1. Regulatory Paradigms for Modern Breeding Drew L. Kershen Earl Sneed Centennial Prof. Emeritus NABC-26 at Cornell University October 9, 2014

2. Wayne Parrott, Ph.D., Professor, Plant Breeding and Genomics, Crop & Soil Sciences, University of Georgia, is coauthor of this PowerPoint. Date of Completion September 6, 2014

3. Modern Breeding Techniques rDNA Breeding (traditional biotechnology) Site Directed Nuclease Techniques – Meganucleases (MNs) – Zinc-finger Nucleases (ZFNs) – Transcription Activator-Like Effector Nucleases (TALENs) – Clustered regularly interspaced short palindromic repeats (CRISPRs-Cas9) RNAi (e.g., gene silencing) Synthetic Biology – customized genetic constructs

4. Policy Issue Plant Breeding Techniques NAS (1987): “Several conclusions can be drawn from this review of the relationship between traditional genetic manipulation techniques and the R-DNA techniques developed during the last 15 years, and of the experience gained from the application of each: – There is no evidence that unique hazards exist either in the use of R-DNA techniques or in the movement of genes between unrelated organisms. – The risks associated with the introduction of R-DNA engineered organisms are the same in kind as those associated with the introduction of unmodified organisms and organisms modified by other methods. – Assessment of the risks of introducing R-DNA engineered organisms into the environment should be based on the nature of the organism and the environment into which it is introduced, not on the method by which it was produced.”

5. Policy Issue Plant Breeding Techniques White House OSTP 1992: “Exercise of oversight in the scope of discretion afforded by statute should be based on the risk posed by the introduction and should not turn on the fact that an organism has been modified by a particular process or technique. … [O]versight will be exercised only where the risk posed by the introduction is unreasonable, that is, when the value of the reduction in risk obtained by additional oversight is greater than the cost thereby imposed.”

6. Policy Issue Plant Breeding Techniques ACRE [UK] (2013): Executive Summary – “Our understanding of genomes does not support a process-based approach to regulation. The continuing adoption of this approach has led to, and will increasingly lead to, problems. This includes problems of consistency, i.e. regulating organisms produced by some techniques and not others irrespective or their capacity to cause environmental harm.” – “Our conclusion, that the EU’s regulatory approach is not fit for purpose for organisms generated by new technologies, also applies to transgenic organisms produced by ‘traditional’ GM technology. … the potential for inconsistency is inherent because they may be phenotypically identical to organisms that are not regulated.”

7. United States Law USDA-APHIS Plant Protection Act – Regulated Article – any organism altered or produced through genetic engineering – Plant Pest Regulated Letters of Inquiry – http://www.aphis.usda.gov/ http://www.aphis.usda.gov/ – Transformation method – Construct (each element – promoter, gene, terminator and source from which derived) – Recipient Organism – Donor Organism – Trait (phenotype) Thirty-four entries on Regulated Letters of Inquiry as of September 04, 2014 – One letter on ZFN-1; one letter on MN-1 Not regulated articles – Knockout effect – No Letters of Inquiry on TALENs or CRISPRs – Two Letters on Synthetic Biology: BioGlow for glowing plants – not regulated Regulatory Reform Needed – Categorical exemptions based on the 30 years of regulatory and field experience – Exercise administrative discretion and not expand regulation by invoking “noxious weeds” authority

8. United States Law Environmental Protection Agency Federal Insecticide Fungicide Rodenticide Act – Pesticide (intended purpose e.g. plant-incorporated protection) – Plant regulator (intended purpose e.g. accelerated or retarded growth) Toxic Substances Control Act – New Chemical (regulatory approach to GMMs) EPA has pondered expanded FIFRA regulation of RNAi plants as pesticides (e.g., virus resistance) and expanded TSCA regulation of synthetic biology as “new chemicals” Regulatory Reform Needed – Exercise of administrative discretion not to expand regulatory terms to include additional breeding techniques – Tiered Risk – expanded exercise of administrative discretion to not use resources on genetic modifications with low risk – focus on traits, not on process definitions

