THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF

October 2015 THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? Commercial ApplicationsofSyntheticBiology TABLE OFCONTENTS Current U.S.OversightofSyntheticBiology Introduction Executive Summary Appendix: NationalEnvironmental PolicyAct(NEPA) FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA) TOXIC SUBSTANCES CONTROL ACT (TSCA) PLANT PROTECTION ACT (PPA) FEDERAL FOOD, BIOSECURITY RENEW INDUSTRIAL CHEMICALS HEAL COORDINATED FRAMEWORKFORREGULATION OFBIOTECHNOLOGY AGRICULTURALENVIRONMENTAL AND INTRODUCTION NEP Biopesticide CaseStudy Synthetic SqualaneCaseStudy Genetically ModifiedPlantCaseStudy Biomining CaseStudy Oxitec CaseStudy Animal andPlantHealthInspectionService Federal Food,Drug,andCosmeticAct A REVIEWIN THE SYNTHETIC BIOLOGYCONTEXT THCARE ABLE ENERGY . . . . . DRUG, AND COSMETIC ACT (FFDCA) . .2 ......

48 25 21 44 39 31 28 35 15 12 49 48 53 50 .

8 6 5 8 7 7 7 6 6 THE DNA OF THE U.S. REGULATORY SYSTEM: Are We Getting It Right for Synthetic Biology?

Written by

Lynn L . Bergeson, Bergeson & Campbell PC Bethami Auerbach, Bergeson & Campbell PC Lisa M . Campbell, Bergeson & Campbell PC Timothy D . Backstrom, Bergeson & Campbell PC Sheryl L . Dolan, Bergeson & Campbell PC Jane S . Vergnes, Ph .D ., Bergeson & Campbell PC Richard E . Engler, Ph D. ,. Bergeson & Campbell PC Jayne P . Bultena, Bergeson & Campbell PC Karin F . Baron, Bergeson & Campbell PC Charles M . Auer, Charles Auer & Associates, LLC

October 2015

The views expressed are the authors own and do not necessarily represent those of the Wilson Center . EXECUTIVE SUMMARY

Recommendations • Developing a long-range, government- wide strategy to assure that, going U .S . regulatory oversight of synthetic forward, the regulation of synthetic biology biology across the board needs to be encourages innovation while timely modernized to reflect and address the identifying and addressing risks through a promising technologies routinely entering science-based, transparent process that the market . From a statutory perspective, encourages public confidence the pertinent laws appear sufficiently broad to empower federal agencies to address Some of these recommendations are potential risks and promote the potential reflected in a July 2, 2015, memorandum benefits of synthetic biology . The regulatory issued by the White House Office of Science infrastructure, however, is ill-suited to address and Technology Policy that directs the all the regulatory implications of new products Environmental Protection Agency (EPA), derived from synthetic biology . Food and Drug Administration (FDA), and the Department of Agriculture (USDA) to Improvements that are urgently needed update the 1986 Coordinated Framework include: for Regulation of Biotechnology, under which these agencies have proceeded for nearly Increased funding to federal agencies, • three decades . The directive to revise the including “embedded” new technology Coordinated Framework is long overdue . stewards in each office of all relevant Developments in synthetic biology will not federal agencies to monitor and halt during the overhaul of the Coordinated coordinate topics of emerging Framework . Improvements in regulatory technologies and share information with oversight can and should be put into place, other agency offices even while the updating of the Coordinated • Dedicated centers of technological Framework is in progress . excellence in pertinent federal offices to stay abreast of new developments Report Summary As highlighted in this report, especially in • Regular routine intervention by industry and academic innovators to brief the illustrative case studies, competing and sometimes conflicting jurisdictional issues

THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF government agencies on trends, developments, and challenges confound, if not frustrate, prompt and effective government oversight of synthetic • Implementation of an ongoing process biology . The novelty of some technologies to demystify synthetic biology and its challenges even government staff in sorting products so that they are more clearly out which agency has primary jurisdiction and accurately understood by federal over a particular product or new technology decision-makers and the public or which office within an agency should be exercising regulatory oversight .

2 The Oxitec case study highlights the threshold derived squalene is the same for regulatory/ regulatory issues that can arise within a labeling purposes as squalene from fish oil or single agency – in this case, the FDA -- in plant oil sources . Consumers are entitled to the synthetic biology context . Oxitec has accuracy in labeling, but neither consumers developed a genetically engineered mosquito nor product developers are well served if that is highly effective in decreasing the the regulatory agency in charge has not population of disease-carrying A. aegypti addressed and clarified the issue ahead of mosquitos through breeding after the the launch of the cosmetic product in the engineered mosquito is released into the wild . commercial market . But the Oxitec mosquito does not fit cleanly into any FDA regulatory category; eventually The fundamental issue of which regulatory it was determined to assess it as an animal statute applies to a synthetic biology product drug by one office of the FDA rather than by can be unexpectedly complex, as depicted another FDA office as a human drug though by the PBAN case study . PBAN is a naturally its ultimate goal is to reduce yellow fever occurring substance that encourages female and allied diseases in human beings -- and insects to produce pheromones to attract males for mating; researchers have developed hence to act as a human drug . Uncertainty a genetically modified strain of E. coli that is expensive . Without a reliably defined yields a synthetic PBAN used in an innovative regulatory assessment pathway, innovation process for moth control is discouraged . For Oxitec, a threshold . Mixed with a sugar question even had arisen whether the USDA, solution, the synthetic PBAN is placed in rather than FDA, should be in charge if the a trap as food for female moths, inducing engineered mosquito could be described as a them to produce pheromones, which in turn attracts male moths into the trap pest control technology . . The use of a biopesticide in a trap for purposes of Where the synthetic biology product is mitigating a pest typically requires registration a cosmetic ingredient, uncertainties are under the Federal Insecticide, Fungicide, and magnified because cosmetics, in most cases, Rodenticide Act (FIFRA), despite a FIFRA are not subject to pre-market review by exemption for pheromones; synthetic PBAN, FDA, which typically relies on enforcement while inducing pheromone production, is not authorities it can deploy against improperly itself a pheromone . Thus PBAN is subject to labeled cosmetics already on the market . FIFRA although it is a more benign approach Accuracy in labeling is a slippery slope when to pest control than is a conventional it comes to synthetic biology, as described in pesticide . As the case study notes, if synthetic the case study on squalene, an emollient in PBAN had obtained the benefit of the FIFRA lotions . The best source of natural squalene exemption, it still might be subject to the is shark oil, but with some shark species Toxic Substances Control Act (TSCA) or other deemed endangered and plant sources often authorities . Depending on its use, and on uneconomical, the biotechnology firm Amyris whether other substances would be placed has developed and is marketing synthetic in the trap along with it, other regulatory squalene, apparently through the engineering scenarios could be triggered . The process of proprietary yeast strains, for cosmetic use . of deciding whether and how to regulate a This poses the question whether synthetically synthetic biology product may well require as

3 much effort as the regulatory process itself . Not only is the underlying legislation often ill-equipped to address the challenge of In some instances, synthetic biology products commercialized synthetic biology, the go without regulatory oversight because the problem is exacerbated at the implementing relevant statute, as read by the implementing agency level . Given the extreme and growing agency, does not cover them . The Plant shortages in government staff and funding Protection Act (PPA) extends only to “plant throughout the federal agencies, including pests,” a defined term that USDA’s Animal and those whose regulatory reach extends to Plant Health Inspection Service (APHIS), in a synthetic biology, technological literacy reading affirmed by a federal appeals court, remains a critical problem . Government construes the term to exclude genetically personnel with institutional know-how and engineered plants from regulation unless expertise are retiring from the workforce the plants themselves, the genetic material, and not always being replaced, and those or the engineering method involve plant who are added are not being provided pests . For this reason, APHIS declined to with opportunities to understand fully new take jurisdiction over either “BioGlow” or the synthetic biology technologies entering the “Glowing Plant” as the case study illustrates . commercial space . In addition to the recom- The former now commercialized and the latter, mendations outlined above, better, more an open-source technology funded through a systematic, and routine communication and Kickstarter campaign . Seeds of the glowing coordination between and among federal plant were made available to consumers agencies is also urgently needed . The as supporter bonuses and in Do-It-Yourself deeply-embedded stove piping confounds (DIY) kits where individuals can make the communication and coordination within genetic transformation themselves . Synthetic and among government offices and blunts biology was far in the future when the original opportunities for more efficient, informed legislation that became the PPA was enacted reviews of new products moving to market . – and it shows . THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF

4 INTRODUCTION

Biology focuses on cells as basic life units, technology in various commercial sectors . and genes as basic units of code that define Next we provide a detailed summary of the heredity . Scientists long ago mastered domestic government oversight of synthetic engineering genes to functionalize desirable biology . The regulation of products of traits and removing genes from one organism synthetic biology is juggled, and not always and inserting them into another organism clearly so, among three federal agencies, to achieve a specific intended scientific or various federal laws, and the Coordinated commercial purpose . While there are many Framework, which the federal government definitions of synthetic biology, key to each recently announced it will modernize . The are the notions of scope and speed . While regulatory framework that has evolved is the underlying principles of synthetic biology complicated, increasingly circuitous, and are the same as those from traditional not for the faint of heart . First-time and recombinant DNA (rDNA) techniques, what experienced innovators alike are increasingly is different about synthetic biology, and vexed by the daunting jurisdictional divides important from a governance perspective, crafted years ago based on fundamentally is the scope and speed of genetic change different kinds of products and technologies . that synthetic biology can achieve . The We illustrate these anomalies through case application of standardized engineering studies under each of the key federal statutes techniques to biology can kick-start quickly -- TSCA, FIFRA, Federal Food, Drug, and and relatively inexpensively the creation of Cosmetic Act (FFDCA), and PPA -- and the organisms and entire biological systems application of the regulatory system under with novel or specialized functionalities, each to new products of synthetic biology . and these techniques are widely accessible These case studies crystalize the challenges to both institutional and non-institutional regulators and innovators face in bringing stakeholders, including the citizen science new products of synthetic biology to market community . and the anomalous and often counterintui- tive if not bewildering governance results that This report discusses synthetic biology, arise under current regulatory frameworks . reviews the U S. . regulatory system that governs products of synthetic biology and Our hope in writing this report is to support assesses whether this system is effective the development of synthetic biology, identify in managing potential risks of synthetic lapses in the current domestic governance biology and maximizing its benefits . We of synthetic biology, and suggest solutions first provide an overview of what synthetic to ensure responsible stewardship of this biology is, provide some historical context, technology . and summarize current applications of this

5 COMMERCIAL APPLICATIONS OF SYNTHETIC BIOLOGY

As with many emerging technologies, AgraCast, another privately-held company applications of synthetic biology are diverse . harnessing the potential of synthetic biology, It is clear synthetic biology is capable of focuses on plant breeding techniques to delivering on its promise of clean energy, improve the “harvestability” of castor oil and personalized medicine, pollution remediation, sweet sorghum crops . The Company has and other benefits . What is less clear is a business unit that is developing natural, how the potential for harm through the anti-fungal products that can be used to inadvertent release of organisms or other treat fruit and vegetables post-harvest to bioactive materials into the environment will make them mold resistant . Many of these be prevented . To appreciate the breadth new technologies build upon traditional rDNA of synthetic biology’s utility and better technology, cloning, and related genetic understand the reasons for both cautious engineering techniques . enthusiasm and guarded concern, we describe below a few of this technology’s Synthetic biology has many applications in the environmental arena . Engineered diverse applications . organisms are being developed to consume Agricultural and Environmental toxic chemicals in water and soil that would not otherwise decompose . Biosurfactants, The utility of rDNA technology is not new naturally produced by bacteria or fungi and to the agricultural community, and plant generally environmentally friendly to aquatic engineering and animal breeding have organisms, can be used to maximize the been part of the agricultural landscape for efficiency of bioremediation efforts 1. Synthetic years . Synthetic biology builds upon these biofilms are being developed for use as techniques and takes them to a whole new environmental biosensors to monitor soil from level . Synthetic biology offers the promise of environmental degradation or nutrient levels diminished reliance on chemicals that may in the soil . leave damaging environmental footprints, greener grass that requires infrequent Healthcare mowing, and the development of a broad array of products that enhance the efficiency As in agribusiness, genetic engineering is of conversion, ultimately from sunlight into no stranger to healthcare and has been used for decades in the medical community

THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF proteins and carbohydrates, and agricultural to engineer bacteria to produce insulin waste material into useful substances . and accelerate the development of other A few examples of commercial applications vaccines . Synthetic biology is expected to illustrate the diversity of synthetic biology in enhance greatly these practices and speed the agricultural sector . Monsanto Company’s and streamline new product development . (Monsanto) acquisition of Agradis, Inc . in With industrial fermentation processes, 2013, a privately-held company focusing on synthetic biology could use engineered/ agricultural biologicals, reflects Monsanto’s created microorganisms as factories to enduring interest in synthetic genomics produce high qualities of medical chemicals and the utility of plant microbes to make at low cost, such as artemisinin, a malaria crops more drought and disease resistant . medication . In this case, a cluster of modified

6 genes taken from the mevalonate pathway walls (not corn) to produce bioalcohols using of plant Artemisia annua are implanted synthetically manipulated biomass 5. Biofuels into yeast that produces a precursor to can also be produced from modified algae artemisinin, artemisinic acid 2. that rely upon photosynthesis to produce bio-oils, including biodiesel, more easily than Synthetic biology is expected to take more conventional chemical processes . “concierge medicine” to a whole new level . Synthetic biology can improve the speed Personalized medicine seeks to harvest the and efficiency of converting biomass into potential of genomics to engineer highly advanced biofuels using less energy and specific, patient-tailored approaches to yielding more by using so-called “super-fer- medical care . Synthetic biology will greatly menting” yeast and bacteria . enhance these efforts and promises one day to offer patient-specific solutions to medical Biosecurity challenges . Custom proteins “may eventually enable the delivery of ‘smart proteins’ or Biosecurity generally refers to measures programmed cells that self-assemble at needed to prevent the misuse of biological disease sites .”3 While these solutions are at agents and organisms with the intent to the early stages of development, their utility do harm 6. The National Science Advisory in solving some of the many challenges Board of Biosecurity, an independent federal healthcare poses is exciting . advisory committee that advises the federal government on biosecurity issues, noted Industrial Chemicals that “[b]iosecurity refers to the protection, control of, and accountability for high- Research using synthetic biology in the consequence biological agents and toxins, manufacture of petroleum-based plastics and critical relevant biological materials is underway . Polylactic acid, acrylic, and and information, to prevent unauthorized isoprene using metabolically engineered possession, loss, theft, misuse, diversion, microorganisms with synthetic gene clusters or international release .”7 Synthetic biology are in production now . Other promising enables the precise identification of applications include the chemical Salmonella biological agents of concern that could be spp ., which can be engineered with synthetic developed synthetically or semi-synthetically . genes encoding silk monomers to produce Researchers may tag or “brand” the genetic 4 spider silk . Saccharomyces cerevisiae yeasts code of new organisms with the hope that are engineered by using synthetic biology this tagging process may dissuade malicious methods to produce fragrances such as uses of the material . Other methods, which synthetic vanilla, biobased succinic acid, and include embedding “suicide” genes into renewable adipic acid . the genome of a new organism to inhibit Renewable Energy survival outside of a contained environment, offer a potentially more reliable means to The production of biofuels and other counter biosecurity threats . Similar tools can renewable energy sources offer especially be developed to ensure planned organism high profile opportunities to diminish reliance death in targeted circumstances . As with any on petroleum-based feedstocks and emerging technology, uncertainties remain reduce global warming emissions . Various regarding the efficacy of such strategies as alternatives to more conventional production research in these applications is at an early techniques using synthetic biology include stage of development . the production of cellulosic ethanol from cell

7 CURRENT U.S. OVERSIGHT OF SYNTHETIC BIOLOGY

Coordinated Framework for Regulation of Biotechnology

There has been no new legislation enacted to Recognizing that many federal agencies have address synthetic biology or related emerging jurisdiction over products of biotechnology, technologies . Instead, the U S. . regulatory the Coordinated Framework sets forth authorities have relied upon existing statutory an organizational blueprint for federal authorizations to address new products . An agencies and establishes lead responsibili- overview of the pertinent federal authorities ties for the federal oversight of products of is presented below . The adequacy of these biotechnology . The core premise of the existing authorities is explored in the case Coordinated Framework is that the legal studies in the next section of this report . authorities that existed in 1986, authorities that remain largely unchanged today, provide The federal oversight of products of federal regulators sufficient authority to biotechnology is directed through the manage any health or environmental risk the Coordinated Framework issued in 1986 by products of biotechnology may pose . the Reagan Administration’s White House Office of Science and Technology Policy The Coordinated Framework was intended to (OSTP) 8. Concern with oversight began much be a flexible governance construct capable earlier . In 1975, growing unease with the of nimbly adjusting to new science and not potential for release of genetically modified shackle legal authorities rigidly to specific organisms into the environment inspired the biotechnology products . Risks are assessed gathering of some 140 scientists, lawyers, on a case-by-case, product-by-product basis ethicists, and others in Monterey, California, and focus on a product’s application and its for the Congress at Asilomar . The Congress intended use, not on the technology itself .

THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF led to the issuance in 1976 of the National This risk-based approach is quite different Institutes of Health (NIH) Recombinant DNA from the European Union’s (EU) approach, Guidelines (NIH Guidelines),9 which offer which is based on the Precautionary Principle recommendations for best practices for and is likely more restrictive when applied producers and users of genetically modified to emerging technologies, as risks tend to organisms . Adherence to the NIH Guidelines be inherently more uncertain, ill-defined, is mandatory for investigations at institutions and incomplete than those of more mature that receive NIH funds doing research technologies 11. involving rDNA 10.

