledge and distributing that prediction to political actors for consumption may lead to the allocation of billions of dollars to a classified biodefense program.[lix] If ten years pass without incident, this could indicate many things. Is the program working? Because such programs operate with public funds, there is always the awareness that public attitudes toward biosecurity risks are reversible. Political leaders could recommend dismantling biodefense programs.

Without question there are actual biosecurity risks afforded by the democratization and power of the tools of synthetic biology; but not everyone shares a view of the implications of this risk for public policy. Risk management is thus an elaborate social production. There are many ways to form policies to manage these risks, and many ways to implement and assess the effectiveness of those policies. In sub-national, national, and international contexts, engineering biosecurity requires expertise not only in acquiring technical knowledge of biological agent detection and therapeutic remedies but in managing the sociology of risk perception as well.[lix]

Many of the biosecurity threats associated with synthetic biology are long-term threats that may only materialize on a scale of decades, when the five main fronts of synthetic biology research mentioned in the introduction have progressed and started converging. It is important to consider that biodefense research programs building capacity to confront long-term risks are actually contributing to the engineering of pathogenic synthetic microorganisms. The paradox of dual-use research for biodefense is that understanding risks and developing vaccines and other remedies begs the question: are we not increasing some biosecurity threats in the process of decreasing others? Classified and unclassified biodefense laboratories are scattered across the country. A classified research community thereby gains access to synthetic pathogens that otherwise might not be created. Perhaps net biosecurity threats are diminished by constructing a robust biodefense research network. But a single well-placed disgruntled employee or terrorist turncoat could spoil everything.

[lx]  LIS Consult and the Synthetic Biology Project. June 2011. “Synthetic Biology Newsletter”. Page 17.

[lxi] Edward You, (Supervisory Special Agent, FBI Weapons of Mass Destruction Directorate, Countermeasures Unit, Bioterrorism Team), March 11, 2010. Powerpoint presentation: Looking Ahead: Biosecurity. http://www.synbioproject.org/process/assets/files/6409/_draft/you_presentation.pdf .

[lxii]  Marchant 2012. “Synthetic Biology”. Powerpoint lecture.

[lxiii]  Ibid.

[lxiv] http://www.ncbi.nlm.nih.gov/genbank/

[lxv]  International Association for Synthetic Biology. 2009. The IASB Code of Conduct for Best Practices in Gene Synthesis. Cambridge, Mass. http://www.ia-sb.eu/tasks/sites/synthetic-biology/assets/File/pdf/iasb_code_of_conduct_final.pdf.

[lxvi]  Drew Endy has suggested that up to 30% of subscribers to the DIY-oriented synthetic biology newsletters are biosecurity professionals, FBI personnel, and members of the intelligence community.

[lxvii]  Biosecurity Engagement Program. 2012. “About the Initiative”. http://www.bepstate.net/about.html. Accessed April 30, 2012. 

[lxviii]    National Research Council. 2012. Biosecurity Challenges of the Global Expansion of High-Containment Biological Laboratories. Washington, DC: The National Academies Press

[lxix]   For example: the Inter-Academy Panel is a global network of 105 academies of science from 100 countries. The IAP Biosecurity Working Group thus has immense capacity to influence network formation, global norm-setting, and a variety of formal and informal governance strategies. http://www.interacademies.net/Activities/Projects/17806/17801.aspx

                                The Federation of American Scientists (FAS) also deserves attention for its online global biosecurity clearinghouse, the Virtual Biosecurity Center. http://virtualbiosecuritycenter.org/.

[lxx]   National Institutes of Health. “NSABB: Frequently Asked Questions.” http://oba.od.nih.gov/oba/ibc/faqs/faqs%20about%20the%20national%20science%20advisory%20board%20for%20biosecurity.pdf. Accessed April 28, 2012.

[lxxi] ETC Group, et al. 2012. Principles for the Oversight of Synthetic Biology. http://www.wilsoncenter.org/sites/default/files/principles_for_the_oversight_of_synthetic_biology.pdf , Accessed April 21, 2012.

[lxxii]  Gary E. Marchant & Douglas J. Sylvester. 2008. “Risk Management Principles for Nanotechnology”. Nanoethics 2: 43-60.

[lxxiii]  Presidential Commission for the Study of Bioethical Issues. 2010. Executive Summary. Washington, D.C.

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