9. United States Law Food & Drug Agency (FDA) Federal Food, Drug & Cosmetic Act (FFDCA), – Food “Voluntary” Consultation; Substantial Equivalence (150+ foods to date); Generally Recognized as Safe (GRAS) Companies have consulted on all GE foods Not a single documented health problem – good system – Human Drug Safe and Efficacious; Pre-market approval; clinical tests Ventria Rehydration Solution (produced in rice) – FDA did not respond; Ventria withdrew application – disagreement about GRAS status or drug status – Animal Drug Guidance (2009) – all GE animals deemed an animal drug Mandatory preapproval and other regulatory requirements AquaBounty salmon -- 20 years and $78 million – no decision – Regulatory Reform Needed Decisions in a timely fashion Tiered risk analysis – not all GE animals pose a novel risk – TALENS transfer of “polled” trait from Angus (beef) to Holsteins (dairy) GRAS status, like food, should apply to identified low risk categories

10. European Union Law 2001/18/EC – Deliberate Release Reg.(EC)No. 1829/2003– Food Feed Import Reg.(EC)No. 1830/2003– labels, traceability Analysis – Focused on Process – distinguishing between techniques – Precautionary Principle – Although coverage is not decided, almost assuredly all modern breeding techniques within these laws

11. New Zealand Sustainability Council against EPA NZ law focuses on process, distinguishing between techniques SCION asked EPA whether trees produced using ZFN-1 and TALENs would be considered genetically modified organisms. EPA answered “No” saying these were like chemical mutagenesis. Sustainability Council appealed EPA administrative decision. High court (trial court) ruled against EPA – EPA must handle SCION field trials under the Hazardous Substances and New Organisms Act – Precautionary Principle – Exempt techniques can only be added by Legislature; administrative agency lacks statutory authority to expand exemptions

12. Regulatory Paradigms Paradigm One – Risk, not Hazard; Product (Trait), not Process – Presumption that regulation often not needed and should focus on novel, unreasonable risks – Science and scientific development trusted and encouraged Paradigm Two – Precautionary Principle – Presumption favoring regulation and risk aversion – Social and Political Consideration should be considered more important than science and scientific development – Will kill synthetic biology before it has a chance to get started

13. Alphabetical List Sources Advisory Committee on Releases to the Environment (ACRE), Report 2: Why a modern understanding of genomes demonstrates the need for a new regulatory system for GMOs. (Sept. 2013) Akst, J., Designer Livestock, The Scientist Magazine Blog (June 1, 2014) at http://www.the- scientist.com/?articles.view/articleNo/40081/title/Designer-Livestock/http://www.the- scientist.com/?articles.view/articleNo/40081/title/Designer-Livestock/ Bar-Yam, S. et al., The Regulation of Synthetic Biology: A Guide to United States and European Union Regulations, Rules and Guidelines (SynBERC and iGEM ver. 9.1 January 10, 2012) Carter, S. et al., Synthetic Biology and the U.S. Biotechnology Regulatory System: Challenges and Options (J. Craig Venter Institute, May 2014) EFSA Panel on GMOs: Scientific opinion addressing the safety assessment of plants developed using ZFNs-3 and other SDN with similar functions, EFSA Journal 2012, 10:2943- 2974 Eriksson, D. et al., (August 2014) The slippery slope of cisgenesis, Nat. Biotech. 32:727 (correspondence) – Shouten, H., (07 August 2014) Reply to Eriksson et al., Online publication doi:10.1038/nbt.2981 European Commission, Directorate-General Environment, Working Group on the Establishment of a List of Techniques Falling under the Scope of Directive 2001/18/EC (unpublished, available as a Web-leaked document, August 2013) European Commission-ERASynBio, Next steps for European synthetic biology: a strategic vision from ERASynBio (April 2014)