8 Under the Coordinated Framework, three in the regulatory system and to prevent federal agencies are principally responsible unnecessary barriers to future innovation for regulating products of biotechnology: and competitiveness by improving the USDA (and, in particular, APHIS), EPA, and transparency, coordination, predictability, and FDA . APHIS is responsible for regulating efficiency of the regulation of biotechnology field trials of genetically modified crops products while continuing to protect health and plants under the PPA . EPA regulates and the environment .” genetically engineered microbes under TSCA and genetically engineered pesticides and The memorandum states that federal pesticides incorporated into plants under agencies regulating biotechnology products “should continually strive to improve FIFRA . FDA regulates a broad spectrum predictability, increase efficiency, and reduce of products, including human and animal uncertainty in their regulatory processes and drugs, cosmetics, dietary supplements, food, requirements food additives, and medical devices, among .” Improvements must: others . Exactly how each agency regulates • Maintain high standards that are based products of biotechnology, pursuant to what on the best available science and legal authority, and when in the commercial- that deliver appropriate health and ization process regulatory oversight attaches environmental protection; varies considerably . These regulatory programs are discussed briefly below . • Establish transparent, coordinated, predictable, and efficient regulatory The White House OSTP, Office of practices across agencies with Management and Budget (OMB), U .S . Trade overlapping jurisdiction; and Representative (USTR), and the Council on Environmental Quality (CEQ) issued a • Promote public confidence in memorandum on July 2, 2015, directing EPA, the oversight of the products of FDA, and USDA to update the Coordinated biotechnology through clear and Framework . A July 2, 2015, OSTP blog transparent public engagement . item entitled “Improving Transparency and The memorandum initiates a process Ensuring Continued Safety in Biotechnology” to help advance these aims, beginning notes that the complexity of the array with the following one-year objectives: (1) of regulations and guidance documents development of an updated Coordinated developed by EPA, FDA, and USDA “can Framework to clarify the roles and respon- make it difficult for the public to understand sibilities of the agencies that regulate the how the safety of biotechnology products products of biotechnology; (2) formulation is evaluated, and navigating the regulatory of a long-term strategy to ensure that the process for these products can be unduly federal regulatory system is equipped to challenging, especially for small companies .” assess efficiently the risks, if any, associated The memorandum states that the with future products of biotechnology while objectives “are to ensure public confidence supporting innovation, protecting health

9 and the environment, promoting public of biotechnology while supporting confidence in the regulatory process, innovation, protecting health and increasing transparency and predictability, the environment, maintaining and reducing unnecessary costs and public confidence in the regulatory burdens; and (3) commissioning an external, process, increasing transparency independent analysis of the future landscape and predictability, and reducing of biotechnology products . According to unnecessary costs and burdens . the memorandum, the following elements will support the process to achieve these • Independent Assessment: EPA, objectives: FDA, and USDA shall commission an external, independent analysis of the • Biotechnology Working Group future landscape of biotechnology Under the Emerging Technologies products that will identify (1) potential Interagency Policy Coordination new risks and frameworks for risk Committee: The Biotechnology assessment, and (2) areas in which Working Group will include representa- the risks or lack of risks relating to the tives from the Executive Office of the products of biotechnology are well President, EPA, FDA, and USDA . understood . The review will help inform future policymaking . Due to the rapid • Mission and Function of the pace of change in this arena, an external Biotechnology Working Group: analysis should be completed at least Within one year of the date of the every five years . memorandum, the Biotechnology Working Group shall take steps detailed • Budgeting for Efficiency: EPA, FDA, below and others, as appropriate, to and USDA shall work with OSTP and increase the transparency, coordination, OMB, within the annual President’s predictability, and efficiency of the budget formulation process, to regulatory system for the products of develop a plan for supporting the biotechnology . The Working Group will: implementation of this memo in agency fiscal year (FY) 2017 budget requests (1) Update the Coordinated Framework and, as appropriate, in future budget

THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF to clarify the current roles and respon- submissions . sibilities of the agencies that regulate the products of biotechnology, after • Annual Reporting: For at least five input from the public; and years, starting one year after the release of the strategy described above, the (2) Develop a long-term strategy Biotechnology Working Group will to ensure that the federal produce an annual report on specific regulatory system is equipped to steps that agencies are taking to assess efficiently the risks, if any, implement that strategy and any other associated with future products

10 steps that the agencies are taking to improve the transparency, coordination, predictability, and efficiency of the regulation of biotechnology products . This report will be made available to the public by the Executive Office of the President .

The OSTP blog item states that the administration recognizes the importance of public engagement throughout this process . As part of this process, the administration will hold three public engagement sessions over the year in different regions of the country . The first listening session will occur in Washington, D .C . in fall 2015 . According to the blog, the update to the Coordinated Framework will undergo public notice and comment before it is issued in final . The blog item includes a link to sign up to be kept up to date on these activities .

11 Federal Food, Drug, and Cosmetic Act

The Food and Drug Administration’s (FDA) be followed for the material’s regulatory oversight under the Federal Food, Drug, and approval, if any . The approval process for Cosmetic Act (FFDCA) is vast . According to a cosmetic ingredient use, for example, is FDA, 20 cents of every dollar spent in the considerably different from the approval U .S . relates to products FDA oversees 12. process for the same substance’s use as a The legal and regulatory framework pertinent food additive . As science and biotechnology to any specific commercial product varies evolve, new approaches to producing considerably and, as such, complicates an drugs, food additives, and cosmetics are effort to draw useful general rules that will rapidly emerging . Regulatory initiatives and apply to the products of new technologies 13. new laws, including the Food and Drug As discussed in depth in an insightful Administration Modernization Act of 1997 scholarly analysis, a consistent theme running (FDAMA) and the Food Safety Modernization throughout the regulatory construct is that Act of 2011 (FSMA), expand upon the ways governance under the FFDCA largely turns on FDA can improve its governance to address the concept of a statutorily defined “product” scientific advances . The core regulatory rather than a defined manufacturing process construct under the FFDCA, however, of which the product of concern is an and the enormous regulatory bureaucracy endpoint 14. built around it challenge the efficient and comprehensive review of products of all new As the Paradise and Fitzpatrick article technologies, including synthetic biology . discusses, the rigidity of an approach driven by statutorily defined “products” makes it A detailed overview of FDA’s authority to less than nimble in the context of synthetic evaluate products of biotechnology is beyond biology . Both the inflexibly defined products this report’s scope . An excellent summary and the separate FDA “Centers” that regulate of FDA’s regulation authority is found in the them contribute to a balkanization of the Venter Report 15. As noted in that report, review process . The inevitable, compart- FDA’s authority is limited to assessing mentalizing “silo” effect that results from human and animal health as FDA has no THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF this approach poses recurring challenges to authority to assess the impact of products FDA’s ability effectively to oversee products of biotechnology on broader ecosystems . that straddle the definitional bright lines that FDA regulatory decisions may trigger were drawn by Congress decades ago, well environmental impacts addressed under the before synthetic biology and other emerging National Environmental Policy Act (NEPA), technologies became real-world regulatory but NEPA bestows no new authority to FDA puzzles . or other federal agencies to address any potential risks that may be identified 16. FDA oversight of a “product” is premised on the concept of intended uses . How a Products of synthetic biology are subject to material is used dictates the process to FDA regulation in several contexts . Biotech-

12 nology-derived drugs and medical devices regulates most familiar biological products have been routinely renewed by FDA going -- such as insulin, glucagon, and growth back to the early 1980s,17 and they will be of hormone -- under the same regulations and increasing interest now and in the foreseeable rubrics as traditional small molecule drugs . future due to the ever-growing research activities in these areas and initiatives The regulatory pathway then splits, based on to commercialize them . FDA makes no whether the article involved is a “new drug” or a “new animal drug,” although both are distinction between traditional recombinant subject to pre-market testing requirements techniques and synthetic ones . “Drug” is the to demonstrate safety and efficacy before fundamental, statutorily-defined term that they can be commercialized, and previously- underpins FDA’s regulatory activities in this approved applications may be withdrawn area . For purposes of the FFDCA, it means, for a variety of reasons after notice and an in relevant part: opportunity for comment . Post-approval (A) articles recognized in the official oversight of manufacturers’ obligations in the United States Pharmacopoeia, official case of human drugs has been a matter of Homeopathic Pharmacopoeia of increasing focus 20. the United States, or official National Formulary, or any supplement to any of An application for a new human drug (NDA) them; and will be subject to FDA’s most thorough and rigorous pre-approval testing, which requires (B) articles intended for use in the a commitment of time and substantial diagnosis, cure, mitigation, treatment, expense for the developer . A new animal or prevention of disease in man or drug application (NADA) will follow a pathway other animals; and that is similar in many, but not all, respects, including a less extensive post-market (C) articles (other than food) intended to oversight regime . To the extent that animals affect the structure or any function of -- and animal “drugs” -- come to reflect the the body of man or other animals; and products of genetic engineering, it is highly (D) articles intended for use as a likely FDA will pay more attention to activities component of any article specified in in this realm . The Paradise and Fitzpatrick clause (A), (B), or (C) . . . 18. article cites FDA’s articulated position that once an NDA or an NADA for an rDNA FDA has long recognized and regulated drug obtains approval, a food that bears or biologics, a sub-set of drugs derived contains that rDNA drug “is not considered from living materials -- human, animal, or adulterated if used in accordance with microorganisms . Chemically synthesized the conditions and indications approved small molecular weight drugs generally have a by the FDA .”21 This includes “an rDNA well-defined structure and can be thoroughly construct” in a genetically engineered animal, characterized . In contrast, biological products including animals used for food, for which are complex in structure, and thus are usually FDA approval has been granted . “Thus,” not fully characterized 19. FDA generally according to Paradise and Fitzpatrick, “the

13 FDA will approve two articles when the and the end user of a food substance to product is a food that humans will consume: ensure that the use of the food substance is (1) the construct as an animal drug and safe and lawful .”25 Identity, technical effect, (2) the food containing that construct as a self-limiting levels of use, dietary exposure, food safe for human consumption .”22 FDA and manufacturing processes are a few of then, as required, will amend its animal the considerations explored by FDA in this drug regulations accordingly . Paradise and Guidance, which should be required reading Fitzpatrick point to regulations adopted for for developers of new technologies subject to rDNA products in goat’s milk as an example the FFDCA . of what must occur from a regulatory standpoint and observes that, to date, the Applications of synthetic biology used rDNA goat’s milk regulation is the only entry to produce food additives or cosmetic 26 in FDA’s regulations on new animal drugs in ingredients invite many questions about genetically engineered animals 23. these factors in the evaluation process much like the inclusion of nanomaterials on a Where FDA is asked to oversee a different manufacturing process . Cosmetics in most category, or categories, of products in a instances are not heavily regulated by FDA, regulatory framework that pre-dates them, but the presence of “something new” may the role of agency guidance can be vital to bring an otherwise ordinary cosmetic into developers seeking to devote resources FDA’s regulatory ambit . Whether producing appropriately and also to ensuring that a flavor additive or a cosmetic ingredient, safety concerns throughout the lifespan of for example, using synthetic biology results the product are explored and addressed . in something new that requires pre-market In a series of guidance documents issued approval by FDA is unclear in the abstract, in June 2014, FDA has taken initial steps but it poses an issue of which to be to address new and/or novel technologies aware . An additive that is intended to alter and existing substances in its oversight certain food properties is considered to role 24. While these FDA guidance documents have a “technical effect” and thus requires focus specifically on nanotechnology, the pre-market review prior to use . Changes message is equally applicable to other in a food additive could result in alterations emerging fields, including synthetic biology . to the food that could materially impact THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF A specific Guidance document alerts assumptions made during the pre-market manufacturers to the potential impact of any review process and upon which the approval, significant manufacturing process change in part or whole, was based . It is not always on the safety and regulatory status of food clear, however, who exactly decides, and substances . FFDCA requires industry to what changes trigger a technical effect that consider the basic fundamentals under would occasion FDA’s regulatory oversight . Sections 402 and 301 (adulteration and It is precisely for this reason FDA issued the misbranding, respectively) and this Guidance Guidance, which is just that, guidance and reminds the regulated community that “it is not binding on the agency . the responsibility of both the manufacturer

14 Oxitec Case Study

Context Current methods for controlling populations of these mosquitos include eliminating their The yellow fever mosquito, known as Aedes preferred habitats (standing water in and aegypti (A. aegypti), has been known to around homes); wearing protective clothing carry and transmit viruses, including yellow to prevent bites (i.e., long sleeve shirts, fever, dengue fever, and chikungunya, pants, socks); applying insect repellents; according to the Centers for Disease Control and spraying pesticides . Spray application and Prevention (CDC) 27. A. aegypti is native of pesticides is documented as achieving to Africa, but has spread to other tropical approximately 50 percent reduction in and subtropical regions, where it prefers mosquito populations 28. This low reduction to occupy and produce offspring in open rate is attributed to their preferred habitat waters with organic matter near populated being in close proximity to residential homes residential areas . Only the female mosquitos and the difficulty in eradicating them using bite and must feed on blood, preferably (but spray methods . not limited to) human blood, to lay eggs . This feeding behavior of the female mosquito is Description of the new technology a key element in the transmission of disease Oxitec, Ltd . (Oxitec), a privately-held to humans . The lifespan of the A. aegypti is company organized under English law,29 has around three weeks . Its eggs, however, can developed a genetically engineered mosquito survive in favorable climates for six months or strain by micro-injection of rDNA into A. longer . aegypti eggs designed to kill the subsequent offspring 30.

15 The Oxitec rDNA construct contains a Sterilization for population reduction has dominant lethal gene that is repressed in had favorable results in controlling insect the presence of adequate concentrations of populations in other species, but has tetracycline . Mosquitos expressing the rDNA not been possible for mosquitos due to transgene are dependent upon the presence technical and regulatory issues . The genetic of tetracycline for their survival . Viable adults modification of these RIDL mosquitos resulting from the micro-injected eggs includes a fluorescent marker for tracking were mated in the laboratory to wild-type them once they are released into the wild, mosquitos, and the resulting hatched as well as the tetracycline controlled kill larvae were screened for expression of the mechanism used to limit the lifespan of fluorescent marker that was also coded in the modified transgenic mosquitos and, the rDNA plasmid vector . The heterozygous in the absence of genetic recombination transgenic strain is described as having a events, preventing the transmission of the single copy of the rDNA construct at a single rDNA construct to future generations of A. site in the mosquito genome . Transgenic aegypti in the wild . The low transformation heterozygotes are sorted by sex at the pupal efficiency described for this rDNA construct stage and, for purposes of implementing the in Phuc’s 2007 publication suggests that insect control approach dubbed Release of spontaneous genetic recombination between Insects carrying a Dominant Lethal (RIDL),31 the rDNA construct and wild type DNA is males would be released from the controlled unlikely, but this is one of the points that environment of the insectary (lab) into the must be addressed with actual data during wild to mate with wild A. aegypti females the regulatory approval process . Phuc’s before dying due to the de-repression of 2007 publication’s description of the strain their dominant lethal gene in the absence from which the current Oxitec transgenic of sufficient dietary tetracycline that is mosquitos are derived also notes that available in their supplemented feed within 3-4 percent of the progeny resulting from the insectary, but not in the wild . Half of the breeding transgenic males with wild type progeny of these RIDL/wild type crosses females resulted in transgenic adults that are expected to be RIDL heterozygotes, survived in the absence of tetracycline . The and half are expected to be wild type . In the precise genetic status and reproductive

THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF absence of dietary tetracycline supplementa- capabilities of transgenic mosquitos that do tion, however, the RIDL larval offspring will not express the dominant lethal trait in the die before reaching the pupal stage, whereas absence of tetracycline is also important in the wild type offspring will be unaffected the assessment of this novel technology . genetically, but may suffer adverse effects due to competition for nutrients with the Discussion of the legal and doomed RIDL larvae . According to Oxitec, procedural issues releasing the appropriate number of RIDL males into the wild could achieve an overall FDA defines “drug” to mean an article 90 percent reduction in the treated A. aegypti “intended for use in the diagnosis, cure, population . mitigation, treatment, or prevention of disease in man or other animals” and/or

16 an article “intended to affect the structure enforcement action if the agency becomes or any function of the body of man or aware of a safety concern . In 2003, FDA other animals .”32 The introduction of a new posted a statement for aquarium fish that modification to the structure or function of the were modified to contain genes that were body of man or animal is, by FDA definitions, fluorescent and not for food use . FDA creation of a new drug . The management concluded that this use of a genetically of drugs within FDA is divided between new engineered animal posed no more of a threat human drugs, as administered by the Center than their “unmodified counterparts .”34 FDA for Drug Evaluation and Research (CDER) conducts a review to comply with NEPA or the Center for Biologics Evaluation and when it reviews and approves an INAD or Research (CBER), and new animal drugs, NADA . NEPA requires federal agencies to as administered by the Center for Veterinary describe in detail and assess the anticipated Medicine (CVM) . New animal drugs are drugs impacts of all “major Federal actions intended for use in animals other than man; significantly affecting the quality of the human animals are further divided into minor and environment .”35 No NEPA review would major species . FDA includes cattle, horses, occur, however, when FDA exercises its swine, chickens, turkeys, dogs, and cats enforcement discretion . among major species and designates all other animals as minor species . FDA defines The Oxitec example in this case study is unique in many ways genetically engineered animals as “those . The field trials animals modified by rDNA techniques, Oxitec proposed include the release of a including the entire lineage of animals that genetically engineered minor species into the environment for population control of contain the modification ”. 33 The Oxitec insects carrying human diseases genetically engineered A. aegypti strain could . Release be regulated by FDA as both a minor species of genetically modified insects to mitigate new animal drug that is subject to pre-market human disease is relatively uncharted territory notification processes through CVM and as for FDA . The release into the wild means an article for the mitigation of disease in man FDA’s enforcement discretion will not be that is subject to the requirements for new exercised, and that CVM will enforce full pre-market approval as a new animal drug human drugs . . The decision regarding CVM jurisdiction with CVM guidance for genetically engineered this case study has been, and continues to animals (GFI 187) indicates that all genetically be, debated . Genetically engineered insects engineered animals are subject to pre-market being developed for plant pest control are approval requirements . FDA has indicated considered under the oversight of USDA’s that, in certain cases, it may not enforce APHIS . Previously approved FDA anti-malaria the requirements for an investigational drugs manufactured using synthetic biology new animal drug (INAD) or a NADA and techniques were managed by CDER/CBER, intends, in such cases, to post this on its not CVM . The reason for this decision is that website . FDA is always authorized to initiate the drug for mitigation of human disease was

17 produced by a modified organism, rather dosage, intended use, and potential than the modified organism mitigating the environmental impact information . The species responsible for causing the disease . process is typically done in cooperation with The Oxitec mosquito could be considered an CVM’s Office of New Animal Drug Evaluation article for mitigating disease . Environmental through the opening of an INAD file . There is group Friends of the Earth (FOE) opines in an a fee structure associated with these activities Issue Brief on this matter that this intended as required through the Animal Drug User Fee use of genetically engineered mosquitos Act of 2003 (ADUFA) 39. This fee structure also “should be considered a medical trial and includes detailed timelines for responses the must follow the strict laws and guidelines in agency must provide for the various aspects place to protect human subjects in medical and steps of the NADA process . trials .”36 FOE believes that this includes free and informed consent by all humans in the The NADA general application provisions release area 37. are detailed in 21 C .F .R . Part 514 . The requirements generally include the following: GFI 187 indicates a new animal drug is Basic identification details on the nature of the deemed unsafe unless FDA has approved it application, and the trade name and location through a NADA for that particular use . There of the applicant are exemption processes for conditional . For genetically engineered approval and indexing unapproved inves- animals, the details on the rDNA construct, tigational animal drugs for the purpose including the number and characterization of of pursuing safety and effectiveness the insertion sites is also necessary . investigations by trained scientific experts . A summary of the chemistry, clinical The Minor Use and Minor Species Animal purposes, and laboratory and clinical studies Health Act of 2004 also provides additional is included . options for streamlined pre-market approval for minor species and treatment Proposed labeling for adequate instructions of uncommon diseases in major animals . for use must accompany the application . The None of these exemptions or streamlined labeling for genetically engineered animals approaches applies to genetically modified should include a description of the common animals 38. The NADA process involves a name, genus, and species with instructions THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF detailed demonstration that the drug in its for handling throughout the animal’s lifecycle . intended use is safe and effective, not only Details on the composition and components to the animal itself, but also to any food utilized in the production of the drug . The GFI products derived from the treated animal . 187 recommends providing the molecular The process also includes consideration of characterization of the article in sufficient potential environmental impacts and safety detail to facilitate evaluation of potential risks assessments for those responsible for due to genetically engineered animal rDNA administration of the drug . that might encode pathogens, toxicants, Developing a NADA requires extensive allergens, mobile DNA sequences, or technical data supporting the proposed sequences that deregulate growth control .

18 Extensive details on the manufacturing how genetically engineered animals are to methods, production facilities, and controls “commit to cGMP” aspects of this process at to allow for sufficient evaluation that the a later date . Non-clinical studies are expected methods described will “preserve the identity, to be conducted in compliance with the strength, quality and purity of the new animal Good Laboratory Practice regulations in drug” are to be provided 40. Evaluation of 21 C .F .R . Part 58, and the reason for any any “interruption of a coding or regulatory non-compliance must be provided . region (insertional mutagenesis)” is also recommended in the GFI 187 41. Each application is to include a claim for categorical exclusion or an environmental CVM could, upon request, also require four assessment that demonstrates that the new identical sets of representative samples animal drug or the genetically engineered for each strength of the finished dosage animal will not significantly impact the quality with all the articles used as components of the human environment . along with reference standards and detailed analytical assaying procedures used to These details are assembled in accordance determine quality specifications . This can with 21 C .F .R . § 514 .1(b)(15), and submitted include detailed experimental protocols to CVM for review . for establishing dosage, and when used Conferences with CVM prior to submission in animals that are also a food source, of a NADA are described in 21 C .F .R . § substantial information on tissue residuals 514 .5 and include conducting field studies, and elimination rates . Samples of the if necessary . Oxitec is currently seeking genetically engineered animal could also be approval to conduct field studies within the required, upon request . CVM encourages United States . Oxitec reports field trials have specific dialogue as part of the INAD file, been and are ongoing in other locations, and as to how to address this aspect of the discussions are currently ongoing with FDA application process . as part of their INAD . The NADA approvals The application is to include evidence of the in general are carried out in stages, and the reviews involve experts in many areas establishment of safety and effectiveness, of science, including veterinarians, animal including proposed labeling . This evidence scientists, biostatisticians, chemists, microbi- must include reports of all the tests, scientific ologists, pharmacologists, and toxicologists 42. literature, and clinical investigations utilized to support the claims, including favorable and All aspects are reviewed, including the product’s final labeling, packaging, and unfavorable results . possible directions for use, prior to CVM Commitments to manufacture in accordance approval . Review of genetically engineered with current Good Manufacturing Practices animals may involve inclusion of addition (cGMP) and conform to advertising technical experts and possible interaction requirements are included in the application . with other agencies (i.e., EPA, CDC, and FDA has indicated it will provide guidance for USDA) . Interactions with EPA and CDC have

19 been part of the ongoing Oxitec field trial used for animal population control as animal discussions within CVM . After the NADA drugs is guiding FDA and the other regulatory is complete, the approval process requires stakeholders in determining a regulatory notification through the Federal Register . pathway for the Oxitec mosquito . As with Once approved and listed in the Federal almost all FDA-related regulatory inquiries, of Register, any significant changes as detailed equal importance is the initial determination in 21 C .F R. . § 514 .8 must be re-substantiat- of the product’s “intended use .” Here, Oxitec ed through a supplemental approval process . and other stakeholders have been careful to describe the use of the product as limiting All approved animal drugs are expected or controlling the population of certain to maintain all aspects of the processes mosquitos . Notably, the product makes detailed in their application in accordance no claim to prevent or mitigate disease in with FDA regulations at all times, and are humans; the product only claims to control or subject to inspection . All adverse events are reduce the population of certain mosquitos . to be investigated and reported . Drug listing, recordkeeping, and periodic reporting are The Oxitec mosquito control technology is all required post-approval . Any significant a novel case for CVM because it employs deviation in quality controls, equipment, rDNA technology in an organism that is facilities, labeling, etc ., must be reviewed and intended to be released into the wild, not approved prior to sale or distribution . simply used to produce an animal drug that would then be used under controlled The legal and regulatory takeaway conditions . Nonetheless, limiting the Oxitec product’s claim to one already within the The intricate details and ongoing jurisdictional ambit of CVM’s prior regulatory experience debate are interesting parts of this complex supports the rationale for regulating the case study . An argument could be made Oxitec mosquito as an animal drug . Any that a technology designed to control a pest future claims that this technology prevents or should be regulated by FIFRA . As discussed, mitigates human disease -- such as dengue past genetically engineered pest control fever or chikungunya -- rather than simply technologies have fallen under the jurisdiction controlling a mosquito population would likely of APHIS . Technologies that control animal raise questions of whether the technology THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF populations by sterilization, however, have is a human drug, and thus subject to CDER been regulated by CVM . Some argue that if jurisdiction . the Oxitec mosquitos are primarily intended to prevent or mitigate a human disease, the Given the complexity of the jurisdictional product should be regulated as a human gauntlet, it is completely unclear how a drug rather than as an animal drug . new product developer would begin the regulatory approval process, as none of After review and consultation, however, the these issues is intuitively self-evident . Little various regulatory authorities determined that guidance exists to direct private entities to the Oxitec mosquitos are most appropriately the appropriate government office to begin regulated by CVM as an animal drug . CVM’s the review process, let alone outline what that precedent of regulating other animal sterilants

20 process is, how long it might take, and how unclear the jurisdictional divide is and how much it might cost before the product can be even the government can be at a loss to commercialized . These are business realities specify which agency has the lead, let alone that must be known to bring a product to outline coherently what the review process market . This case study crystalizes just how might include .

Synthetic Squalane Case Study

Context component of sebum, an oily fluid produced by the sebaceous glands . Squalane -- a cosmetic ingredient that functions as an emollient in lotions and As shark liver oil contains the greatest yield moisturizers -- has been used as a softener potential for squalene, the manufacturing for more than 25 years, according to process to produce squalane often involves the Personal Care Council’s Cosmetic molecular distillation of shark liver oil and Ingredient Review (CIR) 43. Squalane is the hydrogenation of the distillate, followed by saturated branched chain hydrocarbon form a re-distillation step to produce a purity of of squalene . The CIR indicates squalene about 96 percent squalane . The use of shark is a triterpene polyunsaturated aliphatic liver oil is controversial as some species hydrocarbon that is naturally occurring in of shark are listed as endangered and/ large quantities in shark liver oil and other or threatened by the U .S . Fish and Wildlife fish oils and in smaller amounts in plants (i.e., Service 44. Manufacturing squalane using plant olive oil, wheat germ oil, rice bran oil, palm sources is an alternative option . Indications oil) . Squalene also exists in humans as a are the squalene concentrations are much

21 lower in plant sources and costs can be of color additives, do not require FDA prohibitive for cosmetic formulators . approval prior to use in commerce . There are specific ingredients that are prohibited Description of the new technology for use in cosmetics49 and FDA considers any ingredient that can impart a therapeutic As reported in the New York Times on May response or affect the structure or function of 30, 2014, a synthetic biology version of the body to be a drug, not a cosmetic . squalane, manufactured by biotechnology firm Amyris, is commercially available for use For squalane, the intended use as an as a cosmetic ingredient 45. Amyris, according emollient in lotions and moisturizers would to its website, uses “synthetic biology to be considered within FDA’s jurisdiction as a produce target molecules .”46 Based on cosmetic ingredient, provided the intended public information, the production appears to use does not violate the fundamental involve proprietary yeast strains that convert concepts described above (e .g ., does sugar to produce various hydrocarbons of not imply a therapeutic or drug use), interest, in this case, squalane . and it otherwise comports with the basic principles of adulteration and misbranding Discussion of the legal and as defined in FFDCA Sections 402 and 301 . procedural issues Cosmetic manufacturers are expected, but not required, to comply with the FDA FDA regulates cosmetics and other general principles of Good Manufacturing substances under the FFDCA . Under Practices (GMP) . FDA has developed a draft FFDCA, cosmetics are defined to include guidance document50 for the GMP process “(1) articles intended to be rubbed, poured, that provides non-binding recommendations sprinkled, or sprayed on, introduced into, for companies intending to manufacture or otherwise applied to the human body or cosmetics in compliance with GMPs . Under any part thereof for cleansing, beautifying, the general misbranding and adulteration promoting attractiveness, or altering the provisions of the FFDCA, however, FDA appearance, and (2) articles intended for has the authority to pursue enforcement use as a component of any such articles .”47 actions against cosmetic products that are Soap, as defined by FFDCA, is excluded not compliant with the law or regulations . THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF from the definition of a cosmetic because The burden of safety and demonstration of of compositional distinctions and intended intended use fall squarely on the cosmetic uses and is regulated separately by the industry . Consumer Product Safety Commission 48. FDA regulates cosmetics in commerce Finished cosmetics are required to be labeled under its FFDCA authority in conjunction correctly in accordance with FDA and FPLA with the Fair Packaging and Labeling Act statutes and regulations . Cosmetic claims on (FPLA) as administered by the Federal Trade the product label, in promotional literature, Commission (FTC) . Cosmetic ingredients advertising, trade press, and packaging are and finished cosmetics, with the exception critical in assessing compliance with technical

22 regulatory provisions and in determining a derived from synthetic biology but labeled product’s intended use . The requirements in the same manner as a substance usually are set forth in 21 C .F .R . Parts 701 and extracted from conventional sources 740 . The requirements for the declaration of misbranded as defined in Section 301? ingredients are found in 21 C F. .R . § 701 .3 . An even more consequential issue for the FDA states that the ingredients must be private sector is that FDA’s authority in the identified in one of the following ways: by area of cosmetics and cosmetic ingredients being specifically mentioned in 21 C .F .R . § is more limited than in other areas, such as 701 .30; as defined by the Cosmetic, Toiletry for drugs or biologics and Fragrance Association, Inc . (CTFA), the . FDA currently lacks United States Pharmacopeia (USP), National authority to require pre-market approval for cosmetic ingredients (except for color Formulary, Food Chemicals Codex, U .S . additives) Adopted Names (USAN), and USP dictionary . Moreover, FDA’s approach for of drug names; or in absence of being oversight tends to be reactive rather than specifically listed, through the use of a name proactive for this category of product . In that is generally recognized by consumers or short, cosmetics -- whether produced conventionally or through synthetic biology a chemical or other technical name 51. In this techniques -- are not subject to regulatory case, the labeling declaration requirements risk assessment prior to market entry, yet on the finished cosmetic could raise an issue the products are distributed and used by of proper identification with respect to the consumers, arguably the most vulnerable synthetic biology squalane because there and least aware of the consequences of is no recognized or accepted standard to exposure and misuse identify and distinguish squalane produced . The regulatory burden through synthetic biology . remains solely with the cosmetic industry to demonstrate cosmetic and cosmetic The legal and regulatory takeaway ingredients are safe and do not impart any poisonous or deleterious substances that A key issue is whether squalane produced could result in injury to the health of the user, using synthetic biology and generated from or consist, in whole or in part, of filthy, putrid, engineered yeast rather than derived from or decomposed substances . known historical sources (such as shark or olive oil) is considered the same ingredient FDA regulates cosmetic ingredients, whether for regulatory purposes as those currently conventional or from synthetic biology, in commercial use in marketed cosmetic primarily through a process that allows FDA products . Or, conversely, is the synthetic to take action after a product is on the market biology version something different and more if there is evidence that it is causing harm to appropriately described using a descriptive humans or animals . Guidance for industry on generic name? The compliance issue for the FDA’s “current thinking” about how cosmetics cosmetic industry and FDA could be one of can be manufactured in accordance with interpretation of FDA’s current labeling and GMPs is available, but compliance is not enforcement requirements: Is an ingredient mandatory .

23 The key regulatory tools available to FDA squalane source included in the ingredient to regulate risk from cosmetic products label renders the product misbranded for are enforcing ingredient labeling and failure to comply with FDA cosmetic labeling product claims . Currently, products that regulations . include ingredients like squalane derived from synthetic biology use conventional As the cosmetic industry expands its use of labeling and nomenclature to identify synthetic biology in formulating ingredients them . FDA has not yet addressed whether and products, it is essential carefully to monitor enforcement trends and policy cosmetic ingredients from synthetic biology statements from both FDA and FTC are sufficiently the same as those from . As conventional sources to allow use of the these agencies grapple with the implications of synthetic biology in the context of their same nomenclature . current, limited and somewhat outdated The claims used to describe the attributes of regulatory structures, it would be prudent ingredients produced from synthetic biology for industry to exercise judicious scrutiny of may also present a novel enforcement ingredient labeling and proposed claims for issue for FDA and industry . It is unclear, cosmetic products to avoid any potential for example, whether it is appropriate and interpretation that would describe a non-misleading under FDA and the FTC’s therapeutic intention (potentially rendering regulations to claim an ingredient is “natural” the product an unapproved new drug) or if it is the product of genetic manipulation fall beyond the scope of required labeling of a non-conventional source . Similarly, (potentially misbranding the entire product) . it is unclear whether identification of the THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF

24 Federal Insecticide, Fungicide, and Rodenticide Act

Pesticides are regulated by the Environmental contains more active ingredients and has Protection Agency (EPA) under the Federal no significant commercially valuable use Insecticide, Fungicide, and Rodenticide Act as distributed or sold other than use for a (FIFRA)52 and the FFDCA,53 as amended in pesticidal purpose, by itself or in combination 1996 by the Food Quality Protection Act with any other substance, or use for (FQPA) 54. FIFRA defines a pesticide broadly manufacture of a pesticide; or (3) the person as “any substance or mixture of substances who distributes or sells the substance has intended for preventing, destroying, repelling, actual or constructive knowledge that the or mitigating any pest .”55 EPA regulations substance will be used, or is intended to be further define the term “pesticide” as “any used, for a pesticidal purpose 60. substance (or mixture of substances) intended for a pesticidal purpose, i.e., use Under FIFRA, new pesticides must be for the purpose of preventing, destroying, registered with EPA before they can be commercially marketed repelling, or mitigating any pest .”56 FIFRA . As FIFRA is a risk/ defines the term “pest” broadly to mean “(1) benefit statute, EPA must balance the any insect, rodent, nematode, fungus, weed, benefits offered by a pesticide against or (2) any other form of terrestrial or aquatic any potential risks it might pose in making plant or animal life or virus, bacteria, or other the registration decision . It is noteworthy, micro-organism (except viruses, bacteria, or however, that registration of a pesticide other micro-organisms on or in living man or for food uses where there are pesticide residues requires the establishment of a other animals) .”57 In addition to a chemical tolerance, and the standard applicable to that substance, as that term is commonly tolerance decision does not require a benefits understood, a pesticide substance also may assessment be a microbial agent58 or a plant-incorporated . 59 protectant (PIP) . More specifically, to register a pesticide FIFRA is heavily reliant upon the concept of under FIFRA, EPA must determine, among other issues, that the pesticide when intended use . EPA considers a substance used as intended “will not generally cause to be intended for a pesticidal purpose, and unreasonable adverse effects on the thus to be a pesticide requiring registration, environment” when the pesticide product if: (1) the person who distributes or sells the is used as intended substance claims, explicitly or implicitly, that . FIFRA defines the the substance can or should be used as a term “unreasonable adverse effects on the pesticide or consists of or contains an active environment” to mean: “(1) any unreasonable ingredient and can be used to manufacture risk to man or the environment, taking a pesticide; (2) the substance consists of or into account the economic, social, and

25 environmental costs and benefits of the enforcement options under FIFRA to proceed use of any pesticide, or (2) a human dietary against unregistered nanopesticides or those risk from residues that result from a use of found to cause unreasonable adverse effects a pesticide in or on any food inconsistent on human health or the environment . EPA with the standard under section [408 of the therefore has the authority under FIFRA to Federal Food, Drug, and Cosmetic Act .]”61 prohibit the use of nanopesticides presenting In other words, benefits are to be taken into unreasonable adverse effects, and may account for the FIFRA decision itself, but if a restrict other nanopesticides so as to ensure food use tolerance is required for a particular that risks do not become unreasonable . registration, however, EPA must also find with “reasonable certainty” that “no harm EPA’s Office of Pesticide Programs (OPP) will result from aggregate exposure to the is organized into various divisions . The pesticide residue .” Biopesticides and Pollution Prevention Division (BPPD) reviews applications for Persons wishing to register a pesticide the FIFRA registration of pesticides derived under FIFRA must provide significant data from natural materials and microorganisms . demonstrating that the product meets In general, there are three categories of the applicable EPA safety and registration biopesticides . Microbial pesticides are standards, much of it specifically enumerated pesticides that have a microorganism as in EPA regulations and guidance documents . the active ingredient . Bacillus thuringiensis Because FIFRA is product and application (Bt) is an example . The bacterium produces specific, EPA has significant authority over a protein that in turn kills the larvae of products considered to be pesticides, even targeted insects . Biochemical pesticides are when emerging technologies are involved . naturally-occurring substances that control The American Bar Association (ABA) analyzed pests by nontoxic mechanisms; they include FIFRA’s authority to oversee pesticidal hormones, natural plant regulators, and products using nanotechnology, another pheromones . These nontoxic mechanisms emerging technology, and determined interfere with the growth or mating of targeted that EPA has considerable authority under pests . A PIP is a pesticidal substance that FIFRA to prohibit, condition, or allow the plants produce from genetic material that manufacture and use of nanopesticides . Its has been added to the plant . EPA provides THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF regulatory tools include regulation of pre- as an example taking the gene for the Bt registration research and development (R&D) pesticidal protein and introducing that gene through EUP; requirements for pre-regis- into a plant’s own genetic material . With the tration testing; the registration requirement, introduction of the gene, the plant, instead which requires development of data and can of the Bt bacterium, manufactures the impose limits on the use and handling of a substance that controls targeted pests . EPA nanopesticide; requirements for registrants states that in this instance, the protein and its to submit post-registration adverse effects genetic material, but not the plant itself, are information; possible requirements for regulated by EPA . These genetic materials post-registration testing; and reregistration can be introduced to plants either through requirements . Additionally, EPA has strong conventional breeding techniques or through