14. Alphabetical List Sources European Commission-Scientific Committees, Preliminary Opinion on Synthetic Biology I: Definition (4 June 2014) Friends of the Earth et al., The Principles for the Oversight of Synthetic Biology (Oct. 17, 2013) Herring, R. On Risk and Regulation: Bt Crops in India, GM Crops & Food x:xx (manuscript accepted for publication) (in possession of co-authors) Leyser, O., (June 2014) Moving Beyond the GM Debate, PLOS-Biology Open Access e1001887 at www.plosbiology.orgwww.plosbiology.org Lusser, M. et al., (2011) New Plant Breeding Techniques: State-of-the-art and prospects for commercial development (JRC Scientific and Technical Reports) Lusser, M. & Davies, H.V., (2013) Comparative regulatory approaches for groups of new plant breeding techniques, New Biotechnol., 30(5):437-446 McGuiness Institute, An Overview of Genetic Modification in New Zealand 1973-2013: The first forty years (August 2013) Minikel, E. (2013) TALENs and ZFNs, www.cureffi.orgwww.cureffi.org Nagamangala, C., et al., (2014) Looking forward to genetically edited fruit crops, Trends in Biotech. (in press) (available on the Web) National Academy of Science (USA), Introduction of Recombinant DNA-Engineered Organisms into the Environment: Key Issues (1987)

15. Alphabetical List Sources NZ-EPA, Determination of whether or not an organism is a new organism under section 28 of the Hazardous Substances and New Organisms (HSNO) Act 1996, http://www.epa.govt.nz (19 April 2013)http://www.epa.govt.nz OECD, Emerging Policy Issues in Synthetic Biology (2014) Pennisi, E. (2013) The CRISPR Craze, Science 341:833-836 Podevin, N. et. al, (2013) Site-directed nucleases: a paradigm shift in predictable, knowledge-based plant breeding, Trends in Biotechnology, 31:375-383. Pollock C. & Hails, R., (February 2014) The case for reforming the EU regulatory system for GMOs, Trends in Biotech. 32(2):63-64 Presidential Commission for the Study of Bioethical Issues, New Directions: The Ethics of Synthetic Biology and Emerging Technologies (December 2010) Oye, K. et al., (8 Aug. 2014) Regulating Gene Drives, Science 345:626-628 Regalado, A., On the Horns of the GMO Dilemma (2 September 2014) MIT Tech. Rev. Online edition Smyth, S. et al., (March 2014) Investment, regulation, and uncertainty: Managing new plant breeding technologies, GM Crops & Food 5(1):44-57

16. Alphabetical List Sources Sustainability Council of New Zealand Trust against The Environmental Protection Authority, CIV 2013-485- 877, 2014 NZHC 1067 [High Court, Wellington] Synthetic Biology Project et al., Creating a Research Agenda for the Ecological Implications of Synthetic Biology (7 May 2014) ter Meulen, V., Time to settle the synthetic controversy, (08 May 2014) Nature 509:135 – IAP Statement on Realising Global Potential in Synthetic Biology: Scientific Opportunities and Good Governance (7 May 2014) US-APHIS, Regulated Letters of Inquiry at http://www.aphis.usda.gov (viewed September 4, 2014)http://www.aphis.usda.gov US-EPA, Meeting Minutes FIFRA Scientific Advisory Panel on “RNAi Technology as a Pesticide: Problem Formulation for Human Health and Ecological Risk Assessment” (Jan. 28, 2014), http://www.epa.gov/sciploy/sap ; plus especially http://www.epa.gov/sciploy/sap – Written comments to the SAP meeting by James Carrington, President, Donald Danforth Plant Science Center; Craig Mello, Nobel Prize winner, Univ. of Massachusetts Medical School; Weed Science Society of America US-FDA, Regulation of Genetically Engineered Animals Containing Heritable Recomibinant DNA Constructs – Final Guidance for Industry (rev. May 17, 2011) at http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/ http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/ – US-FDA, Fact Sheet on Genetically Engineered Animals (updated May 5, 2014) – US-FDA, General Q&A Genetically Engineered Animals (viewed September 4, 2014) Voytas, D. & Gao, C., (June 204) Precision Genome Engineering and Agriculture: Opportunities and Regulatory Challenges, PLOS-Biology OpenAccess e1001877 at www.plosbiology.orgwww.plosbiology.org World Health Organization, Guidance Framework for Testing of Genetically Modified Mosquitoes – Confidential Draft (unpublished, available as a Web-leaked document, 2013) Xue, K., Synthetic Biology’s New Menagerie, (Sept-Oct 2014), Harvard Magazine pp. 42-49

17. Thank you Drew L. Kershen 300 W. Timberdell Road Norman, OK 73019-5081 dkershen@ou.edu (405) 325-4784