26 more modern biotechnology techniques . other than those otherwise exempted . Containment and monitoring methods Under FIFRA, the statutory definition must be specified in the notice 62. The of pesticide tur ns on the intent of the Biotechnology Notification Process (BNP) for manufacturer to produce a pesticide, not release of a genetically engineered microbial on its manufacturing process . Accordingly, pest control aspect requires review and EPA has interpreted its regulatory authority approval by EPA prior to commencing experi- to include plants that have been genetically mentation 63. The review process is relatively modified through rDNA techniques as they short as EPA intended the BNP to apply to are substances that are fundamentally smaller field test plots of less than an acre . intended for “preventing, destroying, repelling, or mitigating any pest” within the Registration under FIFRA Section 3 for a statutory definition of the term under FIFRA . microbial pesticide is data intensive . The EPA has articulated its position in a series requirements are set forth at 40 C .F .R . § of Federal Register notices that describe its 158 .2120- .2150 and consider, among legal position . other endpoints, potential adverse effects to non-target organisms, environmental EPA’s regulatory program for the registration fate of the microorganism, toxicity, and under FIFRA of biopesticides and natural and pathogenicity . EPA issued the first Section genetically modified microbial materials is 3 registration for a microbial pesticide under comprehensive and well-defined . Research FIFRA to Mycogen Corporation in 1991 for activities are also regulated by EPA, but less two pseudomonas fluorescent strains that robustly . Under the controlling rules, with were genetically engineered to express two exceptions for certain types of testing that types of delta endotoxin genes from Bt for meets specified criteria for research testing, insect control . The registration process for notification must be submitted to EPA at least this product began at least five years earlier 90 days before conducting a small scale test when Mycogen began working with EPA on of a genetically modified microbial pesticide

27 Biopesticide Case Study

small scale field testing . human health or the environment . Context Description of the technology

Pesticides regulated under FIFRA by Pheromones are chemicals secreted by EPA include what may be considered both humans and animals that trigger a “conventional” pesticides and pesticides social response from members of the same derived from natural materials and species (attracting potential mates or in ants microorganisms . Biopesticides are divided being able to lead others to a food source) . into three groups -- microbial pesticides, While they have long been used as effective THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF biochemical pesticides, and plant-incor- attractants for traps, pheromones are often porated protectants -- and are typically difficult and expensive to synthesize . In considered by EPA to be “reduced risk 2014, an International Genetically Engineered pesticides” because of their non-toxic mode Machine Foundation (iGEM)64 team from the of action . While EPA may have developed National Chiao Tung University65 in Taiwan programs to encourage the registration of realized that if they could stimulate female biopesticides, there are ongoing challenges insects to overproduce pheromones, the in determining jurisdiction, assessing the females themselves could be the bait that safety of experimental trials, and ultimately lures males into a trap . In nature, female determining that the biopesticide will not insects produce Pheromone Biosynthesis cause unreasonable adverse effects to Activating Neuropeptide (PBAN) to stimulate

28 the synthesis of pheromones66 to attract requiring FIFRA regulation . Among those males for mating . The iGEM team, which substances are “[p]heromones and identical was a finalist for the grand prize in the or substantially similar compounds labeled international undergraduate student synthetic for use only in pheromone traps (or labeled biology competition, developed a genetically for use in a manner which the Administrator modified strain of E. coli that produces determines poses no greater risk of adverse PBAN . The team mixes the synthetically effects on the environment than use in derived PBAN with a sugar solution, which is pheromone traps), and pheromone traps in then placed in a trap as food . Female moths which those compounds are the sole active enter the trap and eat the sugar solution ingredient(s) .”67 Synthetically produced containing PBAN . The PBAN ingested by compounds are considered “identical” to a the female moths induces them to produce pheromone when “their molecular structures pheromones, which then attracts male moths are identical, or when the only differences into the trap . As long as the females ingest between the molecular structures are the sugar/PBAN mixture, they will continue to between the stereochemical isomer ratios of produce pheromones and attract males . the two compounds, except that a synthetic compound found to have toxicological Discussion of the legal and properties significantly different from a procedural issues pheromone is not identical .”68 There is an important, but subtle, distinction in this case: Biochemical pesticides are among the FIFRA exempts pheromones, but PBAN biopesticides regulated by EPA . These is not a pheromone . PBAN is a hormone pesticides are naturally-occurring substances that acts upon female moths to stimulate that control pests by non-toxic mechanisms pheromone production, so PBAN itself is not and include hormones, natural plant eligible for the pheromone exemption and is regulators, and pheromones . Substances regulated by FIFRA . or articles intended to control bacteria and fungi in or on living humans or animals are If use of PBAN were not regulated under not intended for use against “pests” and thus FIFRA (i.e., if it were a pheromone), it could are not pesticides regulated under FIFRA . be subject to the provisions of TSCA69 or Instead, such substances are regulated under under the jurisdiction of other statutes, FFDCA by FDA . depending, among other factors, on the uses at issue . Note that if a pheromone is used Under the controlling rules, EPA would take in traps in conjunction with conventional the position that the use of a biopesticide pesticides, or in other application methods in a trap for purposes of mitigating (i.e., (other than traps), such that the exemption interfering with the growth or mating of was no longer applicable, the pheromone targeted pests) a pest (i.e., moth) would would be subject to regulation under FIFRA . require registration under FIFRA . On the If the use of the pheromone was intended other hand, EPA has determined that to control bacteria and fungi in or on living certain pesticides are not of a character

29 humans or animals, it would be subject to review periods, and lower fees compared regulation under FFDCA . To complicate to conventional registrations . BPPD also this issue, whether the microbe or PBAN is implements specific programs geared considered a pesticide could well depend towards certain biopesticides . One example on which is introduced into the trap . If the is its pheromones regulatory relief program microbe is used in the trap, it could likely that permits, in part, flexible confidential be considered the active ingredient . If, on statements of formula for pheromone the other hand, the microbe is used only to experimental use permits (EUP) to allow for produce PBAN and only the PBAN is used active ingredient adjustments during the in the trap, PBAN would likely be the active course of experimentation . ingredient regulated by FIFRA . In that case, the microbe could be considered a pesticide Even with the flexibility and benefits that BPPD pr intermediate regulated by TSCA . oducts have, there nevertheless remain certain challenges and complications The legal and policy takeaway companies must navigate through the regulatory process . As the PBAN case above EPA has acknowledged “that use of certain demonstrates, the same substance can types of pheromone products presents potentially be subject to TSCA, FIFRA, or lower risk than conventional pesticides and FFDCA depending on the intent and use of also acknowledges the unique properties of the technology at issue . In addition, although these niche-type products regarding their EPA’s policies are intended to incentivize the inherently narrow host range .”70 EPA’s BPPD registration of biopesticides, the registrant still focuses on all regulatory activities associated needs to generate data, seek EPA’s approval with biopesticides, with a particular focus for experimental testing, and otherwise on registering biopesticide active ingredients provide EPA with the information it needs to and end-use products, including certain assess whether the biopesticide will cause benefits available to biopesticide registration unreasonable adverse effects on human applicants, such as reduced data sets, faster health or the environment . THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF

30 Toxic Substances Control Act

The Toxic Substances Control Act (TSCA) appropriate criteria are met (e.g., for R&D regulates “chemical substances ”. Excluded chemicals) while others require submissions from TSCA and its implementing regulations to and affirmative action by EPA 72. are chemicals that are regulated under other statutes, including food, drugs, cosmetics, EPA interprets “manufacture for commercial purposes” broadly to mean “[t]o import, and pesticides . TSCA was enacted in 1976 in produce, or manufacture with the an era of growing concern about the potential purpose of obtaining an immediate or effects of chemicals in commerce on human eventual commercial advantage for the health and the environment and the lack manufacturer 73 of regulatory oversight . Congress intended .” As such, commercial TSCA to serve as a gap-filler: if a chemical R&D activities are subject to TSCA substance is not regulated under another regulation, including certain procedural and recordkeeping requirements statutory program, it is subject to TSCA . . By the same token, however, noncommercial R&D on Under TSCA’s authority, EPA implements chemical substances is not subject to TSCA . several regulatory programs related to This could include, for example, academic chemical risk assessment and management, research or that conducted by individuals and has promulgated rules for chemical as long as the activities do not meet EPA’s testing, recordkeeping, reporting, importing interpretation of commercial R&D . and exporting . Under TSCA Section 5, a chemical substance is “new” if it is not The Coordinated Framework provides listed on the TSCA Inventory of Chemical that the U .S . Government consider Substances, EPA’s master list of chemical microorganisms and their DNA and rDNA molecules as “chemical substances” as substances in the U S. . economy that are defined under74 75 manufactured or processed for “commercial and thus subject to TSCA . purposes .”71 If a chemical substance is not While this construction supported EPA’s development of its TSCA Biotechnology listed on the TSCA Inventory and it is not Program, it is not without controversy eligible for an exemption, then it must be . There notified to EPA before it is manufactured is no explicit basis in TSCA’s legislative in or imported into the United States for history to suggest Congress intended to include living microorganisms within the a commercial purpose . EPA is afforded a TSCA definition of “chemical substance 76 review period of not less than 90 days in .” which it must assess the notification and Chemical substance, nonetheless, is decide whether to regulate the chemical broadly defined and at their basic level, DNA molecules are chemical substances of “a substance or allow it into the U .S . economy particular molecular identity .” As noted by one without restriction . There also are exemptions commentator, this interpretation of chemical from the TSCA Inventory listing requirement, substance “leads inevitably to the conclusion some of which are self-executing if the

31 that plants and animals (including human meet any of several available exemption beings which are life forms teeming with procedures . EPA’s “intergeneric” policy is DNA molecules) fall within TSCA’s regulatory based on traditional genetic modification scope .”77 Regarding this last point, the techniques and the belief that the transfer of “commercial purposes” requirement noted genetic information from different genera is above effectively limits the scope of EPA’s more likely to create new or modified traits TSCA authority . that could present a risk 82. Commentators have noted, however, that synthetic biology In its biotechnology regulations, EPA states raises the possibility of introducing wholly that “new” microorganisms are those that synthetic genes or gene fragments (i.e., DNA are intergeneric and not already listed on sequences) that do not exist in nature into the TSCA Inventory . The regulation defines an organism and may enable scientists to “microorganism” as an “organism classified, remove a gene fragment from an organism, using the 5-kingdom classification system modify that fragment, and reinsert it back of Whittacker, in the Kingdoms Monera into the same organism . In either case, (or Procaryotae), Protista, Fungi, and the such organisms may not be “intergeneric” Chlorophyta and the Rhodophyta of the under EPA’s definition because they would Plantae, and a virus or virus-like particle 78 .” not include genetic material from organisms An “intergeneric microorganism” is a of different genera 83. Non-intergeneric microorganism formed by the deliberate genetically modified microorganisms currently combination of genetic material originally are not covered by any TSCA Section 5 isolated from organisms of different requirements, thus raising the possibility taxonomic genera 79 . An “intergeneric of a large gap in the TSCA regulation of microorganism” includes “a microorganism genetically modified microorganisms . which contains a mobile genetic element Synthetic biology modifications that were not which was first identified in a microorganism foreseen in the original regulation may have a in a genus different from the recipient greater probability of creating novel traits and microorganism .” It “does not include a risks than the traditional intrageneric transfers microorganism which contains introduced considered by EPA when it developed the genetic material consisting of only well-char- regulation . acterized, non-coding regulatory regions from THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF another genus .”80 EPA states that In an attempt to address preemptively the “[m]icroorganisms that are not intergeneric challenges of synthetic biology chemical are automatically included on the Inventory,”81 substances, EPA states the following on its because conceptually they are existing website regarding microorganisms that are chemical substances . the product of synthetic biology:

EPA’s implementing regulations require When defining “intergeneric microorganism,” manufacturers of new intergeneric in the case of chemically synthesized genes, microorganisms for commercial purposes to the Agency has followed a similar principle . submit a notification to EPA or to otherwise The genetic sequence of the synthesized

32 gene may be identical to a sequence known EPA expressed its concern about R&D to occur in an organism in the same genus activities with microorganisms because as the recipient microorganism . If so, the EPA believes that living microorganisms, resulting microorganism is considered unlike traditional chemical substances, intrageneric and thus not new . Conversely, may “reproduce and increase beyond the the sequence of the synthesized gene may number initially introduced, may establish be different or not known to be identical to in the environment, and may spread a sequence in the genus of the recipient beyond the test site .”86 Consequently, EPA microorganism, in which case, the resulting provided two types of R&D exemptions product is considered intergeneric . EPA for microorganisms . The first, known as a strongly encourages any manufacturer of a contained structure exemption, applies to new microorganism using synthetic DNA to R&D activities conducted with “containment contact the Agency 84. and/or inactivation controls” defined as “any combination of engineering, mechanical, Thus, unless a synthetic biology manufacturer procedural, or biological controls designed can demonstrate that the genetic sequence and operated to restrict environmental of the synthesized gene is identical to a release of viable microorganisms from a sequence known to occur in an organism structure .”87 Under this exemption, certain in the same genus as the recipient conditions must be satisfied in addition to microorganism, EPA takes the position that a the general requirements for an exemption microorganism produced by synthetic biology request, including, among others, that the is a new chemical substance subject to microorganism must be manufactured, TSCA Section 5 requirements . imported, or processed solely for R&D 88 These requirements can be met in any activities and not for a commercial purpose, of several ways that can involve EPA there must not be any “intentional testing of 89 notifications or exemptions from such a microorganism outside of a structure,” notifications depending on factors such the microorganism must be used by, or as whether the activity is for R&D or for directly under the supervision of, a technically 90 commercial use, and whether the activity qualified individual, as defined in EPA’s 91 is conducted in an enclosed structure or regulations, and the manufacturer, importer, it involves environmental release . TSCA or processor must notify all persons in its and EPA’s regulations provide that a employ or to whom it directly distributes the notification exemption application will not microorganism, that are engaged in ex- be granted unless EPA can determine that perimentation, research, or analysis on the the microorganism “will not present an microorganism “of any risk to health” that 92 unreasonable risk of injury to health or the may be associated with the microorganism . environment 85 .” For R&D activities that do not qualify for the In the preamble to the final rule setting contained structure exemption, EPA requires forth the microorganism regulations, the submission of a TERA at least 60 days

33 before the initiation of the proposed R&D data known or reasonably ascertainable by activity . The TERA seeks information identical the submitter concerning potential health and to the information required in a standard environmental effects of the microorganism . notification as well as detailed information on the proposed R&D activity and information Following review of the information provided on monitoring, confinement, mitigation, and in the MCAN as well as any other relevant available information, EPA can take regulatory emergency termination procedures 93. Health action to restrict or ban production or uses and safety data relating to a new microor- or to require testing, if it can satisfy the “may ganism’s health or environmental effects that present an unreasonable risk” regulatory are in the submitter’s possession or control, threshold for issuing a Consent Order under however, must be submitted with the TERA 94. TSCA Section 5(e) The submitter must provide this information . EPA can in addition or to the extent it is “known to or reasonably in the alternative use its authority under Section 5(a)(2) to issue a SNUR, which would ascertainable by the submitter .”95 If EPA require future notifications to EPA concerning determines that the proposed R&D activity “significant new uses” of the microorganism for the microorganism does not “present an . unreasonable risk of injury to health or the EPA has established a two-tiered exemption environment,” EPA will so notify the submitter from notification requirements for com- and the submitter can then proceed with the mercialization of microorganisms that meet 96 proposed activity as specified in the TERA . specified criteria . To qualify for the Tier I If, however, EPA concludes that it cannot exemption: the microorganism must be one determine that the R&D activity will not of ten species specified in the regulations; present such risks, EPA will deny the TERA the microorganism must meet introduced 97 and provide reasons for its denial in writing . genetic material criteria (i.e., limited in size, well-characterized, poorly mobilizable, and For commercial activities, EPA has free of certain toxin-encoding sequences); implemented PMN and exemption the physical containment and control procedures . The notification is referred to technologies of any facility in which the as an MCAN 98. EPA specifies in detail in its microorganism will be manufactured, regulations the information that an MCAN processed, or used must meet certain must contain, including information pertinent THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF criteria; the manufacturer or importer to the microorganism’s identity (including submits a certification at least ten days details about the genetic construction and prior to commencing initial manufacture the phenotype and ecological characteris- or import of the new microorganism; and tics of the new microorganism), its intended the manufacturer or importer complies production volumes and uses, and potential with recordkeeping requirements 99 occupational or environmental exposures . The and releases . The submitter also must Tier II exemption provides for an expedited review of microorganisms that satisfy Tier include any test data in the submitter’s I requirements, except for the requirement possession or control and describe other that the facility meets all necessary physical

34 containment and control technologies microorganism may submit an application requirements 100. Manufacturers and importers for a test marketing exemption (TME) 103. EPA must submit to EPA a Tier II exemption guidance states that test marketing activities application at least 45 days prior to “usually involve limited sale or distribution of commencing initial manufacture or import of a substance within a predetermined period of the new microorganism 101. EPA will approve time to determine its competitive value when or deny the Tier II exemption request no its market is uncertain .”104 EPA will either later than 45 days after EPA receives the approve or deny a TME application no later request 102. than 45 days after receipt, and may impose restrictions with approval 105. The submitter Finally, as an alternative to filing a notification, “may only proceed with test marketing persons who intend to manufacture or activities after receipt of EPA approval .”106 import for commercial purposes a new

Biomining Case Study Context occurring in Chile, Peru, China, and the United States . Copper has all manner of uses, from wiring and building materials to jewelry and Conventional copper mining of low-grade consumer goods . Its extraction has always ore entails draining a highly acidic solution been an expensive, energy-intensive, and through huge piles of crushed rock . The often inefficient process . Copper production leachate is collected and processed to is increasing globally, with most mining capture the copper by electroplating . This

35 technique requires significant energy and extraction is complete the remaining chemicals and leaves behind much useable leachate is reinoculated with microbes copper trapped in the tailings, the low-value and reintroduced at the top of an ore heap rock byproduct of mining . To improve the rather than being disposed and potentially yield of copper, some mines add natural contributing to environmental contamination . microbes to the acid solution . These Because of the routine addition of new organisms are extremophiles, none of which inoculant, the microbes are not engineered is known to be pathogenic, and is capable of for maximum stability and fitness and indeed existing under more extreme conditions, such cannot survive at more neutral pH (>3) . As as those in the acidic leachate . the company looks to test and eventually use these genetically modified microbes in U .S . Description of the new technology copper mining operations, what must they consider from a regulatory standpoint? To make this process more efficient, a company plans to use synthetic biology Discussion of the legal and to develop microbes to extract copper procedural issues more efficiently from the ore . These novel microorganisms will be designed to increase A microbe and its DNA can be considered the solubility and extraction of copper chemical substances subject to TSCA if from ore that, using current technology, either is used in a manner not excluded from either could not be extracted or could TSCA (e.g ., as a drug or pesticide) . The not be extracted by economically-justified precise chemical identity of the synthetic means (e.g., when requisite energy input gene(s) is confidential . If the genes inserted is considered) . The result is an increase in into the naturally existing, recipient organism extraction efficiency for copper recovery are from organisms from the same genus as with less loss of copper in the tailings (which the recipient, the modified organisms can still would represent both an economic loss and be considered naturally occurring, therefore a potential for a release into the environment) . implicitly listed on the TSCA Inventory and no In addition to being more efficient, company TSCA Section 5 notice would be required . If, officials say these novel methods are better on the other hand, the synthetic genes are for the environment as they reduce the not identical to a sequence that occurs in an THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF amount of potentially toxic metals remaining organism in the same genus as the recipient in the tailings . organism or are genes from an organism of a different genus that are inserted into the The company plans to change the microbes recipient organism, the microbe would not by modifying the genetic material to increase be considered naturally occurring and, if the microbes’ efficiency in leaching specific not otherwise listed on the TSCA Inventory, types of low-grade ore and may seek to use would trigger the biotechnology reporting the modified bacteria to recover additional requirement under TSCA Section 5 . Note that copper from tailings . The leaching system EPA strongly encourages any manufacturer of occurs in a loop: Once the primary copper

36 a new microorganism using synthetic DNA to (R&D) field studies to obtain an enhanced contact the agency to discuss the application scientific understanding of aspects such (see http://www .epa .gov/oppt/biotech/pubs/ as the microbes’ survival, migration, etc . fs-001 .htm) . when used in the commercial process . Such understanding could be very helpful to EPA The company is developing the modified in any subsequent review of an MCAN on the micr obe for a commercial purpose . Based microbe . on public information, it is unclear whether the microbe is eligible for a TSCA Tier I or During its review, EPA will assess the Tier II exemption . These exemptions permit potential for risk to human health and producers of modified microbes that meet the environment, including the potential the eligibility requirements to proceed to for the microbe to survive, migrate, and commercial production with either a ten-day out-compete other microbes in the same notice to EPA (Tier I) or an application with a ecosystem; transfer genetic material with 45-day review period (for Tier II) . It is unclear wild microbes; or be pathogenic . If EPA is whether the microbe is one of the species satisfied that the modified microbe is not that is eligible for these exemptions . In likely to pose a risk to human health and addition, it is unclear whether the introduced the environment, it will allow the application genetic material is limited in size, well- to be “dropped from review,” meaning that characterized, poorly mobilizable, and free of EPA will take no further regulatory action and certain toxin-encoding sequences, such that the submitter may proceed with its intended it meets these aspects of the exemptions’ non-exempt commercial production upon eligibility requirements . To the extent that the expiration of the 90-day review period . the use pattern may lead to release of If, however, EPA identifies concerns, it has the microbes, albeit in well-controlled, the authority to ban manufacture or import recirculated water-based leaching systems on of the modified microbe or to negotiate a large metal ore piles, the use would not meet consent order under TSCA Section 5(e) the exemptions’ containment requirements, with the submitter that typically would put in so neither the Tier I nor Tier II exemption is an place restrictions to address the risk concern option . Accordingly, if the modified microbe as well as testing (laboratory and/or field otherwise triggers TSCA Section 5 new testing) needed to understand the microbe’s chemical requirements, EPA would be of the risks, survival, migration, etc . EPA could also view that the manufacturer would be required determine the need for a Significant New Use to file a Microbial Commercial Activity Notice Rule (SNUR) to cap or limit the production, (MCAN) with EPA at least 90 days before the uses, or exposure/release to those specified first non-exempt commercial manufacture of in the MCAN . Of the 55 MCANs received the microbe . As an alternative, the company through 2013, one was withdrawn, one could submit a TSCA Experimental Release was regulated through a TSCA Section 5(e) Application (TERA) which, if approved by consent order, one was regulated through a EPA, would allow the company to conduct rulemaking (a TSCA Section 5 SNUR), and

37 the remaining were allowed to proceed to • 93 percent of conventional chemicals market without restrictions . It is not clear from subject to Premanufacture Notification the available information how many of these (PMN) have not been regulated MCANs involved intentional environmental via a Section 5(e) order or a SNUR release (as opposed to contained use) of the (an additional 5 percent have been microorganism . In addition, we note that only voluntarily withdrawn by the notifier, 2 of 29 valid TERAs submitted to EPA were often in the face of possible EPA action) . not approved . Biomining, however, could represent a The legal and regulatory takeaway use and involve a microbial species not previously considered by EPA . These factors EPA is authorized under TSCA to combined with environmental releases regulate microorganisms created through that, given the size of mining operations, synthetic biology for use in biomining . could be considered large, environmen- This is particularly the case when tally consequential, and ongoing are synthetic sequences are used to modify likely to present novel issues to the TSCA microorganisms in a way that introduces biotechnology program . These complex genetic sequences that are not known to issues have the potential to attract close be identical to those known to occur in an EPA scrutiny that would, at a minimum, organism in the same genus as the recipient likely necessitate voluntary suspensions microorganism . Such genetically modified of the review period, delay the decisional microbes would be considered new chemical process, and increase the likelihood that EPA substances subject to review under TSCA would determine the need to apply testing Section 5 . EPA has a record of reviewing and requirements to improve its understanding regulating biotechnology products that is of potential risk aspects and/or controls on similar to its decisional record on regulating the use . If use of a modified microorganism conventional chemicals: contributed to economic and environmental benefits (e.g., greater recovery of copper, 95 percent of intergeneric • and reduced residual releases to the microorganisms that have been the environment of a toxic metal), these points subject of MCANs have proceeded would be important to discuss and document THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF to commercial distribution without in a Pollution Prevention Information page restriction; attachment to the MCAN . • 93 percent (27 of 29 applications) of intergeneric microorganisms that have been the subject of TERAs have been approved; and

38 Plant Protection Act

In addition to EPA and FDA authorities and ny living stage of any of the following that can activities discussed above, the Coordinated directly or indirectly injure, cause damage Framework relies also on the USDA, to, or cause disease in any plant or plant primarily through the Animal and Plant Health product: Inspection Service (APHIS), to carry out the (A) third prong of the coordinated approach . A protozoan . APHIS is tasked with regulating field trials of (B) A nonhuman animal . genetically modified crops and plants under the Plant Protection Act (PPA), enacted (C) A parasitic plant . in 2000 107. The objective of the PPA is “to (D) A bacterium . prevent the spread of parasitic, diseased, and invasive plants and organisms, and (E) A fungus . it does so through the regulation of ‘plant pests’ and ‘noxious weeds ’”. 108 When the (F) A virus or viroid . Coordinated Framework originally was (G) An infectious agent or other pathogen . launched nearly 30 years ago, the relevant federal statute was the Federal Plant Pest (H) Any article similar to or allied with Act, under the authority of which APHIS first any of the articles specified in the issued the implementing regulations that preceding subparagraphs .”109 govern its activities in regulating genetically modified plants . At that time, noxious The APHIS implementing regulations at 7 110 weeds were addressed separately under the C .F .R . Part 340 define “plant pest” similarly, Federal Noxious Weed Act . In combining as “[a]ny living stage (including active and the regulatory objectives of these two earlier dormant forms) of insects, mites, nematodes, statutes, the PPA does not differ significantly slugs, snails, protozoa, or other invertebrate from either of them in the aspects pertinent animals, bacteria, fungi, other parasitic plants here . or reproductive parts thereof, viruses; or any other organisms similar to or allied with any The key term for purposes of regulating of the foregoing; or any infectious agents or genetically modified plants and crops substances, which can directly or indirectly under the PPA is “plant pest”; unless an injure or cause disease or damage in or to organism falls within the definition, it is any plants or parts thereof, or any processed, outside the regulatory scope of the statute . manufactured, or other products of plants .”111 A fundamental aspect of the definition is the capability of the organism at issue to injure Certain genetically modified organisms are or cause damage or disease in a plant . Thus, deemed “presumptive plant pests” and under the PPA definition, a “plant pest” is “[a] regulated as such by APHIS -- those created through the use of an organism that itself

39 meets the definition of “plant pest .” Any of of its genetic modification . The capability to these is considered a “regulated article,” cause injury, harm, or damage to a plant or defined as: product also must be present . If (and only if), however, a genetically modified plant Any organism which has been altered or meets the definition of a “plant pest” -- which produced through genetic engineering, if the includes that harmful capability -- it is subject donor organism, recipient organism, or vector to regulation by APHIS 113. or vector agent belongs to any genera or taxa designated in [7 C F. R. ]. § 340 2. and meets APHIS oversees three possible pathways for the definition of plant pest, or is an unclassified using genetically modified plants (with the organism and/or an organism whose extent of such use to be determined) . The classification is unknown or any product which simplest is a notification procedure available contains such an organism, or any other under 7 C .F .R . § 340 .3 for a limited subset organism or product altered or produced of plants, subject to specified criteria and through genetic engineering which the [APHIS] performance standards; APHIS will approve Administrator determines is a plant pest or has or deny a notification submitted by an reason to believe is a plant pest 112. applicant 114.

This definition of a “regulated article” More elaborate is the second pathway, incorporates a quite broad assertion of a field testing program under 7 C .F .R . § threshold jurisdiction under the PPA, because 340 .4, which requires a body of information the techniques typically used to create many to be submitted to APHIS in support of genetically modified organisms may involve an application for a field testing permit use of a donor organism and/or a vector for the genetically modified organism for agent that is included in the designated which testing authorization is sought 115. An genera or taxa . A wide range of genetically applicant may pursue a field testing permit modified organisms not confined to as an initial step or may seek such a permit genetically modified plants would satisfy this if APHIS denies the applicant’s notification element for APHIS jurisdiction . Nevertheless, for a specific plant 116. The regulations set out the definition is also limited to those in some detail the information that must be genetically modified organisms that otherwise included in a field testing permit application .

THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF satisfy the general definition of a plant pest . In A permit will be issued only if APHIS decides, practice, most genetically modified organisms based on the applicant’s submission, that that could be deemed to be a potential plant the testing can go forward, subject to any pest are genetically modified plants . necessary conditions, without posing plant pest-associated risks beyond the test Moreover, not every genetically modified site . This enables APHIS, as well as the plant will be deemed to be a potential plant applicant, to obtain data relevant to how the pest . Nothing in the PPA or in the APHIS presumptive plant pest affects other plants regulations states that a genetically modified when introduced into the environment on a plant is a plant pest simply due to the fact limited basis 117.

40 Should a field test yield favorable results 95 genetically engineered crops have been -- that is, if the test results, along with other deregulated as of August 2013 120. relevant data, appear to make a persuasive case that the plant or plant product does APHIS also is authorized under the PPA to 121 not represent a plant risk -- “[a]ny person” regulate “noxious weeds,” but it has not may petition APHIS for a “determination of opted, at least thus far, to use this authority to address genetically modified plants 122 nonregulated status .”118 Also referred to as . The “deregulation,” this is the third option and APHIS regulations in 7 C .F .R . Part 360 -- a clears a pathway for seeking commercial- separate regulatory regime from the one in Part 340 addressing plant pests -- defines ization . The contents of this data-driven, “noxious weed” expansively as “[a]ny plant substantive filing and the procedures for or plant product that can directly or indirectly evaluating it -- including notice in the Federal injure or cause damage to crops (including Register and an opportunity for public nursery stock or plant products), livestock, comment, followed by a further opportunity poultry, or other interests of agriculture, for the petitioner to respond -- are specified irrigation, navigation, the natural resources in the regulations . of the United States, the public health, or Before making a decision to deregulate, the environment .”123 In contrast to the Part APHIS must comply with NEPA, which 340 regulations for plant pests, there is no requires federal agencies to prepare an EIS operative concept of a “presumptive” noxious if an agency action will significantly affect the weed . APHIS may assess and list a plant as a environment 119. APHIS, like other agencies, “noxious weed” on its own initiative and also need not undertake the lengthy and often will evaluate petitions to list or delist a plant . complex EIS process if the “prequel” inquiry A listed plant may not be imported into or also required by NEPA, in the form of an disseminated within the United States except Environmental Assessment (EA), concludes if, and as authorized by, an APHIS-issued that the proposed action will not significantly permit 124. affect the environment . In such instances, the agency will issue a “Finding of No Significant APHIS has been criticized by advocates Impact” (FONSI) and proceed with the of broader and more careful government oversight of genetically engineered or proposed action without preparing the EIS . modified products for (among other things) With nearly three decades of field test declining to exercise its authority to regulate permitting and evaluation of petitions to noxious weeds more expansively and deregulate presumptive plant pests, APHIS proactively to reach genetically modified has played a considerable role in the plants . APHIS likewise has been criticized expanding universe of genetically modified for taking narrow view of its role once it has plant products . According to the Venter conferred deregulated status on a formerly Report, the number of field trials authorized presumptive plant pest by approving a by APHIS on genetically engineered plants petition for such; APHIS consistently has since 1987 has run into the thousands, and taken the position that in the absence of a

41 plant pest, its statutory responsibility under In a systematic opinion that summarized the PPA is at an end . Its position as to what the salient points of the litigation to date, constitutes the injury, disease, or damage in the Ninth Circuit rejected the petitioners’ plants that makes the responsible organism contentions that APHIS had interpreted the in the first place also falls short in the view meaning of “plant pest” too narrowly . The of these advocates for enhanced regulation . petitioners’ position was that “plant pest” This plausible, plain-meaning interpretation includes all genetically engineered plants by APHIS is considered insufficient by those and organisms that have an environmentally who believe that it makes better sense to adverse effect on plants -- in this instance, read these harms to encompass wider the transgenic contamination of conventional environmental and economic harms, such as alfalfa and the increased herbicide use . the potential for a genetically modified plant APHIS’s position was that whether or not ultimately leading to increased herbicide use . the harms alleged by the petitioners were adverse environmental and economic effects The Ninth Circuit upheld APHIS’s reading of associated with RRA, those harms did not the law in 2013 in Center for Food Safety constitute plant disease, injury, or damage, v. Vilsack,125 which involved a challenge to the endpoints identified under the PPA . APHIS’s deregulation of “Roundup Ready Alfalfa” (RRA), a plant genetically modified The court agreed . As described in the to be resistant to the herbicide glyphosate, opinion, RRA was created by transferring a marketed as “Roundup ”. Roundup had gene from Agrobacterium, a naturally-oc- proven problematic in use by alfalfa farmers curring bacterium -- and a listed “plant pest” to control weeds because the alfalfa crop, -- into the genetic structure of the alfalfa as well as the weeds, succumbed to the plant . The effect of inserting this gene was to herbicide . RRA was engineered to enable the alter the genetic structure of the alfalfa plant alfalfa crop to survive the application of the to make it resistant to glyphosate (Roundup) . weed-killing Roundup . Various environmental The presence of Agrobacterium on the list groups and farmers have fought attempts by of plant pests meant that APHIS considered Monsanto and Forage Genetics International RRA as a presumptive plant pest, triggering (Forage Genetics), its producers, to introduce restrictions on its use . After Monsanto and RRA, and a long history of litigation has Forage Genetics applied to deregulate RRA, THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF resulted 126. Opponents of RRA’s use have APHIS’s review of the submitted data and the challenged aspects of APHIS’s deregulation public comments led it to determine that the of RRA over the years, and the Ninth Circuit’s plant pest properties of the Agrobacterium 2013 decision squarely addressed and used to engineer RRA was “disarmed” and upheld APHIS’s determination that RRA was could not injure or damage other plants not a “plant pest” within the meaning of the and presented no greater plant pest harms PPA and thus that its deregulation did not than conventional alfalfa . APHIS granted the violate statutory obligations under NEPA and application and unconditionally deregulated the Endangered Species Act (ESA), as the RRA 128. petitioners had alleged 127.

42 The Ninth Circuit acknowledged the undertake any near-term steps to update petitioners’ assertions of potential this element of the laws addressed under the environmental and economic harm from the Coordinated Framework and that regulation use of RRA (distinguishing between RRA -- and deregulation -- will proceed under itself and its use), but it agreed with APHIS generally the same procedures and rules for that such potential harms were outside the the foreseeable future 132. scope of the PPA . According to the court, “the PPA addresses only the harms caused With new statutory tools for addressing the by plant pests to other plants and APHIS challenges of genetically modified plants can regulate RRA only if it causes plant pest unlikely to materialize in the near-term, the impatience of many critics about APHIS’s harms .”129 Observing that “[t]he PPA was reluctance to be more proactive may have enacted to protect plants, but not to control some merit the burgeoning use of chemicals in crop . One key task of USDA is to production,” the court refused to “interpret promote domestic agriculture, and significant the language of the PPA, which Congress differences will persist among different has not materially amended since 1957, constituencies about how this end best can to address the alleged harms that may be accomplished . Opponents of genetically result from the modification of the plant’s modified plants and plant products will continue to paint APHIS as weak in fulfilling genome .”130 If the law was to be updated, it its role as gatekeeper and as overly was a job for Congress, not the court . Thus, inclined to “promote agriculture” through the court ruled that RRA is not a plant pest deregulation of what these opponents view within the meaning of the PPA . The court as harmful innovations 133 addressed and disposed of, as well, the . At the same time, petitioners’ remaining theories as to why the requirements of the APHIS regulations the deregulation should not stand, including are viewed as burdensome enough by the theory that in evaluating the application many prospective developers of genetically to deregulate RRA, APHIS was required modified plants to incentivize these to determine also whether RRA was a developers to try to bypass the regulatory “noxious weed” under the separate regulatory regime insofar as possible by pursuing genetic modifications that do not make framework for addressing them 131. use of an identified “plant pest” in the first By putting the task of updating or place 134. Where the regulatory hook provided supplementing the PPA to address 21st by the presence of a plant pest is absent century concerns squarely in the lap of -- where the genetic modification technique Congress, Center for Food Safety v. Vilsack does not employ a plant pest -- APHIS underscores some of the reasons why the has concluded that it must stand aside in PPA in its present form could be considered these instances 135. Accordingly, as genetic an imperfect tool for regulating genetically modification techniques become increasingly engineered plants and plant products . It is sophisticated, the numbers of plants and fair to predict that Congress is unlikely to products outside the reach of APHIS’s

43 authority can be expected to expand, even embedded with a gene gun and not through as APHIS will continue to play a critical role a bacterium . By avoiding the use of a plant where plant pests are involved . pest, arguably the authority of federal laws is side-stepped . As the New York Times New techniques employ technologies that pointed out, “companies can get around the are confounding the application of traditional oversight by avoiding components for plant oversight authorities . For example, “genome pests .”136 editing” occurs when foreign genetic material comes exclusively from other plants and is

Genetically Modified Plant Case Study THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF Context Description of the new technology

Ornamental plants have been used for With the advent of synthetic biology, there centuries to add aesthetic appeal to outdoor are new opportunities to modify ornamental and indoor spaces . They are valued for their plants in ways that were not available through flowers, leaves, scents, texture, fruit, stem, traditional techniques . Examples include and bark -- or simply their unique aesthetic novelty plants that are bioluminescent and forms . Ornamental plants have been bred glow in the dark and lawn grasses that to accentuate desirable traits and minimize require less mowing and are deeper green in undesirable ones through traditional cross- color . breeding, grafting, and other techniques .

44 Bioluminescent plants are being developed the source of the donated genetic material for by two companies and each effort the color, thickness, and height properties 142. provides an instructive example of evolving technologies . Scientists at BioGlow LLC These are three examples of a burgeoning market in which companies are seeking to (BioGlow)137 inserted genes from luminous use modern synthetic biology and genetic marine bacteria into Nicotiana alata (jasmine technologies to develop ornamental plants tobacco), a common flowering ornamental with desirable characteristics plant . They have produced a plant that is au- . The source of toluminescent, meaning it glows in the dark genetic material and the manner by which it is introduced into the host plant control how with only standard plant nutrients . BioGlow’s these organisms are regulated -- or not -- as plants have been commercialized and the discussed below company opened a web store in September . 2014 (http://bioglow .us/blogs/news); as of Discussion of the legal and July 2015, the Biobulb™ is listed for sale in the store (http://bioglow .us/collections/ procedural issues glowing-plants-2) . The USDA’s APHIS jurisdiction to regulate Glowing Plant, Inc . (Glowing Plant),138 a genetically modified plants depends on the company funded through a Kickstarter139 use of a plant pest as part of the genetic campaign, also developed a luminescent engineering technique . Until recently, use of plant . Building on technology similar to a plant pest as part of genetic engineering BioGlow’s, Glowing Plant has inserted was a common practice . If, however, genetic material into Arabidopsis thaliana the donor organism, recipient organism, (thale cress) using a “gene gun .” Genes from vector, or vector agent does not meet Photinus pyralis (common eastern firefly) the PPA definition of a plant pest, then and two synthetic variants of genes from APHIS’ position is that it does not have Aequorea victoria (crystal jelly) are inserted regulatory authority over the modified plant . into the plant’s genome . As gene guns and other new synthetic biology techniques typically do not rely on A January 1, 2015, New York Times article plant pests, plants modified through these describes commercial efforts to develop techniques will not be subject to APHIS’ genetically modified grass that requires review . If either the gene donor or recipient less mowing, is deeper green in color, and species is a plant pest, or if a plant pest, such is resistant to damage by the herbicide as an agrobacterium, is used to introduce glyphosate 140. According to the article, the the genetic material into the host, the PPA manufacturer introduces genetic material will apply and APHIS will retain regulatory from other plants that are not considered oversight . plant pests and inserts the genes with a gene gun . Publicly available information141 suggests BioGlow submitted to APHIS the information that Arabidopsis thaliana is the source of the pertinent to support a regulatory review . glyphosate resistance, but does not disclose Following its review, APHIS concluded in a

45 March 21, 2013, letter that it did not have prudent, to confirm that the revised genome regulatory jurisdiction over the plants, stating: similarly is unregulated . As APHIS points out in its response letter: APHIS has determined the plants, as described in the letter, are not plant APHIS’ response that follows evaluated pests, no organisms used as sources of your request for this plant species only the genetic material to create the plants and the transformation, genes and are plant pests, and the method used to donors used to produce this specific genetically engineer the plants did not plant line, therefore, this response is involve plant pests 143. not considered relevant to other plant species, transformation, donors, or BioGlow’s APHIS application protects genetic material 145. the details of the genetic modification so, unfortunately, the genetic source of the biolu- Glowing Plant was funded through minescence and the method used to modify Kickstarter and offered inducements at a the jasmine tobacco cannot be evaluated variety of funding levels, which raise separate here . regulatory issues . Pledges at the $150 level will receive a glowing plant, which as The Glowing Plant luminescent plant uses no discussed above does not appear to be genetic material from a plant pest, does not regulated, at least not by APHIS under the use a plant pest as a recipient organism, and PPA . Pledges of $250, however, receive a no plant pest is used to modify the genes of “DIY MAKER KIT,” which includes “a full set the host plant . Based on these facts, APHIS of instructions and all the ingredients you reached a conclusion similar to BioGlow’s in need to transform your own plant at home, a letter to Glowing Plant dated December 23, in your lab or at school .” Two notable issues 2014: are raised by the DIY kit . First, the DIY kits No plant pests, unclassified organisms, employ agrobacterium to perform the genetic or organisms whose classification is modification on plants . Agrobacterium is unknown are being used to genetically regulated as a plant pest . Consequently, engineer this plant . In addition, APHIS while the Glowing Plant modified by a gene has no reason to believe that this plant is gun may not be regulated under the PPA, THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF a plant pest . Therefore APHIS does not the agrobacterium DIY kit is likely regulated, consider the [genetically engineered (GE)] either under PPA or TSCA . Second, the plant as described in your October 1, supporter who receives the kit appears to 2014 letter to be regulated under 7 CFR be legally responsible for obtaining a permit part 340 144. from APHIS for plants they transform . Given the likely lack of regulatory sophistication Glowing Plant is an open-source technology of the typical Kickstarter supporter, there and the developers encourage others to is a significant opportunity for someone further modify the genome of the plant . If unknowingly to violate one of the statutes others modify the genome of the Glowing that regulate genetically modified plants . Plant, re-submitting notice to APHIS is likely

46 Pledges at the $500 level receive a of genetic combinations at a faster pace message (up to 140 characters of the than previous techniques, thereby meriting donor’s choice) encoded in a string of a conversation about whether pre-market single-stranded, synthetic DNA using Craig review is warranted . To respond to this Venter’s ASCII-to-DNA translation table . increased pace and ability to modify plants, Even though the amounts of DNA produced APHIS has been attempting to update the in this way were exceedingly small, just regulations governing genetically modified a few micrograms, their manufacture is organisms under its purview . APHIS regulated by TSCA and the company was proposed a rule in 2008 and received 88,000 required to notify EPA prior to manufacturing comments 146. After suggesting it would the DNA strands . Glowing Plant opted to proceed with a final rulemaking, APHIS file a low-volume exemption for each of formally abandoned that effort on March 4, the message strings ordered by its eligible 2015 147. The Service announced it would donors . restart discussions on modernizing genetically modified organism regulations, starting with The legal and regulatory takeaway “an open and robust policy dialogue to drive the development of a forward-looking rule Whether these plants pose any risks that will provide a foundation for our future to human health or the environment is regulatory activities .”148 In its communication unclear . Gaps in federal oversight of such withdrawing the rule, APHIS stated “current products, however, allow their market entry regulations have been effective in ensuring absent an assessment of potential risk the safe introduction of GE organisms,” other than simply the presence of plant adding that “revising our biotechnology pests or plant pest genes . Whether these regulations will better position us to address plants may out-compete other plants in the new challenges, as well as meet current ecosystem into which they are introduced, needs in evaluating and addressing the plant have an adverse effect on an animal that pest or noxious weed risks associated with may consume them, or generate allergens, the importation, interstate movement, and are among the issues that have not been field release of certain GE organisms .” This comprehensively examined under current text has since been removed from APHIS’s legal authorities . It is not clear that modern website . synthetic biology techniques raise greater risk issues than traditional cross breeding, grafting, or irradiation techniques that have been used for decades -- or even centuries . These techniques have, in many cases, escaped regulatory scrutiny, but also have not introduced substantial identified risks . It would appear, however, that modern synthetic biology allows a greater range

47 APPENDIX: NATIONAL ENVIRONMENTAL POLICY ACT

Introduction which cannot be avoided should the proposal be implemented, The most venerable of the modern environmental statutes, the National (iii) alternatives to the proposed action, Environmental Policy Act (NEPA),149 is (iv the relationship between local sweeping on its face . It “establishes a short-term uses of man’s ‘national policy [to] encourage productive environment and the maintenance and enjoyable harmony between man and his and enhancement of long-term environment,’ and was intended to reduce productivity, and or eliminate environmental damage and to promote ‘the understanding of the ecological (v) any irreversible and irretrievable systems and natural resources important commitments of resources which to’ the United States .”150 NEPA requires would be involved in the proposed federal agencies to incorporate environmental action should it be implemented 152. considerations in their planning and deci- sion-making through a systematic interdis- The EIS requirement, enacted at the dawn ciplinary approach . It obligates all federal of the modern era of federal environmental agencies to describe in detail and assess the legislation, was intended to assure that anticipated impacts of all “Federal actions concerns that earlier might have been significantly affecting the quality of human overlooked or consigned to the fringes environment .”151 This is the EIS . now would be part of the conversation, at least where the federal government Specifically, the EIS mandate in NEPA Section played a role in initiating, approving, or 102(2) directs all federal agencies to: funding an activity . Thus, the EIS itself was meant “to provide full and fair discussion of (C) include in every recommendation or significant environmental impacts and [to] THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF report on proposals for legislation and inform decisionmakers and the public of the other major Federal actions significantly reasonable alternatives which would avoid affecting the quality of the human or minimize adverse impacts or enhance environment, a detailed statement by the the quality of the human environment .”153 responsible official on— At the same time, NEPA was not intended (i) the environmental impact of the to put a finger on the scale, as opposed to proposed action, creating a process for consideration . It does not mandate any given outcome . Instead, it (ii) any adverse environmental effects “imposes only procedural requirements on

48 federal agencies with a particular focus on forward . Additionally, as discussed below, requiring agencies to undertake analyses of decision-makers are authorized under NEPA’s the environmental impact of their proposals implementing regulations, where the situation and actions .”154 warrants, to truncate their environmental review process before it reaches the EIS In the decades since NEPA was enacted, preparation stage . preparation of an EIS has proven frequently to be a substantial and time-consuming The second limitation is specific to EPA in undertaking . It can be an expensive one as its role of implementing the various federal well, and not only in terms of government environmental statutes that it is charged to resources; where a private party is seeking a administer . For most of the latter purposes, federal approval, the private entity likely will EPA is exempt from NEPA, either because do much of the heavy-lifting, retaining expert of an explicit exemption written into the consultants in the area of interest to survey, statute itself or because the case law over test, analyze, report, and so forth, with the years has acknowledged and validated the work product provided to the relevant a “functional equivalence doctrine” for EPA’s government agency as raw material for its activities . The rationale is that since EPA’s development of the EIS . Public participation mission is protection of the environment, and the involvement of stakeholders add a rigid step-by-step compliance with the time and complexity to the process . In some formalities of NEPA in the course of its instances, an EIS -- or the absence of one activities is unnecessary, assuming that EPA -- ends up in litigation . Opponents of major provide opportunities for public participation projects of all kinds have come to rely on in a given decision-making process and also the EIS process as a potentially powerful considers the public comments in assessing instrument of delay and a weapon of attrition, the substantive environmental factors even where a clear-cut win is unlikely . relevant to the decision . For purposes of regulating synthetic biology under existing NEPA Review in the Synthetic laws, this means that NEPA does not apply in Biology Context connection with EPA’s administration of FIFRA or TSCA . As described below, however, What NEPA can contribute to a federal NEPA comes into play in the implementation regulatory structure for synthetic biology has of both the PPA by APHIS and the FFDCA by its limits, for two reasons . First, as noted the FDA . above, federal agencies are not compelled to treat the results of an environmental impact For purposes of government-wide oversight analysis as a driving factor in decision-mak- and implementation, NEPA established a ing; even where environmental impacts are CEQ, which promulgates regulations that carefully evaluated, the law does not compel are binding on federal agencies 155. Among that they trump the other factors relevant to other things, the CEQ regulations specify the determination of whether, and under what a process for determining whether an EIS conditions, a “major Federal action” will go is necessary in the first instance . Some

49 actions may be “categorically excluded” approaches to animal and plant health from detailed environmental review if they issues .” This provision makes no specific satisfy specified criteria that an agency has reference to genetically engineered species determined previously are indicative that or, for that matter, to any other potential no significant environmental impact will “plant health issues .” Genetically engineered ensue 156. Specific listings of such categorical plants are referenced in Section 372 .5(b), exclusions are found in an individual agency’s which lists actions normally requiring an EA, NEPA regulations . For most actions -- those but not necessarily an EIS; these include, in that are not categorically excluded -- the (b)(4), “[a]pprovals and issuance of permits CEQ regulations call on the federal agency to for proposals involving genetically engineered prepare a written EA to determine whether or or nonindigenous species, except for actions not a contemplated action would significantly that are categorically excluded, as provided affect the environment 157. Absent a in paragraph [372 .5(c)] . . .” The class of “significant impact” finding, the agency need categorically excluded actions, APHIS not proceed to the EIS preparation stage and states in the regulations, shares many of instead will issue a FONSI, which may or may the same characteristics as the class that not include mitigation measures as needed . normally requires an EA (but not necessarily an EIS), the major difference being that “the A. Animal and Plant Health means through which adverse environmental Inspection Service (APHIS) impacts may be avoided or minimized have APHIS regulations implementing NEPA are actually been built right into the actions found at 7 C .F .R . Part 372 . The regulations themselves .” Among the excluded actions, classify agency actions by the level of NEPA under the “licensing and permitting” review they necessitate -- actions normally subheading, is “[p]ermitting, or acknowl- requiring an EIS, under Section 372 .5(a); edgement of notifications for, confined field actions normally requiring an EA but not releases of genetically engineered organisms 158 necessarily an EIS, under Section 372 .5(b); and products .” and actions excluded categorically, under Under these latter provisions, therefore, Section 372 .5(c) . The regulations also specify neither notifications nor field test permitting for exceptions for the categorically excluded genetically modified organisms require either THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF actions -- essentially an override provision an EA or an EIS as a prerequisite 159. Under -- directing that an EIS or an EA is to be Section 372 5(b)(4),. the approval by APHIS of prepared if the decision-maker determines a petition to deregulate a genetically modified that a categorically excluded action may have organism as a “plant pest” requires an EA . the potential to affect significantly the quality of the human environment . As the regulations indicate, in-depth NEPA review is considered unnecessary for Under Section 372 .5(a), APHIS actions most APHIS activities involving genetically normally requiring an EIS encompass a “class modified organism plants . APHIS handles of policymakings and rulemakings” that notification and field test permitting without seeks generally to “establish programmatic

50 reference to an EA, although field test conditions of use . Under this reading of the permit applications must be supported by a law -- even though an EIS for RRA had been body of data specified in 7 C F. .R . § 340 .4 . ordered in an earlier phase of the litigation Some stakeholders and other observers are and then prepared by APHIS -- the extent increasingly critical of what they perceive as to which the EIS realistically could inform insufficient attention by APHIS to the range APHIS’s decision-making as to deregulation of environmental impacts from a proliferating was limited by the PPA itself . group of genetically engineered plant species and insufficient rigor in addressing them . Long before the 2013 Center for Food Safety v. Vilsack decision, NEPA issues When an applicant petitions APHIS for had emerged in the protracted battle over nonregulated status for a genetically modified APHIS’s deregulation of RRA . Some of organism plant that otherwise would be these issues ultimately ended up before the considered a presumptive “plant pest,” Supreme Court, which decided them in 2010 APHIS typically will conduct an EA under in Monsanto Co. v. Geertson Seed Farms 161. Section 372 .5(b)(4) . It will almost never The plaintiff farmers and environmental undertake a full EIS unless the outcome of groups had sued APHIS in federal district litigation compels it to do so . It is fair to say court in 2005, alleging violations of the PPA, that APHIS does not envision its mission as NEPA, and the Endangered Species Act . The delving deeply or widely into an exploration of district court ruled that APHIS had violated potential environmental impacts of genetically NEPA by failing to prepare an EIS prior to modified organism plantings . It also is fair to deregulating RRA, holding that an EIS should say that APHIS’s position on environmental have addressed the environmental effects of review harmonizes with its reading of the weeds becoming resistant to the pesticide PPA, a reading endorsed by the Ninth glyphosate and of transgenic contamination Circuit in Center for Food Safety v. Vilsack,160 on organic farmers raising conventional discussed above, part of the multi-pronged alfalfa . The district court vacated APHIS’s Roundup Ready alfalfa (RRA) litigation . deregulation of RRA until the necessary EIS was prepared, enjoining APHIS from Briefly, the Ninth Circuit held that the PPA deregulating RRA in any aspect or allowing authorizes APHIS to regulate only “plant pest” any subsequent planting of RRA until the EIS harms -- disease, damage, or injury to other was completed . The court did not reach the plants -- and not any corollary environmental PPA or ESA issues the plaintiffs had raised 162. or economic harms that might accompany The Ninth Circuit affirmed on the NEPA the cultivation of a genetically modified issues 163. organism plant . Further, the court agreed that once APHIS has determined that a particular The Supreme Court granted certiorari and genetically modified organism plant is not a reversed the decisions below . As no party “plant pest” within the meaning of the PPA, had challenged the district court’s finding deregulating that plant is a nondiscretionary that APHIS had violated NEPA, the Court action and one to which APHIS cannot attach assumed without deciding that the district

51 court acted properly in vacating APHIS’s pest” under the PPA . As such, APHIS’s decision to deregulate RRA . But -- in a regulatory authority over RRA was at an end, victory for both Monsanto and APHIS -- the a reading that the Ninth Circuit affirmed 166. Court held that the injunctive relief ordered by the district court had gone too far in The long saga of EIS preparation and NEPA prohibiting APHIS from partially regulating compliance in the context of the RRA deregulation underscores the extent to which RRA while it prepared the EIS . The Court the PPA limits the elevation of environmental emphasized that a NEPA violation in and of considerations in APHIS decision-making, itself does not necessarily justify injunctive assuming that APHIS itself desired to give relief and that a party seeking relief under such environmental factors more weight in NEPA must satisfy the traditional four-factor its regulatory choices test for issuance of an injunction 164. In this . The order to prepare instance, the Court held, none of those an EIS provided more information to APHIS, factors supported the wholesale injunction stakeholders, and the public -- and it delayed the deregulation of RRA by some five years -- the district court had ordered . According to but it did not change the ultimate outcome the Court, the injunction was so broad that . it essentially preempted APHIS’s authority to Various litigations similarly accompanied decide whether or not a partial deregulation APHIS’s original decision to deregulate would represent an unacceptable risk of Roundup Ready sugar beets (RRSB) in 165 environmental harm . Likewise, the Court 2005, after APHIS had determined, based held the district court erred in enjoining on on an EA, that RRSBs were not a plant pest a nationwide basis any planting of RRA until risk . As with RRA, the original deregulation APHIS had completed the EIS, irrespective was vacated and APHIS was required to of whether a partial deregulation order might prepare an EIS for RRSBs, which eventually issue in the interim . was granted deregulated status in 2012 . APHIS released its final EIS in December While the EIS was in preparation, four seed companies obtained permits from APHIS 2010, at which point the district court’s order to plant juvenile sugar beet “stecklings” on vacating the earlier deregulation expired, limited acreage in geographically defined because preparation of the EIS met APHIS’s locations; each permit was accompanied by NEPA obligations . The final EIS listed two THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF a NEPA “Decision Worksheet” to the effect “preferred” alternatives -- partial deregulation that the steckling growth would have no and unconditional regulation . Although the significant environmental impacts final EIS characterized continuing regulation . After a of RRA as the environmentally preferable of district court issued a preliminary injunction these two alternatives, APHIS concluded and ordered destruction of the stecklings, that unconditionally deregulating RRA was the Ninth Circuit overturned the injunction the alternative consistent with the agency’s in a decision informed by the Supreme Court’s opinion in Monsanto v. Geertson limited statutory mandate . This conclusion Seed Farms 167 Quoting the Court’s “warning followed, in turn, from APHIS’s earlier . determination that RRA was not a “plant against granting injunctive relief where APHIS’s action is ‘sufficiently limited’ that ‘the

52 risk of gene flow to [Plaintiffs’] crops could engineered species once it has satisfied be virtually nonexistent,’” the Ninth Circuit NEPA’s procedural requirements . ruled that the plaintiffs had failed to show the likelihood of irreparable harm necessary for B. Federal Food, Drug, and injunctive relief and that the district court had Cosmetic Act (FFDCA) abused its discretion in ordering the plants’ As regulation of products of synthetic biology destruction:Plaintiffs have not demonstrated under FFDCA is evolving, so are questions that the permitted steckling plants present a about the role of NEPA review in the process . possibility, much less a likelihood, of genetic The FDA regulations on environmental impact contamination or other irreparable harm . consideration are found at 21 C .F .R . Part 25 . The undisputed evidence indicates that the Under 21 C .F .R . § 25 .15(a), all applications stecklings pose a negligible risk of genetic or petitions requesting FDA action require the contamination, as the juvenile plants are submission of an EA or a claim of categorical biologically incapable of flowering or cross- exclusion . As prescribed by the CEQ, the EA pollinating before February 28, 2011, when “serves to provide sufficient evidence and 168 the permits expire . analysis for an agency to determine whether to prepare an EIS or a FONSI .”170 The Ninth Circuit emphasized that the record revealed no examples of contamination by For FDA actions under FFDCA, preparation of pollination under the restricted conditions an EIS is the exception rather than the rule . that the permit imposed on the limited According to Section 25 .22(a), “[t]here are no plantings: “To the contrary, APHIS has categories of agency actions that routinely permitted over 100 confined field releases significantly affect the quality of the human of Roundup Ready sugar beets with no environment and that therefore ordinarily known ‘loss of confinement,’ as the agency require the preparation of an EIS .” An EIS explained in NEPA documents issued with is required only if review of an EA leads the each permit . Plaintiffs give us little reason responsible official to conclude, pursuant not to defer to APHIS’s technical expertise to the statutory language of NEPA, that “a 169 and judgments on this score .” Deference proposed action may significantly affect the to the implementing agency -- here, APHIS quality of the human environment .”171 -- is a theme in both of the Ninth Circuit opinions discussed here, as well as in Section 25 .20 lists the categories of FDA the Supreme Court decision relating to actions for which an EA must be prepared, genetically engineered plants . Although unless categorically excluded under Sections challengers have succeeded in obtaining 25 .30-25 .34 172. The applicant typically is court orders requiring APHIS to prepare an required to prepare the EA and make any EIS for controversial deregulation decisions, corrections that may be necessary 173. Neither judicial deference to agency decision-makers the regulations on actions necessitating magnifies the burden on those who challenge an EA nor those setting out the various APHIS’s reading of the PPA or its ultimate categorical exclusions from the EA determination to deregulate a genetically preparation requirement specifically reference products of genetic engineering, as do the

53 APHIS regulations previously discussed . The Application) for the use involved 177. Thus, FDA has made it clear, however, that the a NADA typically must be submitted for EA requirement applies to certain approvals a genetically engineered animal; FDA’s relating to the products of synthetic biology . proposed approval of a NADA is subject to an EA requirement under 21 C .F .R . § Where FDA’s pre-market oversight, if any, is 25 .20(m), unless categorically excluded . voluntary, the NEPA review is not required, Each applicant for an NAD approval must whether or not the product created or derived submit either an EA or a claim for categorical is through genetic engineering . Where exclusion 178. pre-market approval is mandatory, as for new human drugs or new animal drugs (NAD), an FDA’s guidance on its regulation of EA is necessary except where categorically genetically engineered animals confirms excluded 174. The regulatory status, and hence that environmental review requirements for the NEPA status, of substances added to conventional NADAs also apply to them . food is not uniform . Those that are classified According to the guidance document: as “food additives” require pre-market An EA that demonstrates the GE animal approval as to their safety, whereas other will not significantly affect the quality of the substances added to food classified as human environment leads to a finding of no “generally recognized as safe” (GRAS) and significant impact (FONSI) do not need to undergo the FDA’s pre-market . We recommend approval process . Approval of food additive that the EA focus on environmental issues and potential impacts related to the use petitions is subject to the EA requirement 175. and disposal of the GE animal and its final FDA specifically addressed its regulatory product, if relevant . The appropriate scope approach to foods derived from genetically and content of the EA may vary widely modified organisms in a policy statement depending on the GE animal product, claim, issued in 1992, stating that most foods and conditions of use 179. derived from genetically modified plants would be presumptively GRAS, like foods derived FDA, as discussed in its GE Guidance, provides for certain exceptions to the EA from conventional plants . By contrast, a requirement for genetically engineered product “that differs significantly in structure,

THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF animals function, or composition from substances . Although all genetically engineered found currently in food” would be treated as a animals are subject to FDA’s pre-market food additive, subject to pre-market approval approval, FDA may opt in some cases to exercise enforcement discretion, in and preparation of an EA 176. which instances NEPA review will not As discussed FDA regulates genetically occur . A categorical exclusion from the EA engineered animals as NADs, and it has requirement for investigational studies on prepared guidance specifically addressing some genetically engineered animals also this area of activity . NADs generally are not may be available 180. considered safe unless FDA has reviewed and approved a NADA (New Animal Drug The issue whether an agency approval for a synthetic biology product requires an EIS and

54 the extent to which activities must be limited circumstances change, FDA may determine while the EIS is being prepared, has not to issue further guidance and/or to revise its been aired extensively through litigation for environmental review regulations accordingly . FFDCA approvals, as they have been for PPA approvals . If and when this occurs, as more such products fall within FDA’s jurisdiction, NEPA review in the FFDCA context will be fleshed out further . Additionally, as needs and ENDNOTES

1 New Directions: The Ethics of Synthetic Biol- Nucleic Acid Molecules (Nov . 2013), available ogy and Emerging Technologies, Presidential at http://oba .od .nih .gov/rdna/nih_guide- Commission for the Study of Bioethical lines-oba .html . Issues (Dec . 2010), (Presidential Commis- sion Report) at 69, available at http://www . 10 Id. bioethics .gov/synthetic-biology-report . 11 According to the Friends of the Earth, International Center for Technology Assess- 2 Ro DK, Paradise EM, Ouellet M, Fisher KJ, ment, and the ETC Group’s “Principles for the Newman KL, Ndungu JM, Ho KA, Eachus Oversight of Synthetic Biology,” the Precau- RA, Ham TS, Kirby J, Chang MC, Withers ST, tionary Principle must be applied to synthetic Shiba Y, Sarpong R, Keasling JD, Production biology because the risk of the technology of the antimalarial drug precursor artemisinic is inherently unpredictable with potentially acid in engineered yeast, Nature, 440(7086): far-reaching and irreversible impacts . Apply- 940-943, 2006; Paddon CJ and Keasling JD, ing the Precautionary Principle to the field of Semi-synthetic artemisinin: a model for the synthetic biology first necessitates a mora- use of synthetic biology in pharmaceutical torium on the release and commercial use of development, Nature Reviews Microbiology, synthetic organisms, cells, or genomes until 12(5): 355-367, 2014 . government bodies, with full participation 3 Presidential Commission Report at 67 . of the public, have: developed a research agenda guided by the public interest; ensured 4 Widmaier DM, Tullman-Ercek D, Mirsky EA, that alternative approaches to synthetic biol- Hill R, Govindarajan S, Minshull J, Voigt CA, ogy applications have fully been considered; Engineering the Salmonella type III secretion conducted full and inclusive assessments of system to export spider silk monomers, Mol the implications of this technology, including Syst Biol . 5:309, 2009 . but not limited to devising a comprehensive 5 Presidential Commission Report at 57 . means of assessing the human health, envi- ronmental, and socio-economic impacts of 6 Presidential Commission Report at 71 . synthetic biology and preventing harms where 7 Id. they are present; and developed national and international oversight and security mecha- 8 51 Fed . Reg . 23302 (June 26, 1986) . nisms equipped to keep pace with the risks 9 NIH, Office of Science Policy, Office of as synthetic biology technologies develop . Biotechnology Activities, NIH Guidelines for Principles at 3, available at http://www .foe . Research Involving Recombinant or Synthetic

55 org/news/archives/2012-03-global-coali- human beings .” PHS Act § 351, 42 U S. .C . § tion-calls-oversight-synthetic-biology . 262 . Note that biological products subject to the PHS Act also meet the definition of drugs 12 FDA, Strategic Priorities: 2014-1018 (Sept . under the FFDCA . Accordingly, products such 2014) at 2, available at http://www .fda .gov/ as insulin, glucagon, and growth hormone are aboutfda/reportsmanualsforms/reports/ regulated by FDA as drugs . ucm227527 .htm. 20 The enhancement of FDA’s post-approval 13 An exploration of the differences with respect regulatory authority was an impetus for the to how products are approved for use under Food and Drug Administration Amendments FFDCA requires a detailed analysis of specific Act of 2007 (FDAAA) . commercial products that is beyond the scope of this paper . 21 Paradise and Fitzpatrick at 69 . 14 J . Paradise and E . Fitzpatrick, “Does Re-Writ- 22 Id . ing Nature Require Re-Writing Regulation?,” 23 Id . at 69-70 . Penn. State Law Review, Vol . 117, at 53 (Paradise and Fitzpatrick) . 24 FDA, Guidance for Industry: Safety of Nano- materials in Cosmetic Products. (Guidance 15 S . Carter, M . Rodemeyer, M . Garfinkel, and R . on Nanomaterials in Cosmetics), available Friedman, Synthetic Biology and the U.S. Bio- at http://www .fda .gov/Cosmetics/Guid- technology Regulatory System: Challenges anceRegulation/GuidanceDocuments/ and Options, J . Craig Venter Institute (Venter Report) (May 2014) at 18-22 (Venter Report), ucm300886 .htm; FDA, Guidance for available at www jcvi. .org/cms/fileadmin/site/ Industry: Assessing the Effects of Significant research/projects/synthetic-biology-and-the- Manufacturing Process Changes, Includ- us-regulatory-system/full-report pdf. . ing Emerging Technologies, on the Safety and Regulatory Status of Food Ingredients 16 Under NEPA, federal agencies engaged in and Food Contact Substances, Including “major Federal actions significantly affecting Food Ingredients that Are Color Additives” the quality of the human environment” must (Guidance on Effects of Emerging Technolo- prepare detailed statements assessing the gies on Food Ingredients and Food Contact environmental impact of and alternatives to Substances), available at http://www .fda . such actions . NEPA § 102(2)(C), 42 U .S C. . § 4332(2)(C) . gov/Food/GuidanceRegulation/Guid- anceDocumentsRegulatoryInformation/ 17 For example, Bovine somatotrophin (BST), ucm300661 .htm . also known as bovine growth hormone

THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF (BGH), was developed in the 1970s, sub- 25 Guidance on Effects of Emerging Technolo- mitted for approval to FDA and ultimately gies on Food Ingredients and Food Contact approved by the agency for use in feed Substances at 7 . animals in 1993 . 26 “Cosmetic” is defined in FFDCA § 201(i), 21 18 FFDCA § 201(g)(1), 21 U .S C. . § 321(g)(1) . U .S .C . § 321(i), as “(1) articles intended to be rubbed, poured, sprinkled, or sprayed on, 19 Section 351 of the Public Health Service introduced into, or otherwise applied to the (PHS) Act defines a biological product as human body or any part thereof for cleansing, a “virus, therapeutic serum, toxin, anti- beautifying, promoting attractiveness, or alter- toxin, vaccine, blood, blood component or ing the appearance, and (2) articles intended derivative, allergenic product, or analogous for use as a component of any such articles; product, … applicable to the prevention, except that the term shall not include soap .” treatment, or cure of a disease or condition of

56 27 CDC, Dengue Homepage: Entomology & 40 21 C .F .R . § 514 1(b)(5). . Ecology, available at http://www .cdc .gov/ 41 GFI 187 at 17 . dengue/entomologyecology/ . 42 FDA, From an Idea to the Marketplace: 28 Florida Keys Mosquito Control District, The Journey of an Animal Drug through the Questions and Answers on GM Mosquitoes, Approval Process, available at http://www . available at http://keysmosquito .org/ques- fda .gov/AnimalVeterinary/Resourcesfo- tion-answers-on-gm-mosquitoes/ . rYou/AnimalHealthLiteracy/ucm219207 . 29 Oxitec, available at http://www .oxitec . htm . com/ . 43 Cosmetic Ingredient Review accessed at 30 H .K . Phuc, et al. (2007) . “Late-Acting Domi- http://www cir-safety. org/ingredients. . nant Lethal Genetic Systems and Mosquito 44 U S. . Fish and Wildlife Service’s endangered Control,” BMC Biology 5:11 . and threatened species list is accessible at 31 Oxitec, How the Self-Limiting Gene Works, http://ecos .fws .gov/speciesProfile/pro- available at http://www .oxitec com/ridl-. file/speciesProfile?spcode=E0CL . science/understanding-ridl-science/ 45 Stephanie Strom, Companies Quietly Apply molecular-biology/ . Biofuel Tools to Household Products, The N .Y . Times, May 30, 2014, accessed at 32 FFDCA § 201(g)(1), 21 U .S .C . § 321(g)(1) . http://www .nytimes .com/2014/05/31/ 33 CVM (2009), Guidance for Industry Regu- business/biofuel-tools-applied-to-household- lation of Genetically Engineered Animals soaps html?_r=0. . Containing Heritable Recombinant DNA Con- 46 Amyris, accessed at https://amyris .com/inno- structs (GFI 187), available at http://www . vation/industrial-production/ . fda .gov/downloads/AnimalVeterinary/ 47 FFDCA § 201(i), 21 U .S .C . § 321(i) . GuidanceComplianceEnforcement/Guid- anceforIndustry/UCM113903 .pdf . 48 FDA, Is It a Cosmetic, a Drug, or Both? (Or Is It Soap?), available at http://www . 34 FDA (2003), Statement Regarding Glofish, fda .gov/Cosmetics/GuidanceRegula- available at http://www .fda .gov/animal- tion/LawsRegulations/ucm074201 . veterinary/developmentapprovalprocess/ htm#Definecosmetic . geneticengineering/geneticallyengineere- danimals/ucm413959 .htm . 49 For example, bithional, chlorofluorocarbon propellants, methylene chloride, and vinyl 35 NEPA § 102(2)(C), 42 U S. .C . § 4332(2)(C) . chloride, among others, are prohibited for use 36 FOE, Issue Brief: Genetically Engineered as cosmetic ingredients . See 21 C .F .R . §§ Mosquitoes in the U.S., at 3, available at 700 .11-700 .35 . http://libcloud .s3 .amazonaws .com/93/ 50 FDA, Draft Guidance for Industry: Cos- df/1/959/5/Issue_brief_GE_mosquitoes_ metic Good Manufacturing Practices (Feb . in_U .S .pdf . 12, 1997; revised Apr . 24, 2008, and June 2013), available at http://www .fda .gov/ 37 Id. Cosmetics/GuidanceRegulation/Guid- 38 21 U S. C. . §§ 360ccc(a)(3)(A) and 360ccc-1(a)(2) . anceDocuments/ucm353046 .htm . 39 FDA, ADUFA, available at http://www .fda . 51 FDA, Summary of Labeling Requirements, gov/ForIndustry/UserFees/AnimalDru- available at http://www fda. gov/Cosmetics/. gUserFeeActADUFA/default .htm . Labeling/Regulations/ucm126438 htm. . 57 52 7 U S. .C . §§ 136-136y . 67 40 C F. .R . § 152 .25(b) . A pheromone trap is “a device containing a pheromone or an 53 21 U S. .C . §§ 301-399d . identical or substantially similar compound 54 Pub . L . No . 104-170, 110 Stat . 1489 . used for the sole purpose of attracting, and trapping or killing, target arthropods . Phero- 55 FIFRA § 2(u), 7 U .S .C . § 136(u) . FIFRA also mone traps are intended to achieve pest defines the term “active ingredient,” in perti- control by removal of target organisms from nent part, to mean “an ingredient which will their natural environment and do not result in prevent, destroy, repel, or mitigate any pest .” increased levels of pheromones or identical or FIFRA § 2(a)(1), 7 U S. .C . § 136(a)(1) . substantially similar compounds over a signifi- 56 40 C F. R. . § 152 .15 . cant fraction of the treated area .” 40 C .F .R . § 152 .25(b)(4) . 57 FIFRA § 2(t), 7 U .S .C . § 136(t); see also 40 C F. .R . § 152 .5 . 68 40 C F. .R . § 152 .25(b)(2) . 58 40 C F. R. . § 158 .2100(b) . 69 15 U .S .C . §§ 2601-2695d . 59 40 C F. R. . § 174 .3 . 70 EPA, Pesticide Registration Manual: Chap- ter 3 -- Additional Considerations for 60 40 C F. R. . § 152 .15(a)-(c) . EPA’s regulations provide exemptions from FIFRA regulation . Biopesticide Products, available at http:// These include the following: certain sub- www2 .epa .gov/pesticide-registration/ stances or articles are not intended for use pesticide-registration-manual-chapter- against “pests” and thus are not pesticides; 3-additional-considerations#pheromone . certain products are not intended to prevent, destroy, mitigate, or repel pests and thus 71 TSCA §§ 5(a)(1) and 8(f), 15 U .S .C . §§ are not pesticides; certain pesticides are 2601(a)(1) and 2607(f) . regulated by other federal agencies and are 72 See for example TSCA Sections 5(h)(1) and exempt from all FIFRA requirements; certain (4), and associated regulations . pesticides or classes of pesticides are of a character not requiring FIFRA registration; 73 40 C .F R. . §§ 704 .3, 716 .3, 717 3(e),. 720 .3(r) . and certain otherwise regulated pesticides 74 TSCA § 3(2)(A), 15 U .S C. . § 2602(A) . may be transferred, sold, or distributed with- out registration . 75 Commercial chemical substances produced by microorganisms are also separately 61 FIFRA § 2(bb), 7 U .S .C . § 136(bb) . subject to new chemical requirements if the 62 40 C F. R. . § 172 .48 . substances are not otherwise listed on the TSCA Inventory of chemical substances . THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF 63 40 C F. R. . § 172 .50 . 76 This absence is a bit conspicuous given the 64 iGEM, iGEM Competition, available at http:// Asilomar Conference was convened in 1975, igem .org/Main_Page . a year before Congress enacted TSCA . Sena- tor John V . Tunney, a California Democrat, 65 National Chiao Tung University’s iGEM introduced the Senate bill that eventually was Team, available at http://2014 .igem .org/ enacted . Given the interest in the Asilomar Team:NCTU_Formosa . Conference, it seems a little odd to conclude that genetically engineered organisms are 66 Wikipedia, Pheromone biosynthesis acti- plainly within TSCA’s scope despite Con- vating neuropeptide, available at http:// gress’s complete silence on the subject . en .wikipedia .org/wiki/Pheromone_bio- synthesis_activating_neuropeptide .

58 77 Louis S . Sorell, Biotechnology Regulation the company can satisfy the criteria for any of Under the Toxic Substances Control Act, 3 these exemptions, it may, depending on the Pace Envtl. Rev. 57(2985) at 66 . Note also particular exemption, commence manufac- that as a matter of policy, EPA, in its pro- ture or importation without notifying EPA (in posed TSCA biotechnology rule (59 Fed . the case of R&D activities conducted “inside Reg . 45527 (Sept . 1, 1994)), limited the rule- a structure,” as discussed further below) making to microorganisms while stating that or may obtain expedited EPA review (i.e., a “plants and animals could also be chemical 45-day review for a TME rather than a 90-day substances under TSCA .” MCAN review) . 78 40 C F. R. . § 725 .3 . 86 62 Fed . Reg . 17909, 17923 . (Apr . 11, 1997) . 79 40 C F. R. . § 725 .1(a), 725 .3 . 87 40 C .F R. . §§ 725 .234(d), 725 .3 . EPA further provides the following regarding the con- 80 40 C F. R. . § 725 .3 . tainment and/or inactivation controls: “(1) 81 40 C F. R. . § 725 .8(b) Selection and use of containment and/or inactivation controls inside a structure for 82 G . Mandel and G . Marchant, Evolving Tech- a particular microorganism shall take into nology Regulation: Governance at a Temporal account the following: (i) Factors relevant Distance, included in Bridging Distances in to the organism’s ability to survive in the Technology and Regulation, edited by R . environment . (ii) Potential routes of release in Leenes & E . Kosta (2013) . air, solids and liquids; in or on waste materi- 83 With the advent of synthetic biology, EPA’s als and equipment; in or on people, including distinction between intergeneric and non- maintenance and custodial personnel; and intergeneric microorganisms actually runs in or on other organisms, such as insects afoul of the dictate of the Coordinated Frame- and rodents . (iii) Procedures for transfer of work that the products of biotechnology materials between facilities . (2) The technically should be regulated based on the product qualified individual’s selection of containment itself, not based on the process by which it and/or inactivation controls shall be approved was made (Office of Science and Technology and certified by an authorized official (other Policy 1986) . EPA’s current regulations would than the TQI) of the institution that is conduct- differentiate between intergeneric micro- ing the test prior to the commencement of organism produced by traditional genetic the test . (3) Records shall be developed and modification techniques (which would be maintained describing the selection and use subject to the regulations) and the identical of containment and/or inactivation controls, microorganism which is produced de novo as specified in Section 725 .235(c) . These using synthetic biology techniques (potentially records, which must be maintained at the not subject to the regulations because it did location where the research and development not involve an “intergeneric” transfer) . activity is being conducted, shall be submit- ted to EPA upon written request and within 84 EPA, Microbial Products of Biotechnology the time frame specified in EPA’s request . Summary of Regulations under the Toxic (4) Subsequent to EPA review of records in Substances Control Act, available at http:// accordance with paragraph (d)(3) of this sec- www epa. .gov/biotech_rule/pubs/fs-001 . tion, changes to the containment/inactivation htm . controls selected under paragraph (d)(1) of this section must be made upon EPA order . 85 40 C .F R. . § 725 67(a),. (b) . Exemptions from Failure to comply with EPA’s order shall result notification requirements include: (1) the R&D in automatic loss of eligibility for an exemption exemption; (2) the Tier I or Tier II exemption; under this section .” 40 C .F R. . § 725 .234(d) . and (3) the Test Market Exemption (TME) . If

59 88 40 C F. R. . §§ 725 205,. 725 .234(a) . a plantlet culture, pollen, a shrub, a vine, a cutting, a graft, a scion, a bud, a bulb, a root, 89 40 C F. R. . § 725 .234(c) . and a seed .” 7 U .S .C . § 7702(13) . It defines 90 40 C F. R. . § 725 .234(b) . “plant product” as “(A) any flower, fruit, veg- etable, root, bulb, seed, or other plant part 91 40 C F. R. . § 725 .3 . that is not included in the definition of plant; 92 40 C F. R. . § 725 .234(e) . EPA’s regulations or (B) any manufactured or processed plant set forth when notification procedures are or plant part .” 7 U .S C. . § 7702(15) . required, and if so, the procedure in which 110 Part 340 is entitled “Introduction of Organ- such notifications must be made . See 40 isms and Products Altered or Produced C F. .R . § 725 .235(a), (b) . Through Genetic Engineering Which Are Plant 93 40 C F. R. . § 725 .255 . Pests or Which There Is Reason to Believe Are Plant Pests ”. 94 40 C F. R. . §§ 725 260,. 725 .3 . 111 7 C .F R. . § 340 .1 . This regulatory definition 95 40 C F. R. . § 725 .260 . closely tracks the definition of “plant pest” in 96 40 C F. R. . § 725 .270(b) . the PPA, at 7 U S. .C . § 7702(14) . 97 Id. 112 7 C .F .R . § 340 .1 . The corresponding “groups 98 40 C F. R. . Part 725, Subpart D . of organisms which are or contain plant pests” are listed at length in Section 340 .2(a), 99 40 C F. R. . § 725 .424 . EPA is considering subject to the exemptions identified in Sec- adding certain strains of two additional micro- tion 340 2(b). . organisms to this general exemption (77 Fed . Reg . 54499 (Sept . 5, 2012)) . 113 A note to Section 340 0. states that “the intro- duction of organisms and products altered or 100 40 C F. R. . § 725 .428 . produced through genetic engineering that 101 40 C .F R. . § 725 .450(b) . are plant pests or are believed to be plant pests” are within the coverage of Part 340 . 7 102 40 C .F R. . § 725 .470(e) . C .F R. . § 340 .0 n . 1 . 103 40 C .F R. . §§ 725 .300, 725 305. . 114 Notification is characterized as applying 104 EPA, “Points to Consider in the Prepara- typically to low-risk plants, but a critic of tion of TSCA Biotechnology Submissions for APHIS’s implementation of the PPA cites Microorganisms” (Points to Consider) (June widespread use of this pathway and points to what she views as pervasive deficiencies in 2, 1997) at 13, available at http://www .epa . the process . See E . Montgomery, Genetically

THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF . gov/biotech_rule/pubs/pdf/ptcbio .pdf Modified Plants and Regulatory Loopholes 105 40 C .F .R . § 725 .370 . and Weaknesses Under the Plant Protection Act, 37 Vt . L . Rev 351, 366-367 (2012-2013) 106 40 C .F .R . § 725 .370 . (Montgomery) . 107 7 U .S C. . § 7701 et seq . 115 See 7 C .F .R . § 340 .4, addressing “permits for 108 Center for Food Safety v. Vilsack, 718 F .3d the introduction of a regulated article .” 829, 834 (9th Cir . 2013) . 116 7 C .F R. . § 340 .6 . 109 7 U .S C. . § 7702(14) . 117 See Center for Food Safety v. Vilsack, 718 The PPA defines “plant” as “any plant F 3d. at 835 . The data APHIS reviews include, (including any plant part) for or capable of but are not limited to, the field test results . propagation, including a tree, a tissue culture, 118 7 C .F .R . § 340 .6 .

60 119 42 U S. .C . § 4321 et seq. 133 See, e.g ., Montgomery at 366-369 . 120 Venter Report at 25 . 134 See id. at 369-370 . 121 7 U .S .C . § 7712(f) . 135 See Venter Report at 25-27 . 122 See Center for Food Safety v. Vilsack, 718 136 Reportedly, other companies are using F .3d at 836 and 843 . genome-editing techniques to sell herbicide- resistant canola . See infra, note 140 . 123 7 C .F .R . § 360 .100 . 124 7 C .F .R . § 360 .300 . 137 BioGlow, available at http://www .bioglow- tech .com/ . 125 718 F .3d 829, supra, note 108 . 138 Glowing Plant, available at http://www . 126 The related litigation includes the lawsuit that culminated in the Supreme Court’s decision glowingplant .com/ . in Monsanto Co. v. Geertson Seed Farms, 139 Kickstarter, Glowing Plants: Nautral Lighting 561 U .S . 139 (2010) . The lawsuit sought to with no Electricity, available at https://www . require APHIS to prepare an EIS in connec- kickstarter .com/projects/antonyevans/ tion with the deregulation of RRA . The Ninth Circuit noted that the Supreme Court deci- glowing-plants-natural-lighting-with-no- sion was directed only to the scope of the electricit . injunction issued by a district court pending 140 Andrew Pollack, By “Editing” Plant Genes, preparation of the EIS by APHIS and therefore Companies Avoid Regulation, N Y. . Times, did not affect the issues for decision in Center Jan . 1, 2015, accessed at http://www . for Food Safety v. Vilsack, 718 F .3d at 837- 838 . nytimes .com/2015/01/02/business/ energy-environment/a-gray-area-in- 127 In so doing, the Ninth Circuit affirmed a regulation-of-genetically-modified-crops . district court ruling upholding the deregulation decision . See Center for Food Safety v. Vil- html?_r=0 . sack, 844 F . Supp . 2d 1006 (N .D . Cal . 2012) . 141 Letter from Richard Shank, Ph D. ., Senior 128 718 F .3d at 836-837 . Vice President Regulatory and Government Affairs, The Scotts Miracle-Gro Company, 129 Id. at 841 . to Tom Vilsack, Secretary, U .S . Department 130 Id . of Agriculture (USDA), September 13, 2010, available at http://www .aphis .usda .gov/ 131 Id . at 843 . brs/aphisdocs/scotts_kbg .pdf (response 132 Perceived deficiencies in the PPA as a tool to Dr . Richard Shank, The Scotts Miracle-Gro for regulating genetically modified plants Company, from Michael C . Gregoire, Deputy and crops are doubtless magnified by a Administrator, USDA APHIS, July 1, 2011, recent judicial ruling that the PPA expressly available at http://www .aphis .usda .gov/ preempts state or local laws prohibiting the brs/aphisdocs/scotts_kbg_resp .pdf) . cultivation of genetically modified plants to the extent that those plants are regulated under 142 Letter from Richard Shank, Ph .D ,. Senior federal law and 7 C F. .R . Part 340 . Hawaii Flo- Vice President Regulatory and Governmental riculture & Nursery Ass’n v. County of Hawaii, Affairs, The Scotts Miracle-Gro Company, to No . 14-cv-00267 (D . Hawaii) (Nov . 26, 2014) . Michael C . Gregoire, Deputy Administrator, As a result, the district court issued an injunc- Biotechnology Regulatory Services, April 5, tion against the implementation of Hawaii 2013, available at http://www .aphis .usda . County Ordinance 13-121 .

61 gov/biotechnology/downloads/reg_loi/ 154 Department of Transp. v. Public Citizen, scotts_tall_fescue_air_cbidel_20130903 . 541 U .S . at 756-57 . The corollary is that a court’s only role in reviewing agency action pdf . for compliance with the NEPA “is to insure 143 Letter from Michael C . Gregoire, USDA that the agency has taken a hard look at APHIS, to Dr . Alexander Krichevsky, BioGlow environmental consequences .” Coalition on LLC, March 21, 2013, available at http:// West Valley Nuclear Wastes v. Chu, 592 F .3d www .aphis .usda .gov/biotechnology/ 306, 310 (2d Cir . 2009) (internal quotation downloads/reg_loi/aphis_response_bio- marks omitted) . “Significantly, ‘if the adverse environmental effects of the proposed action glow_032113 .pdf . are adequately identified and evaluated, the 144 Letter from Michael Firko, Ph .D ., Deputy agency is not constrained by NEPA from Administrator, Biotechnology Regulatory deciding that other values outweigh the envi- Services, to Mr . Antony Evans, Glowing ronmental costs .’” NRDC v. FAA, 564 F .3d Plant, Inc ,. December 23, 2014, available at 556, quoting Robertson v. Methow Valley at https://www .dropbox .com/s/h8au- Citizens Council, 490 U .S . 332, 350 (1989) . jio5whb1nfw/Aphis%20am%20I%20 155 40 C .F .R . §§ 1500-15081 . regulated%20response .rotated .pdf?dl=0, 156 40 C .F .R . §§ 1507 .3(b)(2), 1508 4. . linked from http://blog .glowingplant .com/ . 157 40 C .F .R . §§ 1508 .9(a), 1508 .13 . If it 145 Id . becomes apparent that an EIS will be 146 APHIS, Biotechnology Regulatory Services, required, the agency may proceed directly to that stage without undertaking the exercise of Factsheet (Feb . 2015), available at http:// an EA . www aphis. .usda gov/publications/bio-. technology/2015/faq_withdrawal .pdf . 158 7 C .F R. . § 372 5(c)(3)(ii). . 147 Importation, Interstate Movement, and 159 Notification and field testing under APHIS Release Into the Environment of Certain regulations are discussed above . Genetically Engineered Organisms, 80 Fed . 160 718 F 3d. 829, supra, note 108 . Reg . 11598 (Mar . 4, 2015), available at 161 561 U .S . 139, supra, note 126 . http://www .aphis .usda .gov/brs/fedregis- ter/brs_20150304 pdf. . 162 Geertson Seed Farms v. Johanns, No . C06–01075, 2007 WL 518624, at *10–12 148 Id . (N .D Cal. . Feb . 13, 2007) (unpublished deci- sion) .

THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF 149 42 U .S .C . § 4321 et seq . 150 Department of Transp. v. Public Citizen, 541 163 Geertson Seed Farms v. Johanns, 570 F 3d. U .S . 752, 756 (2004) (quoting 42 U .S .C . § 1130, 1133-34 (9th Cir . 2009), cert. granted 4321) . sub nom. Monsanto Co. v. Geertson Seed Farms, 130 S . Ct . 1133 (2010) . 151 NEPA § 102(2)(C), 42 U S. .C . § 4332(2)(C) . Federal actions are considered to include 164 The four necessary factors are irreparable funding for projects not directly initiated by a harm, inadequacy of legal remedies, a bal- federal agency . ance of hardships favoring the moving party, and the absence of injury to the public inter- 152 42 U .S .C . § 4332(2) . est if an injunction is issued . 153 NRDC v. FAA, 564 F 3d. 549, 556 (2d Cir . 165 The Court elaborated as follows on the 2009) (internal quotation marks omitted) . flaws in the district court’s approach: “ . .

62 .[T]he terms of the District Court’s injunc- proposed action may significantly affect the tion do not just enjoin the particular partial quality of the human environment (see 40 deregulation embodied in APHIS’s proposed CFR 1508 .27 for examples of significant judgment . Instead, the District Court barred impacts) . Examples of such extraordinary the agency from pursuing any deregulation circumstances include: -- no matter how limited the geographic area Actions for which available data establish in which planting of RRA would be allowed, that, at the expected level of exposure, there how great the isolation distances mandated is the potential for serious harm to the envi- between RRA fields and fields for grow- ronment; and ing non-genetically-engineered alfalfa, how stringent the regulations governing harvesting (b) Actions that adversely affect a species or and distribution, how robust the enforce- the critical habitat of a species determined ment mechanisms available at the time of the under the Endangered Species Act or the decision, and -- consequently -- no matter Convention on International Trade in Endan- how small the risk that the planting authorized gered Species of Wild Flora and Fauna to under such conditions would adversely affect be endangered or threatened or wild flora or the environment in general and respondents fauna that are entitled to special protection in particular ”. 561 U .S . at 161 . under some other Federal law . 166 See the discussion of Center for Food Safety 173 40 C .F R. . § 25 .40(b) . v. Vilsack, above . As summarized by the 174 40 C .F R. . § 25 .20(l) and (m), respectively . court, “[t]he 2011 ROD [Record of Decision] noted that although RRA was created using a 175 40 C .F R. . § 25 .20(i) . plant pest (the Agrobacterium), the genetically 176 FDA, Statement of Policy -- Foods Derived modified plant did not present any direct or from New Plant Varieties, 57 Fed . Reg . indirect plant pest risks and therefore should 22984 (May 29, 1992), available at http:// be granted ‘nonregulated status ’. The ROD stated that because RRA will not damage www .fda .gov/Food/GuidanceRegulation/ or injure other plants, it does not present GuidanceDocumentsRegulatoryInforma- a greater plant pest risk than conventional tion/Biotechnology/ucm096095 .htm alfalfa .” 718 F 3d. at 838 . (discussed in a Library of Congress report, “Restrictions on Genetically Modified Prod- 167 Center for Food Safety v. Vilsack, 636 F .3d 1166 (9th Cir . 2011) . ucts: United States,” available at http:// www .loc .gov/law/help/restrictions-on- 168 Id . at 1173 . gmos/usa .php) . 169 Id. 177 21 U .S C. . § 360b(a) . 170 40 C .F R. . § 1508 .9; 21 C F. .R . § 25 .40(a) . 178 21 C .F R. . § 514 .1(b)(14) . 171 21 C .F R. . § 25 .22(b) . 179 FDA, Guidance for Industry: Regulation of 172 Consistent with CEQA’s regulations, under Genetically Engineered Animals Containing 40 C .F R. . § 25 .21, in extraordinary circum- Heritable rDNA Constructs (June 2015) (GE stances an EA (at a minimum) will be required Guidance) at 20, available at http://www . for actions that otherwise would be categori- fda .gov/downloads/AnimalVeterinary/ cally excluded: GuidanceComplianceEnforcement/Guid- As required under 40 CFR 1508 .4, FDA will anceforIndustry/UCM113903 .pdf . require at least an EA for any specific action that ordinarily would be excluded if extraordi- 180 Id at 12 . nary circumstances indicate that the specific 63 THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? www.synbioproject.org F 202/691/4001 T 202/691/4000 Washington, DC20004-3027 1300 Pennsylvania Ave., N.W. Plaza One Woodrow Wilson 65 THE DNA OF THE U.S. REGULATORY SYSTEM: ARE WE GETTING IT RIGHT FOR SYNTHETIC BIOLOGY? ARE SYSTEM: REGULATORY THE U.S. THE DNA OF

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